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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Compartment syndrome'. | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CHLOROQUINE | DrugsGivenReaction | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Encephalopathy'. | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CHLOROQUINE | DrugsGivenReaction | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypokalaemia'. | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CHLOROQUINE | DrugsGivenReaction | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intentional overdose'. | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CHLOROQUINE | DrugsGivenReaction | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metabolic acidosis'. | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CHLOROQUINE | DrugsGivenReaction | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Peripheral artery stenosis'. | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CHLOROQUINE | DrugsGivenReaction | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory depression'. | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CHLOROQUINE | DrugsGivenReaction | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Suicide attempt'. | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CHLOROQUINE | DrugsGivenReaction | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxicity to various agents'. | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CHLOROQUINE | DrugsGivenReaction | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Trismus'. | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CHLOROQUINE | DrugsGivenReaction | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ventricular dysfunction'. | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CHLOROQUINE | DrugsGivenReaction | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ventricular tachycardia'. | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CHLOROQUINE | DrugsGivenReaction | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
What was the administration route of drug 'CHLOROQUINE'? | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Oral | DrugAdministrationRoute | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
What was the outcome of reaction 'Bradypnoea'? | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
What was the outcome of reaction 'Cardiac arrest'? | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
What was the outcome of reaction 'Cardiotoxicity'? | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
What was the outcome of reaction 'Circulatory collapse'? | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
What was the outcome of reaction 'Compartment syndrome'? | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
What was the outcome of reaction 'Encephalopathy'? | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
What was the outcome of reaction 'Hypokalaemia'? | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
What was the outcome of reaction 'Metabolic acidosis'? | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
What was the outcome of reaction 'Peripheral artery stenosis'? | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
What was the outcome of reaction 'Respiratory depression'? | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
What was the outcome of reaction 'Toxicity to various agents'? | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
What was the outcome of reaction 'Trismus'? | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
What was the outcome of reaction 'Ventricular dysfunction'? | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
What was the outcome of reaction 'Ventricular tachycardia'? | Extracorporeal cardiopulmonary resuscitation for severe chloroquine intoxication in a child - a case report.
BACKGROUND
Chloroquine use has increased worldwide recently in the setting of experimental treatment for the novel coronavirus disease (Covid-19). Nevertheless, in case of chloroquine intoxication, it can be life threatening, with cardiac arrest, due to its cardiac toxicity.
METHODS
This case study reports on a 14-years-old girl who presented in cardiac arrest after an uncommon suicide attempt by ingesting 3 g of chloroquine. After 66 min of cardio-pulmonary resuscitation (CPR), extracorporeal cardiopulmonary resuscitation (ECPR) was initiated, allowing cardiac function to recover.
CONCLUSIONS
Chloroquine intoxication is a rare but serious condition due to its cardiac toxicity. Use of ECPR in this case of transient toxicity allowed a favorable evolution with little neurological impairment.
Background
Chloroquine is a worldwide recognized treatment for varied conditions such as malaria, rheumatoid arthritis and lupus erythematosus. Its use has recently been significantly expanded as an experimental treatment for COVID-19. Overdose however, can lead to life threatening complications [1], and with the lack of a specific antidote, treatment remains supportive, extracorporeal membrane oxygenation (ECMO) being the last resort. We report the case of a teenager who suffered cardiac arrest due to chloroquine, and who survived to ECMO decannulation. To our knowledge, this is the first published pediatric case of chloroquine intoxication requiring extracorporeal cardiopulmonary resuscitation (ECPR).
Case presentation
A 14-years-old girl, with a weight of 68 kg and a history of suicidal thoughts presented in cardiopulmonary arrest following a suicide attempt with ingestion of 3 gram of chloroquine without history of any other substance ingestion. Upon the arrival of the ambulance, she was unconscious with a Glasgow coma scale score (GCS) of 6 (1–1–4), bradypneic and with a trismus. The electrocardiogram (ECG) showed ST-segment changes, with pulseless ventricular tachycardia immediately following. Cardio-pulmonary resuscitation was initiated but despite chest compressions, defibrillation and adrenaline, there was no return to spontaneous circulation. Twelve minutes later, upon arrival at the hospital, she had a pulseless idioventricular rhythm and cardiopulmonary resuscitation was continued. The patient was intubated and external massage was taken over by a Lucas® chest compression system (Stryker Medical, Portage, MI49002 US).
Blood gas revealed severe hypokalemia (potassium 1.8 mmol/l) and a severe mixed acidosis (pH 6.97, pCO2 95 mmHg, glucose 14.5 mmol/l, lactate 7.4 mmol/l, base excess − 9.7 mmol/l, bicarbonate 12.7 mmol/l). Resuscitation was continued with three additional doses of adrenaline followed by continuous adrenaline infusion as well as correction of hypokalemia, administration of an amiodarone bolus, a bicarbonate bolus, fluid resuscitation and intravenous lipid emulsion infusion. Despite these measures, resuscitation was unsuccessful.
Peripheral right femoral veno-arterial extracorporeal membrane oxygenation (ECMO)ʼ was therefore initiated after 66 minutes of resuscitation to provide full cardiac support. During transfer to our pediatric intensive care unit (PICU), she was sedated and paralyzed, ventilated, hemodynamically stable on ECMO with a blood flow of 1.7 L/min/m2 and an adrenaline infusion of 0.1mcg/kg/min, a temperature of 34.9 °C. Cerebral computed tomography scan performed on admission was normal. On arrival in PICU, cardiac ultrasound on ECMO showed left ventricular dysfunction with an estimated ejection fraction of 35 %, no left or right ventricular dilatation and without mitral valve regurgitation. Plasma hydroxychloroquine level taken a few hours after PICU admission (equal to ten hours post ingestion) was 0.06mcmol/L. Urinary toxic screening was positive for THC/cannabinoid, benzodiazepine and opioid (benzodiazepine and opioid being administered during initial medical care) and negative for acetaminophen, amphetamine/metamphetamine, barbiturate, cocaine, methadone, phencyclidine, tricyclic antidepressor.
ECMO blood flow was increased to 2L/min/m2 and adrenaline infusion weaned shortly after her admission, and heparin infusion started with ACT target range of 180–220. Targeted temperature management in the range of 34–35 °C was done for 48 h. ECMO course was uneventful. Cardiac ultrasound 46 hours post event showed recovery with systolic ejection fraction of 52 % and mild right diastolic dysfunction, allowing weaning from ECMO. A few hours later, a poor perfusion of the right lower limb was observed with a vascular doppler ultrasound revealing a significant reduction of arterial flow of the right common femoral artery. Immediate wound exploration revealed right common femoral artery stenosis without thrombosis at the site of the cannula insertion. Consequently, an arterial vascular surgical reconstruction was done with a venous patch. She developed a compartment syndrome of the right leg in the hours following, requiring fasciotomy.
When sedation was discontinued on day 4, the patient showed minimal interaction and no intentional movement. Striatal lesions were described on cerebral magnetic resonance imaging (MRI). Electroencephalogram (EEG) on day 6 revealed moderate reactive encephalopathy. On day 7, significant neurological improvement was observed, and the patient was extubated. Neurological exam revealed full consciousness, good spatiotemporal orientation, some memory deficit, and no focal neurologic deficit except hypoesthesia L5-S1 of the right foot and a right elevator muscle deficit secondary to right leg compartment syndrome. She was discharged from PICU at day 11 and then transferred from our tertiary center to her local rehabilitation hospital to continue intensive neuro-muscular physiotherapy.
Discussion
Chloroquine intoxication is a rare condition, associated with severe cardiotoxicity due to its quinidine-like properties. It is a strong membrane stabilizer acting like a class Ia antiarrhythmic agent (action on voltage-dependent sodium channel). Symptoms appear from two to three hours post ingestion and usually resolve within 24 hours, despite a long half-life (14 days). Cardiac toxicity is the result of the rapid rise in chloroquine plasma level during the first two hours, but it can extend to the first twenty-four hours. Cardiac toxicity includes negative inotropism, inhibition of spontaneous depolarization, slowing of atrioventricular conduction, increasing of the refractory period, prolongation of the QT segment and QRS interval, Torsades de pointes and multiple ventricular arrhythmias [2]. An ingestion of more than 20 mg/kg is considered a toxic dose with a lethal dose if it’s over 30 mg/kg. More than 4 grams of chloroquine ingested, chloroquine plasma levels > 25 mcmol/L and hypokalemia have been linked to poor prognosis [3], the severity of hypokalemia being related to the severity of the intoxication. Rebound hyperkalemia can be observed after aggressive correction so hypokalemia treatment should be cautious. Chloroquine also affects the respiratory, neurological (irritability, drowsiness, dystonia and seizures) and digestive systems and metabolic acidosis is common.
In our patient, severe intoxication had to be considered, with potentially more than 40 mg/kg of chloroquine ingested. The clinical presentation, similar to the above literature, confirmed the overdose: respiratory depression and neurological symptoms (drowsiness and dystonia), followed by pulseless ventricular tachycardia and cardiovascular collapse, profound metabolic acidosis and severe hypokalemia. Surprisingly, hydroxychloroquine plasma level was much lower (0,06mcmol/L) than the toxic levels found in literature (usually around 10–30 mcmol/L). We hypothesize that three reasons may explain this result. The first is possible adsorption of chloroquine by the ECMO system (tubing and oxygenator) or binding by of the intravenous lipid emulsion treatment. The second is the hemodilution by both the ECMO circuit and the fluid administration during CPR and on ECMO support. The last is the quality of the sample itself, possibly altered by dilution or sampling procedure error. In our patient, the chloroquine plasma level was not clinically relevant as management was driven by the patient’s condition.
Overdose cases remain rare, so there are no strong recommendations for management. However, from the existing literature, specific treatment combines assisted ventilation and administration of diazepam, adrenaline and intravenous lipid emulsion [2, 4]. Diazepam administration is controversial. It is part of the supportive treatment: used for sedation, in case of seizures and for its presumed antiarrhythmic properties [4]. However, there is no evidence that this treatment alone, as a potential antidote, significantly improves the outcome of moderately intoxicated patients. Adrenaline counteracts vasodilation and myocardial depression, playing a key role in resuscitation of the severely intoxicated patients [2]. Our patient received both treatments (adrenaline and diazepam), before stabilization on ECMO.
Intravenous lipid emulsion has been used in systemic anesthetic toxicity and in poisoning with other lipophilic drugs. As chloroquine is highly lipophilic, the early use of intravenous lipid emulsion in chloroquine intoxication could possibly reduce its plasma peak level of chloroquine and therefore reduce its toxicity. Our patient received a bolus followed by a continuous, but it was rapidly stopped when on ECMO support; indeed, ECMO is a relative contraindication due to a potential obstructive effect on oxygen filter, fat emulsion agglutination and increased blood clot formation in the circuit [5].
When given early enough after ingestion, implying the time of ingestion is known, activated charcoal could prevent absorption of any chloroquine remaining in the stomach. The use of intravenous bicarbonate is mentioned in case of widening of QRS complex. Hemodialysis and hemoperfusion on the other hand are not effective due to the high volume of distribution of chloroquine, therefore these modalities were not considered in our patient [6]
As chloroquine intoxication is a reversible phenomenon, mainly causing symptoms of direct cardiotoxicity, rapid efficient advanced cardiac life support (ACLS) is key to its management, including ECPR. ECMO is described as an option for selected poisoned patients, as it provides organ support during the acute phase of intoxication [7]. Available data show that the use of ECPR offers the possibility of survival with good neurologic recovery in adult out-of-hospital cardiac arrest (OHCA) of varying causes [8]. A shockable rhythm, female gender, short no flow time or witnessed cardiac arrest, short low-flow time and good quality CPR seem to play a positive role on outcome despite ongoing discrepancy about these prognostic factors in the literature [8]. Furthermore, the outcome of ECPR is improved when provided by experienced and trained centers. ECPR is currently provided on a case-by-case basis, where it can be quickly implemented and in patients for whom the etiology of the cardiac arrest is potentially reversible within a limited period of mechanical cardiorespiratory support [7]. For the pediatric population, ECPR use is described for in-hospital cardiac arrest (IHCA) [9–14] and mainly related to children with underlying cardiac disease or after cardiac surgery. Pediatric ECPR has a high mortality, with survival to decannulation and to hospital discharge of 58 % and 42 % respectively in the last ELSO registry report [15]. For OHCA and intoxication cases, data on children are, on the contrary, very sparse. Despite high mortality in pediatric ECPR, selected intoxication cases might, in our opinion, benefit from ECPR support because of their reversibility, as illustrated in this case.
In summary, outcome of our patient depended on the patient’s favorable prognostic factors, the quality of initial resuscitation and the experience of all the staff involved in the ECMO support. Despite morbidity linked to sustained muscle weakness of her right lower limb secondary to arterial ischemia, the overall neurological outcome was favorable, considering the severity of the insult and the prolonged resuscitation.
Conclusions
Chloroquine intoxication can be life threatening, with cardiac arrest, due to cardiotoxicity. Its management is mainly supportive as no antidote is available. This patient fulfilled criteria for optimal use of ECPR, despite the lack of strong evidence for this procedure in intoxication and OHCA in children. Patient criteria and specific protocols regarding use of ECPR are still under study, aiming to improve outcome after pediatric OHCA. Severe reversible intoxication could be one of its indications and should be considered on a case-by-case basis.
Abbreviations
Covid-19 Novel coronavirus disease
CPR Cardio-pulmonary resuscitation
ECPR Extracorporeal cardiopulmonary resuscitation
ECMO Extracorporeal membrane oxygenation
GCS Glasgow coma scale score
ECG Electrocardiogram
PICU Pediatric intensive care unit
MRI Magnetic resonance imaging
EEG Electroencephalogram
ACLS Advanced cardiac life support
OHCA Out-of-hospital cardiac arrest
IHCA In-hospital cardiac arrest
Acknowledgements
none.
Authors’ contributions
TF and DL conceptualized the case report, analyzed the data and wrote the manuscript. VA, JN, MHP, RP, SC read and completed with modifications the manuscript. The author(s) read and approved the final manuscript.
Funding
The authors did not receive any funds related to this case report.
Availability of data and materials
The data used for this case report are part of the personal clinical electronic file and are not pubicly available for confidentiality reasons, but anonymous data are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
the authors declare that the patient and its legal representative have given consent for publication.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33722251 | 19,131,661 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myocarditis'. | Recurrent myocarditis in a patient with active ulcerative colitis: a case report and review of the literature.
Inflammatory bowel diseases such as ulcerative colitis (UC) may be complicated by several extraintestinal manifestations. These involve joints, skin, eyes and less commonly lungs and heart. Myocarditis may result from the toxic effect of drugs (ie, mesalazine) commonly used for the treatment of UC or due to infections (eg, Coxsackieviruses, enteroviruses, adenovirus). Here, we report a case of a 26-year old man affected by UC and complicated by two episodes of myocarditis. Both episodes occurred during two severe exacerbations of UC. However, in both cases the aetiology of myocarditis remains uncertain being ascribable to extraintestinal manifestation, drug toxicity or both.
Introduction
Inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn’s disease, are chronic inflammatory intestinal disorders, characterised by alternating periods of remission and relapse. It is well known that many factors including genetics, immune system, environment and gut microbiome may contribute to the onset of IBD.1–4 The incidence of IBD is increasing worldwide with 6,8 million cases in 2017.5
Moreover, IBD can be associated with several extra-intestinal manifestations, mainly during acute exacerbations, in up to 30% of patients.6 Extraintestinal complications of IBD include joints (ankylosing spondylitis and spondyloarthropathies), eyes (uveitis), skin (pyoderma gangrenosum and erythema nodosum) and less commonly lugs (pleuritis) and heart (pericarditis and myocarditis) disorders.6 Myocarditis is a rare extraintestinal complication of IBD with a reported incidence of 6 cases over 15 000 patients.7 Interestingly, the incidence of myocarditis was slightly higher among patients with IBD compared with the general population.2 Despite rare, cardiac extraintestinal manifestations, such as pericarditis and myocarditis, are more commonly reported to occur in UC than Crohn’s disease patients.7 In addition, in patients with IBD myocarditis could be triggered by drugs currently used to treat this condition8–19 such as mesalazine (MSZ) or biological agents,20 and in newly diagnosed IBD.21 Last but not least, Coxackie viruses, Parvovirus B19, Adenoviruses and enteroviruses can be aetiological agents for myocarditis.
Here, we report a clinical case of a young man affected by UC who had two episodes of myocarditis.
Case report
A 26-year-old male patient was admitted to our Internal Medicine Unit of SS Annunziata Hospital in Cento (Ferrara, Italy) in July 2018 because of fever, bloody diarrhoea (up to 10 bowel movements per day) and abdominal pain. His medical history reported a previous diagnosis of pancolitis in July 2017 successfully treated with oral MSZ (4.8 g/day) and beclomethasone (5 mg/day). The patient had no cardiovascular risk factors. On admission, laboratory tests showed an increase in white cell count (WCC) (18.28×109/L; normal value (n.v.): 4.00–11.00 x 109/L), C reactive protein (CRP) (8.51 mg/dL; n.v.:<0.5 mg/dL) and faecal calprotectin (4763 mg/kg; n.v.: <50 mg/kg). During the hospitalisation, the patient reported several episodes of severe chest pain associated with dyspnoea with no ECG abnormalities. Due to the persistence of these episodes, the patient was tested for troponin I (TnI) that turned to be positive (0.24 ng/mL; n.v.: <0.04 ng/mL). Echocardiography showed a hypokinetic area of the apical anterior aspect of the myocardium with a reduced ejection fraction (50%). Thus, a cardiac MRI was performed. According to Lake Louis Criterion, cardiac MRI, with at least 2 (oedema and necrosis) positive criteria, confirmed a diagnosis of myocarditis (figure 1A). The patient was tested for common infective causes of myocarditis. Stool examination for Adenovirus and bacteria (Shigella, Salmonella, Campylobacter, Escherichia coli O157h7, and Yersinia enterocolitica) resulted negative. Specific viral serological antibodies resulted negative: IgG anti-Coxackie B virus was 2.4 U/mL (n.v.: <11 U/mL; positive >15 U/mL), and IgM anti-Coxackie B virus 6.3 U/mL (n.v.:<10 U/mL; positive >15 U/mL), IgM anti-Herpes simplex 1 and 2 was 0.53 (n.v.: <0.9; positive >1.1), and IgM anti-Herpes zoster 0.26 (n.v.: <0.9; positive >1.1). Thus, these data led us to think that myocarditis was attributed to MSZ and the treatment was shifted to azathioprine (AZA) 150 mg/day associated with methylprednisolone 1 mg/kg/day for 7 days, tapered down until discontinuation. This therapeutic approach promoted remission of UC and troponin I (TnI) normalisation within 7 days. The clinical picture and the lab tests improved (WCC: 16.98×103/µL; CRP: 0.21 mg/dL; TnI: 0.01 ng/L; faecal calprotectin: 3213 mg/kg) and the patient was discharged. One month later (September 2018), a colonoscopy revealed a sub-acute ulcerative pancolitis with Mayo score 1.5 22–24 In December 2018, a follow-up cardiac MRI documented the resolution of myocarditis (figure 1B), and the echocardiography revealed the normalisation of the ventricular ejection fraction (68%).
Figure 1 (A) Cardiac MRI showing myocardial oedema of the apical anterior and septal site compatible with myocarditis (red arrow); (B) the oedema previously reported in the left ventricle was no longer detectable. Some interstitium/myocellular abnormalities, compatible with myocarditis, are present in the apical lateral site; (C) picture illustrating a small and nuanced area of oedema in the apical lateral site with subepicardial localisation (red arrow), compatible with a recent inflammation.
In July 2019, due to a new exacerbation (acute proctosigmoiditis; Mayo 3) AZA treatment was discontinued, and vedolizumab was started (300 mg intravenous every 8 weeks). A month later (August 2019), the patient was re-hospitalised because of the occurrence of symptom relapse characterised by bloody diarrhoea, tachycardia and chest pain with an increase of high-sensitive TnI (358 ng/L) without ECG abnormalities. The patient was investigated for the third time with a cardiac MRI showing a new inflammatory lesion suggestive of myocarditis (figure 1C). A second diagnosis of myocarditis was established, certainly unrelated to MSZ since this drug was discontinued 1 year before. During the hospitalisation the patient was treated with intravenous methylprednisolone 1 mg/kg/day for 7 days associated with vedolizumab. Intestinal symptoms improved along with a reduction of the inflammatory markers: WBC from 15.19 to 9.36 x 103/µL; CRP from 3.21 to 0.83 mg/dL; TnI from 358 to 27 ng/L. At discharge, the treatment regimen included intravenous vedolizumab 300 mg every 8 weeks, methylprednisolone 32 mg/day (tapered down until complete discontinuation), topical beclometasone 3 mg/day, bisoprolol 2.5 mg/day and ramipril 5 mg/day. A follow-up endoscopy (January 2020) showed ulcerative proctosigmoiditis with mild endoscopic activity, Mayo score 1. The patient is currently well and follows a therapy with intravenous vedolizumab 300 mg every 8 weeks, bisoprolol 2.5 mg and ramipril 5 mg, both on a daily basis.
Discussion
UC is often accompanied by extra-intestinal manifestations as anaemia, arthropathy, metabolic bone abnormalities, cutaneous diseases (erythema nodosum and pyoderma gangrenosum), ocular (episcleritis and uveitis), hepatobiliary diseases (primary sclerosing cholangitis, pericholangitis, steatosis, chronic hepatitis, cirrhosis and gallstone formation), and less commonly, cardiovascular complications.25 However, cardiac manifestations can occur with a higher frequency than what it is clinically documented, as they may remain undiagnosed.7 Up to one-third of patients with IBD, particularly those with UC,7 can develop myocarditis or pericarditis with a higher rate of complications, and fatal outcomes in comparison with patients affected by Crohn’s disease.26 Therefore, despite myocarditis has been considered a rare extra-intestinal manifestation of UC, this condition has been documented in many literature reports.1 27–29 Cardiac manifestations in UC may be overlooked because of non-specific symptoms (eg, fatigue, dyspnoea and chest pain), which either resolve without any specific treatment or rapidly progress up to more severe heart complications, for example, cardiogenic shock.30
MSZ is a 5-aminosalicylic acid agent usually prescribed as a first-line therapy in the treatment of UC.31 MSZ mechanism of action has not been completely understood. However, it is thought that it reduces inflammation by inhibiting the cyclooxygenase enzyme and the peroxisome proliferator-activated receptor gamma cascade, thus reducing the proinflammatory signalling pathway of the nuclear factor κB.10 12 Along with the most common MSZ-evoked side effects (eg, dyspepsia, pancreatitis, blood dyscrasias, nausea and headache), this drug can trigger the onset of cardiac inflammation, such as pericarditis, myocarditis and coronary vasculitis.9 The mechanisms leading to cardiotoxicity have not been elucidated yet; however, different theories have been proposed: (1) MSZ may increase the eosinophil-stimulating cytokines, promoting a hypersensitivity reaction; (2) a hypersensitivity reaction triggered by antibodies directed against the drug and a cross-reacting with the cardiac tissue; (3) an immunoglobulin E-mediated allergic reaction promoted by its toxicity on the myopericardium.12 MSZ induced myocarditis usually appears within 4 weeks from the beginning of the treatment, but concomitant corticosteroid use could delay the onset of the cardiotoxicity. MSZ-induced myocarditis has been reported in literature both in the treatment of UC,8–16 Crohn’s disease17–19 and in newly diagnosed IBD.21 Up to now, more than 51 cases of MSZ induced myocarditis have been reported.32
The Food and Drug Administration has approved tumour necrosis factor-alpha (TNF-α) blockers (such as infliximab, adalimumab and golimumab) for the treatment of UC, and the use of these drugs has been associated with worsening of congestive heart failure.20 Namely, cardiomyopathy has been reported as a severe adverse reaction of adalimumab,33 34 myocarditis and perimyocarditis have been ascribed to infliximab,35–37 and heart failure onset or worsening has been specified on the safety information of golimumab as new onset or worsening of congestive heart failure have been reported with this compound.38 Although a cardiac death has been reported in a 66-year-old male 14 days after the first induction dose of vedolizumab (an integrin receptor antagonist currently used to treat UC), it should be emphasised that this patient had a 2-year history of chronic ischaemic heart disease,39 making unlikely that this drug exerted a toxic effect. In this line, the safety of vedolizumab has been well documented both in naive or in patients previously treated with anti-TNF-α agent,40–43 and in studies with a long-term follow-up (up to 5 years).40 44–47
Based on the data emerged by our case report, the first episode of myocarditis could be attributable to MSZ therapy even though it is not possible to rule out a previously misdiagnosed extra-intestinal manifestation of UC perhaps triggered by MSZ. On the other hand, the second episode was likely an extraintestinal manifestation of UC, since vedolizumab treatment was not discontinued at time of the diagnosis of myocarditis, which progressively resolved with corticosteroid use and never relapsed.
This case reports a patient with recurrent extensive UC flares. On two independent situations separated by a period of more than 1 year, he presented with severe chest pain, elevated TnI levels and MRI changes typical of myocarditis. Treatment with steroids led to rapid resolution. The first episode appeared during a severe pancolitis exacerbation that was initially treated with MSZ. Because myocarditis has been attributed to MSZ, its use was terminated. Moreover, even the second episode of myocarditis occurred during a disease flare when endoscopic changes were severe and extensive. Complete resolution of cardiac and colonic findings with steroids suggested that immune factors played a role in both recurrent disorders. On the other hand, myocarditis could also occur during acute intestinal diseases due to increased intestinal permeability.48 This is the case of enteroviral infections, in which products of the enteroviral genome (eg, viral protease 2A) can spread systemically through the leaky gut and cleave host proteins, like dystrophin, causing cardiac dysfunction.48 49 Further studies to elucidate molecular mechanisms associated with these clinical phenomena are needed. We could speculate that even the very first episode of myocarditis was not drug related since the toxicity usually appears within 4 months from MSZ starting and the patient was at the twelfth month of therapy. From this point of view, the hypothesis of an extraintestinal manifestation related to disease flare and increased intestinal permeability is suggestive but cannot be proved.
Finally, it is worth noting that, regardless the aetiology of myocarditis in patients affected by UC, a timely diagnosis of cardiac complication is crucial to avoid life-threatening complications often aggravated by fatal outcome.29
We would like to acknowledge the Registered Nurse, Dr. Daniela Mazzoni, for her technical help.
Contributors: GC, LL and FC: drafting the manuscript, literature review and critical revision of the final manuscript. GC, GZ and RDG: conceptualisation and critical revision of the final manuscript. EZ, MM, MCM and UV: involved in patient care and critical revision of the final manuscript. All authors approved the final version of the article and are accountable for its content. RDG and GZ share last authorship.
Funding: GC, GZ and RDG are supported by research (F.A.R.) funds from University of Ferrara.
Competing interests: None declared.
Patient consent for publication: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: Data are available on reasonable request. | BISOPROLOL, MESALAMINE, RAMIPRIL, VEDOLIZUMAB | DrugsGivenReaction | CC BY-NC | 33722804 | 19,092,598 | 2021-03 |
What was the administration route of drug 'VEDOLIZUMAB'? | Recurrent myocarditis in a patient with active ulcerative colitis: a case report and review of the literature.
Inflammatory bowel diseases such as ulcerative colitis (UC) may be complicated by several extraintestinal manifestations. These involve joints, skin, eyes and less commonly lungs and heart. Myocarditis may result from the toxic effect of drugs (ie, mesalazine) commonly used for the treatment of UC or due to infections (eg, Coxsackieviruses, enteroviruses, adenovirus). Here, we report a case of a 26-year old man affected by UC and complicated by two episodes of myocarditis. Both episodes occurred during two severe exacerbations of UC. However, in both cases the aetiology of myocarditis remains uncertain being ascribable to extraintestinal manifestation, drug toxicity or both.
Introduction
Inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn’s disease, are chronic inflammatory intestinal disorders, characterised by alternating periods of remission and relapse. It is well known that many factors including genetics, immune system, environment and gut microbiome may contribute to the onset of IBD.1–4 The incidence of IBD is increasing worldwide with 6,8 million cases in 2017.5
Moreover, IBD can be associated with several extra-intestinal manifestations, mainly during acute exacerbations, in up to 30% of patients.6 Extraintestinal complications of IBD include joints (ankylosing spondylitis and spondyloarthropathies), eyes (uveitis), skin (pyoderma gangrenosum and erythema nodosum) and less commonly lugs (pleuritis) and heart (pericarditis and myocarditis) disorders.6 Myocarditis is a rare extraintestinal complication of IBD with a reported incidence of 6 cases over 15 000 patients.7 Interestingly, the incidence of myocarditis was slightly higher among patients with IBD compared with the general population.2 Despite rare, cardiac extraintestinal manifestations, such as pericarditis and myocarditis, are more commonly reported to occur in UC than Crohn’s disease patients.7 In addition, in patients with IBD myocarditis could be triggered by drugs currently used to treat this condition8–19 such as mesalazine (MSZ) or biological agents,20 and in newly diagnosed IBD.21 Last but not least, Coxackie viruses, Parvovirus B19, Adenoviruses and enteroviruses can be aetiological agents for myocarditis.
Here, we report a clinical case of a young man affected by UC who had two episodes of myocarditis.
Case report
A 26-year-old male patient was admitted to our Internal Medicine Unit of SS Annunziata Hospital in Cento (Ferrara, Italy) in July 2018 because of fever, bloody diarrhoea (up to 10 bowel movements per day) and abdominal pain. His medical history reported a previous diagnosis of pancolitis in July 2017 successfully treated with oral MSZ (4.8 g/day) and beclomethasone (5 mg/day). The patient had no cardiovascular risk factors. On admission, laboratory tests showed an increase in white cell count (WCC) (18.28×109/L; normal value (n.v.): 4.00–11.00 x 109/L), C reactive protein (CRP) (8.51 mg/dL; n.v.:<0.5 mg/dL) and faecal calprotectin (4763 mg/kg; n.v.: <50 mg/kg). During the hospitalisation, the patient reported several episodes of severe chest pain associated with dyspnoea with no ECG abnormalities. Due to the persistence of these episodes, the patient was tested for troponin I (TnI) that turned to be positive (0.24 ng/mL; n.v.: <0.04 ng/mL). Echocardiography showed a hypokinetic area of the apical anterior aspect of the myocardium with a reduced ejection fraction (50%). Thus, a cardiac MRI was performed. According to Lake Louis Criterion, cardiac MRI, with at least 2 (oedema and necrosis) positive criteria, confirmed a diagnosis of myocarditis (figure 1A). The patient was tested for common infective causes of myocarditis. Stool examination for Adenovirus and bacteria (Shigella, Salmonella, Campylobacter, Escherichia coli O157h7, and Yersinia enterocolitica) resulted negative. Specific viral serological antibodies resulted negative: IgG anti-Coxackie B virus was 2.4 U/mL (n.v.: <11 U/mL; positive >15 U/mL), and IgM anti-Coxackie B virus 6.3 U/mL (n.v.:<10 U/mL; positive >15 U/mL), IgM anti-Herpes simplex 1 and 2 was 0.53 (n.v.: <0.9; positive >1.1), and IgM anti-Herpes zoster 0.26 (n.v.: <0.9; positive >1.1). Thus, these data led us to think that myocarditis was attributed to MSZ and the treatment was shifted to azathioprine (AZA) 150 mg/day associated with methylprednisolone 1 mg/kg/day for 7 days, tapered down until discontinuation. This therapeutic approach promoted remission of UC and troponin I (TnI) normalisation within 7 days. The clinical picture and the lab tests improved (WCC: 16.98×103/µL; CRP: 0.21 mg/dL; TnI: 0.01 ng/L; faecal calprotectin: 3213 mg/kg) and the patient was discharged. One month later (September 2018), a colonoscopy revealed a sub-acute ulcerative pancolitis with Mayo score 1.5 22–24 In December 2018, a follow-up cardiac MRI documented the resolution of myocarditis (figure 1B), and the echocardiography revealed the normalisation of the ventricular ejection fraction (68%).
Figure 1 (A) Cardiac MRI showing myocardial oedema of the apical anterior and septal site compatible with myocarditis (red arrow); (B) the oedema previously reported in the left ventricle was no longer detectable. Some interstitium/myocellular abnormalities, compatible with myocarditis, are present in the apical lateral site; (C) picture illustrating a small and nuanced area of oedema in the apical lateral site with subepicardial localisation (red arrow), compatible with a recent inflammation.
In July 2019, due to a new exacerbation (acute proctosigmoiditis; Mayo 3) AZA treatment was discontinued, and vedolizumab was started (300 mg intravenous every 8 weeks). A month later (August 2019), the patient was re-hospitalised because of the occurrence of symptom relapse characterised by bloody diarrhoea, tachycardia and chest pain with an increase of high-sensitive TnI (358 ng/L) without ECG abnormalities. The patient was investigated for the third time with a cardiac MRI showing a new inflammatory lesion suggestive of myocarditis (figure 1C). A second diagnosis of myocarditis was established, certainly unrelated to MSZ since this drug was discontinued 1 year before. During the hospitalisation the patient was treated with intravenous methylprednisolone 1 mg/kg/day for 7 days associated with vedolizumab. Intestinal symptoms improved along with a reduction of the inflammatory markers: WBC from 15.19 to 9.36 x 103/µL; CRP from 3.21 to 0.83 mg/dL; TnI from 358 to 27 ng/L. At discharge, the treatment regimen included intravenous vedolizumab 300 mg every 8 weeks, methylprednisolone 32 mg/day (tapered down until complete discontinuation), topical beclometasone 3 mg/day, bisoprolol 2.5 mg/day and ramipril 5 mg/day. A follow-up endoscopy (January 2020) showed ulcerative proctosigmoiditis with mild endoscopic activity, Mayo score 1. The patient is currently well and follows a therapy with intravenous vedolizumab 300 mg every 8 weeks, bisoprolol 2.5 mg and ramipril 5 mg, both on a daily basis.
Discussion
UC is often accompanied by extra-intestinal manifestations as anaemia, arthropathy, metabolic bone abnormalities, cutaneous diseases (erythema nodosum and pyoderma gangrenosum), ocular (episcleritis and uveitis), hepatobiliary diseases (primary sclerosing cholangitis, pericholangitis, steatosis, chronic hepatitis, cirrhosis and gallstone formation), and less commonly, cardiovascular complications.25 However, cardiac manifestations can occur with a higher frequency than what it is clinically documented, as they may remain undiagnosed.7 Up to one-third of patients with IBD, particularly those with UC,7 can develop myocarditis or pericarditis with a higher rate of complications, and fatal outcomes in comparison with patients affected by Crohn’s disease.26 Therefore, despite myocarditis has been considered a rare extra-intestinal manifestation of UC, this condition has been documented in many literature reports.1 27–29 Cardiac manifestations in UC may be overlooked because of non-specific symptoms (eg, fatigue, dyspnoea and chest pain), which either resolve without any specific treatment or rapidly progress up to more severe heart complications, for example, cardiogenic shock.30
MSZ is a 5-aminosalicylic acid agent usually prescribed as a first-line therapy in the treatment of UC.31 MSZ mechanism of action has not been completely understood. However, it is thought that it reduces inflammation by inhibiting the cyclooxygenase enzyme and the peroxisome proliferator-activated receptor gamma cascade, thus reducing the proinflammatory signalling pathway of the nuclear factor κB.10 12 Along with the most common MSZ-evoked side effects (eg, dyspepsia, pancreatitis, blood dyscrasias, nausea and headache), this drug can trigger the onset of cardiac inflammation, such as pericarditis, myocarditis and coronary vasculitis.9 The mechanisms leading to cardiotoxicity have not been elucidated yet; however, different theories have been proposed: (1) MSZ may increase the eosinophil-stimulating cytokines, promoting a hypersensitivity reaction; (2) a hypersensitivity reaction triggered by antibodies directed against the drug and a cross-reacting with the cardiac tissue; (3) an immunoglobulin E-mediated allergic reaction promoted by its toxicity on the myopericardium.12 MSZ induced myocarditis usually appears within 4 weeks from the beginning of the treatment, but concomitant corticosteroid use could delay the onset of the cardiotoxicity. MSZ-induced myocarditis has been reported in literature both in the treatment of UC,8–16 Crohn’s disease17–19 and in newly diagnosed IBD.21 Up to now, more than 51 cases of MSZ induced myocarditis have been reported.32
The Food and Drug Administration has approved tumour necrosis factor-alpha (TNF-α) blockers (such as infliximab, adalimumab and golimumab) for the treatment of UC, and the use of these drugs has been associated with worsening of congestive heart failure.20 Namely, cardiomyopathy has been reported as a severe adverse reaction of adalimumab,33 34 myocarditis and perimyocarditis have been ascribed to infliximab,35–37 and heart failure onset or worsening has been specified on the safety information of golimumab as new onset or worsening of congestive heart failure have been reported with this compound.38 Although a cardiac death has been reported in a 66-year-old male 14 days after the first induction dose of vedolizumab (an integrin receptor antagonist currently used to treat UC), it should be emphasised that this patient had a 2-year history of chronic ischaemic heart disease,39 making unlikely that this drug exerted a toxic effect. In this line, the safety of vedolizumab has been well documented both in naive or in patients previously treated with anti-TNF-α agent,40–43 and in studies with a long-term follow-up (up to 5 years).40 44–47
Based on the data emerged by our case report, the first episode of myocarditis could be attributable to MSZ therapy even though it is not possible to rule out a previously misdiagnosed extra-intestinal manifestation of UC perhaps triggered by MSZ. On the other hand, the second episode was likely an extraintestinal manifestation of UC, since vedolizumab treatment was not discontinued at time of the diagnosis of myocarditis, which progressively resolved with corticosteroid use and never relapsed.
This case reports a patient with recurrent extensive UC flares. On two independent situations separated by a period of more than 1 year, he presented with severe chest pain, elevated TnI levels and MRI changes typical of myocarditis. Treatment with steroids led to rapid resolution. The first episode appeared during a severe pancolitis exacerbation that was initially treated with MSZ. Because myocarditis has been attributed to MSZ, its use was terminated. Moreover, even the second episode of myocarditis occurred during a disease flare when endoscopic changes were severe and extensive. Complete resolution of cardiac and colonic findings with steroids suggested that immune factors played a role in both recurrent disorders. On the other hand, myocarditis could also occur during acute intestinal diseases due to increased intestinal permeability.48 This is the case of enteroviral infections, in which products of the enteroviral genome (eg, viral protease 2A) can spread systemically through the leaky gut and cleave host proteins, like dystrophin, causing cardiac dysfunction.48 49 Further studies to elucidate molecular mechanisms associated with these clinical phenomena are needed. We could speculate that even the very first episode of myocarditis was not drug related since the toxicity usually appears within 4 months from MSZ starting and the patient was at the twelfth month of therapy. From this point of view, the hypothesis of an extraintestinal manifestation related to disease flare and increased intestinal permeability is suggestive but cannot be proved.
Finally, it is worth noting that, regardless the aetiology of myocarditis in patients affected by UC, a timely diagnosis of cardiac complication is crucial to avoid life-threatening complications often aggravated by fatal outcome.29
We would like to acknowledge the Registered Nurse, Dr. Daniela Mazzoni, for her technical help.
Contributors: GC, LL and FC: drafting the manuscript, literature review and critical revision of the final manuscript. GC, GZ and RDG: conceptualisation and critical revision of the final manuscript. EZ, MM, MCM and UV: involved in patient care and critical revision of the final manuscript. All authors approved the final version of the article and are accountable for its content. RDG and GZ share last authorship.
Funding: GC, GZ and RDG are supported by research (F.A.R.) funds from University of Ferrara.
Competing interests: None declared.
Patient consent for publication: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: Data are available on reasonable request. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33722804 | 19,092,598 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'C-reactive protein increased'. | Neck swelling and airway narrowing as an initial manifestation of giant cell arteritis.
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery. Face and neck swelling and trismus are under-recognised features of giant cell arteritis and can present as the initial symptom prior to the development of classical temporal tenderness and jaw claudication. The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss. In this paper, we present a case of neck swelling and airway narrowing as the initial manifestation of giant cell arteritis.
Background
Giant cell arteritis is a vasculitis that affects large-sized and medium-sized vessels, including the aorta and branches of the external carotid arteries. Histologically, it is characterised by a granulomatous process with infiltration of multinucleated cells, causing elastic laminae destruction and adventitial fibrosis. The inflammatory process is reflected in blood tests as a raised erythrocyte sedimentation rate and C reactive protein. Diagnosis of giant cell arteritis is based on the American College of Rheumatology’s 1990 guideline, with the presence of three or more criteria out of five.1
Giant cell arteritis is common in the elderly population, with an estimated incidence rate of 15–30 cases per 100 000 individuals.1 Due to the numerous structures supplied by the aorta and the external carotid arteries, giant cell arteritis can produce a broad range of symptoms. The most common symptoms of giant cell arteritis include fatigue, fever, headache, mastication pain and visual changes.
Facial and neck swelling is a subtle change that may feature early and insidiously in giant cell arteritis, although it is seldom reported.2 Other otolaryngologic symptoms including cough, trismus, sore throat, voice changes, dysphagia, hearing loss and tongue claudication.2 3 Aortic involvement can produce thoracic pain, limb swelling and thoracic aortic aneurysm and dissection.
The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss.
Case presentation
An 87-year-old woman presented repeatedly to the Launceston General Hospital with a history of neck swelling (figure 1). The acute onset of swelling started at the left angle of her jaw and spread inferoanteriorly to her neck. This was associated with trismus-like sensation and dyspnoea. She denied any recent respiratory illness or dysphagia.
Figure 1 Initial presentation with face and neck swelling (A: frontal, B: lateral).
The patient’s medical history included hypertension treated with irbesartan/hydrochlorothiazide, hypercholesterolemia on atorvastatin and osteoporosis on denosumab. In addition, she had been taking aspirin for primary prevention of ischaemic heart disease. There were no medication changes in the preceding 3 years.
During the initial presentation, the patient had a low-grade temperature of 37.8°C and remained haemodynamically stable with a heart rate of 100 bpm, blood pressure of 170/80 mm Hg and an oxygen saturation of 98% on room air. There was no change in voice, stridor, palpable neck nodules or collection on physical examination. The patient was tender over her temporomandibular joints bilaterally and had normal mouth opening to three finger breadths despite sensation of trismus.
Blood investigation revealed normocytic anaemia (haemoglobin of 88 g/L and mean cell volume (MCV) of 89 fL), an elevated white cell count of 17.5×109/L (14.2×109/L neutrophils, 1.4×109/L lymphocyte) and a platelet count of 371×109/L. C reactive protein was elevated at 115 mg/L with a normal antinuclear antibody titre. Thyroid, renal and liver function tests were unremarkable. Contrast-enhanced CT of the neck did not reveal any structural abnormality of the oral cavity, tongue, larynx, thyroid, carotids or lymph nodes other than mild subcutaneous oedema.
The patient was managed as potentially having Ludwig’s angina by the local ear, nose and throat team and was commenced on intravenous piperacillin/tazobactam (Tazocin). A throat swab was obtained, which did not isolate any beta-haemolytic Streptococcus sp. The patient completed 3 days of intravenous antibiotic treatment and was discharged with an oral course of amoxicillin/clavulanic acid (Augmentin Duo forte).
However, she represented 2 days later with worsening of her neck swelling with a new bifrontal headache. Antibiotic was switched to oral ciprofloxacin and clindamycin due to concern of potential betalactam induced angio-oedema.
The patient was reviewed by her general practitioner (GP) 2 days post second discharge and was noted to have worsening erythema over her neck with a fever of 38.4°C. She was transferred back to the Launceston General Hospital (LGH) for further investigations. Clinical examination now revealed trismus, with mouth opening limited to two finger breadths.
Investigations
Blood assays from the third presentation were similar to the first and second presentation (haemoglobin 72 g/L, white cell count 19×109/L, neutrophils 13.3×109/L, platelet 395×109/L and C reactive protein 152 mg/L). Thyroid function tests were deranged with a thyroid-stimulating hormone of 0.14 mU/L and free T4 of 21 pmol/L. Repeated CT scan demonstrated marked inflammation of the lower pharynx and larynx, with swelling of the epiglottis. Severe left-sided wall thickening effaced the left parapharyngeal space, with mild stranding within the peripharyngeal space. Salivary glands were normal and no collections were identified. Severe oedema of the airway resulted in a 14 mm segment of narrowing with a luminal diameter of 2–3 mm (figure 2).
Figure 2 CT showing airway narrowing in (A) sagittal and (B) coronal views.
Twenty milligram of intravenous dexamethasone was administered on receiving the CT findings and an urgent ear, nose and throat review was organised. The flexible nasoendoscopy performed was unremarkable, with normal base of tongue, valleculae, epiglottis and mobile vocal cords. There were no signs of pharyngitis or laryngitis.
Differential diagnosis
Due to the discordance of the CT and direct nasoendoscopy findings, the patient came in under the care of the General Medicine team for further investigations. A wide range of differential diagnoses were considered including atypical infections, drug-induced angio-oedema, hereditary angioedema, autoimmune diseases, haematological malignancy and osteonecrosis of the jaw.
Respiratory multiplex PCR, parvovirus and HIV screen were performed to rule out atypical infections. Aspirin and irbesartan were ceased to rule out drug causes, while a C1 esterase inhibitor and complement levels were organised to investigate hereditary angioedema. Autoimmune screen including antinuclear antibodies, antineutrophil cytoplasmic antibody, extractable nuclear antibody, double-stranded DNA antibodies and erythrocyte sedimentation rate were done, while an orthopantomogram was undertaken and ruled out ONJ (osteonecrosis of the jaw) and local dental infection.
On subsequent review, a more detailed headache history was obtained from the patient. The headache was more severe over the left forehead and was associated with trismus like sensation. Of note, the patient denies any jaw claudication. On examination, the left temporal and frontal regions were tender to palpate, with a palpable vessel noted over the left forehead. The erythrocyte sedimentation rate returned at 121 mm/hour, which raised the suspicion of giant cell arteritis. A left temporal artery biopsy was performed and showed classical findings of giant cell arteritis with fragmentation of elastic lamina, fibrosis of the adventitia and the presence of multinucleated giant cells (figure 3).
Figure 3 Temporal artery histology from patient (A): (H&E 5×) thick-walled artery with an associated inflammatory infiltrate. (B): (Orecin Giemsa 10×) elastin stain highlights fragmentation and reduplication of the elastic lamina. (C): (H&E 20×) narked intimal thickening, smooth muscle disorganisation and adventitial fibrosis. (D): (H&E 40×) lympho-histocystic infiltrate with occasional; multinucleated cells.
TREATMENT
As the patient did not have any ocular involvement at diagnosis, she was started on 50 mg of oral prednisolone per day (1 mg/kg). Adjunctive glucocorticoid-sparing agents such as tocilizumab and methotrexate were considered but due to the dramatic presentation of a threatened airway, a clinical decision was made to streamline treatment with single-agent prednisolone.
Adjunctive methotrexate when used at low doses of 10–15 mg per week has been shown to lower relapse rate, though its glucocorticoid-sparing properties were not evident.4 Tocilizumab, an IL6 receptor antagonist, has demonstrated promising results in reducing glucocorticoid exposure and giant cell arteritis relapse rate, though its role in induction therapy is still yet to be defined.5
Outcome and follow-up
The patient responded to the prednisolone course and had resolution of her facial and neck swelling within 3 days (figure 4). She was discharged home with complete resolution of her symptoms. The high-dose prednisolone was maintained for 4 weeks with a tapering plan of 10 mg reduction every 2 weeks till 20 mg per day. Ongoing weaning will be decided based on clinical symptoms and inflammatory markers at follow-up. At the 6-month phone review, patient remains symptom free on 10 mg prednisolone per day.
Figure 4 Resolution of neck swelling post prednisolone treatment (A): frontal, (B): lateral.
Discussion
Face and neck swelling is a non-specific sign, which has a lengthy list of differential diagnoses. Temporal fossa swelling is well recognised in giant cell arteritis however face and neck swelling is less common, occurring in 6.5% of cases.2 The swelling follows a waning and waxing pattern and may be due to spasm and collateralisation of the facial artery.2 6 7 The raised inflammatory markers can cause physicians to treat the initial presentation as an infection and to attribute the resolution of swelling to antibiotic response, as illustrated in our case.
Trismus (reduced jaw opening) has a prevalence of 6.8% in giant cell arteritis but is seldom reported due to its overlap with jaw claudication.8 Our case demonstrates that trismus can occur in isolation from jaw claudication. The mechanism for trismus in giant cell arteritis is uncertain but thought to be due to restricted blood flow to the masseter muscles via distal branches of the external carotid arteries.9 Interestingly, the patient developed subclinical hyperthyroidism during her admission, though it is uncertain if this is related to giant cell arteritis affecting the superior thyroid or a sick euthyroid state. Thyroid dysfunction has been described in giant cell arteritis, though no clear correlation was established due to the overlapping patient epidemiology of giant cell arteritis and thyroid diseases.10 11
The third presentation with airway narrowing stipulated a revisit of the patient’s diagnosis and presented as one of the first cases of CT-documented airway narrowing secondary to giant cell arteritis. Inflammation of the external carotid artery, where the superior laryngeal artery originates from, likely caused local ischaemia and oedema of the superior larynx. Fortunately, for the patient, giant cell arteritis was recognised early in her illness, with complete resolution of symptoms once corticosteroid treatment was commenced.
Patient’s perspective
Patient’s perspective (written with assistance from her daughter)
The whole situation is like going on an adventure, but it was not a good adventure. Not being diagnosed for 2 weeks with a swollen jaw was horrible. For my third trip to the hospital, I was not able to open my jaw and can only eat baby food. Having a doctor who found a diagnosis for me was a relief. When they started treatment, my frightening condition eased quickly.
Learning points
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery.
Face and neck swelling and trismus are under-recognised feature of giant cell arteritis and can be transient prior to developing classic giant cell arteritis symptoms.
Trismus can occur in isolation from jaw claudication in giant cell arteritis.
We recommend that any patient above the age of 50, who presents with face and neck swelling or trismus, to have giant cell arteritis considered as a differiential diagnosis.
Contributors: This case was managed by CS as the Consultant, with ZSL as the Medical Registrar. ZSL wrote up the case with supervision, some direction and editing by CS.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ASPIRIN, ATORVASTATIN, DENOSUMAB, HYDROCHLOROTHIAZIDE\IRBESARTAN, PREDNISOLONE | DrugsGivenReaction | CC BY-NC | 33722908 | 19,711,728 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Giant cell arteritis'. | Neck swelling and airway narrowing as an initial manifestation of giant cell arteritis.
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery. Face and neck swelling and trismus are under-recognised features of giant cell arteritis and can present as the initial symptom prior to the development of classical temporal tenderness and jaw claudication. The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss. In this paper, we present a case of neck swelling and airway narrowing as the initial manifestation of giant cell arteritis.
Background
Giant cell arteritis is a vasculitis that affects large-sized and medium-sized vessels, including the aorta and branches of the external carotid arteries. Histologically, it is characterised by a granulomatous process with infiltration of multinucleated cells, causing elastic laminae destruction and adventitial fibrosis. The inflammatory process is reflected in blood tests as a raised erythrocyte sedimentation rate and C reactive protein. Diagnosis of giant cell arteritis is based on the American College of Rheumatology’s 1990 guideline, with the presence of three or more criteria out of five.1
Giant cell arteritis is common in the elderly population, with an estimated incidence rate of 15–30 cases per 100 000 individuals.1 Due to the numerous structures supplied by the aorta and the external carotid arteries, giant cell arteritis can produce a broad range of symptoms. The most common symptoms of giant cell arteritis include fatigue, fever, headache, mastication pain and visual changes.
Facial and neck swelling is a subtle change that may feature early and insidiously in giant cell arteritis, although it is seldom reported.2 Other otolaryngologic symptoms including cough, trismus, sore throat, voice changes, dysphagia, hearing loss and tongue claudication.2 3 Aortic involvement can produce thoracic pain, limb swelling and thoracic aortic aneurysm and dissection.
The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss.
Case presentation
An 87-year-old woman presented repeatedly to the Launceston General Hospital with a history of neck swelling (figure 1). The acute onset of swelling started at the left angle of her jaw and spread inferoanteriorly to her neck. This was associated with trismus-like sensation and dyspnoea. She denied any recent respiratory illness or dysphagia.
Figure 1 Initial presentation with face and neck swelling (A: frontal, B: lateral).
The patient’s medical history included hypertension treated with irbesartan/hydrochlorothiazide, hypercholesterolemia on atorvastatin and osteoporosis on denosumab. In addition, she had been taking aspirin for primary prevention of ischaemic heart disease. There were no medication changes in the preceding 3 years.
During the initial presentation, the patient had a low-grade temperature of 37.8°C and remained haemodynamically stable with a heart rate of 100 bpm, blood pressure of 170/80 mm Hg and an oxygen saturation of 98% on room air. There was no change in voice, stridor, palpable neck nodules or collection on physical examination. The patient was tender over her temporomandibular joints bilaterally and had normal mouth opening to three finger breadths despite sensation of trismus.
Blood investigation revealed normocytic anaemia (haemoglobin of 88 g/L and mean cell volume (MCV) of 89 fL), an elevated white cell count of 17.5×109/L (14.2×109/L neutrophils, 1.4×109/L lymphocyte) and a platelet count of 371×109/L. C reactive protein was elevated at 115 mg/L with a normal antinuclear antibody titre. Thyroid, renal and liver function tests were unremarkable. Contrast-enhanced CT of the neck did not reveal any structural abnormality of the oral cavity, tongue, larynx, thyroid, carotids or lymph nodes other than mild subcutaneous oedema.
The patient was managed as potentially having Ludwig’s angina by the local ear, nose and throat team and was commenced on intravenous piperacillin/tazobactam (Tazocin). A throat swab was obtained, which did not isolate any beta-haemolytic Streptococcus sp. The patient completed 3 days of intravenous antibiotic treatment and was discharged with an oral course of amoxicillin/clavulanic acid (Augmentin Duo forte).
However, she represented 2 days later with worsening of her neck swelling with a new bifrontal headache. Antibiotic was switched to oral ciprofloxacin and clindamycin due to concern of potential betalactam induced angio-oedema.
The patient was reviewed by her general practitioner (GP) 2 days post second discharge and was noted to have worsening erythema over her neck with a fever of 38.4°C. She was transferred back to the Launceston General Hospital (LGH) for further investigations. Clinical examination now revealed trismus, with mouth opening limited to two finger breadths.
Investigations
Blood assays from the third presentation were similar to the first and second presentation (haemoglobin 72 g/L, white cell count 19×109/L, neutrophils 13.3×109/L, platelet 395×109/L and C reactive protein 152 mg/L). Thyroid function tests were deranged with a thyroid-stimulating hormone of 0.14 mU/L and free T4 of 21 pmol/L. Repeated CT scan demonstrated marked inflammation of the lower pharynx and larynx, with swelling of the epiglottis. Severe left-sided wall thickening effaced the left parapharyngeal space, with mild stranding within the peripharyngeal space. Salivary glands were normal and no collections were identified. Severe oedema of the airway resulted in a 14 mm segment of narrowing with a luminal diameter of 2–3 mm (figure 2).
Figure 2 CT showing airway narrowing in (A) sagittal and (B) coronal views.
Twenty milligram of intravenous dexamethasone was administered on receiving the CT findings and an urgent ear, nose and throat review was organised. The flexible nasoendoscopy performed was unremarkable, with normal base of tongue, valleculae, epiglottis and mobile vocal cords. There were no signs of pharyngitis or laryngitis.
Differential diagnosis
Due to the discordance of the CT and direct nasoendoscopy findings, the patient came in under the care of the General Medicine team for further investigations. A wide range of differential diagnoses were considered including atypical infections, drug-induced angio-oedema, hereditary angioedema, autoimmune diseases, haematological malignancy and osteonecrosis of the jaw.
Respiratory multiplex PCR, parvovirus and HIV screen were performed to rule out atypical infections. Aspirin and irbesartan were ceased to rule out drug causes, while a C1 esterase inhibitor and complement levels were organised to investigate hereditary angioedema. Autoimmune screen including antinuclear antibodies, antineutrophil cytoplasmic antibody, extractable nuclear antibody, double-stranded DNA antibodies and erythrocyte sedimentation rate were done, while an orthopantomogram was undertaken and ruled out ONJ (osteonecrosis of the jaw) and local dental infection.
On subsequent review, a more detailed headache history was obtained from the patient. The headache was more severe over the left forehead and was associated with trismus like sensation. Of note, the patient denies any jaw claudication. On examination, the left temporal and frontal regions were tender to palpate, with a palpable vessel noted over the left forehead. The erythrocyte sedimentation rate returned at 121 mm/hour, which raised the suspicion of giant cell arteritis. A left temporal artery biopsy was performed and showed classical findings of giant cell arteritis with fragmentation of elastic lamina, fibrosis of the adventitia and the presence of multinucleated giant cells (figure 3).
Figure 3 Temporal artery histology from patient (A): (H&E 5×) thick-walled artery with an associated inflammatory infiltrate. (B): (Orecin Giemsa 10×) elastin stain highlights fragmentation and reduplication of the elastic lamina. (C): (H&E 20×) narked intimal thickening, smooth muscle disorganisation and adventitial fibrosis. (D): (H&E 40×) lympho-histocystic infiltrate with occasional; multinucleated cells.
TREATMENT
As the patient did not have any ocular involvement at diagnosis, she was started on 50 mg of oral prednisolone per day (1 mg/kg). Adjunctive glucocorticoid-sparing agents such as tocilizumab and methotrexate were considered but due to the dramatic presentation of a threatened airway, a clinical decision was made to streamline treatment with single-agent prednisolone.
Adjunctive methotrexate when used at low doses of 10–15 mg per week has been shown to lower relapse rate, though its glucocorticoid-sparing properties were not evident.4 Tocilizumab, an IL6 receptor antagonist, has demonstrated promising results in reducing glucocorticoid exposure and giant cell arteritis relapse rate, though its role in induction therapy is still yet to be defined.5
Outcome and follow-up
The patient responded to the prednisolone course and had resolution of her facial and neck swelling within 3 days (figure 4). She was discharged home with complete resolution of her symptoms. The high-dose prednisolone was maintained for 4 weeks with a tapering plan of 10 mg reduction every 2 weeks till 20 mg per day. Ongoing weaning will be decided based on clinical symptoms and inflammatory markers at follow-up. At the 6-month phone review, patient remains symptom free on 10 mg prednisolone per day.
Figure 4 Resolution of neck swelling post prednisolone treatment (A): frontal, (B): lateral.
Discussion
Face and neck swelling is a non-specific sign, which has a lengthy list of differential diagnoses. Temporal fossa swelling is well recognised in giant cell arteritis however face and neck swelling is less common, occurring in 6.5% of cases.2 The swelling follows a waning and waxing pattern and may be due to spasm and collateralisation of the facial artery.2 6 7 The raised inflammatory markers can cause physicians to treat the initial presentation as an infection and to attribute the resolution of swelling to antibiotic response, as illustrated in our case.
Trismus (reduced jaw opening) has a prevalence of 6.8% in giant cell arteritis but is seldom reported due to its overlap with jaw claudication.8 Our case demonstrates that trismus can occur in isolation from jaw claudication. The mechanism for trismus in giant cell arteritis is uncertain but thought to be due to restricted blood flow to the masseter muscles via distal branches of the external carotid arteries.9 Interestingly, the patient developed subclinical hyperthyroidism during her admission, though it is uncertain if this is related to giant cell arteritis affecting the superior thyroid or a sick euthyroid state. Thyroid dysfunction has been described in giant cell arteritis, though no clear correlation was established due to the overlapping patient epidemiology of giant cell arteritis and thyroid diseases.10 11
The third presentation with airway narrowing stipulated a revisit of the patient’s diagnosis and presented as one of the first cases of CT-documented airway narrowing secondary to giant cell arteritis. Inflammation of the external carotid artery, where the superior laryngeal artery originates from, likely caused local ischaemia and oedema of the superior larynx. Fortunately, for the patient, giant cell arteritis was recognised early in her illness, with complete resolution of symptoms once corticosteroid treatment was commenced.
Patient’s perspective
Patient’s perspective (written with assistance from her daughter)
The whole situation is like going on an adventure, but it was not a good adventure. Not being diagnosed for 2 weeks with a swollen jaw was horrible. For my third trip to the hospital, I was not able to open my jaw and can only eat baby food. Having a doctor who found a diagnosis for me was a relief. When they started treatment, my frightening condition eased quickly.
Learning points
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery.
Face and neck swelling and trismus are under-recognised feature of giant cell arteritis and can be transient prior to developing classic giant cell arteritis symptoms.
Trismus can occur in isolation from jaw claudication in giant cell arteritis.
We recommend that any patient above the age of 50, who presents with face and neck swelling or trismus, to have giant cell arteritis considered as a differiential diagnosis.
Contributors: This case was managed by CS as the Consultant, with ZSL as the Medical Registrar. ZSL wrote up the case with supervision, some direction and editing by CS.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ASPIRIN, ATORVASTATIN, DENOSUMAB, HYDROCHLOROTHIAZIDE\IRBESARTAN, PREDNISOLONE | DrugsGivenReaction | CC BY-NC | 33722908 | 19,711,728 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ludwig angina'. | Neck swelling and airway narrowing as an initial manifestation of giant cell arteritis.
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery. Face and neck swelling and trismus are under-recognised features of giant cell arteritis and can present as the initial symptom prior to the development of classical temporal tenderness and jaw claudication. The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss. In this paper, we present a case of neck swelling and airway narrowing as the initial manifestation of giant cell arteritis.
Background
Giant cell arteritis is a vasculitis that affects large-sized and medium-sized vessels, including the aorta and branches of the external carotid arteries. Histologically, it is characterised by a granulomatous process with infiltration of multinucleated cells, causing elastic laminae destruction and adventitial fibrosis. The inflammatory process is reflected in blood tests as a raised erythrocyte sedimentation rate and C reactive protein. Diagnosis of giant cell arteritis is based on the American College of Rheumatology’s 1990 guideline, with the presence of three or more criteria out of five.1
Giant cell arteritis is common in the elderly population, with an estimated incidence rate of 15–30 cases per 100 000 individuals.1 Due to the numerous structures supplied by the aorta and the external carotid arteries, giant cell arteritis can produce a broad range of symptoms. The most common symptoms of giant cell arteritis include fatigue, fever, headache, mastication pain and visual changes.
Facial and neck swelling is a subtle change that may feature early and insidiously in giant cell arteritis, although it is seldom reported.2 Other otolaryngologic symptoms including cough, trismus, sore throat, voice changes, dysphagia, hearing loss and tongue claudication.2 3 Aortic involvement can produce thoracic pain, limb swelling and thoracic aortic aneurysm and dissection.
The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss.
Case presentation
An 87-year-old woman presented repeatedly to the Launceston General Hospital with a history of neck swelling (figure 1). The acute onset of swelling started at the left angle of her jaw and spread inferoanteriorly to her neck. This was associated with trismus-like sensation and dyspnoea. She denied any recent respiratory illness or dysphagia.
Figure 1 Initial presentation with face and neck swelling (A: frontal, B: lateral).
The patient’s medical history included hypertension treated with irbesartan/hydrochlorothiazide, hypercholesterolemia on atorvastatin and osteoporosis on denosumab. In addition, she had been taking aspirin for primary prevention of ischaemic heart disease. There were no medication changes in the preceding 3 years.
During the initial presentation, the patient had a low-grade temperature of 37.8°C and remained haemodynamically stable with a heart rate of 100 bpm, blood pressure of 170/80 mm Hg and an oxygen saturation of 98% on room air. There was no change in voice, stridor, palpable neck nodules or collection on physical examination. The patient was tender over her temporomandibular joints bilaterally and had normal mouth opening to three finger breadths despite sensation of trismus.
Blood investigation revealed normocytic anaemia (haemoglobin of 88 g/L and mean cell volume (MCV) of 89 fL), an elevated white cell count of 17.5×109/L (14.2×109/L neutrophils, 1.4×109/L lymphocyte) and a platelet count of 371×109/L. C reactive protein was elevated at 115 mg/L with a normal antinuclear antibody titre. Thyroid, renal and liver function tests were unremarkable. Contrast-enhanced CT of the neck did not reveal any structural abnormality of the oral cavity, tongue, larynx, thyroid, carotids or lymph nodes other than mild subcutaneous oedema.
The patient was managed as potentially having Ludwig’s angina by the local ear, nose and throat team and was commenced on intravenous piperacillin/tazobactam (Tazocin). A throat swab was obtained, which did not isolate any beta-haemolytic Streptococcus sp. The patient completed 3 days of intravenous antibiotic treatment and was discharged with an oral course of amoxicillin/clavulanic acid (Augmentin Duo forte).
However, she represented 2 days later with worsening of her neck swelling with a new bifrontal headache. Antibiotic was switched to oral ciprofloxacin and clindamycin due to concern of potential betalactam induced angio-oedema.
The patient was reviewed by her general practitioner (GP) 2 days post second discharge and was noted to have worsening erythema over her neck with a fever of 38.4°C. She was transferred back to the Launceston General Hospital (LGH) for further investigations. Clinical examination now revealed trismus, with mouth opening limited to two finger breadths.
Investigations
Blood assays from the third presentation were similar to the first and second presentation (haemoglobin 72 g/L, white cell count 19×109/L, neutrophils 13.3×109/L, platelet 395×109/L and C reactive protein 152 mg/L). Thyroid function tests were deranged with a thyroid-stimulating hormone of 0.14 mU/L and free T4 of 21 pmol/L. Repeated CT scan demonstrated marked inflammation of the lower pharynx and larynx, with swelling of the epiglottis. Severe left-sided wall thickening effaced the left parapharyngeal space, with mild stranding within the peripharyngeal space. Salivary glands were normal and no collections were identified. Severe oedema of the airway resulted in a 14 mm segment of narrowing with a luminal diameter of 2–3 mm (figure 2).
Figure 2 CT showing airway narrowing in (A) sagittal and (B) coronal views.
Twenty milligram of intravenous dexamethasone was administered on receiving the CT findings and an urgent ear, nose and throat review was organised. The flexible nasoendoscopy performed was unremarkable, with normal base of tongue, valleculae, epiglottis and mobile vocal cords. There were no signs of pharyngitis or laryngitis.
Differential diagnosis
Due to the discordance of the CT and direct nasoendoscopy findings, the patient came in under the care of the General Medicine team for further investigations. A wide range of differential diagnoses were considered including atypical infections, drug-induced angio-oedema, hereditary angioedema, autoimmune diseases, haematological malignancy and osteonecrosis of the jaw.
Respiratory multiplex PCR, parvovirus and HIV screen were performed to rule out atypical infections. Aspirin and irbesartan were ceased to rule out drug causes, while a C1 esterase inhibitor and complement levels were organised to investigate hereditary angioedema. Autoimmune screen including antinuclear antibodies, antineutrophil cytoplasmic antibody, extractable nuclear antibody, double-stranded DNA antibodies and erythrocyte sedimentation rate were done, while an orthopantomogram was undertaken and ruled out ONJ (osteonecrosis of the jaw) and local dental infection.
On subsequent review, a more detailed headache history was obtained from the patient. The headache was more severe over the left forehead and was associated with trismus like sensation. Of note, the patient denies any jaw claudication. On examination, the left temporal and frontal regions were tender to palpate, with a palpable vessel noted over the left forehead. The erythrocyte sedimentation rate returned at 121 mm/hour, which raised the suspicion of giant cell arteritis. A left temporal artery biopsy was performed and showed classical findings of giant cell arteritis with fragmentation of elastic lamina, fibrosis of the adventitia and the presence of multinucleated giant cells (figure 3).
Figure 3 Temporal artery histology from patient (A): (H&E 5×) thick-walled artery with an associated inflammatory infiltrate. (B): (Orecin Giemsa 10×) elastin stain highlights fragmentation and reduplication of the elastic lamina. (C): (H&E 20×) narked intimal thickening, smooth muscle disorganisation and adventitial fibrosis. (D): (H&E 40×) lympho-histocystic infiltrate with occasional; multinucleated cells.
TREATMENT
As the patient did not have any ocular involvement at diagnosis, she was started on 50 mg of oral prednisolone per day (1 mg/kg). Adjunctive glucocorticoid-sparing agents such as tocilizumab and methotrexate were considered but due to the dramatic presentation of a threatened airway, a clinical decision was made to streamline treatment with single-agent prednisolone.
Adjunctive methotrexate when used at low doses of 10–15 mg per week has been shown to lower relapse rate, though its glucocorticoid-sparing properties were not evident.4 Tocilizumab, an IL6 receptor antagonist, has demonstrated promising results in reducing glucocorticoid exposure and giant cell arteritis relapse rate, though its role in induction therapy is still yet to be defined.5
Outcome and follow-up
The patient responded to the prednisolone course and had resolution of her facial and neck swelling within 3 days (figure 4). She was discharged home with complete resolution of her symptoms. The high-dose prednisolone was maintained for 4 weeks with a tapering plan of 10 mg reduction every 2 weeks till 20 mg per day. Ongoing weaning will be decided based on clinical symptoms and inflammatory markers at follow-up. At the 6-month phone review, patient remains symptom free on 10 mg prednisolone per day.
Figure 4 Resolution of neck swelling post prednisolone treatment (A): frontal, (B): lateral.
Discussion
Face and neck swelling is a non-specific sign, which has a lengthy list of differential diagnoses. Temporal fossa swelling is well recognised in giant cell arteritis however face and neck swelling is less common, occurring in 6.5% of cases.2 The swelling follows a waning and waxing pattern and may be due to spasm and collateralisation of the facial artery.2 6 7 The raised inflammatory markers can cause physicians to treat the initial presentation as an infection and to attribute the resolution of swelling to antibiotic response, as illustrated in our case.
Trismus (reduced jaw opening) has a prevalence of 6.8% in giant cell arteritis but is seldom reported due to its overlap with jaw claudication.8 Our case demonstrates that trismus can occur in isolation from jaw claudication. The mechanism for trismus in giant cell arteritis is uncertain but thought to be due to restricted blood flow to the masseter muscles via distal branches of the external carotid arteries.9 Interestingly, the patient developed subclinical hyperthyroidism during her admission, though it is uncertain if this is related to giant cell arteritis affecting the superior thyroid or a sick euthyroid state. Thyroid dysfunction has been described in giant cell arteritis, though no clear correlation was established due to the overlapping patient epidemiology of giant cell arteritis and thyroid diseases.10 11
The third presentation with airway narrowing stipulated a revisit of the patient’s diagnosis and presented as one of the first cases of CT-documented airway narrowing secondary to giant cell arteritis. Inflammation of the external carotid artery, where the superior laryngeal artery originates from, likely caused local ischaemia and oedema of the superior larynx. Fortunately, for the patient, giant cell arteritis was recognised early in her illness, with complete resolution of symptoms once corticosteroid treatment was commenced.
Patient’s perspective
Patient’s perspective (written with assistance from her daughter)
The whole situation is like going on an adventure, but it was not a good adventure. Not being diagnosed for 2 weeks with a swollen jaw was horrible. For my third trip to the hospital, I was not able to open my jaw and can only eat baby food. Having a doctor who found a diagnosis for me was a relief. When they started treatment, my frightening condition eased quickly.
Learning points
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery.
Face and neck swelling and trismus are under-recognised feature of giant cell arteritis and can be transient prior to developing classic giant cell arteritis symptoms.
Trismus can occur in isolation from jaw claudication in giant cell arteritis.
We recommend that any patient above the age of 50, who presents with face and neck swelling or trismus, to have giant cell arteritis considered as a differiential diagnosis.
Contributors: This case was managed by CS as the Consultant, with ZSL as the Medical Registrar. ZSL wrote up the case with supervision, some direction and editing by CS.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ASPIRIN, ATORVASTATIN, DENOSUMAB, HYDROCHLOROTHIAZIDE\IRBESARTAN, PREDNISOLONE | DrugsGivenReaction | CC BY-NC | 33722908 | 19,711,728 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Normocytic anaemia'. | Neck swelling and airway narrowing as an initial manifestation of giant cell arteritis.
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery. Face and neck swelling and trismus are under-recognised features of giant cell arteritis and can present as the initial symptom prior to the development of classical temporal tenderness and jaw claudication. The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss. In this paper, we present a case of neck swelling and airway narrowing as the initial manifestation of giant cell arteritis.
Background
Giant cell arteritis is a vasculitis that affects large-sized and medium-sized vessels, including the aorta and branches of the external carotid arteries. Histologically, it is characterised by a granulomatous process with infiltration of multinucleated cells, causing elastic laminae destruction and adventitial fibrosis. The inflammatory process is reflected in blood tests as a raised erythrocyte sedimentation rate and C reactive protein. Diagnosis of giant cell arteritis is based on the American College of Rheumatology’s 1990 guideline, with the presence of three or more criteria out of five.1
Giant cell arteritis is common in the elderly population, with an estimated incidence rate of 15–30 cases per 100 000 individuals.1 Due to the numerous structures supplied by the aorta and the external carotid arteries, giant cell arteritis can produce a broad range of symptoms. The most common symptoms of giant cell arteritis include fatigue, fever, headache, mastication pain and visual changes.
Facial and neck swelling is a subtle change that may feature early and insidiously in giant cell arteritis, although it is seldom reported.2 Other otolaryngologic symptoms including cough, trismus, sore throat, voice changes, dysphagia, hearing loss and tongue claudication.2 3 Aortic involvement can produce thoracic pain, limb swelling and thoracic aortic aneurysm and dissection.
The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss.
Case presentation
An 87-year-old woman presented repeatedly to the Launceston General Hospital with a history of neck swelling (figure 1). The acute onset of swelling started at the left angle of her jaw and spread inferoanteriorly to her neck. This was associated with trismus-like sensation and dyspnoea. She denied any recent respiratory illness or dysphagia.
Figure 1 Initial presentation with face and neck swelling (A: frontal, B: lateral).
The patient’s medical history included hypertension treated with irbesartan/hydrochlorothiazide, hypercholesterolemia on atorvastatin and osteoporosis on denosumab. In addition, she had been taking aspirin for primary prevention of ischaemic heart disease. There were no medication changes in the preceding 3 years.
During the initial presentation, the patient had a low-grade temperature of 37.8°C and remained haemodynamically stable with a heart rate of 100 bpm, blood pressure of 170/80 mm Hg and an oxygen saturation of 98% on room air. There was no change in voice, stridor, palpable neck nodules or collection on physical examination. The patient was tender over her temporomandibular joints bilaterally and had normal mouth opening to three finger breadths despite sensation of trismus.
Blood investigation revealed normocytic anaemia (haemoglobin of 88 g/L and mean cell volume (MCV) of 89 fL), an elevated white cell count of 17.5×109/L (14.2×109/L neutrophils, 1.4×109/L lymphocyte) and a platelet count of 371×109/L. C reactive protein was elevated at 115 mg/L with a normal antinuclear antibody titre. Thyroid, renal and liver function tests were unremarkable. Contrast-enhanced CT of the neck did not reveal any structural abnormality of the oral cavity, tongue, larynx, thyroid, carotids or lymph nodes other than mild subcutaneous oedema.
The patient was managed as potentially having Ludwig’s angina by the local ear, nose and throat team and was commenced on intravenous piperacillin/tazobactam (Tazocin). A throat swab was obtained, which did not isolate any beta-haemolytic Streptococcus sp. The patient completed 3 days of intravenous antibiotic treatment and was discharged with an oral course of amoxicillin/clavulanic acid (Augmentin Duo forte).
However, she represented 2 days later with worsening of her neck swelling with a new bifrontal headache. Antibiotic was switched to oral ciprofloxacin and clindamycin due to concern of potential betalactam induced angio-oedema.
The patient was reviewed by her general practitioner (GP) 2 days post second discharge and was noted to have worsening erythema over her neck with a fever of 38.4°C. She was transferred back to the Launceston General Hospital (LGH) for further investigations. Clinical examination now revealed trismus, with mouth opening limited to two finger breadths.
Investigations
Blood assays from the third presentation were similar to the first and second presentation (haemoglobin 72 g/L, white cell count 19×109/L, neutrophils 13.3×109/L, platelet 395×109/L and C reactive protein 152 mg/L). Thyroid function tests were deranged with a thyroid-stimulating hormone of 0.14 mU/L and free T4 of 21 pmol/L. Repeated CT scan demonstrated marked inflammation of the lower pharynx and larynx, with swelling of the epiglottis. Severe left-sided wall thickening effaced the left parapharyngeal space, with mild stranding within the peripharyngeal space. Salivary glands were normal and no collections were identified. Severe oedema of the airway resulted in a 14 mm segment of narrowing with a luminal diameter of 2–3 mm (figure 2).
Figure 2 CT showing airway narrowing in (A) sagittal and (B) coronal views.
Twenty milligram of intravenous dexamethasone was administered on receiving the CT findings and an urgent ear, nose and throat review was organised. The flexible nasoendoscopy performed was unremarkable, with normal base of tongue, valleculae, epiglottis and mobile vocal cords. There were no signs of pharyngitis or laryngitis.
Differential diagnosis
Due to the discordance of the CT and direct nasoendoscopy findings, the patient came in under the care of the General Medicine team for further investigations. A wide range of differential diagnoses were considered including atypical infections, drug-induced angio-oedema, hereditary angioedema, autoimmune diseases, haematological malignancy and osteonecrosis of the jaw.
Respiratory multiplex PCR, parvovirus and HIV screen were performed to rule out atypical infections. Aspirin and irbesartan were ceased to rule out drug causes, while a C1 esterase inhibitor and complement levels were organised to investigate hereditary angioedema. Autoimmune screen including antinuclear antibodies, antineutrophil cytoplasmic antibody, extractable nuclear antibody, double-stranded DNA antibodies and erythrocyte sedimentation rate were done, while an orthopantomogram was undertaken and ruled out ONJ (osteonecrosis of the jaw) and local dental infection.
On subsequent review, a more detailed headache history was obtained from the patient. The headache was more severe over the left forehead and was associated with trismus like sensation. Of note, the patient denies any jaw claudication. On examination, the left temporal and frontal regions were tender to palpate, with a palpable vessel noted over the left forehead. The erythrocyte sedimentation rate returned at 121 mm/hour, which raised the suspicion of giant cell arteritis. A left temporal artery biopsy was performed and showed classical findings of giant cell arteritis with fragmentation of elastic lamina, fibrosis of the adventitia and the presence of multinucleated giant cells (figure 3).
Figure 3 Temporal artery histology from patient (A): (H&E 5×) thick-walled artery with an associated inflammatory infiltrate. (B): (Orecin Giemsa 10×) elastin stain highlights fragmentation and reduplication of the elastic lamina. (C): (H&E 20×) narked intimal thickening, smooth muscle disorganisation and adventitial fibrosis. (D): (H&E 40×) lympho-histocystic infiltrate with occasional; multinucleated cells.
TREATMENT
As the patient did not have any ocular involvement at diagnosis, she was started on 50 mg of oral prednisolone per day (1 mg/kg). Adjunctive glucocorticoid-sparing agents such as tocilizumab and methotrexate were considered but due to the dramatic presentation of a threatened airway, a clinical decision was made to streamline treatment with single-agent prednisolone.
Adjunctive methotrexate when used at low doses of 10–15 mg per week has been shown to lower relapse rate, though its glucocorticoid-sparing properties were not evident.4 Tocilizumab, an IL6 receptor antagonist, has demonstrated promising results in reducing glucocorticoid exposure and giant cell arteritis relapse rate, though its role in induction therapy is still yet to be defined.5
Outcome and follow-up
The patient responded to the prednisolone course and had resolution of her facial and neck swelling within 3 days (figure 4). She was discharged home with complete resolution of her symptoms. The high-dose prednisolone was maintained for 4 weeks with a tapering plan of 10 mg reduction every 2 weeks till 20 mg per day. Ongoing weaning will be decided based on clinical symptoms and inflammatory markers at follow-up. At the 6-month phone review, patient remains symptom free on 10 mg prednisolone per day.
Figure 4 Resolution of neck swelling post prednisolone treatment (A): frontal, (B): lateral.
Discussion
Face and neck swelling is a non-specific sign, which has a lengthy list of differential diagnoses. Temporal fossa swelling is well recognised in giant cell arteritis however face and neck swelling is less common, occurring in 6.5% of cases.2 The swelling follows a waning and waxing pattern and may be due to spasm and collateralisation of the facial artery.2 6 7 The raised inflammatory markers can cause physicians to treat the initial presentation as an infection and to attribute the resolution of swelling to antibiotic response, as illustrated in our case.
Trismus (reduced jaw opening) has a prevalence of 6.8% in giant cell arteritis but is seldom reported due to its overlap with jaw claudication.8 Our case demonstrates that trismus can occur in isolation from jaw claudication. The mechanism for trismus in giant cell arteritis is uncertain but thought to be due to restricted blood flow to the masseter muscles via distal branches of the external carotid arteries.9 Interestingly, the patient developed subclinical hyperthyroidism during her admission, though it is uncertain if this is related to giant cell arteritis affecting the superior thyroid or a sick euthyroid state. Thyroid dysfunction has been described in giant cell arteritis, though no clear correlation was established due to the overlapping patient epidemiology of giant cell arteritis and thyroid diseases.10 11
The third presentation with airway narrowing stipulated a revisit of the patient’s diagnosis and presented as one of the first cases of CT-documented airway narrowing secondary to giant cell arteritis. Inflammation of the external carotid artery, where the superior laryngeal artery originates from, likely caused local ischaemia and oedema of the superior larynx. Fortunately, for the patient, giant cell arteritis was recognised early in her illness, with complete resolution of symptoms once corticosteroid treatment was commenced.
Patient’s perspective
Patient’s perspective (written with assistance from her daughter)
The whole situation is like going on an adventure, but it was not a good adventure. Not being diagnosed for 2 weeks with a swollen jaw was horrible. For my third trip to the hospital, I was not able to open my jaw and can only eat baby food. Having a doctor who found a diagnosis for me was a relief. When they started treatment, my frightening condition eased quickly.
Learning points
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery.
Face and neck swelling and trismus are under-recognised feature of giant cell arteritis and can be transient prior to developing classic giant cell arteritis symptoms.
Trismus can occur in isolation from jaw claudication in giant cell arteritis.
We recommend that any patient above the age of 50, who presents with face and neck swelling or trismus, to have giant cell arteritis considered as a differiential diagnosis.
Contributors: This case was managed by CS as the Consultant, with ZSL as the Medical Registrar. ZSL wrote up the case with supervision, some direction and editing by CS.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ASPIRIN, ATORVASTATIN, DENOSUMAB, HYDROCHLOROTHIAZIDE\IRBESARTAN, PREDNISOLONE | DrugsGivenReaction | CC BY-NC | 33722908 | 19,711,728 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'White blood cell count increased'. | Neck swelling and airway narrowing as an initial manifestation of giant cell arteritis.
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery. Face and neck swelling and trismus are under-recognised features of giant cell arteritis and can present as the initial symptom prior to the development of classical temporal tenderness and jaw claudication. The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss. In this paper, we present a case of neck swelling and airway narrowing as the initial manifestation of giant cell arteritis.
Background
Giant cell arteritis is a vasculitis that affects large-sized and medium-sized vessels, including the aorta and branches of the external carotid arteries. Histologically, it is characterised by a granulomatous process with infiltration of multinucleated cells, causing elastic laminae destruction and adventitial fibrosis. The inflammatory process is reflected in blood tests as a raised erythrocyte sedimentation rate and C reactive protein. Diagnosis of giant cell arteritis is based on the American College of Rheumatology’s 1990 guideline, with the presence of three or more criteria out of five.1
Giant cell arteritis is common in the elderly population, with an estimated incidence rate of 15–30 cases per 100 000 individuals.1 Due to the numerous structures supplied by the aorta and the external carotid arteries, giant cell arteritis can produce a broad range of symptoms. The most common symptoms of giant cell arteritis include fatigue, fever, headache, mastication pain and visual changes.
Facial and neck swelling is a subtle change that may feature early and insidiously in giant cell arteritis, although it is seldom reported.2 Other otolaryngologic symptoms including cough, trismus, sore throat, voice changes, dysphagia, hearing loss and tongue claudication.2 3 Aortic involvement can produce thoracic pain, limb swelling and thoracic aortic aneurysm and dissection.
The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss.
Case presentation
An 87-year-old woman presented repeatedly to the Launceston General Hospital with a history of neck swelling (figure 1). The acute onset of swelling started at the left angle of her jaw and spread inferoanteriorly to her neck. This was associated with trismus-like sensation and dyspnoea. She denied any recent respiratory illness or dysphagia.
Figure 1 Initial presentation with face and neck swelling (A: frontal, B: lateral).
The patient’s medical history included hypertension treated with irbesartan/hydrochlorothiazide, hypercholesterolemia on atorvastatin and osteoporosis on denosumab. In addition, she had been taking aspirin for primary prevention of ischaemic heart disease. There were no medication changes in the preceding 3 years.
During the initial presentation, the patient had a low-grade temperature of 37.8°C and remained haemodynamically stable with a heart rate of 100 bpm, blood pressure of 170/80 mm Hg and an oxygen saturation of 98% on room air. There was no change in voice, stridor, palpable neck nodules or collection on physical examination. The patient was tender over her temporomandibular joints bilaterally and had normal mouth opening to three finger breadths despite sensation of trismus.
Blood investigation revealed normocytic anaemia (haemoglobin of 88 g/L and mean cell volume (MCV) of 89 fL), an elevated white cell count of 17.5×109/L (14.2×109/L neutrophils, 1.4×109/L lymphocyte) and a platelet count of 371×109/L. C reactive protein was elevated at 115 mg/L with a normal antinuclear antibody titre. Thyroid, renal and liver function tests were unremarkable. Contrast-enhanced CT of the neck did not reveal any structural abnormality of the oral cavity, tongue, larynx, thyroid, carotids or lymph nodes other than mild subcutaneous oedema.
The patient was managed as potentially having Ludwig’s angina by the local ear, nose and throat team and was commenced on intravenous piperacillin/tazobactam (Tazocin). A throat swab was obtained, which did not isolate any beta-haemolytic Streptococcus sp. The patient completed 3 days of intravenous antibiotic treatment and was discharged with an oral course of amoxicillin/clavulanic acid (Augmentin Duo forte).
However, she represented 2 days later with worsening of her neck swelling with a new bifrontal headache. Antibiotic was switched to oral ciprofloxacin and clindamycin due to concern of potential betalactam induced angio-oedema.
The patient was reviewed by her general practitioner (GP) 2 days post second discharge and was noted to have worsening erythema over her neck with a fever of 38.4°C. She was transferred back to the Launceston General Hospital (LGH) for further investigations. Clinical examination now revealed trismus, with mouth opening limited to two finger breadths.
Investigations
Blood assays from the third presentation were similar to the first and second presentation (haemoglobin 72 g/L, white cell count 19×109/L, neutrophils 13.3×109/L, platelet 395×109/L and C reactive protein 152 mg/L). Thyroid function tests were deranged with a thyroid-stimulating hormone of 0.14 mU/L and free T4 of 21 pmol/L. Repeated CT scan demonstrated marked inflammation of the lower pharynx and larynx, with swelling of the epiglottis. Severe left-sided wall thickening effaced the left parapharyngeal space, with mild stranding within the peripharyngeal space. Salivary glands were normal and no collections were identified. Severe oedema of the airway resulted in a 14 mm segment of narrowing with a luminal diameter of 2–3 mm (figure 2).
Figure 2 CT showing airway narrowing in (A) sagittal and (B) coronal views.
Twenty milligram of intravenous dexamethasone was administered on receiving the CT findings and an urgent ear, nose and throat review was organised. The flexible nasoendoscopy performed was unremarkable, with normal base of tongue, valleculae, epiglottis and mobile vocal cords. There were no signs of pharyngitis or laryngitis.
Differential diagnosis
Due to the discordance of the CT and direct nasoendoscopy findings, the patient came in under the care of the General Medicine team for further investigations. A wide range of differential diagnoses were considered including atypical infections, drug-induced angio-oedema, hereditary angioedema, autoimmune diseases, haematological malignancy and osteonecrosis of the jaw.
Respiratory multiplex PCR, parvovirus and HIV screen were performed to rule out atypical infections. Aspirin and irbesartan were ceased to rule out drug causes, while a C1 esterase inhibitor and complement levels were organised to investigate hereditary angioedema. Autoimmune screen including antinuclear antibodies, antineutrophil cytoplasmic antibody, extractable nuclear antibody, double-stranded DNA antibodies and erythrocyte sedimentation rate were done, while an orthopantomogram was undertaken and ruled out ONJ (osteonecrosis of the jaw) and local dental infection.
On subsequent review, a more detailed headache history was obtained from the patient. The headache was more severe over the left forehead and was associated with trismus like sensation. Of note, the patient denies any jaw claudication. On examination, the left temporal and frontal regions were tender to palpate, with a palpable vessel noted over the left forehead. The erythrocyte sedimentation rate returned at 121 mm/hour, which raised the suspicion of giant cell arteritis. A left temporal artery biopsy was performed and showed classical findings of giant cell arteritis with fragmentation of elastic lamina, fibrosis of the adventitia and the presence of multinucleated giant cells (figure 3).
Figure 3 Temporal artery histology from patient (A): (H&E 5×) thick-walled artery with an associated inflammatory infiltrate. (B): (Orecin Giemsa 10×) elastin stain highlights fragmentation and reduplication of the elastic lamina. (C): (H&E 20×) narked intimal thickening, smooth muscle disorganisation and adventitial fibrosis. (D): (H&E 40×) lympho-histocystic infiltrate with occasional; multinucleated cells.
TREATMENT
As the patient did not have any ocular involvement at diagnosis, she was started on 50 mg of oral prednisolone per day (1 mg/kg). Adjunctive glucocorticoid-sparing agents such as tocilizumab and methotrexate were considered but due to the dramatic presentation of a threatened airway, a clinical decision was made to streamline treatment with single-agent prednisolone.
Adjunctive methotrexate when used at low doses of 10–15 mg per week has been shown to lower relapse rate, though its glucocorticoid-sparing properties were not evident.4 Tocilizumab, an IL6 receptor antagonist, has demonstrated promising results in reducing glucocorticoid exposure and giant cell arteritis relapse rate, though its role in induction therapy is still yet to be defined.5
Outcome and follow-up
The patient responded to the prednisolone course and had resolution of her facial and neck swelling within 3 days (figure 4). She was discharged home with complete resolution of her symptoms. The high-dose prednisolone was maintained for 4 weeks with a tapering plan of 10 mg reduction every 2 weeks till 20 mg per day. Ongoing weaning will be decided based on clinical symptoms and inflammatory markers at follow-up. At the 6-month phone review, patient remains symptom free on 10 mg prednisolone per day.
Figure 4 Resolution of neck swelling post prednisolone treatment (A): frontal, (B): lateral.
Discussion
Face and neck swelling is a non-specific sign, which has a lengthy list of differential diagnoses. Temporal fossa swelling is well recognised in giant cell arteritis however face and neck swelling is less common, occurring in 6.5% of cases.2 The swelling follows a waning and waxing pattern and may be due to spasm and collateralisation of the facial artery.2 6 7 The raised inflammatory markers can cause physicians to treat the initial presentation as an infection and to attribute the resolution of swelling to antibiotic response, as illustrated in our case.
Trismus (reduced jaw opening) has a prevalence of 6.8% in giant cell arteritis but is seldom reported due to its overlap with jaw claudication.8 Our case demonstrates that trismus can occur in isolation from jaw claudication. The mechanism for trismus in giant cell arteritis is uncertain but thought to be due to restricted blood flow to the masseter muscles via distal branches of the external carotid arteries.9 Interestingly, the patient developed subclinical hyperthyroidism during her admission, though it is uncertain if this is related to giant cell arteritis affecting the superior thyroid or a sick euthyroid state. Thyroid dysfunction has been described in giant cell arteritis, though no clear correlation was established due to the overlapping patient epidemiology of giant cell arteritis and thyroid diseases.10 11
The third presentation with airway narrowing stipulated a revisit of the patient’s diagnosis and presented as one of the first cases of CT-documented airway narrowing secondary to giant cell arteritis. Inflammation of the external carotid artery, where the superior laryngeal artery originates from, likely caused local ischaemia and oedema of the superior larynx. Fortunately, for the patient, giant cell arteritis was recognised early in her illness, with complete resolution of symptoms once corticosteroid treatment was commenced.
Patient’s perspective
Patient’s perspective (written with assistance from her daughter)
The whole situation is like going on an adventure, but it was not a good adventure. Not being diagnosed for 2 weeks with a swollen jaw was horrible. For my third trip to the hospital, I was not able to open my jaw and can only eat baby food. Having a doctor who found a diagnosis for me was a relief. When they started treatment, my frightening condition eased quickly.
Learning points
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery.
Face and neck swelling and trismus are under-recognised feature of giant cell arteritis and can be transient prior to developing classic giant cell arteritis symptoms.
Trismus can occur in isolation from jaw claudication in giant cell arteritis.
We recommend that any patient above the age of 50, who presents with face and neck swelling or trismus, to have giant cell arteritis considered as a differiential diagnosis.
Contributors: This case was managed by CS as the Consultant, with ZSL as the Medical Registrar. ZSL wrote up the case with supervision, some direction and editing by CS.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ASPIRIN, ATORVASTATIN, DENOSUMAB, HYDROCHLOROTHIAZIDE\IRBESARTAN, PREDNISOLONE | DrugsGivenReaction | CC BY-NC | 33722908 | 19,711,728 | 2021-03-15 |
What was the administration route of drug 'PREDNISOLONE'? | Neck swelling and airway narrowing as an initial manifestation of giant cell arteritis.
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery. Face and neck swelling and trismus are under-recognised features of giant cell arteritis and can present as the initial symptom prior to the development of classical temporal tenderness and jaw claudication. The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss. In this paper, we present a case of neck swelling and airway narrowing as the initial manifestation of giant cell arteritis.
Background
Giant cell arteritis is a vasculitis that affects large-sized and medium-sized vessels, including the aorta and branches of the external carotid arteries. Histologically, it is characterised by a granulomatous process with infiltration of multinucleated cells, causing elastic laminae destruction and adventitial fibrosis. The inflammatory process is reflected in blood tests as a raised erythrocyte sedimentation rate and C reactive protein. Diagnosis of giant cell arteritis is based on the American College of Rheumatology’s 1990 guideline, with the presence of three or more criteria out of five.1
Giant cell arteritis is common in the elderly population, with an estimated incidence rate of 15–30 cases per 100 000 individuals.1 Due to the numerous structures supplied by the aorta and the external carotid arteries, giant cell arteritis can produce a broad range of symptoms. The most common symptoms of giant cell arteritis include fatigue, fever, headache, mastication pain and visual changes.
Facial and neck swelling is a subtle change that may feature early and insidiously in giant cell arteritis, although it is seldom reported.2 Other otolaryngologic symptoms including cough, trismus, sore throat, voice changes, dysphagia, hearing loss and tongue claudication.2 3 Aortic involvement can produce thoracic pain, limb swelling and thoracic aortic aneurysm and dissection.
The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss.
Case presentation
An 87-year-old woman presented repeatedly to the Launceston General Hospital with a history of neck swelling (figure 1). The acute onset of swelling started at the left angle of her jaw and spread inferoanteriorly to her neck. This was associated with trismus-like sensation and dyspnoea. She denied any recent respiratory illness or dysphagia.
Figure 1 Initial presentation with face and neck swelling (A: frontal, B: lateral).
The patient’s medical history included hypertension treated with irbesartan/hydrochlorothiazide, hypercholesterolemia on atorvastatin and osteoporosis on denosumab. In addition, she had been taking aspirin for primary prevention of ischaemic heart disease. There were no medication changes in the preceding 3 years.
During the initial presentation, the patient had a low-grade temperature of 37.8°C and remained haemodynamically stable with a heart rate of 100 bpm, blood pressure of 170/80 mm Hg and an oxygen saturation of 98% on room air. There was no change in voice, stridor, palpable neck nodules or collection on physical examination. The patient was tender over her temporomandibular joints bilaterally and had normal mouth opening to three finger breadths despite sensation of trismus.
Blood investigation revealed normocytic anaemia (haemoglobin of 88 g/L and mean cell volume (MCV) of 89 fL), an elevated white cell count of 17.5×109/L (14.2×109/L neutrophils, 1.4×109/L lymphocyte) and a platelet count of 371×109/L. C reactive protein was elevated at 115 mg/L with a normal antinuclear antibody titre. Thyroid, renal and liver function tests were unremarkable. Contrast-enhanced CT of the neck did not reveal any structural abnormality of the oral cavity, tongue, larynx, thyroid, carotids or lymph nodes other than mild subcutaneous oedema.
The patient was managed as potentially having Ludwig’s angina by the local ear, nose and throat team and was commenced on intravenous piperacillin/tazobactam (Tazocin). A throat swab was obtained, which did not isolate any beta-haemolytic Streptococcus sp. The patient completed 3 days of intravenous antibiotic treatment and was discharged with an oral course of amoxicillin/clavulanic acid (Augmentin Duo forte).
However, she represented 2 days later with worsening of her neck swelling with a new bifrontal headache. Antibiotic was switched to oral ciprofloxacin and clindamycin due to concern of potential betalactam induced angio-oedema.
The patient was reviewed by her general practitioner (GP) 2 days post second discharge and was noted to have worsening erythema over her neck with a fever of 38.4°C. She was transferred back to the Launceston General Hospital (LGH) for further investigations. Clinical examination now revealed trismus, with mouth opening limited to two finger breadths.
Investigations
Blood assays from the third presentation were similar to the first and second presentation (haemoglobin 72 g/L, white cell count 19×109/L, neutrophils 13.3×109/L, platelet 395×109/L and C reactive protein 152 mg/L). Thyroid function tests were deranged with a thyroid-stimulating hormone of 0.14 mU/L and free T4 of 21 pmol/L. Repeated CT scan demonstrated marked inflammation of the lower pharynx and larynx, with swelling of the epiglottis. Severe left-sided wall thickening effaced the left parapharyngeal space, with mild stranding within the peripharyngeal space. Salivary glands were normal and no collections were identified. Severe oedema of the airway resulted in a 14 mm segment of narrowing with a luminal diameter of 2–3 mm (figure 2).
Figure 2 CT showing airway narrowing in (A) sagittal and (B) coronal views.
Twenty milligram of intravenous dexamethasone was administered on receiving the CT findings and an urgent ear, nose and throat review was organised. The flexible nasoendoscopy performed was unremarkable, with normal base of tongue, valleculae, epiglottis and mobile vocal cords. There were no signs of pharyngitis or laryngitis.
Differential diagnosis
Due to the discordance of the CT and direct nasoendoscopy findings, the patient came in under the care of the General Medicine team for further investigations. A wide range of differential diagnoses were considered including atypical infections, drug-induced angio-oedema, hereditary angioedema, autoimmune diseases, haematological malignancy and osteonecrosis of the jaw.
Respiratory multiplex PCR, parvovirus and HIV screen were performed to rule out atypical infections. Aspirin and irbesartan were ceased to rule out drug causes, while a C1 esterase inhibitor and complement levels were organised to investigate hereditary angioedema. Autoimmune screen including antinuclear antibodies, antineutrophil cytoplasmic antibody, extractable nuclear antibody, double-stranded DNA antibodies and erythrocyte sedimentation rate were done, while an orthopantomogram was undertaken and ruled out ONJ (osteonecrosis of the jaw) and local dental infection.
On subsequent review, a more detailed headache history was obtained from the patient. The headache was more severe over the left forehead and was associated with trismus like sensation. Of note, the patient denies any jaw claudication. On examination, the left temporal and frontal regions were tender to palpate, with a palpable vessel noted over the left forehead. The erythrocyte sedimentation rate returned at 121 mm/hour, which raised the suspicion of giant cell arteritis. A left temporal artery biopsy was performed and showed classical findings of giant cell arteritis with fragmentation of elastic lamina, fibrosis of the adventitia and the presence of multinucleated giant cells (figure 3).
Figure 3 Temporal artery histology from patient (A): (H&E 5×) thick-walled artery with an associated inflammatory infiltrate. (B): (Orecin Giemsa 10×) elastin stain highlights fragmentation and reduplication of the elastic lamina. (C): (H&E 20×) narked intimal thickening, smooth muscle disorganisation and adventitial fibrosis. (D): (H&E 40×) lympho-histocystic infiltrate with occasional; multinucleated cells.
TREATMENT
As the patient did not have any ocular involvement at diagnosis, she was started on 50 mg of oral prednisolone per day (1 mg/kg). Adjunctive glucocorticoid-sparing agents such as tocilizumab and methotrexate were considered but due to the dramatic presentation of a threatened airway, a clinical decision was made to streamline treatment with single-agent prednisolone.
Adjunctive methotrexate when used at low doses of 10–15 mg per week has been shown to lower relapse rate, though its glucocorticoid-sparing properties were not evident.4 Tocilizumab, an IL6 receptor antagonist, has demonstrated promising results in reducing glucocorticoid exposure and giant cell arteritis relapse rate, though its role in induction therapy is still yet to be defined.5
Outcome and follow-up
The patient responded to the prednisolone course and had resolution of her facial and neck swelling within 3 days (figure 4). She was discharged home with complete resolution of her symptoms. The high-dose prednisolone was maintained for 4 weeks with a tapering plan of 10 mg reduction every 2 weeks till 20 mg per day. Ongoing weaning will be decided based on clinical symptoms and inflammatory markers at follow-up. At the 6-month phone review, patient remains symptom free on 10 mg prednisolone per day.
Figure 4 Resolution of neck swelling post prednisolone treatment (A): frontal, (B): lateral.
Discussion
Face and neck swelling is a non-specific sign, which has a lengthy list of differential diagnoses. Temporal fossa swelling is well recognised in giant cell arteritis however face and neck swelling is less common, occurring in 6.5% of cases.2 The swelling follows a waning and waxing pattern and may be due to spasm and collateralisation of the facial artery.2 6 7 The raised inflammatory markers can cause physicians to treat the initial presentation as an infection and to attribute the resolution of swelling to antibiotic response, as illustrated in our case.
Trismus (reduced jaw opening) has a prevalence of 6.8% in giant cell arteritis but is seldom reported due to its overlap with jaw claudication.8 Our case demonstrates that trismus can occur in isolation from jaw claudication. The mechanism for trismus in giant cell arteritis is uncertain but thought to be due to restricted blood flow to the masseter muscles via distal branches of the external carotid arteries.9 Interestingly, the patient developed subclinical hyperthyroidism during her admission, though it is uncertain if this is related to giant cell arteritis affecting the superior thyroid or a sick euthyroid state. Thyroid dysfunction has been described in giant cell arteritis, though no clear correlation was established due to the overlapping patient epidemiology of giant cell arteritis and thyroid diseases.10 11
The third presentation with airway narrowing stipulated a revisit of the patient’s diagnosis and presented as one of the first cases of CT-documented airway narrowing secondary to giant cell arteritis. Inflammation of the external carotid artery, where the superior laryngeal artery originates from, likely caused local ischaemia and oedema of the superior larynx. Fortunately, for the patient, giant cell arteritis was recognised early in her illness, with complete resolution of symptoms once corticosteroid treatment was commenced.
Patient’s perspective
Patient’s perspective (written with assistance from her daughter)
The whole situation is like going on an adventure, but it was not a good adventure. Not being diagnosed for 2 weeks with a swollen jaw was horrible. For my third trip to the hospital, I was not able to open my jaw and can only eat baby food. Having a doctor who found a diagnosis for me was a relief. When they started treatment, my frightening condition eased quickly.
Learning points
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery.
Face and neck swelling and trismus are under-recognised feature of giant cell arteritis and can be transient prior to developing classic giant cell arteritis symptoms.
Trismus can occur in isolation from jaw claudication in giant cell arteritis.
We recommend that any patient above the age of 50, who presents with face and neck swelling or trismus, to have giant cell arteritis considered as a differiential diagnosis.
Contributors: This case was managed by CS as the Consultant, with ZSL as the Medical Registrar. ZSL wrote up the case with supervision, some direction and editing by CS.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33722908 | 19,130,173 | 2021-03-15 |
What was the dosage of drug 'PREDNISOLONE'? | Neck swelling and airway narrowing as an initial manifestation of giant cell arteritis.
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery. Face and neck swelling and trismus are under-recognised features of giant cell arteritis and can present as the initial symptom prior to the development of classical temporal tenderness and jaw claudication. The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss. In this paper, we present a case of neck swelling and airway narrowing as the initial manifestation of giant cell arteritis.
Background
Giant cell arteritis is a vasculitis that affects large-sized and medium-sized vessels, including the aorta and branches of the external carotid arteries. Histologically, it is characterised by a granulomatous process with infiltration of multinucleated cells, causing elastic laminae destruction and adventitial fibrosis. The inflammatory process is reflected in blood tests as a raised erythrocyte sedimentation rate and C reactive protein. Diagnosis of giant cell arteritis is based on the American College of Rheumatology’s 1990 guideline, with the presence of three or more criteria out of five.1
Giant cell arteritis is common in the elderly population, with an estimated incidence rate of 15–30 cases per 100 000 individuals.1 Due to the numerous structures supplied by the aorta and the external carotid arteries, giant cell arteritis can produce a broad range of symptoms. The most common symptoms of giant cell arteritis include fatigue, fever, headache, mastication pain and visual changes.
Facial and neck swelling is a subtle change that may feature early and insidiously in giant cell arteritis, although it is seldom reported.2 Other otolaryngologic symptoms including cough, trismus, sore throat, voice changes, dysphagia, hearing loss and tongue claudication.2 3 Aortic involvement can produce thoracic pain, limb swelling and thoracic aortic aneurysm and dissection.
The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss.
Case presentation
An 87-year-old woman presented repeatedly to the Launceston General Hospital with a history of neck swelling (figure 1). The acute onset of swelling started at the left angle of her jaw and spread inferoanteriorly to her neck. This was associated with trismus-like sensation and dyspnoea. She denied any recent respiratory illness or dysphagia.
Figure 1 Initial presentation with face and neck swelling (A: frontal, B: lateral).
The patient’s medical history included hypertension treated with irbesartan/hydrochlorothiazide, hypercholesterolemia on atorvastatin and osteoporosis on denosumab. In addition, she had been taking aspirin for primary prevention of ischaemic heart disease. There were no medication changes in the preceding 3 years.
During the initial presentation, the patient had a low-grade temperature of 37.8°C and remained haemodynamically stable with a heart rate of 100 bpm, blood pressure of 170/80 mm Hg and an oxygen saturation of 98% on room air. There was no change in voice, stridor, palpable neck nodules or collection on physical examination. The patient was tender over her temporomandibular joints bilaterally and had normal mouth opening to three finger breadths despite sensation of trismus.
Blood investigation revealed normocytic anaemia (haemoglobin of 88 g/L and mean cell volume (MCV) of 89 fL), an elevated white cell count of 17.5×109/L (14.2×109/L neutrophils, 1.4×109/L lymphocyte) and a platelet count of 371×109/L. C reactive protein was elevated at 115 mg/L with a normal antinuclear antibody titre. Thyroid, renal and liver function tests were unremarkable. Contrast-enhanced CT of the neck did not reveal any structural abnormality of the oral cavity, tongue, larynx, thyroid, carotids or lymph nodes other than mild subcutaneous oedema.
The patient was managed as potentially having Ludwig’s angina by the local ear, nose and throat team and was commenced on intravenous piperacillin/tazobactam (Tazocin). A throat swab was obtained, which did not isolate any beta-haemolytic Streptococcus sp. The patient completed 3 days of intravenous antibiotic treatment and was discharged with an oral course of amoxicillin/clavulanic acid (Augmentin Duo forte).
However, she represented 2 days later with worsening of her neck swelling with a new bifrontal headache. Antibiotic was switched to oral ciprofloxacin and clindamycin due to concern of potential betalactam induced angio-oedema.
The patient was reviewed by her general practitioner (GP) 2 days post second discharge and was noted to have worsening erythema over her neck with a fever of 38.4°C. She was transferred back to the Launceston General Hospital (LGH) for further investigations. Clinical examination now revealed trismus, with mouth opening limited to two finger breadths.
Investigations
Blood assays from the third presentation were similar to the first and second presentation (haemoglobin 72 g/L, white cell count 19×109/L, neutrophils 13.3×109/L, platelet 395×109/L and C reactive protein 152 mg/L). Thyroid function tests were deranged with a thyroid-stimulating hormone of 0.14 mU/L and free T4 of 21 pmol/L. Repeated CT scan demonstrated marked inflammation of the lower pharynx and larynx, with swelling of the epiglottis. Severe left-sided wall thickening effaced the left parapharyngeal space, with mild stranding within the peripharyngeal space. Salivary glands were normal and no collections were identified. Severe oedema of the airway resulted in a 14 mm segment of narrowing with a luminal diameter of 2–3 mm (figure 2).
Figure 2 CT showing airway narrowing in (A) sagittal and (B) coronal views.
Twenty milligram of intravenous dexamethasone was administered on receiving the CT findings and an urgent ear, nose and throat review was organised. The flexible nasoendoscopy performed was unremarkable, with normal base of tongue, valleculae, epiglottis and mobile vocal cords. There were no signs of pharyngitis or laryngitis.
Differential diagnosis
Due to the discordance of the CT and direct nasoendoscopy findings, the patient came in under the care of the General Medicine team for further investigations. A wide range of differential diagnoses were considered including atypical infections, drug-induced angio-oedema, hereditary angioedema, autoimmune diseases, haematological malignancy and osteonecrosis of the jaw.
Respiratory multiplex PCR, parvovirus and HIV screen were performed to rule out atypical infections. Aspirin and irbesartan were ceased to rule out drug causes, while a C1 esterase inhibitor and complement levels were organised to investigate hereditary angioedema. Autoimmune screen including antinuclear antibodies, antineutrophil cytoplasmic antibody, extractable nuclear antibody, double-stranded DNA antibodies and erythrocyte sedimentation rate were done, while an orthopantomogram was undertaken and ruled out ONJ (osteonecrosis of the jaw) and local dental infection.
On subsequent review, a more detailed headache history was obtained from the patient. The headache was more severe over the left forehead and was associated with trismus like sensation. Of note, the patient denies any jaw claudication. On examination, the left temporal and frontal regions were tender to palpate, with a palpable vessel noted over the left forehead. The erythrocyte sedimentation rate returned at 121 mm/hour, which raised the suspicion of giant cell arteritis. A left temporal artery biopsy was performed and showed classical findings of giant cell arteritis with fragmentation of elastic lamina, fibrosis of the adventitia and the presence of multinucleated giant cells (figure 3).
Figure 3 Temporal artery histology from patient (A): (H&E 5×) thick-walled artery with an associated inflammatory infiltrate. (B): (Orecin Giemsa 10×) elastin stain highlights fragmentation and reduplication of the elastic lamina. (C): (H&E 20×) narked intimal thickening, smooth muscle disorganisation and adventitial fibrosis. (D): (H&E 40×) lympho-histocystic infiltrate with occasional; multinucleated cells.
TREATMENT
As the patient did not have any ocular involvement at diagnosis, she was started on 50 mg of oral prednisolone per day (1 mg/kg). Adjunctive glucocorticoid-sparing agents such as tocilizumab and methotrexate were considered but due to the dramatic presentation of a threatened airway, a clinical decision was made to streamline treatment with single-agent prednisolone.
Adjunctive methotrexate when used at low doses of 10–15 mg per week has been shown to lower relapse rate, though its glucocorticoid-sparing properties were not evident.4 Tocilizumab, an IL6 receptor antagonist, has demonstrated promising results in reducing glucocorticoid exposure and giant cell arteritis relapse rate, though its role in induction therapy is still yet to be defined.5
Outcome and follow-up
The patient responded to the prednisolone course and had resolution of her facial and neck swelling within 3 days (figure 4). She was discharged home with complete resolution of her symptoms. The high-dose prednisolone was maintained for 4 weeks with a tapering plan of 10 mg reduction every 2 weeks till 20 mg per day. Ongoing weaning will be decided based on clinical symptoms and inflammatory markers at follow-up. At the 6-month phone review, patient remains symptom free on 10 mg prednisolone per day.
Figure 4 Resolution of neck swelling post prednisolone treatment (A): frontal, (B): lateral.
Discussion
Face and neck swelling is a non-specific sign, which has a lengthy list of differential diagnoses. Temporal fossa swelling is well recognised in giant cell arteritis however face and neck swelling is less common, occurring in 6.5% of cases.2 The swelling follows a waning and waxing pattern and may be due to spasm and collateralisation of the facial artery.2 6 7 The raised inflammatory markers can cause physicians to treat the initial presentation as an infection and to attribute the resolution of swelling to antibiotic response, as illustrated in our case.
Trismus (reduced jaw opening) has a prevalence of 6.8% in giant cell arteritis but is seldom reported due to its overlap with jaw claudication.8 Our case demonstrates that trismus can occur in isolation from jaw claudication. The mechanism for trismus in giant cell arteritis is uncertain but thought to be due to restricted blood flow to the masseter muscles via distal branches of the external carotid arteries.9 Interestingly, the patient developed subclinical hyperthyroidism during her admission, though it is uncertain if this is related to giant cell arteritis affecting the superior thyroid or a sick euthyroid state. Thyroid dysfunction has been described in giant cell arteritis, though no clear correlation was established due to the overlapping patient epidemiology of giant cell arteritis and thyroid diseases.10 11
The third presentation with airway narrowing stipulated a revisit of the patient’s diagnosis and presented as one of the first cases of CT-documented airway narrowing secondary to giant cell arteritis. Inflammation of the external carotid artery, where the superior laryngeal artery originates from, likely caused local ischaemia and oedema of the superior larynx. Fortunately, for the patient, giant cell arteritis was recognised early in her illness, with complete resolution of symptoms once corticosteroid treatment was commenced.
Patient’s perspective
Patient’s perspective (written with assistance from her daughter)
The whole situation is like going on an adventure, but it was not a good adventure. Not being diagnosed for 2 weeks with a swollen jaw was horrible. For my third trip to the hospital, I was not able to open my jaw and can only eat baby food. Having a doctor who found a diagnosis for me was a relief. When they started treatment, my frightening condition eased quickly.
Learning points
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery.
Face and neck swelling and trismus are under-recognised feature of giant cell arteritis and can be transient prior to developing classic giant cell arteritis symptoms.
Trismus can occur in isolation from jaw claudication in giant cell arteritis.
We recommend that any patient above the age of 50, who presents with face and neck swelling or trismus, to have giant cell arteritis considered as a differiential diagnosis.
Contributors: This case was managed by CS as the Consultant, with ZSL as the Medical Registrar. ZSL wrote up the case with supervision, some direction and editing by CS.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | 50 UNK, QD | DrugDosageText | CC BY-NC | 33722908 | 19,130,173 | 2021-03-15 |
What was the outcome of reaction 'C-reactive protein increased'? | Neck swelling and airway narrowing as an initial manifestation of giant cell arteritis.
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery. Face and neck swelling and trismus are under-recognised features of giant cell arteritis and can present as the initial symptom prior to the development of classical temporal tenderness and jaw claudication. The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss. In this paper, we present a case of neck swelling and airway narrowing as the initial manifestation of giant cell arteritis.
Background
Giant cell arteritis is a vasculitis that affects large-sized and medium-sized vessels, including the aorta and branches of the external carotid arteries. Histologically, it is characterised by a granulomatous process with infiltration of multinucleated cells, causing elastic laminae destruction and adventitial fibrosis. The inflammatory process is reflected in blood tests as a raised erythrocyte sedimentation rate and C reactive protein. Diagnosis of giant cell arteritis is based on the American College of Rheumatology’s 1990 guideline, with the presence of three or more criteria out of five.1
Giant cell arteritis is common in the elderly population, with an estimated incidence rate of 15–30 cases per 100 000 individuals.1 Due to the numerous structures supplied by the aorta and the external carotid arteries, giant cell arteritis can produce a broad range of symptoms. The most common symptoms of giant cell arteritis include fatigue, fever, headache, mastication pain and visual changes.
Facial and neck swelling is a subtle change that may feature early and insidiously in giant cell arteritis, although it is seldom reported.2 Other otolaryngologic symptoms including cough, trismus, sore throat, voice changes, dysphagia, hearing loss and tongue claudication.2 3 Aortic involvement can produce thoracic pain, limb swelling and thoracic aortic aneurysm and dissection.
The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss.
Case presentation
An 87-year-old woman presented repeatedly to the Launceston General Hospital with a history of neck swelling (figure 1). The acute onset of swelling started at the left angle of her jaw and spread inferoanteriorly to her neck. This was associated with trismus-like sensation and dyspnoea. She denied any recent respiratory illness or dysphagia.
Figure 1 Initial presentation with face and neck swelling (A: frontal, B: lateral).
The patient’s medical history included hypertension treated with irbesartan/hydrochlorothiazide, hypercholesterolemia on atorvastatin and osteoporosis on denosumab. In addition, she had been taking aspirin for primary prevention of ischaemic heart disease. There were no medication changes in the preceding 3 years.
During the initial presentation, the patient had a low-grade temperature of 37.8°C and remained haemodynamically stable with a heart rate of 100 bpm, blood pressure of 170/80 mm Hg and an oxygen saturation of 98% on room air. There was no change in voice, stridor, palpable neck nodules or collection on physical examination. The patient was tender over her temporomandibular joints bilaterally and had normal mouth opening to three finger breadths despite sensation of trismus.
Blood investigation revealed normocytic anaemia (haemoglobin of 88 g/L and mean cell volume (MCV) of 89 fL), an elevated white cell count of 17.5×109/L (14.2×109/L neutrophils, 1.4×109/L lymphocyte) and a platelet count of 371×109/L. C reactive protein was elevated at 115 mg/L with a normal antinuclear antibody titre. Thyroid, renal and liver function tests were unremarkable. Contrast-enhanced CT of the neck did not reveal any structural abnormality of the oral cavity, tongue, larynx, thyroid, carotids or lymph nodes other than mild subcutaneous oedema.
The patient was managed as potentially having Ludwig’s angina by the local ear, nose and throat team and was commenced on intravenous piperacillin/tazobactam (Tazocin). A throat swab was obtained, which did not isolate any beta-haemolytic Streptococcus sp. The patient completed 3 days of intravenous antibiotic treatment and was discharged with an oral course of amoxicillin/clavulanic acid (Augmentin Duo forte).
However, she represented 2 days later with worsening of her neck swelling with a new bifrontal headache. Antibiotic was switched to oral ciprofloxacin and clindamycin due to concern of potential betalactam induced angio-oedema.
The patient was reviewed by her general practitioner (GP) 2 days post second discharge and was noted to have worsening erythema over her neck with a fever of 38.4°C. She was transferred back to the Launceston General Hospital (LGH) for further investigations. Clinical examination now revealed trismus, with mouth opening limited to two finger breadths.
Investigations
Blood assays from the third presentation were similar to the first and second presentation (haemoglobin 72 g/L, white cell count 19×109/L, neutrophils 13.3×109/L, platelet 395×109/L and C reactive protein 152 mg/L). Thyroid function tests were deranged with a thyroid-stimulating hormone of 0.14 mU/L and free T4 of 21 pmol/L. Repeated CT scan demonstrated marked inflammation of the lower pharynx and larynx, with swelling of the epiglottis. Severe left-sided wall thickening effaced the left parapharyngeal space, with mild stranding within the peripharyngeal space. Salivary glands were normal and no collections were identified. Severe oedema of the airway resulted in a 14 mm segment of narrowing with a luminal diameter of 2–3 mm (figure 2).
Figure 2 CT showing airway narrowing in (A) sagittal and (B) coronal views.
Twenty milligram of intravenous dexamethasone was administered on receiving the CT findings and an urgent ear, nose and throat review was organised. The flexible nasoendoscopy performed was unremarkable, with normal base of tongue, valleculae, epiglottis and mobile vocal cords. There were no signs of pharyngitis or laryngitis.
Differential diagnosis
Due to the discordance of the CT and direct nasoendoscopy findings, the patient came in under the care of the General Medicine team for further investigations. A wide range of differential diagnoses were considered including atypical infections, drug-induced angio-oedema, hereditary angioedema, autoimmune diseases, haematological malignancy and osteonecrosis of the jaw.
Respiratory multiplex PCR, parvovirus and HIV screen were performed to rule out atypical infections. Aspirin and irbesartan were ceased to rule out drug causes, while a C1 esterase inhibitor and complement levels were organised to investigate hereditary angioedema. Autoimmune screen including antinuclear antibodies, antineutrophil cytoplasmic antibody, extractable nuclear antibody, double-stranded DNA antibodies and erythrocyte sedimentation rate were done, while an orthopantomogram was undertaken and ruled out ONJ (osteonecrosis of the jaw) and local dental infection.
On subsequent review, a more detailed headache history was obtained from the patient. The headache was more severe over the left forehead and was associated with trismus like sensation. Of note, the patient denies any jaw claudication. On examination, the left temporal and frontal regions were tender to palpate, with a palpable vessel noted over the left forehead. The erythrocyte sedimentation rate returned at 121 mm/hour, which raised the suspicion of giant cell arteritis. A left temporal artery biopsy was performed and showed classical findings of giant cell arteritis with fragmentation of elastic lamina, fibrosis of the adventitia and the presence of multinucleated giant cells (figure 3).
Figure 3 Temporal artery histology from patient (A): (H&E 5×) thick-walled artery with an associated inflammatory infiltrate. (B): (Orecin Giemsa 10×) elastin stain highlights fragmentation and reduplication of the elastic lamina. (C): (H&E 20×) narked intimal thickening, smooth muscle disorganisation and adventitial fibrosis. (D): (H&E 40×) lympho-histocystic infiltrate with occasional; multinucleated cells.
TREATMENT
As the patient did not have any ocular involvement at diagnosis, she was started on 50 mg of oral prednisolone per day (1 mg/kg). Adjunctive glucocorticoid-sparing agents such as tocilizumab and methotrexate were considered but due to the dramatic presentation of a threatened airway, a clinical decision was made to streamline treatment with single-agent prednisolone.
Adjunctive methotrexate when used at low doses of 10–15 mg per week has been shown to lower relapse rate, though its glucocorticoid-sparing properties were not evident.4 Tocilizumab, an IL6 receptor antagonist, has demonstrated promising results in reducing glucocorticoid exposure and giant cell arteritis relapse rate, though its role in induction therapy is still yet to be defined.5
Outcome and follow-up
The patient responded to the prednisolone course and had resolution of her facial and neck swelling within 3 days (figure 4). She was discharged home with complete resolution of her symptoms. The high-dose prednisolone was maintained for 4 weeks with a tapering plan of 10 mg reduction every 2 weeks till 20 mg per day. Ongoing weaning will be decided based on clinical symptoms and inflammatory markers at follow-up. At the 6-month phone review, patient remains symptom free on 10 mg prednisolone per day.
Figure 4 Resolution of neck swelling post prednisolone treatment (A): frontal, (B): lateral.
Discussion
Face and neck swelling is a non-specific sign, which has a lengthy list of differential diagnoses. Temporal fossa swelling is well recognised in giant cell arteritis however face and neck swelling is less common, occurring in 6.5% of cases.2 The swelling follows a waning and waxing pattern and may be due to spasm and collateralisation of the facial artery.2 6 7 The raised inflammatory markers can cause physicians to treat the initial presentation as an infection and to attribute the resolution of swelling to antibiotic response, as illustrated in our case.
Trismus (reduced jaw opening) has a prevalence of 6.8% in giant cell arteritis but is seldom reported due to its overlap with jaw claudication.8 Our case demonstrates that trismus can occur in isolation from jaw claudication. The mechanism for trismus in giant cell arteritis is uncertain but thought to be due to restricted blood flow to the masseter muscles via distal branches of the external carotid arteries.9 Interestingly, the patient developed subclinical hyperthyroidism during her admission, though it is uncertain if this is related to giant cell arteritis affecting the superior thyroid or a sick euthyroid state. Thyroid dysfunction has been described in giant cell arteritis, though no clear correlation was established due to the overlapping patient epidemiology of giant cell arteritis and thyroid diseases.10 11
The third presentation with airway narrowing stipulated a revisit of the patient’s diagnosis and presented as one of the first cases of CT-documented airway narrowing secondary to giant cell arteritis. Inflammation of the external carotid artery, where the superior laryngeal artery originates from, likely caused local ischaemia and oedema of the superior larynx. Fortunately, for the patient, giant cell arteritis was recognised early in her illness, with complete resolution of symptoms once corticosteroid treatment was commenced.
Patient’s perspective
Patient’s perspective (written with assistance from her daughter)
The whole situation is like going on an adventure, but it was not a good adventure. Not being diagnosed for 2 weeks with a swollen jaw was horrible. For my third trip to the hospital, I was not able to open my jaw and can only eat baby food. Having a doctor who found a diagnosis for me was a relief. When they started treatment, my frightening condition eased quickly.
Learning points
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery.
Face and neck swelling and trismus are under-recognised feature of giant cell arteritis and can be transient prior to developing classic giant cell arteritis symptoms.
Trismus can occur in isolation from jaw claudication in giant cell arteritis.
We recommend that any patient above the age of 50, who presents with face and neck swelling or trismus, to have giant cell arteritis considered as a differiential diagnosis.
Contributors: This case was managed by CS as the Consultant, with ZSL as the Medical Registrar. ZSL wrote up the case with supervision, some direction and editing by CS.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33722908 | 19,130,173 | 2021-03-15 |
What was the outcome of reaction 'Giant cell arteritis'? | Neck swelling and airway narrowing as an initial manifestation of giant cell arteritis.
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery. Face and neck swelling and trismus are under-recognised features of giant cell arteritis and can present as the initial symptom prior to the development of classical temporal tenderness and jaw claudication. The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss. In this paper, we present a case of neck swelling and airway narrowing as the initial manifestation of giant cell arteritis.
Background
Giant cell arteritis is a vasculitis that affects large-sized and medium-sized vessels, including the aorta and branches of the external carotid arteries. Histologically, it is characterised by a granulomatous process with infiltration of multinucleated cells, causing elastic laminae destruction and adventitial fibrosis. The inflammatory process is reflected in blood tests as a raised erythrocyte sedimentation rate and C reactive protein. Diagnosis of giant cell arteritis is based on the American College of Rheumatology’s 1990 guideline, with the presence of three or more criteria out of five.1
Giant cell arteritis is common in the elderly population, with an estimated incidence rate of 15–30 cases per 100 000 individuals.1 Due to the numerous structures supplied by the aorta and the external carotid arteries, giant cell arteritis can produce a broad range of symptoms. The most common symptoms of giant cell arteritis include fatigue, fever, headache, mastication pain and visual changes.
Facial and neck swelling is a subtle change that may feature early and insidiously in giant cell arteritis, although it is seldom reported.2 Other otolaryngologic symptoms including cough, trismus, sore throat, voice changes, dysphagia, hearing loss and tongue claudication.2 3 Aortic involvement can produce thoracic pain, limb swelling and thoracic aortic aneurysm and dissection.
The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss.
Case presentation
An 87-year-old woman presented repeatedly to the Launceston General Hospital with a history of neck swelling (figure 1). The acute onset of swelling started at the left angle of her jaw and spread inferoanteriorly to her neck. This was associated with trismus-like sensation and dyspnoea. She denied any recent respiratory illness or dysphagia.
Figure 1 Initial presentation with face and neck swelling (A: frontal, B: lateral).
The patient’s medical history included hypertension treated with irbesartan/hydrochlorothiazide, hypercholesterolemia on atorvastatin and osteoporosis on denosumab. In addition, she had been taking aspirin for primary prevention of ischaemic heart disease. There were no medication changes in the preceding 3 years.
During the initial presentation, the patient had a low-grade temperature of 37.8°C and remained haemodynamically stable with a heart rate of 100 bpm, blood pressure of 170/80 mm Hg and an oxygen saturation of 98% on room air. There was no change in voice, stridor, palpable neck nodules or collection on physical examination. The patient was tender over her temporomandibular joints bilaterally and had normal mouth opening to three finger breadths despite sensation of trismus.
Blood investigation revealed normocytic anaemia (haemoglobin of 88 g/L and mean cell volume (MCV) of 89 fL), an elevated white cell count of 17.5×109/L (14.2×109/L neutrophils, 1.4×109/L lymphocyte) and a platelet count of 371×109/L. C reactive protein was elevated at 115 mg/L with a normal antinuclear antibody titre. Thyroid, renal and liver function tests were unremarkable. Contrast-enhanced CT of the neck did not reveal any structural abnormality of the oral cavity, tongue, larynx, thyroid, carotids or lymph nodes other than mild subcutaneous oedema.
The patient was managed as potentially having Ludwig’s angina by the local ear, nose and throat team and was commenced on intravenous piperacillin/tazobactam (Tazocin). A throat swab was obtained, which did not isolate any beta-haemolytic Streptococcus sp. The patient completed 3 days of intravenous antibiotic treatment and was discharged with an oral course of amoxicillin/clavulanic acid (Augmentin Duo forte).
However, she represented 2 days later with worsening of her neck swelling with a new bifrontal headache. Antibiotic was switched to oral ciprofloxacin and clindamycin due to concern of potential betalactam induced angio-oedema.
The patient was reviewed by her general practitioner (GP) 2 days post second discharge and was noted to have worsening erythema over her neck with a fever of 38.4°C. She was transferred back to the Launceston General Hospital (LGH) for further investigations. Clinical examination now revealed trismus, with mouth opening limited to two finger breadths.
Investigations
Blood assays from the third presentation were similar to the first and second presentation (haemoglobin 72 g/L, white cell count 19×109/L, neutrophils 13.3×109/L, platelet 395×109/L and C reactive protein 152 mg/L). Thyroid function tests were deranged with a thyroid-stimulating hormone of 0.14 mU/L and free T4 of 21 pmol/L. Repeated CT scan demonstrated marked inflammation of the lower pharynx and larynx, with swelling of the epiglottis. Severe left-sided wall thickening effaced the left parapharyngeal space, with mild stranding within the peripharyngeal space. Salivary glands were normal and no collections were identified. Severe oedema of the airway resulted in a 14 mm segment of narrowing with a luminal diameter of 2–3 mm (figure 2).
Figure 2 CT showing airway narrowing in (A) sagittal and (B) coronal views.
Twenty milligram of intravenous dexamethasone was administered on receiving the CT findings and an urgent ear, nose and throat review was organised. The flexible nasoendoscopy performed was unremarkable, with normal base of tongue, valleculae, epiglottis and mobile vocal cords. There were no signs of pharyngitis or laryngitis.
Differential diagnosis
Due to the discordance of the CT and direct nasoendoscopy findings, the patient came in under the care of the General Medicine team for further investigations. A wide range of differential diagnoses were considered including atypical infections, drug-induced angio-oedema, hereditary angioedema, autoimmune diseases, haematological malignancy and osteonecrosis of the jaw.
Respiratory multiplex PCR, parvovirus and HIV screen were performed to rule out atypical infections. Aspirin and irbesartan were ceased to rule out drug causes, while a C1 esterase inhibitor and complement levels were organised to investigate hereditary angioedema. Autoimmune screen including antinuclear antibodies, antineutrophil cytoplasmic antibody, extractable nuclear antibody, double-stranded DNA antibodies and erythrocyte sedimentation rate were done, while an orthopantomogram was undertaken and ruled out ONJ (osteonecrosis of the jaw) and local dental infection.
On subsequent review, a more detailed headache history was obtained from the patient. The headache was more severe over the left forehead and was associated with trismus like sensation. Of note, the patient denies any jaw claudication. On examination, the left temporal and frontal regions were tender to palpate, with a palpable vessel noted over the left forehead. The erythrocyte sedimentation rate returned at 121 mm/hour, which raised the suspicion of giant cell arteritis. A left temporal artery biopsy was performed and showed classical findings of giant cell arteritis with fragmentation of elastic lamina, fibrosis of the adventitia and the presence of multinucleated giant cells (figure 3).
Figure 3 Temporal artery histology from patient (A): (H&E 5×) thick-walled artery with an associated inflammatory infiltrate. (B): (Orecin Giemsa 10×) elastin stain highlights fragmentation and reduplication of the elastic lamina. (C): (H&E 20×) narked intimal thickening, smooth muscle disorganisation and adventitial fibrosis. (D): (H&E 40×) lympho-histocystic infiltrate with occasional; multinucleated cells.
TREATMENT
As the patient did not have any ocular involvement at diagnosis, she was started on 50 mg of oral prednisolone per day (1 mg/kg). Adjunctive glucocorticoid-sparing agents such as tocilizumab and methotrexate were considered but due to the dramatic presentation of a threatened airway, a clinical decision was made to streamline treatment with single-agent prednisolone.
Adjunctive methotrexate when used at low doses of 10–15 mg per week has been shown to lower relapse rate, though its glucocorticoid-sparing properties were not evident.4 Tocilizumab, an IL6 receptor antagonist, has demonstrated promising results in reducing glucocorticoid exposure and giant cell arteritis relapse rate, though its role in induction therapy is still yet to be defined.5
Outcome and follow-up
The patient responded to the prednisolone course and had resolution of her facial and neck swelling within 3 days (figure 4). She was discharged home with complete resolution of her symptoms. The high-dose prednisolone was maintained for 4 weeks with a tapering plan of 10 mg reduction every 2 weeks till 20 mg per day. Ongoing weaning will be decided based on clinical symptoms and inflammatory markers at follow-up. At the 6-month phone review, patient remains symptom free on 10 mg prednisolone per day.
Figure 4 Resolution of neck swelling post prednisolone treatment (A): frontal, (B): lateral.
Discussion
Face and neck swelling is a non-specific sign, which has a lengthy list of differential diagnoses. Temporal fossa swelling is well recognised in giant cell arteritis however face and neck swelling is less common, occurring in 6.5% of cases.2 The swelling follows a waning and waxing pattern and may be due to spasm and collateralisation of the facial artery.2 6 7 The raised inflammatory markers can cause physicians to treat the initial presentation as an infection and to attribute the resolution of swelling to antibiotic response, as illustrated in our case.
Trismus (reduced jaw opening) has a prevalence of 6.8% in giant cell arteritis but is seldom reported due to its overlap with jaw claudication.8 Our case demonstrates that trismus can occur in isolation from jaw claudication. The mechanism for trismus in giant cell arteritis is uncertain but thought to be due to restricted blood flow to the masseter muscles via distal branches of the external carotid arteries.9 Interestingly, the patient developed subclinical hyperthyroidism during her admission, though it is uncertain if this is related to giant cell arteritis affecting the superior thyroid or a sick euthyroid state. Thyroid dysfunction has been described in giant cell arteritis, though no clear correlation was established due to the overlapping patient epidemiology of giant cell arteritis and thyroid diseases.10 11
The third presentation with airway narrowing stipulated a revisit of the patient’s diagnosis and presented as one of the first cases of CT-documented airway narrowing secondary to giant cell arteritis. Inflammation of the external carotid artery, where the superior laryngeal artery originates from, likely caused local ischaemia and oedema of the superior larynx. Fortunately, for the patient, giant cell arteritis was recognised early in her illness, with complete resolution of symptoms once corticosteroid treatment was commenced.
Patient’s perspective
Patient’s perspective (written with assistance from her daughter)
The whole situation is like going on an adventure, but it was not a good adventure. Not being diagnosed for 2 weeks with a swollen jaw was horrible. For my third trip to the hospital, I was not able to open my jaw and can only eat baby food. Having a doctor who found a diagnosis for me was a relief. When they started treatment, my frightening condition eased quickly.
Learning points
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery.
Face and neck swelling and trismus are under-recognised feature of giant cell arteritis and can be transient prior to developing classic giant cell arteritis symptoms.
Trismus can occur in isolation from jaw claudication in giant cell arteritis.
We recommend that any patient above the age of 50, who presents with face and neck swelling or trismus, to have giant cell arteritis considered as a differiential diagnosis.
Contributors: This case was managed by CS as the Consultant, with ZSL as the Medical Registrar. ZSL wrote up the case with supervision, some direction and editing by CS.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33722908 | 19,130,173 | 2021-03-15 |
What was the outcome of reaction 'Ludwig angina'? | Neck swelling and airway narrowing as an initial manifestation of giant cell arteritis.
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery. Face and neck swelling and trismus are under-recognised features of giant cell arteritis and can present as the initial symptom prior to the development of classical temporal tenderness and jaw claudication. The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss. In this paper, we present a case of neck swelling and airway narrowing as the initial manifestation of giant cell arteritis.
Background
Giant cell arteritis is a vasculitis that affects large-sized and medium-sized vessels, including the aorta and branches of the external carotid arteries. Histologically, it is characterised by a granulomatous process with infiltration of multinucleated cells, causing elastic laminae destruction and adventitial fibrosis. The inflammatory process is reflected in blood tests as a raised erythrocyte sedimentation rate and C reactive protein. Diagnosis of giant cell arteritis is based on the American College of Rheumatology’s 1990 guideline, with the presence of three or more criteria out of five.1
Giant cell arteritis is common in the elderly population, with an estimated incidence rate of 15–30 cases per 100 000 individuals.1 Due to the numerous structures supplied by the aorta and the external carotid arteries, giant cell arteritis can produce a broad range of symptoms. The most common symptoms of giant cell arteritis include fatigue, fever, headache, mastication pain and visual changes.
Facial and neck swelling is a subtle change that may feature early and insidiously in giant cell arteritis, although it is seldom reported.2 Other otolaryngologic symptoms including cough, trismus, sore throat, voice changes, dysphagia, hearing loss and tongue claudication.2 3 Aortic involvement can produce thoracic pain, limb swelling and thoracic aortic aneurysm and dissection.
The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss.
Case presentation
An 87-year-old woman presented repeatedly to the Launceston General Hospital with a history of neck swelling (figure 1). The acute onset of swelling started at the left angle of her jaw and spread inferoanteriorly to her neck. This was associated with trismus-like sensation and dyspnoea. She denied any recent respiratory illness or dysphagia.
Figure 1 Initial presentation with face and neck swelling (A: frontal, B: lateral).
The patient’s medical history included hypertension treated with irbesartan/hydrochlorothiazide, hypercholesterolemia on atorvastatin and osteoporosis on denosumab. In addition, she had been taking aspirin for primary prevention of ischaemic heart disease. There were no medication changes in the preceding 3 years.
During the initial presentation, the patient had a low-grade temperature of 37.8°C and remained haemodynamically stable with a heart rate of 100 bpm, blood pressure of 170/80 mm Hg and an oxygen saturation of 98% on room air. There was no change in voice, stridor, palpable neck nodules or collection on physical examination. The patient was tender over her temporomandibular joints bilaterally and had normal mouth opening to three finger breadths despite sensation of trismus.
Blood investigation revealed normocytic anaemia (haemoglobin of 88 g/L and mean cell volume (MCV) of 89 fL), an elevated white cell count of 17.5×109/L (14.2×109/L neutrophils, 1.4×109/L lymphocyte) and a platelet count of 371×109/L. C reactive protein was elevated at 115 mg/L with a normal antinuclear antibody titre. Thyroid, renal and liver function tests were unremarkable. Contrast-enhanced CT of the neck did not reveal any structural abnormality of the oral cavity, tongue, larynx, thyroid, carotids or lymph nodes other than mild subcutaneous oedema.
The patient was managed as potentially having Ludwig’s angina by the local ear, nose and throat team and was commenced on intravenous piperacillin/tazobactam (Tazocin). A throat swab was obtained, which did not isolate any beta-haemolytic Streptococcus sp. The patient completed 3 days of intravenous antibiotic treatment and was discharged with an oral course of amoxicillin/clavulanic acid (Augmentin Duo forte).
However, she represented 2 days later with worsening of her neck swelling with a new bifrontal headache. Antibiotic was switched to oral ciprofloxacin and clindamycin due to concern of potential betalactam induced angio-oedema.
The patient was reviewed by her general practitioner (GP) 2 days post second discharge and was noted to have worsening erythema over her neck with a fever of 38.4°C. She was transferred back to the Launceston General Hospital (LGH) for further investigations. Clinical examination now revealed trismus, with mouth opening limited to two finger breadths.
Investigations
Blood assays from the third presentation were similar to the first and second presentation (haemoglobin 72 g/L, white cell count 19×109/L, neutrophils 13.3×109/L, platelet 395×109/L and C reactive protein 152 mg/L). Thyroid function tests were deranged with a thyroid-stimulating hormone of 0.14 mU/L and free T4 of 21 pmol/L. Repeated CT scan demonstrated marked inflammation of the lower pharynx and larynx, with swelling of the epiglottis. Severe left-sided wall thickening effaced the left parapharyngeal space, with mild stranding within the peripharyngeal space. Salivary glands were normal and no collections were identified. Severe oedema of the airway resulted in a 14 mm segment of narrowing with a luminal diameter of 2–3 mm (figure 2).
Figure 2 CT showing airway narrowing in (A) sagittal and (B) coronal views.
Twenty milligram of intravenous dexamethasone was administered on receiving the CT findings and an urgent ear, nose and throat review was organised. The flexible nasoendoscopy performed was unremarkable, with normal base of tongue, valleculae, epiglottis and mobile vocal cords. There were no signs of pharyngitis or laryngitis.
Differential diagnosis
Due to the discordance of the CT and direct nasoendoscopy findings, the patient came in under the care of the General Medicine team for further investigations. A wide range of differential diagnoses were considered including atypical infections, drug-induced angio-oedema, hereditary angioedema, autoimmune diseases, haematological malignancy and osteonecrosis of the jaw.
Respiratory multiplex PCR, parvovirus and HIV screen were performed to rule out atypical infections. Aspirin and irbesartan were ceased to rule out drug causes, while a C1 esterase inhibitor and complement levels were organised to investigate hereditary angioedema. Autoimmune screen including antinuclear antibodies, antineutrophil cytoplasmic antibody, extractable nuclear antibody, double-stranded DNA antibodies and erythrocyte sedimentation rate were done, while an orthopantomogram was undertaken and ruled out ONJ (osteonecrosis of the jaw) and local dental infection.
On subsequent review, a more detailed headache history was obtained from the patient. The headache was more severe over the left forehead and was associated with trismus like sensation. Of note, the patient denies any jaw claudication. On examination, the left temporal and frontal regions were tender to palpate, with a palpable vessel noted over the left forehead. The erythrocyte sedimentation rate returned at 121 mm/hour, which raised the suspicion of giant cell arteritis. A left temporal artery biopsy was performed and showed classical findings of giant cell arteritis with fragmentation of elastic lamina, fibrosis of the adventitia and the presence of multinucleated giant cells (figure 3).
Figure 3 Temporal artery histology from patient (A): (H&E 5×) thick-walled artery with an associated inflammatory infiltrate. (B): (Orecin Giemsa 10×) elastin stain highlights fragmentation and reduplication of the elastic lamina. (C): (H&E 20×) narked intimal thickening, smooth muscle disorganisation and adventitial fibrosis. (D): (H&E 40×) lympho-histocystic infiltrate with occasional; multinucleated cells.
TREATMENT
As the patient did not have any ocular involvement at diagnosis, she was started on 50 mg of oral prednisolone per day (1 mg/kg). Adjunctive glucocorticoid-sparing agents such as tocilizumab and methotrexate were considered but due to the dramatic presentation of a threatened airway, a clinical decision was made to streamline treatment with single-agent prednisolone.
Adjunctive methotrexate when used at low doses of 10–15 mg per week has been shown to lower relapse rate, though its glucocorticoid-sparing properties were not evident.4 Tocilizumab, an IL6 receptor antagonist, has demonstrated promising results in reducing glucocorticoid exposure and giant cell arteritis relapse rate, though its role in induction therapy is still yet to be defined.5
Outcome and follow-up
The patient responded to the prednisolone course and had resolution of her facial and neck swelling within 3 days (figure 4). She was discharged home with complete resolution of her symptoms. The high-dose prednisolone was maintained for 4 weeks with a tapering plan of 10 mg reduction every 2 weeks till 20 mg per day. Ongoing weaning will be decided based on clinical symptoms and inflammatory markers at follow-up. At the 6-month phone review, patient remains symptom free on 10 mg prednisolone per day.
Figure 4 Resolution of neck swelling post prednisolone treatment (A): frontal, (B): lateral.
Discussion
Face and neck swelling is a non-specific sign, which has a lengthy list of differential diagnoses. Temporal fossa swelling is well recognised in giant cell arteritis however face and neck swelling is less common, occurring in 6.5% of cases.2 The swelling follows a waning and waxing pattern and may be due to spasm and collateralisation of the facial artery.2 6 7 The raised inflammatory markers can cause physicians to treat the initial presentation as an infection and to attribute the resolution of swelling to antibiotic response, as illustrated in our case.
Trismus (reduced jaw opening) has a prevalence of 6.8% in giant cell arteritis but is seldom reported due to its overlap with jaw claudication.8 Our case demonstrates that trismus can occur in isolation from jaw claudication. The mechanism for trismus in giant cell arteritis is uncertain but thought to be due to restricted blood flow to the masseter muscles via distal branches of the external carotid arteries.9 Interestingly, the patient developed subclinical hyperthyroidism during her admission, though it is uncertain if this is related to giant cell arteritis affecting the superior thyroid or a sick euthyroid state. Thyroid dysfunction has been described in giant cell arteritis, though no clear correlation was established due to the overlapping patient epidemiology of giant cell arteritis and thyroid diseases.10 11
The third presentation with airway narrowing stipulated a revisit of the patient’s diagnosis and presented as one of the first cases of CT-documented airway narrowing secondary to giant cell arteritis. Inflammation of the external carotid artery, where the superior laryngeal artery originates from, likely caused local ischaemia and oedema of the superior larynx. Fortunately, for the patient, giant cell arteritis was recognised early in her illness, with complete resolution of symptoms once corticosteroid treatment was commenced.
Patient’s perspective
Patient’s perspective (written with assistance from her daughter)
The whole situation is like going on an adventure, but it was not a good adventure. Not being diagnosed for 2 weeks with a swollen jaw was horrible. For my third trip to the hospital, I was not able to open my jaw and can only eat baby food. Having a doctor who found a diagnosis for me was a relief. When they started treatment, my frightening condition eased quickly.
Learning points
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery.
Face and neck swelling and trismus are under-recognised feature of giant cell arteritis and can be transient prior to developing classic giant cell arteritis symptoms.
Trismus can occur in isolation from jaw claudication in giant cell arteritis.
We recommend that any patient above the age of 50, who presents with face and neck swelling or trismus, to have giant cell arteritis considered as a differiential diagnosis.
Contributors: This case was managed by CS as the Consultant, with ZSL as the Medical Registrar. ZSL wrote up the case with supervision, some direction and editing by CS.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33722908 | 19,130,173 | 2021-03-15 |
What was the outcome of reaction 'Normocytic anaemia'? | Neck swelling and airway narrowing as an initial manifestation of giant cell arteritis.
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery. Face and neck swelling and trismus are under-recognised features of giant cell arteritis and can present as the initial symptom prior to the development of classical temporal tenderness and jaw claudication. The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss. In this paper, we present a case of neck swelling and airway narrowing as the initial manifestation of giant cell arteritis.
Background
Giant cell arteritis is a vasculitis that affects large-sized and medium-sized vessels, including the aorta and branches of the external carotid arteries. Histologically, it is characterised by a granulomatous process with infiltration of multinucleated cells, causing elastic laminae destruction and adventitial fibrosis. The inflammatory process is reflected in blood tests as a raised erythrocyte sedimentation rate and C reactive protein. Diagnosis of giant cell arteritis is based on the American College of Rheumatology’s 1990 guideline, with the presence of three or more criteria out of five.1
Giant cell arteritis is common in the elderly population, with an estimated incidence rate of 15–30 cases per 100 000 individuals.1 Due to the numerous structures supplied by the aorta and the external carotid arteries, giant cell arteritis can produce a broad range of symptoms. The most common symptoms of giant cell arteritis include fatigue, fever, headache, mastication pain and visual changes.
Facial and neck swelling is a subtle change that may feature early and insidiously in giant cell arteritis, although it is seldom reported.2 Other otolaryngologic symptoms including cough, trismus, sore throat, voice changes, dysphagia, hearing loss and tongue claudication.2 3 Aortic involvement can produce thoracic pain, limb swelling and thoracic aortic aneurysm and dissection.
The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss.
Case presentation
An 87-year-old woman presented repeatedly to the Launceston General Hospital with a history of neck swelling (figure 1). The acute onset of swelling started at the left angle of her jaw and spread inferoanteriorly to her neck. This was associated with trismus-like sensation and dyspnoea. She denied any recent respiratory illness or dysphagia.
Figure 1 Initial presentation with face and neck swelling (A: frontal, B: lateral).
The patient’s medical history included hypertension treated with irbesartan/hydrochlorothiazide, hypercholesterolemia on atorvastatin and osteoporosis on denosumab. In addition, she had been taking aspirin for primary prevention of ischaemic heart disease. There were no medication changes in the preceding 3 years.
During the initial presentation, the patient had a low-grade temperature of 37.8°C and remained haemodynamically stable with a heart rate of 100 bpm, blood pressure of 170/80 mm Hg and an oxygen saturation of 98% on room air. There was no change in voice, stridor, palpable neck nodules or collection on physical examination. The patient was tender over her temporomandibular joints bilaterally and had normal mouth opening to three finger breadths despite sensation of trismus.
Blood investigation revealed normocytic anaemia (haemoglobin of 88 g/L and mean cell volume (MCV) of 89 fL), an elevated white cell count of 17.5×109/L (14.2×109/L neutrophils, 1.4×109/L lymphocyte) and a platelet count of 371×109/L. C reactive protein was elevated at 115 mg/L with a normal antinuclear antibody titre. Thyroid, renal and liver function tests were unremarkable. Contrast-enhanced CT of the neck did not reveal any structural abnormality of the oral cavity, tongue, larynx, thyroid, carotids or lymph nodes other than mild subcutaneous oedema.
The patient was managed as potentially having Ludwig’s angina by the local ear, nose and throat team and was commenced on intravenous piperacillin/tazobactam (Tazocin). A throat swab was obtained, which did not isolate any beta-haemolytic Streptococcus sp. The patient completed 3 days of intravenous antibiotic treatment and was discharged with an oral course of amoxicillin/clavulanic acid (Augmentin Duo forte).
However, she represented 2 days later with worsening of her neck swelling with a new bifrontal headache. Antibiotic was switched to oral ciprofloxacin and clindamycin due to concern of potential betalactam induced angio-oedema.
The patient was reviewed by her general practitioner (GP) 2 days post second discharge and was noted to have worsening erythema over her neck with a fever of 38.4°C. She was transferred back to the Launceston General Hospital (LGH) for further investigations. Clinical examination now revealed trismus, with mouth opening limited to two finger breadths.
Investigations
Blood assays from the third presentation were similar to the first and second presentation (haemoglobin 72 g/L, white cell count 19×109/L, neutrophils 13.3×109/L, platelet 395×109/L and C reactive protein 152 mg/L). Thyroid function tests were deranged with a thyroid-stimulating hormone of 0.14 mU/L and free T4 of 21 pmol/L. Repeated CT scan demonstrated marked inflammation of the lower pharynx and larynx, with swelling of the epiglottis. Severe left-sided wall thickening effaced the left parapharyngeal space, with mild stranding within the peripharyngeal space. Salivary glands were normal and no collections were identified. Severe oedema of the airway resulted in a 14 mm segment of narrowing with a luminal diameter of 2–3 mm (figure 2).
Figure 2 CT showing airway narrowing in (A) sagittal and (B) coronal views.
Twenty milligram of intravenous dexamethasone was administered on receiving the CT findings and an urgent ear, nose and throat review was organised. The flexible nasoendoscopy performed was unremarkable, with normal base of tongue, valleculae, epiglottis and mobile vocal cords. There were no signs of pharyngitis or laryngitis.
Differential diagnosis
Due to the discordance of the CT and direct nasoendoscopy findings, the patient came in under the care of the General Medicine team for further investigations. A wide range of differential diagnoses were considered including atypical infections, drug-induced angio-oedema, hereditary angioedema, autoimmune diseases, haematological malignancy and osteonecrosis of the jaw.
Respiratory multiplex PCR, parvovirus and HIV screen were performed to rule out atypical infections. Aspirin and irbesartan were ceased to rule out drug causes, while a C1 esterase inhibitor and complement levels were organised to investigate hereditary angioedema. Autoimmune screen including antinuclear antibodies, antineutrophil cytoplasmic antibody, extractable nuclear antibody, double-stranded DNA antibodies and erythrocyte sedimentation rate were done, while an orthopantomogram was undertaken and ruled out ONJ (osteonecrosis of the jaw) and local dental infection.
On subsequent review, a more detailed headache history was obtained from the patient. The headache was more severe over the left forehead and was associated with trismus like sensation. Of note, the patient denies any jaw claudication. On examination, the left temporal and frontal regions were tender to palpate, with a palpable vessel noted over the left forehead. The erythrocyte sedimentation rate returned at 121 mm/hour, which raised the suspicion of giant cell arteritis. A left temporal artery biopsy was performed and showed classical findings of giant cell arteritis with fragmentation of elastic lamina, fibrosis of the adventitia and the presence of multinucleated giant cells (figure 3).
Figure 3 Temporal artery histology from patient (A): (H&E 5×) thick-walled artery with an associated inflammatory infiltrate. (B): (Orecin Giemsa 10×) elastin stain highlights fragmentation and reduplication of the elastic lamina. (C): (H&E 20×) narked intimal thickening, smooth muscle disorganisation and adventitial fibrosis. (D): (H&E 40×) lympho-histocystic infiltrate with occasional; multinucleated cells.
TREATMENT
As the patient did not have any ocular involvement at diagnosis, she was started on 50 mg of oral prednisolone per day (1 mg/kg). Adjunctive glucocorticoid-sparing agents such as tocilizumab and methotrexate were considered but due to the dramatic presentation of a threatened airway, a clinical decision was made to streamline treatment with single-agent prednisolone.
Adjunctive methotrexate when used at low doses of 10–15 mg per week has been shown to lower relapse rate, though its glucocorticoid-sparing properties were not evident.4 Tocilizumab, an IL6 receptor antagonist, has demonstrated promising results in reducing glucocorticoid exposure and giant cell arteritis relapse rate, though its role in induction therapy is still yet to be defined.5
Outcome and follow-up
The patient responded to the prednisolone course and had resolution of her facial and neck swelling within 3 days (figure 4). She was discharged home with complete resolution of her symptoms. The high-dose prednisolone was maintained for 4 weeks with a tapering plan of 10 mg reduction every 2 weeks till 20 mg per day. Ongoing weaning will be decided based on clinical symptoms and inflammatory markers at follow-up. At the 6-month phone review, patient remains symptom free on 10 mg prednisolone per day.
Figure 4 Resolution of neck swelling post prednisolone treatment (A): frontal, (B): lateral.
Discussion
Face and neck swelling is a non-specific sign, which has a lengthy list of differential diagnoses. Temporal fossa swelling is well recognised in giant cell arteritis however face and neck swelling is less common, occurring in 6.5% of cases.2 The swelling follows a waning and waxing pattern and may be due to spasm and collateralisation of the facial artery.2 6 7 The raised inflammatory markers can cause physicians to treat the initial presentation as an infection and to attribute the resolution of swelling to antibiotic response, as illustrated in our case.
Trismus (reduced jaw opening) has a prevalence of 6.8% in giant cell arteritis but is seldom reported due to its overlap with jaw claudication.8 Our case demonstrates that trismus can occur in isolation from jaw claudication. The mechanism for trismus in giant cell arteritis is uncertain but thought to be due to restricted blood flow to the masseter muscles via distal branches of the external carotid arteries.9 Interestingly, the patient developed subclinical hyperthyroidism during her admission, though it is uncertain if this is related to giant cell arteritis affecting the superior thyroid or a sick euthyroid state. Thyroid dysfunction has been described in giant cell arteritis, though no clear correlation was established due to the overlapping patient epidemiology of giant cell arteritis and thyroid diseases.10 11
The third presentation with airway narrowing stipulated a revisit of the patient’s diagnosis and presented as one of the first cases of CT-documented airway narrowing secondary to giant cell arteritis. Inflammation of the external carotid artery, where the superior laryngeal artery originates from, likely caused local ischaemia and oedema of the superior larynx. Fortunately, for the patient, giant cell arteritis was recognised early in her illness, with complete resolution of symptoms once corticosteroid treatment was commenced.
Patient’s perspective
Patient’s perspective (written with assistance from her daughter)
The whole situation is like going on an adventure, but it was not a good adventure. Not being diagnosed for 2 weeks with a swollen jaw was horrible. For my third trip to the hospital, I was not able to open my jaw and can only eat baby food. Having a doctor who found a diagnosis for me was a relief. When they started treatment, my frightening condition eased quickly.
Learning points
Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery.
Face and neck swelling and trismus are under-recognised feature of giant cell arteritis and can be transient prior to developing classic giant cell arteritis symptoms.
Trismus can occur in isolation from jaw claudication in giant cell arteritis.
We recommend that any patient above the age of 50, who presents with face and neck swelling or trismus, to have giant cell arteritis considered as a differiential diagnosis.
Contributors: This case was managed by CS as the Consultant, with ZSL as the Medical Registrar. ZSL wrote up the case with supervision, some direction and editing by CS.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33722908 | 19,130,173 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Angina unstable'. | Life-Threatening Complications Related to Delayed Diagnosis of Euglycemic Diabetic Ketoacidosis Associated with Sodium-Glucose Cotransporter-2 Inhibitors: A Report of 2 Cases.
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are widely used owing to their effective glycemic control and protective effects against heart and kidney failure. Euglycemic diabetic ketoacidosis (eu-DKA) is a complication of treatment with SGLT2is. Eu-DKA often leads to delayed diagnosis and results in life-threatening complications. We report 2 critical cases of SGLT2i-associated eu-DKA. CASE REPORT Case 1 was 52-year-old woman with unstable angina scheduled for elective coronary artery bypass grafting surgery. Preoperatively, she underwent tooth extraction which led to poor food intake because of pain. Three days before surgery, the patient had SGLT2i-associated eu-DKA and myocardial infraction, requiring percutaneous coronary intervention and peripheral venoarterial extracorporeal membrane oxygenation. The patient had taken SGLT2i until the morning of admission to the intensive care unit. Case 2 was a 76-year-old woman experiencing SGLT2i-associated eu-DKA and sinus arrest, necessitating a temporary pacemaker, followed by elective gastrojejunal bypass surgery. The SGLT2i was discontinued the day before surgery. On day 3 following surgery, the patient's metabolic acidosis improved, and sinus arrest resolved. CONCLUSIONS Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delay in diagnosis because of a lack of evidence of hyperglycemia could contribute to the development and worsening of life-threatening complications. This reiterates the importance of reviewing ongoing medications of patients with diabetes and considering eu-DKA as a differential diagnosis for patients with high anion gap metabolic acidosis to ensure early intervention. SGLT2i-associated DKA likely develops perioperatively; therefore, clinicians should pay attention to the discontinuation period of SGLT2i before any surgical intervention.
Background
Sodium-glucose cotransporter-transporter-2 inhibitors (SGLT2is) are used widely owing to their protective effects against heart and kidney failure and effective glycemic control [1–6]. SGLT2is decrease glycated hemoglobin, body weight, and blood pressure [1,2]. Recent randomized control trials have demonstrated that SGLT2is reduce the risk of heart failure, cardiovascular death, and serious renal outcomes in patients with or without diabetes [4–6]. However, diabetic ketoacidosis (DKA) has been reported as a complication of SGLT2is [7,8]. It was reported that, compared with dipeptidyl peptidase-4 inhibitors, SGLT2is have a higher risk of DKA (hazard ratio, 2.85) [7]. Caloric restriction, surgical stress, acute illness, risk of dehydration, and medication changes have been reported as precipitating factors of SGLT2i-associated DKA, and nausea and vomiting have been reported as its clinical presentation [9–11]. The incidence of SGLT2i-associated DKA perioperatively has been reported to be as high as 19% to 28% [12,13]. In a review of 47 cases of perioperative SGLT2i-associated DKA, 4 cases of severe acidemia or metabolic acidosis were reported (pH <7.0 in 2 cases; bicarbonate [HCO3–] level <5 mEq/L in 2 cases) [10]. Unlike with typical DKA, some patients have a normal blood glucose level. This type of DKA is known as euglycemic DKA (eu-DKA). Eu-DKA sometimes leads to delayed diagnosis and results in life-threatening complications [8,9]. Because the use of SGLT2i is expected to become increasingly widespread owing to its effectiveness, it is important to report this adverse drug reaction that can delay diagnosis.
We encountered 2 severe cases of SGLT2i-associated eu-DKA caused by delayed diagnosis in the intensive care unit (ICU). Both patients consented to the publication of this case report.
Case Reports
Case 1
A 52-year-old woman weighing 51 kg and receiving medications for type 2 diabetes mellitus (empagliflozin 10 mg daily and sitagliptin 50 mg daily), dyslipidemia (ezetimibe 10 mg daily and rosuvastatin 20 mg daily), and an old cerebral infarction (clopidogrel 75 mg daily) was diagnosed with unstable angina. She was scheduled for elective coronary artery bypass grafting surgery. Following hospital admission, the patient underwent a preoperative examination for the surgery. On days 12 and 15 of admission, she underwent tooth extraction for perioperative management. Subsequently, her oral food intake decreased because of pain. On day 22 of hospitalization, 3 days before the scheduled elective coronary artery bypass grafting surgery, she developed tachypnea, vomiting, and decreased blood pressure. She had high anion gap metabolic acidosis (pH, 6.84; HCO3– level, 2.1 mEq/L; base excess, −20.0 mmol/L; anion gap, 31.9 mmol/L; and lactate level, 2.4 mmol/L), while her blood glucose remained at normal levels (178 mg/dL). Empagliflozin was administered until the morning of that day. Although elevated cardiac troponin levels (serum troponin I, 324.5 pg/mL) were detected, no ST-segment elevation was observed on the electrocardiogram. Supportive therapy to manage metabolic acidosis was initiated. She was intubated for hypotension (systolic artery pressure, 78 mmHg; infusion with noradrenaline 0.06 μg/kg/h), severe acidemia, and tachypnea. The oral administration of empagliflozin was discontinued. Despite sodium bicarbonate infusion and continuous renal replacement therapy instituted for the life-threatening acidemia, the patient’s metabolic acidosis did not improve. On day 2 of ICU admission, based on elevated blood β-hydroxybutyrate levels (12.9 mmol/L), dextrose and insulin were administered to manage the eu-DKA. The acidosis was resolved within 24 h of treatment initiation; in addition, blood β-hydroxybutyrate levels decreased (4.3 mmol/L). On day 3 of ICU admission, she developed pulmonary edema but still required large doses of inotropes and vasopressors. As the metabolic acidosis improved, the status of her coronary arteries was evaluated. Following insertion of a percutaneous mechanical circulatory support device (Impella 2.5; Abiomed, Danvers, MA, USA) to ensure left ventricular unloading, percutaneous coronary intervention was performed. Stents were placed at 3 points, including the left anterior descending artery. Subsequently, there was a need for peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) owing to the prevailing potentially life-threatening poor oxygenation (ratio of arterial oxygen partial pressure to fractional inspired oxygen was 57.5 under 10 cmH2O positive end-expiratory pressure) and low output syndrome. VA-ECMO, continuous renal replacement therapy, Impella 2.5, and mechanical ventilation were required for 6, 6, 7, and 13 days, respectively. In addition, she had a hemorrhagic cerebral infarction on day 10 of ICU admission. She was discharged from the ICU on day 15 and transferred to a rehabilitation hospital on day 51 of admission.
Case 2
A 76-year-old woman weighing 63 kg and receiving medications for type 2 diabetes mellitus (canagliflozin 100 mg daily and metformin 500 mg daily), hypertension (cilnidipine 20 mg daily), and dyslipidemia (fenofibrate 80 mg daily) was diagnosed with duodenal cancer and scheduled for elective gastrojejunal bypass surgery. Canagliflozin was administered until the day before the surgery. After surgery, she was admitted to the ICU for postoperative management. On arrival, she had euglycemia (100 mg/dL), but with metabolic acidosis (pH, 7.25; HCO3– level, −17.3 mEq/L; base excess, −9.1; anion gap, 16.2 mmol/L; and lactate level, 0.8 mmol/L). Sodium bicarbonate infusion was initiated; however, the patient’s metabolic acidosis continued to worsen. On day 2 of ICU admission, she had cardiac sinus arrest and experienced loss of consciousness with metabolic acidosis (pH, 7.27; HCO3– level, 13.5 mEq/L; base excess, −12.1; anion gap, 23.7 mmol/L; and lactate level, 1.1 mmol/L). Elevated blood β-hydroxybutyrate (18.6 mmol/L) levels were noted, and an infusion of dextrose and insulin was initiated for the management of eu-DKA. Within 2 h of initiating eu-DKA treatment, she had another cardiac sinus arrest, lost consciousness, and continued to experience metabolic acidosis (pH, 7.30; HCO3– level, 16.0 mEq/L; base excess, −9.3; anion gap, 18.0 mmol/L; and lactate level, 1.0 mmol/L). Coronary angiography showed no myocardial ischemia, and a temporary pacemaker was intravenously inserted as an emergency intervention. On day 3 of ICU admission, the patient’s metabolic acidosis improved, her blood β-hydroxybutyrate level decreased (3.2 mmol/L), and sinus arrest resolved. The patient was discharged from the ICU on day 5. Glycosuria was also observed on day 6 (blood glucose level, 140 mg/dL) but was not observed on day 12 (blood glucose level, 163 mg/dL). The temporary pacemaker was removed on day 11, and no signs of sinus arrest were detected using a 24-h Holter monitor on day 14. She was discharged from the hospital on day 18.
Discussion
We encountered 2 cases of life-threatening complications caused by SGLT2i-associated eu-DKA. Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delay in diagnosis due to lack of evidence of hyperglycemia could have contributed to the development and deterioration of the life-threatening complications in our patients.
The underlying condition leading to eu-DKA was a caloric restriction in case 1 and surgical stress in case 2, and these conditions might have contributed to the development and worsening of life-threatening complications. Preoperative fasting, very low-calorie diets, and surgical stress are reported as precipitating factors of SGLT2i-associated DKA [10,11]. In case 1, tooth extraction resulted in poor food intake, whereas in case 2, DKA developed after surgery. Persistent glycosuria induced by SGLT2i lowers the amount of the body glucose pool [14], and in this situation, when caloric intake decreases, the blood glucose level cannot be increased, insulin secretion is suppressed, and ketone body production is induced. Surgical stress increases counter-regulatory hormones such as adrenaline and cortisol, and these hormones induce increased insulin resistance [10]. Increased insulin resistance causes impaired sugar utilization and ketogenesis. Additionally, surgical stress induces glucagon secretion [10]. Glucagon promotes lipolysis and fatty acid oxidation in the liver and increases ketogenesis [15].
In case 1, it remained unclear whether DKA or myocardial ischemia occurred first. In this patient, tooth extraction resulted in poor food intake; therefore, DKA might have developed before the myocardial ischemia. Several studies have illustrated that acute metabolic acidosis can have critical effects on the cardiovascular system [16,17]. The cardiovascular effects of acidosis include arterial vasodilatation contributing to hypotension [18], a decrease of contractility and cardiac output [19,20], sinus dysfunction [21], and a predisposition to cardiac arrhythmias associated with sudden death [22]. The patient in case 1 had severe coronary artery disease requiring coronary artery bypass grafting. Acidemia due to eu-DKA caused peripheral vasodilation, resulting in hypotension and decreased cardiac contractility due to increased left ventricular end-diastolic pressure. This potentially reduced coronary perfusion pressure and led to the myocardial infarction. Another possible association with DKA and acute coronary syndrome includes the supply-demand mismatch caused by an increased oxygen demand in the myocardium by counter-regulatory hormones, such as adrenaline, cortisol, and glucagon, released during DKA [23].
The patient in case 2 underwent major surgery, and the surgical stress resulted in SGLT2i-associated eu-DKA. A few cases of life-threatening complications due to SGLT2i-associated DKA in the postoperative period have been reported [24,25]. A postoperative gastric bypass case of SGLT2i-associated DKA requiring mechanical ventilation and hemodialysis was reported [24]. A patient that developed SGLT2i-associated DKA 2 days after laparoscopic appendectomy also developed encephalopathy and required mechanical ventilation and hemo-dialysis [25]; however, there are few reports on patients with severe complications requiring urgent pacemaker insertion for sinus arrest, as in our case 2. Sinus dysfunction and sudden death have been reported to be associated with metabolic acidosis [18,21]. Additionally, in case 2, coronary artery stenosis was not detected on coronary angiography. Once the acidemia improved, the sinus arrest resolved, with a Holter electrocardiogram reaffirming this result. Therefore, we believe that acidemia was the probable cause of the sinus arrest.
Delayed diagnosis due to lack of evidence of hyperglycemia may have contributed to the development of life-threatening complications in our patients. Although SGLT2i has become widely used in recent years, its complication, eu-DKA, appears to be under-recognized, especially by surgeons. Furthermore, eu-DKA often results in blood glucose levels below 200 mg/dL, which may delay its detection [8,9]. Even our cases were followed up with supportive therapy without an accurate diagnosis of metabolic acidosis. Therefore, SGLT2i-associated eu-DKA should be considered a probable differential diagnosis in patients with diabetes and metabolic acidosis. Furthermore, SGLT2i was not discontinued in both of our cases. Because case 1 was an emergency, ongoing medications could not be terminated, while in case 2, canagliflozin was discontinued the day before the surgery. Generally, elimination from the body takes about 5 times as long as the half-life of the drug. The average half-life time of canagliflozin is reported to be 10.2 h, and 5 times the half-time is 51 h. The U.S. Food and Drug Administration in 2020 announced the approval of a change in the prescription of SGLT2i diabetes medicines, thereby recommending them to be terminated temporarily 3 or 4 days before scheduled surgery to prevent perioperative SGLT2i-associated ketoacidosis [26]. In our case 2, glycosuria was still detected on day 6 (7 days after the last oral administration of canagliflozin). We believed that the effect of canagliflozin remained at least until that time. In SGLT2i-associated DKA, glycosuria persisted for 3 to 10 days after the discontinuation of SGLT2is [27]. In case 2, canagliflozin may have required a washout period longer than 3 days.
Conclusions
We reported 2 cases of life-threatening complications that were caused or worsened by SGLT2i-associated eu-DKA. Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delayed diagnosis due to lack of evidence of hyperglycemia may have contributed to the development and worsening of these life-threatening complications. In situations in which SGLT2i is expected to become increasingly widespread owing to its effectiveness, the number of SGLT2i-associated DKA is expected to increase. It is imperative to assess the existing medication history of patients with diabetes and consider eu-DKA as an important differential diagnosis of patients with high anion gap metabolic acidosis to ensure early intervention. Additionally, SGLT2i-associated DKA is likely to develop perioperatively; therefore, clinicians should pay attention to the discontinuation period of SGLT2i prior to any surgical intervention.
We would like to thank Editage (www.editage.com) for English language editing.
Department and Institution Where the Work Was Performed
Department of Intensive Care Medicine, Tokyo Women’s Medical University, Tokyo, Japan
Conflict of Interest
None. | CLOPIDOGREL BISULFATE, EMPAGLIFLOZIN, EZETIMIBE, ROSUVASTATIN, SITAGLIPTIN | DrugsGivenReaction | CC BY-NC-ND | 33723205 | 19,780,336 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Euglycaemic diabetic ketoacidosis'. | Life-Threatening Complications Related to Delayed Diagnosis of Euglycemic Diabetic Ketoacidosis Associated with Sodium-Glucose Cotransporter-2 Inhibitors: A Report of 2 Cases.
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are widely used owing to their effective glycemic control and protective effects against heart and kidney failure. Euglycemic diabetic ketoacidosis (eu-DKA) is a complication of treatment with SGLT2is. Eu-DKA often leads to delayed diagnosis and results in life-threatening complications. We report 2 critical cases of SGLT2i-associated eu-DKA. CASE REPORT Case 1 was 52-year-old woman with unstable angina scheduled for elective coronary artery bypass grafting surgery. Preoperatively, she underwent tooth extraction which led to poor food intake because of pain. Three days before surgery, the patient had SGLT2i-associated eu-DKA and myocardial infraction, requiring percutaneous coronary intervention and peripheral venoarterial extracorporeal membrane oxygenation. The patient had taken SGLT2i until the morning of admission to the intensive care unit. Case 2 was a 76-year-old woman experiencing SGLT2i-associated eu-DKA and sinus arrest, necessitating a temporary pacemaker, followed by elective gastrojejunal bypass surgery. The SGLT2i was discontinued the day before surgery. On day 3 following surgery, the patient's metabolic acidosis improved, and sinus arrest resolved. CONCLUSIONS Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delay in diagnosis because of a lack of evidence of hyperglycemia could contribute to the development and worsening of life-threatening complications. This reiterates the importance of reviewing ongoing medications of patients with diabetes and considering eu-DKA as a differential diagnosis for patients with high anion gap metabolic acidosis to ensure early intervention. SGLT2i-associated DKA likely develops perioperatively; therefore, clinicians should pay attention to the discontinuation period of SGLT2i before any surgical intervention.
Background
Sodium-glucose cotransporter-transporter-2 inhibitors (SGLT2is) are used widely owing to their protective effects against heart and kidney failure and effective glycemic control [1–6]. SGLT2is decrease glycated hemoglobin, body weight, and blood pressure [1,2]. Recent randomized control trials have demonstrated that SGLT2is reduce the risk of heart failure, cardiovascular death, and serious renal outcomes in patients with or without diabetes [4–6]. However, diabetic ketoacidosis (DKA) has been reported as a complication of SGLT2is [7,8]. It was reported that, compared with dipeptidyl peptidase-4 inhibitors, SGLT2is have a higher risk of DKA (hazard ratio, 2.85) [7]. Caloric restriction, surgical stress, acute illness, risk of dehydration, and medication changes have been reported as precipitating factors of SGLT2i-associated DKA, and nausea and vomiting have been reported as its clinical presentation [9–11]. The incidence of SGLT2i-associated DKA perioperatively has been reported to be as high as 19% to 28% [12,13]. In a review of 47 cases of perioperative SGLT2i-associated DKA, 4 cases of severe acidemia or metabolic acidosis were reported (pH <7.0 in 2 cases; bicarbonate [HCO3–] level <5 mEq/L in 2 cases) [10]. Unlike with typical DKA, some patients have a normal blood glucose level. This type of DKA is known as euglycemic DKA (eu-DKA). Eu-DKA sometimes leads to delayed diagnosis and results in life-threatening complications [8,9]. Because the use of SGLT2i is expected to become increasingly widespread owing to its effectiveness, it is important to report this adverse drug reaction that can delay diagnosis.
We encountered 2 severe cases of SGLT2i-associated eu-DKA caused by delayed diagnosis in the intensive care unit (ICU). Both patients consented to the publication of this case report.
Case Reports
Case 1
A 52-year-old woman weighing 51 kg and receiving medications for type 2 diabetes mellitus (empagliflozin 10 mg daily and sitagliptin 50 mg daily), dyslipidemia (ezetimibe 10 mg daily and rosuvastatin 20 mg daily), and an old cerebral infarction (clopidogrel 75 mg daily) was diagnosed with unstable angina. She was scheduled for elective coronary artery bypass grafting surgery. Following hospital admission, the patient underwent a preoperative examination for the surgery. On days 12 and 15 of admission, she underwent tooth extraction for perioperative management. Subsequently, her oral food intake decreased because of pain. On day 22 of hospitalization, 3 days before the scheduled elective coronary artery bypass grafting surgery, she developed tachypnea, vomiting, and decreased blood pressure. She had high anion gap metabolic acidosis (pH, 6.84; HCO3– level, 2.1 mEq/L; base excess, −20.0 mmol/L; anion gap, 31.9 mmol/L; and lactate level, 2.4 mmol/L), while her blood glucose remained at normal levels (178 mg/dL). Empagliflozin was administered until the morning of that day. Although elevated cardiac troponin levels (serum troponin I, 324.5 pg/mL) were detected, no ST-segment elevation was observed on the electrocardiogram. Supportive therapy to manage metabolic acidosis was initiated. She was intubated for hypotension (systolic artery pressure, 78 mmHg; infusion with noradrenaline 0.06 μg/kg/h), severe acidemia, and tachypnea. The oral administration of empagliflozin was discontinued. Despite sodium bicarbonate infusion and continuous renal replacement therapy instituted for the life-threatening acidemia, the patient’s metabolic acidosis did not improve. On day 2 of ICU admission, based on elevated blood β-hydroxybutyrate levels (12.9 mmol/L), dextrose and insulin were administered to manage the eu-DKA. The acidosis was resolved within 24 h of treatment initiation; in addition, blood β-hydroxybutyrate levels decreased (4.3 mmol/L). On day 3 of ICU admission, she developed pulmonary edema but still required large doses of inotropes and vasopressors. As the metabolic acidosis improved, the status of her coronary arteries was evaluated. Following insertion of a percutaneous mechanical circulatory support device (Impella 2.5; Abiomed, Danvers, MA, USA) to ensure left ventricular unloading, percutaneous coronary intervention was performed. Stents were placed at 3 points, including the left anterior descending artery. Subsequently, there was a need for peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) owing to the prevailing potentially life-threatening poor oxygenation (ratio of arterial oxygen partial pressure to fractional inspired oxygen was 57.5 under 10 cmH2O positive end-expiratory pressure) and low output syndrome. VA-ECMO, continuous renal replacement therapy, Impella 2.5, and mechanical ventilation were required for 6, 6, 7, and 13 days, respectively. In addition, she had a hemorrhagic cerebral infarction on day 10 of ICU admission. She was discharged from the ICU on day 15 and transferred to a rehabilitation hospital on day 51 of admission.
Case 2
A 76-year-old woman weighing 63 kg and receiving medications for type 2 diabetes mellitus (canagliflozin 100 mg daily and metformin 500 mg daily), hypertension (cilnidipine 20 mg daily), and dyslipidemia (fenofibrate 80 mg daily) was diagnosed with duodenal cancer and scheduled for elective gastrojejunal bypass surgery. Canagliflozin was administered until the day before the surgery. After surgery, she was admitted to the ICU for postoperative management. On arrival, she had euglycemia (100 mg/dL), but with metabolic acidosis (pH, 7.25; HCO3– level, −17.3 mEq/L; base excess, −9.1; anion gap, 16.2 mmol/L; and lactate level, 0.8 mmol/L). Sodium bicarbonate infusion was initiated; however, the patient’s metabolic acidosis continued to worsen. On day 2 of ICU admission, she had cardiac sinus arrest and experienced loss of consciousness with metabolic acidosis (pH, 7.27; HCO3– level, 13.5 mEq/L; base excess, −12.1; anion gap, 23.7 mmol/L; and lactate level, 1.1 mmol/L). Elevated blood β-hydroxybutyrate (18.6 mmol/L) levels were noted, and an infusion of dextrose and insulin was initiated for the management of eu-DKA. Within 2 h of initiating eu-DKA treatment, she had another cardiac sinus arrest, lost consciousness, and continued to experience metabolic acidosis (pH, 7.30; HCO3– level, 16.0 mEq/L; base excess, −9.3; anion gap, 18.0 mmol/L; and lactate level, 1.0 mmol/L). Coronary angiography showed no myocardial ischemia, and a temporary pacemaker was intravenously inserted as an emergency intervention. On day 3 of ICU admission, the patient’s metabolic acidosis improved, her blood β-hydroxybutyrate level decreased (3.2 mmol/L), and sinus arrest resolved. The patient was discharged from the ICU on day 5. Glycosuria was also observed on day 6 (blood glucose level, 140 mg/dL) but was not observed on day 12 (blood glucose level, 163 mg/dL). The temporary pacemaker was removed on day 11, and no signs of sinus arrest were detected using a 24-h Holter monitor on day 14. She was discharged from the hospital on day 18.
Discussion
We encountered 2 cases of life-threatening complications caused by SGLT2i-associated eu-DKA. Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delay in diagnosis due to lack of evidence of hyperglycemia could have contributed to the development and deterioration of the life-threatening complications in our patients.
The underlying condition leading to eu-DKA was a caloric restriction in case 1 and surgical stress in case 2, and these conditions might have contributed to the development and worsening of life-threatening complications. Preoperative fasting, very low-calorie diets, and surgical stress are reported as precipitating factors of SGLT2i-associated DKA [10,11]. In case 1, tooth extraction resulted in poor food intake, whereas in case 2, DKA developed after surgery. Persistent glycosuria induced by SGLT2i lowers the amount of the body glucose pool [14], and in this situation, when caloric intake decreases, the blood glucose level cannot be increased, insulin secretion is suppressed, and ketone body production is induced. Surgical stress increases counter-regulatory hormones such as adrenaline and cortisol, and these hormones induce increased insulin resistance [10]. Increased insulin resistance causes impaired sugar utilization and ketogenesis. Additionally, surgical stress induces glucagon secretion [10]. Glucagon promotes lipolysis and fatty acid oxidation in the liver and increases ketogenesis [15].
In case 1, it remained unclear whether DKA or myocardial ischemia occurred first. In this patient, tooth extraction resulted in poor food intake; therefore, DKA might have developed before the myocardial ischemia. Several studies have illustrated that acute metabolic acidosis can have critical effects on the cardiovascular system [16,17]. The cardiovascular effects of acidosis include arterial vasodilatation contributing to hypotension [18], a decrease of contractility and cardiac output [19,20], sinus dysfunction [21], and a predisposition to cardiac arrhythmias associated with sudden death [22]. The patient in case 1 had severe coronary artery disease requiring coronary artery bypass grafting. Acidemia due to eu-DKA caused peripheral vasodilation, resulting in hypotension and decreased cardiac contractility due to increased left ventricular end-diastolic pressure. This potentially reduced coronary perfusion pressure and led to the myocardial infarction. Another possible association with DKA and acute coronary syndrome includes the supply-demand mismatch caused by an increased oxygen demand in the myocardium by counter-regulatory hormones, such as adrenaline, cortisol, and glucagon, released during DKA [23].
The patient in case 2 underwent major surgery, and the surgical stress resulted in SGLT2i-associated eu-DKA. A few cases of life-threatening complications due to SGLT2i-associated DKA in the postoperative period have been reported [24,25]. A postoperative gastric bypass case of SGLT2i-associated DKA requiring mechanical ventilation and hemodialysis was reported [24]. A patient that developed SGLT2i-associated DKA 2 days after laparoscopic appendectomy also developed encephalopathy and required mechanical ventilation and hemo-dialysis [25]; however, there are few reports on patients with severe complications requiring urgent pacemaker insertion for sinus arrest, as in our case 2. Sinus dysfunction and sudden death have been reported to be associated with metabolic acidosis [18,21]. Additionally, in case 2, coronary artery stenosis was not detected on coronary angiography. Once the acidemia improved, the sinus arrest resolved, with a Holter electrocardiogram reaffirming this result. Therefore, we believe that acidemia was the probable cause of the sinus arrest.
Delayed diagnosis due to lack of evidence of hyperglycemia may have contributed to the development of life-threatening complications in our patients. Although SGLT2i has become widely used in recent years, its complication, eu-DKA, appears to be under-recognized, especially by surgeons. Furthermore, eu-DKA often results in blood glucose levels below 200 mg/dL, which may delay its detection [8,9]. Even our cases were followed up with supportive therapy without an accurate diagnosis of metabolic acidosis. Therefore, SGLT2i-associated eu-DKA should be considered a probable differential diagnosis in patients with diabetes and metabolic acidosis. Furthermore, SGLT2i was not discontinued in both of our cases. Because case 1 was an emergency, ongoing medications could not be terminated, while in case 2, canagliflozin was discontinued the day before the surgery. Generally, elimination from the body takes about 5 times as long as the half-life of the drug. The average half-life time of canagliflozin is reported to be 10.2 h, and 5 times the half-time is 51 h. The U.S. Food and Drug Administration in 2020 announced the approval of a change in the prescription of SGLT2i diabetes medicines, thereby recommending them to be terminated temporarily 3 or 4 days before scheduled surgery to prevent perioperative SGLT2i-associated ketoacidosis [26]. In our case 2, glycosuria was still detected on day 6 (7 days after the last oral administration of canagliflozin). We believed that the effect of canagliflozin remained at least until that time. In SGLT2i-associated DKA, glycosuria persisted for 3 to 10 days after the discontinuation of SGLT2is [27]. In case 2, canagliflozin may have required a washout period longer than 3 days.
Conclusions
We reported 2 cases of life-threatening complications that were caused or worsened by SGLT2i-associated eu-DKA. Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delayed diagnosis due to lack of evidence of hyperglycemia may have contributed to the development and worsening of these life-threatening complications. In situations in which SGLT2i is expected to become increasingly widespread owing to its effectiveness, the number of SGLT2i-associated DKA is expected to increase. It is imperative to assess the existing medication history of patients with diabetes and consider eu-DKA as an important differential diagnosis of patients with high anion gap metabolic acidosis to ensure early intervention. Additionally, SGLT2i-associated DKA is likely to develop perioperatively; therefore, clinicians should pay attention to the discontinuation period of SGLT2i prior to any surgical intervention.
We would like to thank Editage (www.editage.com) for English language editing.
Department and Institution Where the Work Was Performed
Department of Intensive Care Medicine, Tokyo Women’s Medical University, Tokyo, Japan
Conflict of Interest
None. | CLOPIDOGREL BISULFATE, EMPAGLIFLOZIN, EZETIMIBE, ROSUVASTATIN, SITAGLIPTIN | DrugsGivenReaction | CC BY-NC-ND | 33723205 | 19,780,336 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemorrhagic cerebral infarction'. | Life-Threatening Complications Related to Delayed Diagnosis of Euglycemic Diabetic Ketoacidosis Associated with Sodium-Glucose Cotransporter-2 Inhibitors: A Report of 2 Cases.
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are widely used owing to their effective glycemic control and protective effects against heart and kidney failure. Euglycemic diabetic ketoacidosis (eu-DKA) is a complication of treatment with SGLT2is. Eu-DKA often leads to delayed diagnosis and results in life-threatening complications. We report 2 critical cases of SGLT2i-associated eu-DKA. CASE REPORT Case 1 was 52-year-old woman with unstable angina scheduled for elective coronary artery bypass grafting surgery. Preoperatively, she underwent tooth extraction which led to poor food intake because of pain. Three days before surgery, the patient had SGLT2i-associated eu-DKA and myocardial infraction, requiring percutaneous coronary intervention and peripheral venoarterial extracorporeal membrane oxygenation. The patient had taken SGLT2i until the morning of admission to the intensive care unit. Case 2 was a 76-year-old woman experiencing SGLT2i-associated eu-DKA and sinus arrest, necessitating a temporary pacemaker, followed by elective gastrojejunal bypass surgery. The SGLT2i was discontinued the day before surgery. On day 3 following surgery, the patient's metabolic acidosis improved, and sinus arrest resolved. CONCLUSIONS Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delay in diagnosis because of a lack of evidence of hyperglycemia could contribute to the development and worsening of life-threatening complications. This reiterates the importance of reviewing ongoing medications of patients with diabetes and considering eu-DKA as a differential diagnosis for patients with high anion gap metabolic acidosis to ensure early intervention. SGLT2i-associated DKA likely develops perioperatively; therefore, clinicians should pay attention to the discontinuation period of SGLT2i before any surgical intervention.
Background
Sodium-glucose cotransporter-transporter-2 inhibitors (SGLT2is) are used widely owing to their protective effects against heart and kidney failure and effective glycemic control [1–6]. SGLT2is decrease glycated hemoglobin, body weight, and blood pressure [1,2]. Recent randomized control trials have demonstrated that SGLT2is reduce the risk of heart failure, cardiovascular death, and serious renal outcomes in patients with or without diabetes [4–6]. However, diabetic ketoacidosis (DKA) has been reported as a complication of SGLT2is [7,8]. It was reported that, compared with dipeptidyl peptidase-4 inhibitors, SGLT2is have a higher risk of DKA (hazard ratio, 2.85) [7]. Caloric restriction, surgical stress, acute illness, risk of dehydration, and medication changes have been reported as precipitating factors of SGLT2i-associated DKA, and nausea and vomiting have been reported as its clinical presentation [9–11]. The incidence of SGLT2i-associated DKA perioperatively has been reported to be as high as 19% to 28% [12,13]. In a review of 47 cases of perioperative SGLT2i-associated DKA, 4 cases of severe acidemia or metabolic acidosis were reported (pH <7.0 in 2 cases; bicarbonate [HCO3–] level <5 mEq/L in 2 cases) [10]. Unlike with typical DKA, some patients have a normal blood glucose level. This type of DKA is known as euglycemic DKA (eu-DKA). Eu-DKA sometimes leads to delayed diagnosis and results in life-threatening complications [8,9]. Because the use of SGLT2i is expected to become increasingly widespread owing to its effectiveness, it is important to report this adverse drug reaction that can delay diagnosis.
We encountered 2 severe cases of SGLT2i-associated eu-DKA caused by delayed diagnosis in the intensive care unit (ICU). Both patients consented to the publication of this case report.
Case Reports
Case 1
A 52-year-old woman weighing 51 kg and receiving medications for type 2 diabetes mellitus (empagliflozin 10 mg daily and sitagliptin 50 mg daily), dyslipidemia (ezetimibe 10 mg daily and rosuvastatin 20 mg daily), and an old cerebral infarction (clopidogrel 75 mg daily) was diagnosed with unstable angina. She was scheduled for elective coronary artery bypass grafting surgery. Following hospital admission, the patient underwent a preoperative examination for the surgery. On days 12 and 15 of admission, she underwent tooth extraction for perioperative management. Subsequently, her oral food intake decreased because of pain. On day 22 of hospitalization, 3 days before the scheduled elective coronary artery bypass grafting surgery, she developed tachypnea, vomiting, and decreased blood pressure. She had high anion gap metabolic acidosis (pH, 6.84; HCO3– level, 2.1 mEq/L; base excess, −20.0 mmol/L; anion gap, 31.9 mmol/L; and lactate level, 2.4 mmol/L), while her blood glucose remained at normal levels (178 mg/dL). Empagliflozin was administered until the morning of that day. Although elevated cardiac troponin levels (serum troponin I, 324.5 pg/mL) were detected, no ST-segment elevation was observed on the electrocardiogram. Supportive therapy to manage metabolic acidosis was initiated. She was intubated for hypotension (systolic artery pressure, 78 mmHg; infusion with noradrenaline 0.06 μg/kg/h), severe acidemia, and tachypnea. The oral administration of empagliflozin was discontinued. Despite sodium bicarbonate infusion and continuous renal replacement therapy instituted for the life-threatening acidemia, the patient’s metabolic acidosis did not improve. On day 2 of ICU admission, based on elevated blood β-hydroxybutyrate levels (12.9 mmol/L), dextrose and insulin were administered to manage the eu-DKA. The acidosis was resolved within 24 h of treatment initiation; in addition, blood β-hydroxybutyrate levels decreased (4.3 mmol/L). On day 3 of ICU admission, she developed pulmonary edema but still required large doses of inotropes and vasopressors. As the metabolic acidosis improved, the status of her coronary arteries was evaluated. Following insertion of a percutaneous mechanical circulatory support device (Impella 2.5; Abiomed, Danvers, MA, USA) to ensure left ventricular unloading, percutaneous coronary intervention was performed. Stents were placed at 3 points, including the left anterior descending artery. Subsequently, there was a need for peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) owing to the prevailing potentially life-threatening poor oxygenation (ratio of arterial oxygen partial pressure to fractional inspired oxygen was 57.5 under 10 cmH2O positive end-expiratory pressure) and low output syndrome. VA-ECMO, continuous renal replacement therapy, Impella 2.5, and mechanical ventilation were required for 6, 6, 7, and 13 days, respectively. In addition, she had a hemorrhagic cerebral infarction on day 10 of ICU admission. She was discharged from the ICU on day 15 and transferred to a rehabilitation hospital on day 51 of admission.
Case 2
A 76-year-old woman weighing 63 kg and receiving medications for type 2 diabetes mellitus (canagliflozin 100 mg daily and metformin 500 mg daily), hypertension (cilnidipine 20 mg daily), and dyslipidemia (fenofibrate 80 mg daily) was diagnosed with duodenal cancer and scheduled for elective gastrojejunal bypass surgery. Canagliflozin was administered until the day before the surgery. After surgery, she was admitted to the ICU for postoperative management. On arrival, she had euglycemia (100 mg/dL), but with metabolic acidosis (pH, 7.25; HCO3– level, −17.3 mEq/L; base excess, −9.1; anion gap, 16.2 mmol/L; and lactate level, 0.8 mmol/L). Sodium bicarbonate infusion was initiated; however, the patient’s metabolic acidosis continued to worsen. On day 2 of ICU admission, she had cardiac sinus arrest and experienced loss of consciousness with metabolic acidosis (pH, 7.27; HCO3– level, 13.5 mEq/L; base excess, −12.1; anion gap, 23.7 mmol/L; and lactate level, 1.1 mmol/L). Elevated blood β-hydroxybutyrate (18.6 mmol/L) levels were noted, and an infusion of dextrose and insulin was initiated for the management of eu-DKA. Within 2 h of initiating eu-DKA treatment, she had another cardiac sinus arrest, lost consciousness, and continued to experience metabolic acidosis (pH, 7.30; HCO3– level, 16.0 mEq/L; base excess, −9.3; anion gap, 18.0 mmol/L; and lactate level, 1.0 mmol/L). Coronary angiography showed no myocardial ischemia, and a temporary pacemaker was intravenously inserted as an emergency intervention. On day 3 of ICU admission, the patient’s metabolic acidosis improved, her blood β-hydroxybutyrate level decreased (3.2 mmol/L), and sinus arrest resolved. The patient was discharged from the ICU on day 5. Glycosuria was also observed on day 6 (blood glucose level, 140 mg/dL) but was not observed on day 12 (blood glucose level, 163 mg/dL). The temporary pacemaker was removed on day 11, and no signs of sinus arrest were detected using a 24-h Holter monitor on day 14. She was discharged from the hospital on day 18.
Discussion
We encountered 2 cases of life-threatening complications caused by SGLT2i-associated eu-DKA. Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delay in diagnosis due to lack of evidence of hyperglycemia could have contributed to the development and deterioration of the life-threatening complications in our patients.
The underlying condition leading to eu-DKA was a caloric restriction in case 1 and surgical stress in case 2, and these conditions might have contributed to the development and worsening of life-threatening complications. Preoperative fasting, very low-calorie diets, and surgical stress are reported as precipitating factors of SGLT2i-associated DKA [10,11]. In case 1, tooth extraction resulted in poor food intake, whereas in case 2, DKA developed after surgery. Persistent glycosuria induced by SGLT2i lowers the amount of the body glucose pool [14], and in this situation, when caloric intake decreases, the blood glucose level cannot be increased, insulin secretion is suppressed, and ketone body production is induced. Surgical stress increases counter-regulatory hormones such as adrenaline and cortisol, and these hormones induce increased insulin resistance [10]. Increased insulin resistance causes impaired sugar utilization and ketogenesis. Additionally, surgical stress induces glucagon secretion [10]. Glucagon promotes lipolysis and fatty acid oxidation in the liver and increases ketogenesis [15].
In case 1, it remained unclear whether DKA or myocardial ischemia occurred first. In this patient, tooth extraction resulted in poor food intake; therefore, DKA might have developed before the myocardial ischemia. Several studies have illustrated that acute metabolic acidosis can have critical effects on the cardiovascular system [16,17]. The cardiovascular effects of acidosis include arterial vasodilatation contributing to hypotension [18], a decrease of contractility and cardiac output [19,20], sinus dysfunction [21], and a predisposition to cardiac arrhythmias associated with sudden death [22]. The patient in case 1 had severe coronary artery disease requiring coronary artery bypass grafting. Acidemia due to eu-DKA caused peripheral vasodilation, resulting in hypotension and decreased cardiac contractility due to increased left ventricular end-diastolic pressure. This potentially reduced coronary perfusion pressure and led to the myocardial infarction. Another possible association with DKA and acute coronary syndrome includes the supply-demand mismatch caused by an increased oxygen demand in the myocardium by counter-regulatory hormones, such as adrenaline, cortisol, and glucagon, released during DKA [23].
The patient in case 2 underwent major surgery, and the surgical stress resulted in SGLT2i-associated eu-DKA. A few cases of life-threatening complications due to SGLT2i-associated DKA in the postoperative period have been reported [24,25]. A postoperative gastric bypass case of SGLT2i-associated DKA requiring mechanical ventilation and hemodialysis was reported [24]. A patient that developed SGLT2i-associated DKA 2 days after laparoscopic appendectomy also developed encephalopathy and required mechanical ventilation and hemo-dialysis [25]; however, there are few reports on patients with severe complications requiring urgent pacemaker insertion for sinus arrest, as in our case 2. Sinus dysfunction and sudden death have been reported to be associated with metabolic acidosis [18,21]. Additionally, in case 2, coronary artery stenosis was not detected on coronary angiography. Once the acidemia improved, the sinus arrest resolved, with a Holter electrocardiogram reaffirming this result. Therefore, we believe that acidemia was the probable cause of the sinus arrest.
Delayed diagnosis due to lack of evidence of hyperglycemia may have contributed to the development of life-threatening complications in our patients. Although SGLT2i has become widely used in recent years, its complication, eu-DKA, appears to be under-recognized, especially by surgeons. Furthermore, eu-DKA often results in blood glucose levels below 200 mg/dL, which may delay its detection [8,9]. Even our cases were followed up with supportive therapy without an accurate diagnosis of metabolic acidosis. Therefore, SGLT2i-associated eu-DKA should be considered a probable differential diagnosis in patients with diabetes and metabolic acidosis. Furthermore, SGLT2i was not discontinued in both of our cases. Because case 1 was an emergency, ongoing medications could not be terminated, while in case 2, canagliflozin was discontinued the day before the surgery. Generally, elimination from the body takes about 5 times as long as the half-life of the drug. The average half-life time of canagliflozin is reported to be 10.2 h, and 5 times the half-time is 51 h. The U.S. Food and Drug Administration in 2020 announced the approval of a change in the prescription of SGLT2i diabetes medicines, thereby recommending them to be terminated temporarily 3 or 4 days before scheduled surgery to prevent perioperative SGLT2i-associated ketoacidosis [26]. In our case 2, glycosuria was still detected on day 6 (7 days after the last oral administration of canagliflozin). We believed that the effect of canagliflozin remained at least until that time. In SGLT2i-associated DKA, glycosuria persisted for 3 to 10 days after the discontinuation of SGLT2is [27]. In case 2, canagliflozin may have required a washout period longer than 3 days.
Conclusions
We reported 2 cases of life-threatening complications that were caused or worsened by SGLT2i-associated eu-DKA. Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delayed diagnosis due to lack of evidence of hyperglycemia may have contributed to the development and worsening of these life-threatening complications. In situations in which SGLT2i is expected to become increasingly widespread owing to its effectiveness, the number of SGLT2i-associated DKA is expected to increase. It is imperative to assess the existing medication history of patients with diabetes and consider eu-DKA as an important differential diagnosis of patients with high anion gap metabolic acidosis to ensure early intervention. Additionally, SGLT2i-associated DKA is likely to develop perioperatively; therefore, clinicians should pay attention to the discontinuation period of SGLT2i prior to any surgical intervention.
We would like to thank Editage (www.editage.com) for English language editing.
Department and Institution Where the Work Was Performed
Department of Intensive Care Medicine, Tokyo Women’s Medical University, Tokyo, Japan
Conflict of Interest
None. | CLOPIDOGREL BISULFATE, EMPAGLIFLOZIN, EZETIMIBE, ROSUVASTATIN, SITAGLIPTIN | DrugsGivenReaction | CC BY-NC-ND | 33723205 | 19,780,336 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Low cardiac output syndrome'. | Life-Threatening Complications Related to Delayed Diagnosis of Euglycemic Diabetic Ketoacidosis Associated with Sodium-Glucose Cotransporter-2 Inhibitors: A Report of 2 Cases.
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are widely used owing to their effective glycemic control and protective effects against heart and kidney failure. Euglycemic diabetic ketoacidosis (eu-DKA) is a complication of treatment with SGLT2is. Eu-DKA often leads to delayed diagnosis and results in life-threatening complications. We report 2 critical cases of SGLT2i-associated eu-DKA. CASE REPORT Case 1 was 52-year-old woman with unstable angina scheduled for elective coronary artery bypass grafting surgery. Preoperatively, she underwent tooth extraction which led to poor food intake because of pain. Three days before surgery, the patient had SGLT2i-associated eu-DKA and myocardial infraction, requiring percutaneous coronary intervention and peripheral venoarterial extracorporeal membrane oxygenation. The patient had taken SGLT2i until the morning of admission to the intensive care unit. Case 2 was a 76-year-old woman experiencing SGLT2i-associated eu-DKA and sinus arrest, necessitating a temporary pacemaker, followed by elective gastrojejunal bypass surgery. The SGLT2i was discontinued the day before surgery. On day 3 following surgery, the patient's metabolic acidosis improved, and sinus arrest resolved. CONCLUSIONS Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delay in diagnosis because of a lack of evidence of hyperglycemia could contribute to the development and worsening of life-threatening complications. This reiterates the importance of reviewing ongoing medications of patients with diabetes and considering eu-DKA as a differential diagnosis for patients with high anion gap metabolic acidosis to ensure early intervention. SGLT2i-associated DKA likely develops perioperatively; therefore, clinicians should pay attention to the discontinuation period of SGLT2i before any surgical intervention.
Background
Sodium-glucose cotransporter-transporter-2 inhibitors (SGLT2is) are used widely owing to their protective effects against heart and kidney failure and effective glycemic control [1–6]. SGLT2is decrease glycated hemoglobin, body weight, and blood pressure [1,2]. Recent randomized control trials have demonstrated that SGLT2is reduce the risk of heart failure, cardiovascular death, and serious renal outcomes in patients with or without diabetes [4–6]. However, diabetic ketoacidosis (DKA) has been reported as a complication of SGLT2is [7,8]. It was reported that, compared with dipeptidyl peptidase-4 inhibitors, SGLT2is have a higher risk of DKA (hazard ratio, 2.85) [7]. Caloric restriction, surgical stress, acute illness, risk of dehydration, and medication changes have been reported as precipitating factors of SGLT2i-associated DKA, and nausea and vomiting have been reported as its clinical presentation [9–11]. The incidence of SGLT2i-associated DKA perioperatively has been reported to be as high as 19% to 28% [12,13]. In a review of 47 cases of perioperative SGLT2i-associated DKA, 4 cases of severe acidemia or metabolic acidosis were reported (pH <7.0 in 2 cases; bicarbonate [HCO3–] level <5 mEq/L in 2 cases) [10]. Unlike with typical DKA, some patients have a normal blood glucose level. This type of DKA is known as euglycemic DKA (eu-DKA). Eu-DKA sometimes leads to delayed diagnosis and results in life-threatening complications [8,9]. Because the use of SGLT2i is expected to become increasingly widespread owing to its effectiveness, it is important to report this adverse drug reaction that can delay diagnosis.
We encountered 2 severe cases of SGLT2i-associated eu-DKA caused by delayed diagnosis in the intensive care unit (ICU). Both patients consented to the publication of this case report.
Case Reports
Case 1
A 52-year-old woman weighing 51 kg and receiving medications for type 2 diabetes mellitus (empagliflozin 10 mg daily and sitagliptin 50 mg daily), dyslipidemia (ezetimibe 10 mg daily and rosuvastatin 20 mg daily), and an old cerebral infarction (clopidogrel 75 mg daily) was diagnosed with unstable angina. She was scheduled for elective coronary artery bypass grafting surgery. Following hospital admission, the patient underwent a preoperative examination for the surgery. On days 12 and 15 of admission, she underwent tooth extraction for perioperative management. Subsequently, her oral food intake decreased because of pain. On day 22 of hospitalization, 3 days before the scheduled elective coronary artery bypass grafting surgery, she developed tachypnea, vomiting, and decreased blood pressure. She had high anion gap metabolic acidosis (pH, 6.84; HCO3– level, 2.1 mEq/L; base excess, −20.0 mmol/L; anion gap, 31.9 mmol/L; and lactate level, 2.4 mmol/L), while her blood glucose remained at normal levels (178 mg/dL). Empagliflozin was administered until the morning of that day. Although elevated cardiac troponin levels (serum troponin I, 324.5 pg/mL) were detected, no ST-segment elevation was observed on the electrocardiogram. Supportive therapy to manage metabolic acidosis was initiated. She was intubated for hypotension (systolic artery pressure, 78 mmHg; infusion with noradrenaline 0.06 μg/kg/h), severe acidemia, and tachypnea. The oral administration of empagliflozin was discontinued. Despite sodium bicarbonate infusion and continuous renal replacement therapy instituted for the life-threatening acidemia, the patient’s metabolic acidosis did not improve. On day 2 of ICU admission, based on elevated blood β-hydroxybutyrate levels (12.9 mmol/L), dextrose and insulin were administered to manage the eu-DKA. The acidosis was resolved within 24 h of treatment initiation; in addition, blood β-hydroxybutyrate levels decreased (4.3 mmol/L). On day 3 of ICU admission, she developed pulmonary edema but still required large doses of inotropes and vasopressors. As the metabolic acidosis improved, the status of her coronary arteries was evaluated. Following insertion of a percutaneous mechanical circulatory support device (Impella 2.5; Abiomed, Danvers, MA, USA) to ensure left ventricular unloading, percutaneous coronary intervention was performed. Stents were placed at 3 points, including the left anterior descending artery. Subsequently, there was a need for peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) owing to the prevailing potentially life-threatening poor oxygenation (ratio of arterial oxygen partial pressure to fractional inspired oxygen was 57.5 under 10 cmH2O positive end-expiratory pressure) and low output syndrome. VA-ECMO, continuous renal replacement therapy, Impella 2.5, and mechanical ventilation were required for 6, 6, 7, and 13 days, respectively. In addition, she had a hemorrhagic cerebral infarction on day 10 of ICU admission. She was discharged from the ICU on day 15 and transferred to a rehabilitation hospital on day 51 of admission.
Case 2
A 76-year-old woman weighing 63 kg and receiving medications for type 2 diabetes mellitus (canagliflozin 100 mg daily and metformin 500 mg daily), hypertension (cilnidipine 20 mg daily), and dyslipidemia (fenofibrate 80 mg daily) was diagnosed with duodenal cancer and scheduled for elective gastrojejunal bypass surgery. Canagliflozin was administered until the day before the surgery. After surgery, she was admitted to the ICU for postoperative management. On arrival, she had euglycemia (100 mg/dL), but with metabolic acidosis (pH, 7.25; HCO3– level, −17.3 mEq/L; base excess, −9.1; anion gap, 16.2 mmol/L; and lactate level, 0.8 mmol/L). Sodium bicarbonate infusion was initiated; however, the patient’s metabolic acidosis continued to worsen. On day 2 of ICU admission, she had cardiac sinus arrest and experienced loss of consciousness with metabolic acidosis (pH, 7.27; HCO3– level, 13.5 mEq/L; base excess, −12.1; anion gap, 23.7 mmol/L; and lactate level, 1.1 mmol/L). Elevated blood β-hydroxybutyrate (18.6 mmol/L) levels were noted, and an infusion of dextrose and insulin was initiated for the management of eu-DKA. Within 2 h of initiating eu-DKA treatment, she had another cardiac sinus arrest, lost consciousness, and continued to experience metabolic acidosis (pH, 7.30; HCO3– level, 16.0 mEq/L; base excess, −9.3; anion gap, 18.0 mmol/L; and lactate level, 1.0 mmol/L). Coronary angiography showed no myocardial ischemia, and a temporary pacemaker was intravenously inserted as an emergency intervention. On day 3 of ICU admission, the patient’s metabolic acidosis improved, her blood β-hydroxybutyrate level decreased (3.2 mmol/L), and sinus arrest resolved. The patient was discharged from the ICU on day 5. Glycosuria was also observed on day 6 (blood glucose level, 140 mg/dL) but was not observed on day 12 (blood glucose level, 163 mg/dL). The temporary pacemaker was removed on day 11, and no signs of sinus arrest were detected using a 24-h Holter monitor on day 14. She was discharged from the hospital on day 18.
Discussion
We encountered 2 cases of life-threatening complications caused by SGLT2i-associated eu-DKA. Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delay in diagnosis due to lack of evidence of hyperglycemia could have contributed to the development and deterioration of the life-threatening complications in our patients.
The underlying condition leading to eu-DKA was a caloric restriction in case 1 and surgical stress in case 2, and these conditions might have contributed to the development and worsening of life-threatening complications. Preoperative fasting, very low-calorie diets, and surgical stress are reported as precipitating factors of SGLT2i-associated DKA [10,11]. In case 1, tooth extraction resulted in poor food intake, whereas in case 2, DKA developed after surgery. Persistent glycosuria induced by SGLT2i lowers the amount of the body glucose pool [14], and in this situation, when caloric intake decreases, the blood glucose level cannot be increased, insulin secretion is suppressed, and ketone body production is induced. Surgical stress increases counter-regulatory hormones such as adrenaline and cortisol, and these hormones induce increased insulin resistance [10]. Increased insulin resistance causes impaired sugar utilization and ketogenesis. Additionally, surgical stress induces glucagon secretion [10]. Glucagon promotes lipolysis and fatty acid oxidation in the liver and increases ketogenesis [15].
In case 1, it remained unclear whether DKA or myocardial ischemia occurred first. In this patient, tooth extraction resulted in poor food intake; therefore, DKA might have developed before the myocardial ischemia. Several studies have illustrated that acute metabolic acidosis can have critical effects on the cardiovascular system [16,17]. The cardiovascular effects of acidosis include arterial vasodilatation contributing to hypotension [18], a decrease of contractility and cardiac output [19,20], sinus dysfunction [21], and a predisposition to cardiac arrhythmias associated with sudden death [22]. The patient in case 1 had severe coronary artery disease requiring coronary artery bypass grafting. Acidemia due to eu-DKA caused peripheral vasodilation, resulting in hypotension and decreased cardiac contractility due to increased left ventricular end-diastolic pressure. This potentially reduced coronary perfusion pressure and led to the myocardial infarction. Another possible association with DKA and acute coronary syndrome includes the supply-demand mismatch caused by an increased oxygen demand in the myocardium by counter-regulatory hormones, such as adrenaline, cortisol, and glucagon, released during DKA [23].
The patient in case 2 underwent major surgery, and the surgical stress resulted in SGLT2i-associated eu-DKA. A few cases of life-threatening complications due to SGLT2i-associated DKA in the postoperative period have been reported [24,25]. A postoperative gastric bypass case of SGLT2i-associated DKA requiring mechanical ventilation and hemodialysis was reported [24]. A patient that developed SGLT2i-associated DKA 2 days after laparoscopic appendectomy also developed encephalopathy and required mechanical ventilation and hemo-dialysis [25]; however, there are few reports on patients with severe complications requiring urgent pacemaker insertion for sinus arrest, as in our case 2. Sinus dysfunction and sudden death have been reported to be associated with metabolic acidosis [18,21]. Additionally, in case 2, coronary artery stenosis was not detected on coronary angiography. Once the acidemia improved, the sinus arrest resolved, with a Holter electrocardiogram reaffirming this result. Therefore, we believe that acidemia was the probable cause of the sinus arrest.
Delayed diagnosis due to lack of evidence of hyperglycemia may have contributed to the development of life-threatening complications in our patients. Although SGLT2i has become widely used in recent years, its complication, eu-DKA, appears to be under-recognized, especially by surgeons. Furthermore, eu-DKA often results in blood glucose levels below 200 mg/dL, which may delay its detection [8,9]. Even our cases were followed up with supportive therapy without an accurate diagnosis of metabolic acidosis. Therefore, SGLT2i-associated eu-DKA should be considered a probable differential diagnosis in patients with diabetes and metabolic acidosis. Furthermore, SGLT2i was not discontinued in both of our cases. Because case 1 was an emergency, ongoing medications could not be terminated, while in case 2, canagliflozin was discontinued the day before the surgery. Generally, elimination from the body takes about 5 times as long as the half-life of the drug. The average half-life time of canagliflozin is reported to be 10.2 h, and 5 times the half-time is 51 h. The U.S. Food and Drug Administration in 2020 announced the approval of a change in the prescription of SGLT2i diabetes medicines, thereby recommending them to be terminated temporarily 3 or 4 days before scheduled surgery to prevent perioperative SGLT2i-associated ketoacidosis [26]. In our case 2, glycosuria was still detected on day 6 (7 days after the last oral administration of canagliflozin). We believed that the effect of canagliflozin remained at least until that time. In SGLT2i-associated DKA, glycosuria persisted for 3 to 10 days after the discontinuation of SGLT2is [27]. In case 2, canagliflozin may have required a washout period longer than 3 days.
Conclusions
We reported 2 cases of life-threatening complications that were caused or worsened by SGLT2i-associated eu-DKA. Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delayed diagnosis due to lack of evidence of hyperglycemia may have contributed to the development and worsening of these life-threatening complications. In situations in which SGLT2i is expected to become increasingly widespread owing to its effectiveness, the number of SGLT2i-associated DKA is expected to increase. It is imperative to assess the existing medication history of patients with diabetes and consider eu-DKA as an important differential diagnosis of patients with high anion gap metabolic acidosis to ensure early intervention. Additionally, SGLT2i-associated DKA is likely to develop perioperatively; therefore, clinicians should pay attention to the discontinuation period of SGLT2i prior to any surgical intervention.
We would like to thank Editage (www.editage.com) for English language editing.
Department and Institution Where the Work Was Performed
Department of Intensive Care Medicine, Tokyo Women’s Medical University, Tokyo, Japan
Conflict of Interest
None. | CLOPIDOGREL BISULFATE, EMPAGLIFLOZIN, EZETIMIBE, ROSUVASTATIN, SITAGLIPTIN | DrugsGivenReaction | CC BY-NC-ND | 33723205 | 19,780,336 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary oedema'. | Life-Threatening Complications Related to Delayed Diagnosis of Euglycemic Diabetic Ketoacidosis Associated with Sodium-Glucose Cotransporter-2 Inhibitors: A Report of 2 Cases.
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are widely used owing to their effective glycemic control and protective effects against heart and kidney failure. Euglycemic diabetic ketoacidosis (eu-DKA) is a complication of treatment with SGLT2is. Eu-DKA often leads to delayed diagnosis and results in life-threatening complications. We report 2 critical cases of SGLT2i-associated eu-DKA. CASE REPORT Case 1 was 52-year-old woman with unstable angina scheduled for elective coronary artery bypass grafting surgery. Preoperatively, she underwent tooth extraction which led to poor food intake because of pain. Three days before surgery, the patient had SGLT2i-associated eu-DKA and myocardial infraction, requiring percutaneous coronary intervention and peripheral venoarterial extracorporeal membrane oxygenation. The patient had taken SGLT2i until the morning of admission to the intensive care unit. Case 2 was a 76-year-old woman experiencing SGLT2i-associated eu-DKA and sinus arrest, necessitating a temporary pacemaker, followed by elective gastrojejunal bypass surgery. The SGLT2i was discontinued the day before surgery. On day 3 following surgery, the patient's metabolic acidosis improved, and sinus arrest resolved. CONCLUSIONS Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delay in diagnosis because of a lack of evidence of hyperglycemia could contribute to the development and worsening of life-threatening complications. This reiterates the importance of reviewing ongoing medications of patients with diabetes and considering eu-DKA as a differential diagnosis for patients with high anion gap metabolic acidosis to ensure early intervention. SGLT2i-associated DKA likely develops perioperatively; therefore, clinicians should pay attention to the discontinuation period of SGLT2i before any surgical intervention.
Background
Sodium-glucose cotransporter-transporter-2 inhibitors (SGLT2is) are used widely owing to their protective effects against heart and kidney failure and effective glycemic control [1–6]. SGLT2is decrease glycated hemoglobin, body weight, and blood pressure [1,2]. Recent randomized control trials have demonstrated that SGLT2is reduce the risk of heart failure, cardiovascular death, and serious renal outcomes in patients with or without diabetes [4–6]. However, diabetic ketoacidosis (DKA) has been reported as a complication of SGLT2is [7,8]. It was reported that, compared with dipeptidyl peptidase-4 inhibitors, SGLT2is have a higher risk of DKA (hazard ratio, 2.85) [7]. Caloric restriction, surgical stress, acute illness, risk of dehydration, and medication changes have been reported as precipitating factors of SGLT2i-associated DKA, and nausea and vomiting have been reported as its clinical presentation [9–11]. The incidence of SGLT2i-associated DKA perioperatively has been reported to be as high as 19% to 28% [12,13]. In a review of 47 cases of perioperative SGLT2i-associated DKA, 4 cases of severe acidemia or metabolic acidosis were reported (pH <7.0 in 2 cases; bicarbonate [HCO3–] level <5 mEq/L in 2 cases) [10]. Unlike with typical DKA, some patients have a normal blood glucose level. This type of DKA is known as euglycemic DKA (eu-DKA). Eu-DKA sometimes leads to delayed diagnosis and results in life-threatening complications [8,9]. Because the use of SGLT2i is expected to become increasingly widespread owing to its effectiveness, it is important to report this adverse drug reaction that can delay diagnosis.
We encountered 2 severe cases of SGLT2i-associated eu-DKA caused by delayed diagnosis in the intensive care unit (ICU). Both patients consented to the publication of this case report.
Case Reports
Case 1
A 52-year-old woman weighing 51 kg and receiving medications for type 2 diabetes mellitus (empagliflozin 10 mg daily and sitagliptin 50 mg daily), dyslipidemia (ezetimibe 10 mg daily and rosuvastatin 20 mg daily), and an old cerebral infarction (clopidogrel 75 mg daily) was diagnosed with unstable angina. She was scheduled for elective coronary artery bypass grafting surgery. Following hospital admission, the patient underwent a preoperative examination for the surgery. On days 12 and 15 of admission, she underwent tooth extraction for perioperative management. Subsequently, her oral food intake decreased because of pain. On day 22 of hospitalization, 3 days before the scheduled elective coronary artery bypass grafting surgery, she developed tachypnea, vomiting, and decreased blood pressure. She had high anion gap metabolic acidosis (pH, 6.84; HCO3– level, 2.1 mEq/L; base excess, −20.0 mmol/L; anion gap, 31.9 mmol/L; and lactate level, 2.4 mmol/L), while her blood glucose remained at normal levels (178 mg/dL). Empagliflozin was administered until the morning of that day. Although elevated cardiac troponin levels (serum troponin I, 324.5 pg/mL) were detected, no ST-segment elevation was observed on the electrocardiogram. Supportive therapy to manage metabolic acidosis was initiated. She was intubated for hypotension (systolic artery pressure, 78 mmHg; infusion with noradrenaline 0.06 μg/kg/h), severe acidemia, and tachypnea. The oral administration of empagliflozin was discontinued. Despite sodium bicarbonate infusion and continuous renal replacement therapy instituted for the life-threatening acidemia, the patient’s metabolic acidosis did not improve. On day 2 of ICU admission, based on elevated blood β-hydroxybutyrate levels (12.9 mmol/L), dextrose and insulin were administered to manage the eu-DKA. The acidosis was resolved within 24 h of treatment initiation; in addition, blood β-hydroxybutyrate levels decreased (4.3 mmol/L). On day 3 of ICU admission, she developed pulmonary edema but still required large doses of inotropes and vasopressors. As the metabolic acidosis improved, the status of her coronary arteries was evaluated. Following insertion of a percutaneous mechanical circulatory support device (Impella 2.5; Abiomed, Danvers, MA, USA) to ensure left ventricular unloading, percutaneous coronary intervention was performed. Stents were placed at 3 points, including the left anterior descending artery. Subsequently, there was a need for peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) owing to the prevailing potentially life-threatening poor oxygenation (ratio of arterial oxygen partial pressure to fractional inspired oxygen was 57.5 under 10 cmH2O positive end-expiratory pressure) and low output syndrome. VA-ECMO, continuous renal replacement therapy, Impella 2.5, and mechanical ventilation were required for 6, 6, 7, and 13 days, respectively. In addition, she had a hemorrhagic cerebral infarction on day 10 of ICU admission. She was discharged from the ICU on day 15 and transferred to a rehabilitation hospital on day 51 of admission.
Case 2
A 76-year-old woman weighing 63 kg and receiving medications for type 2 diabetes mellitus (canagliflozin 100 mg daily and metformin 500 mg daily), hypertension (cilnidipine 20 mg daily), and dyslipidemia (fenofibrate 80 mg daily) was diagnosed with duodenal cancer and scheduled for elective gastrojejunal bypass surgery. Canagliflozin was administered until the day before the surgery. After surgery, she was admitted to the ICU for postoperative management. On arrival, she had euglycemia (100 mg/dL), but with metabolic acidosis (pH, 7.25; HCO3– level, −17.3 mEq/L; base excess, −9.1; anion gap, 16.2 mmol/L; and lactate level, 0.8 mmol/L). Sodium bicarbonate infusion was initiated; however, the patient’s metabolic acidosis continued to worsen. On day 2 of ICU admission, she had cardiac sinus arrest and experienced loss of consciousness with metabolic acidosis (pH, 7.27; HCO3– level, 13.5 mEq/L; base excess, −12.1; anion gap, 23.7 mmol/L; and lactate level, 1.1 mmol/L). Elevated blood β-hydroxybutyrate (18.6 mmol/L) levels were noted, and an infusion of dextrose and insulin was initiated for the management of eu-DKA. Within 2 h of initiating eu-DKA treatment, she had another cardiac sinus arrest, lost consciousness, and continued to experience metabolic acidosis (pH, 7.30; HCO3– level, 16.0 mEq/L; base excess, −9.3; anion gap, 18.0 mmol/L; and lactate level, 1.0 mmol/L). Coronary angiography showed no myocardial ischemia, and a temporary pacemaker was intravenously inserted as an emergency intervention. On day 3 of ICU admission, the patient’s metabolic acidosis improved, her blood β-hydroxybutyrate level decreased (3.2 mmol/L), and sinus arrest resolved. The patient was discharged from the ICU on day 5. Glycosuria was also observed on day 6 (blood glucose level, 140 mg/dL) but was not observed on day 12 (blood glucose level, 163 mg/dL). The temporary pacemaker was removed on day 11, and no signs of sinus arrest were detected using a 24-h Holter monitor on day 14. She was discharged from the hospital on day 18.
Discussion
We encountered 2 cases of life-threatening complications caused by SGLT2i-associated eu-DKA. Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delay in diagnosis due to lack of evidence of hyperglycemia could have contributed to the development and deterioration of the life-threatening complications in our patients.
The underlying condition leading to eu-DKA was a caloric restriction in case 1 and surgical stress in case 2, and these conditions might have contributed to the development and worsening of life-threatening complications. Preoperative fasting, very low-calorie diets, and surgical stress are reported as precipitating factors of SGLT2i-associated DKA [10,11]. In case 1, tooth extraction resulted in poor food intake, whereas in case 2, DKA developed after surgery. Persistent glycosuria induced by SGLT2i lowers the amount of the body glucose pool [14], and in this situation, when caloric intake decreases, the blood glucose level cannot be increased, insulin secretion is suppressed, and ketone body production is induced. Surgical stress increases counter-regulatory hormones such as adrenaline and cortisol, and these hormones induce increased insulin resistance [10]. Increased insulin resistance causes impaired sugar utilization and ketogenesis. Additionally, surgical stress induces glucagon secretion [10]. Glucagon promotes lipolysis and fatty acid oxidation in the liver and increases ketogenesis [15].
In case 1, it remained unclear whether DKA or myocardial ischemia occurred first. In this patient, tooth extraction resulted in poor food intake; therefore, DKA might have developed before the myocardial ischemia. Several studies have illustrated that acute metabolic acidosis can have critical effects on the cardiovascular system [16,17]. The cardiovascular effects of acidosis include arterial vasodilatation contributing to hypotension [18], a decrease of contractility and cardiac output [19,20], sinus dysfunction [21], and a predisposition to cardiac arrhythmias associated with sudden death [22]. The patient in case 1 had severe coronary artery disease requiring coronary artery bypass grafting. Acidemia due to eu-DKA caused peripheral vasodilation, resulting in hypotension and decreased cardiac contractility due to increased left ventricular end-diastolic pressure. This potentially reduced coronary perfusion pressure and led to the myocardial infarction. Another possible association with DKA and acute coronary syndrome includes the supply-demand mismatch caused by an increased oxygen demand in the myocardium by counter-regulatory hormones, such as adrenaline, cortisol, and glucagon, released during DKA [23].
The patient in case 2 underwent major surgery, and the surgical stress resulted in SGLT2i-associated eu-DKA. A few cases of life-threatening complications due to SGLT2i-associated DKA in the postoperative period have been reported [24,25]. A postoperative gastric bypass case of SGLT2i-associated DKA requiring mechanical ventilation and hemodialysis was reported [24]. A patient that developed SGLT2i-associated DKA 2 days after laparoscopic appendectomy also developed encephalopathy and required mechanical ventilation and hemo-dialysis [25]; however, there are few reports on patients with severe complications requiring urgent pacemaker insertion for sinus arrest, as in our case 2. Sinus dysfunction and sudden death have been reported to be associated with metabolic acidosis [18,21]. Additionally, in case 2, coronary artery stenosis was not detected on coronary angiography. Once the acidemia improved, the sinus arrest resolved, with a Holter electrocardiogram reaffirming this result. Therefore, we believe that acidemia was the probable cause of the sinus arrest.
Delayed diagnosis due to lack of evidence of hyperglycemia may have contributed to the development of life-threatening complications in our patients. Although SGLT2i has become widely used in recent years, its complication, eu-DKA, appears to be under-recognized, especially by surgeons. Furthermore, eu-DKA often results in blood glucose levels below 200 mg/dL, which may delay its detection [8,9]. Even our cases were followed up with supportive therapy without an accurate diagnosis of metabolic acidosis. Therefore, SGLT2i-associated eu-DKA should be considered a probable differential diagnosis in patients with diabetes and metabolic acidosis. Furthermore, SGLT2i was not discontinued in both of our cases. Because case 1 was an emergency, ongoing medications could not be terminated, while in case 2, canagliflozin was discontinued the day before the surgery. Generally, elimination from the body takes about 5 times as long as the half-life of the drug. The average half-life time of canagliflozin is reported to be 10.2 h, and 5 times the half-time is 51 h. The U.S. Food and Drug Administration in 2020 announced the approval of a change in the prescription of SGLT2i diabetes medicines, thereby recommending them to be terminated temporarily 3 or 4 days before scheduled surgery to prevent perioperative SGLT2i-associated ketoacidosis [26]. In our case 2, glycosuria was still detected on day 6 (7 days after the last oral administration of canagliflozin). We believed that the effect of canagliflozin remained at least until that time. In SGLT2i-associated DKA, glycosuria persisted for 3 to 10 days after the discontinuation of SGLT2is [27]. In case 2, canagliflozin may have required a washout period longer than 3 days.
Conclusions
We reported 2 cases of life-threatening complications that were caused or worsened by SGLT2i-associated eu-DKA. Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delayed diagnosis due to lack of evidence of hyperglycemia may have contributed to the development and worsening of these life-threatening complications. In situations in which SGLT2i is expected to become increasingly widespread owing to its effectiveness, the number of SGLT2i-associated DKA is expected to increase. It is imperative to assess the existing medication history of patients with diabetes and consider eu-DKA as an important differential diagnosis of patients with high anion gap metabolic acidosis to ensure early intervention. Additionally, SGLT2i-associated DKA is likely to develop perioperatively; therefore, clinicians should pay attention to the discontinuation period of SGLT2i prior to any surgical intervention.
We would like to thank Editage (www.editage.com) for English language editing.
Department and Institution Where the Work Was Performed
Department of Intensive Care Medicine, Tokyo Women’s Medical University, Tokyo, Japan
Conflict of Interest
None. | CLOPIDOGREL BISULFATE, EMPAGLIFLOZIN, EZETIMIBE, ROSUVASTATIN, SITAGLIPTIN | DrugsGivenReaction | CC BY-NC-ND | 33723205 | 19,780,336 | 2021-03-16 |
What is the weight of the patient? | Life-Threatening Complications Related to Delayed Diagnosis of Euglycemic Diabetic Ketoacidosis Associated with Sodium-Glucose Cotransporter-2 Inhibitors: A Report of 2 Cases.
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are widely used owing to their effective glycemic control and protective effects against heart and kidney failure. Euglycemic diabetic ketoacidosis (eu-DKA) is a complication of treatment with SGLT2is. Eu-DKA often leads to delayed diagnosis and results in life-threatening complications. We report 2 critical cases of SGLT2i-associated eu-DKA. CASE REPORT Case 1 was 52-year-old woman with unstable angina scheduled for elective coronary artery bypass grafting surgery. Preoperatively, she underwent tooth extraction which led to poor food intake because of pain. Three days before surgery, the patient had SGLT2i-associated eu-DKA and myocardial infraction, requiring percutaneous coronary intervention and peripheral venoarterial extracorporeal membrane oxygenation. The patient had taken SGLT2i until the morning of admission to the intensive care unit. Case 2 was a 76-year-old woman experiencing SGLT2i-associated eu-DKA and sinus arrest, necessitating a temporary pacemaker, followed by elective gastrojejunal bypass surgery. The SGLT2i was discontinued the day before surgery. On day 3 following surgery, the patient's metabolic acidosis improved, and sinus arrest resolved. CONCLUSIONS Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delay in diagnosis because of a lack of evidence of hyperglycemia could contribute to the development and worsening of life-threatening complications. This reiterates the importance of reviewing ongoing medications of patients with diabetes and considering eu-DKA as a differential diagnosis for patients with high anion gap metabolic acidosis to ensure early intervention. SGLT2i-associated DKA likely develops perioperatively; therefore, clinicians should pay attention to the discontinuation period of SGLT2i before any surgical intervention.
Background
Sodium-glucose cotransporter-transporter-2 inhibitors (SGLT2is) are used widely owing to their protective effects against heart and kidney failure and effective glycemic control [1–6]. SGLT2is decrease glycated hemoglobin, body weight, and blood pressure [1,2]. Recent randomized control trials have demonstrated that SGLT2is reduce the risk of heart failure, cardiovascular death, and serious renal outcomes in patients with or without diabetes [4–6]. However, diabetic ketoacidosis (DKA) has been reported as a complication of SGLT2is [7,8]. It was reported that, compared with dipeptidyl peptidase-4 inhibitors, SGLT2is have a higher risk of DKA (hazard ratio, 2.85) [7]. Caloric restriction, surgical stress, acute illness, risk of dehydration, and medication changes have been reported as precipitating factors of SGLT2i-associated DKA, and nausea and vomiting have been reported as its clinical presentation [9–11]. The incidence of SGLT2i-associated DKA perioperatively has been reported to be as high as 19% to 28% [12,13]. In a review of 47 cases of perioperative SGLT2i-associated DKA, 4 cases of severe acidemia or metabolic acidosis were reported (pH <7.0 in 2 cases; bicarbonate [HCO3–] level <5 mEq/L in 2 cases) [10]. Unlike with typical DKA, some patients have a normal blood glucose level. This type of DKA is known as euglycemic DKA (eu-DKA). Eu-DKA sometimes leads to delayed diagnosis and results in life-threatening complications [8,9]. Because the use of SGLT2i is expected to become increasingly widespread owing to its effectiveness, it is important to report this adverse drug reaction that can delay diagnosis.
We encountered 2 severe cases of SGLT2i-associated eu-DKA caused by delayed diagnosis in the intensive care unit (ICU). Both patients consented to the publication of this case report.
Case Reports
Case 1
A 52-year-old woman weighing 51 kg and receiving medications for type 2 diabetes mellitus (empagliflozin 10 mg daily and sitagliptin 50 mg daily), dyslipidemia (ezetimibe 10 mg daily and rosuvastatin 20 mg daily), and an old cerebral infarction (clopidogrel 75 mg daily) was diagnosed with unstable angina. She was scheduled for elective coronary artery bypass grafting surgery. Following hospital admission, the patient underwent a preoperative examination for the surgery. On days 12 and 15 of admission, she underwent tooth extraction for perioperative management. Subsequently, her oral food intake decreased because of pain. On day 22 of hospitalization, 3 days before the scheduled elective coronary artery bypass grafting surgery, she developed tachypnea, vomiting, and decreased blood pressure. She had high anion gap metabolic acidosis (pH, 6.84; HCO3– level, 2.1 mEq/L; base excess, −20.0 mmol/L; anion gap, 31.9 mmol/L; and lactate level, 2.4 mmol/L), while her blood glucose remained at normal levels (178 mg/dL). Empagliflozin was administered until the morning of that day. Although elevated cardiac troponin levels (serum troponin I, 324.5 pg/mL) were detected, no ST-segment elevation was observed on the electrocardiogram. Supportive therapy to manage metabolic acidosis was initiated. She was intubated for hypotension (systolic artery pressure, 78 mmHg; infusion with noradrenaline 0.06 μg/kg/h), severe acidemia, and tachypnea. The oral administration of empagliflozin was discontinued. Despite sodium bicarbonate infusion and continuous renal replacement therapy instituted for the life-threatening acidemia, the patient’s metabolic acidosis did not improve. On day 2 of ICU admission, based on elevated blood β-hydroxybutyrate levels (12.9 mmol/L), dextrose and insulin were administered to manage the eu-DKA. The acidosis was resolved within 24 h of treatment initiation; in addition, blood β-hydroxybutyrate levels decreased (4.3 mmol/L). On day 3 of ICU admission, she developed pulmonary edema but still required large doses of inotropes and vasopressors. As the metabolic acidosis improved, the status of her coronary arteries was evaluated. Following insertion of a percutaneous mechanical circulatory support device (Impella 2.5; Abiomed, Danvers, MA, USA) to ensure left ventricular unloading, percutaneous coronary intervention was performed. Stents were placed at 3 points, including the left anterior descending artery. Subsequently, there was a need for peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) owing to the prevailing potentially life-threatening poor oxygenation (ratio of arterial oxygen partial pressure to fractional inspired oxygen was 57.5 under 10 cmH2O positive end-expiratory pressure) and low output syndrome. VA-ECMO, continuous renal replacement therapy, Impella 2.5, and mechanical ventilation were required for 6, 6, 7, and 13 days, respectively. In addition, she had a hemorrhagic cerebral infarction on day 10 of ICU admission. She was discharged from the ICU on day 15 and transferred to a rehabilitation hospital on day 51 of admission.
Case 2
A 76-year-old woman weighing 63 kg and receiving medications for type 2 diabetes mellitus (canagliflozin 100 mg daily and metformin 500 mg daily), hypertension (cilnidipine 20 mg daily), and dyslipidemia (fenofibrate 80 mg daily) was diagnosed with duodenal cancer and scheduled for elective gastrojejunal bypass surgery. Canagliflozin was administered until the day before the surgery. After surgery, she was admitted to the ICU for postoperative management. On arrival, she had euglycemia (100 mg/dL), but with metabolic acidosis (pH, 7.25; HCO3– level, −17.3 mEq/L; base excess, −9.1; anion gap, 16.2 mmol/L; and lactate level, 0.8 mmol/L). Sodium bicarbonate infusion was initiated; however, the patient’s metabolic acidosis continued to worsen. On day 2 of ICU admission, she had cardiac sinus arrest and experienced loss of consciousness with metabolic acidosis (pH, 7.27; HCO3– level, 13.5 mEq/L; base excess, −12.1; anion gap, 23.7 mmol/L; and lactate level, 1.1 mmol/L). Elevated blood β-hydroxybutyrate (18.6 mmol/L) levels were noted, and an infusion of dextrose and insulin was initiated for the management of eu-DKA. Within 2 h of initiating eu-DKA treatment, she had another cardiac sinus arrest, lost consciousness, and continued to experience metabolic acidosis (pH, 7.30; HCO3– level, 16.0 mEq/L; base excess, −9.3; anion gap, 18.0 mmol/L; and lactate level, 1.0 mmol/L). Coronary angiography showed no myocardial ischemia, and a temporary pacemaker was intravenously inserted as an emergency intervention. On day 3 of ICU admission, the patient’s metabolic acidosis improved, her blood β-hydroxybutyrate level decreased (3.2 mmol/L), and sinus arrest resolved. The patient was discharged from the ICU on day 5. Glycosuria was also observed on day 6 (blood glucose level, 140 mg/dL) but was not observed on day 12 (blood glucose level, 163 mg/dL). The temporary pacemaker was removed on day 11, and no signs of sinus arrest were detected using a 24-h Holter monitor on day 14. She was discharged from the hospital on day 18.
Discussion
We encountered 2 cases of life-threatening complications caused by SGLT2i-associated eu-DKA. Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delay in diagnosis due to lack of evidence of hyperglycemia could have contributed to the development and deterioration of the life-threatening complications in our patients.
The underlying condition leading to eu-DKA was a caloric restriction in case 1 and surgical stress in case 2, and these conditions might have contributed to the development and worsening of life-threatening complications. Preoperative fasting, very low-calorie diets, and surgical stress are reported as precipitating factors of SGLT2i-associated DKA [10,11]. In case 1, tooth extraction resulted in poor food intake, whereas in case 2, DKA developed after surgery. Persistent glycosuria induced by SGLT2i lowers the amount of the body glucose pool [14], and in this situation, when caloric intake decreases, the blood glucose level cannot be increased, insulin secretion is suppressed, and ketone body production is induced. Surgical stress increases counter-regulatory hormones such as adrenaline and cortisol, and these hormones induce increased insulin resistance [10]. Increased insulin resistance causes impaired sugar utilization and ketogenesis. Additionally, surgical stress induces glucagon secretion [10]. Glucagon promotes lipolysis and fatty acid oxidation in the liver and increases ketogenesis [15].
In case 1, it remained unclear whether DKA or myocardial ischemia occurred first. In this patient, tooth extraction resulted in poor food intake; therefore, DKA might have developed before the myocardial ischemia. Several studies have illustrated that acute metabolic acidosis can have critical effects on the cardiovascular system [16,17]. The cardiovascular effects of acidosis include arterial vasodilatation contributing to hypotension [18], a decrease of contractility and cardiac output [19,20], sinus dysfunction [21], and a predisposition to cardiac arrhythmias associated with sudden death [22]. The patient in case 1 had severe coronary artery disease requiring coronary artery bypass grafting. Acidemia due to eu-DKA caused peripheral vasodilation, resulting in hypotension and decreased cardiac contractility due to increased left ventricular end-diastolic pressure. This potentially reduced coronary perfusion pressure and led to the myocardial infarction. Another possible association with DKA and acute coronary syndrome includes the supply-demand mismatch caused by an increased oxygen demand in the myocardium by counter-regulatory hormones, such as adrenaline, cortisol, and glucagon, released during DKA [23].
The patient in case 2 underwent major surgery, and the surgical stress resulted in SGLT2i-associated eu-DKA. A few cases of life-threatening complications due to SGLT2i-associated DKA in the postoperative period have been reported [24,25]. A postoperative gastric bypass case of SGLT2i-associated DKA requiring mechanical ventilation and hemodialysis was reported [24]. A patient that developed SGLT2i-associated DKA 2 days after laparoscopic appendectomy also developed encephalopathy and required mechanical ventilation and hemo-dialysis [25]; however, there are few reports on patients with severe complications requiring urgent pacemaker insertion for sinus arrest, as in our case 2. Sinus dysfunction and sudden death have been reported to be associated with metabolic acidosis [18,21]. Additionally, in case 2, coronary artery stenosis was not detected on coronary angiography. Once the acidemia improved, the sinus arrest resolved, with a Holter electrocardiogram reaffirming this result. Therefore, we believe that acidemia was the probable cause of the sinus arrest.
Delayed diagnosis due to lack of evidence of hyperglycemia may have contributed to the development of life-threatening complications in our patients. Although SGLT2i has become widely used in recent years, its complication, eu-DKA, appears to be under-recognized, especially by surgeons. Furthermore, eu-DKA often results in blood glucose levels below 200 mg/dL, which may delay its detection [8,9]. Even our cases were followed up with supportive therapy without an accurate diagnosis of metabolic acidosis. Therefore, SGLT2i-associated eu-DKA should be considered a probable differential diagnosis in patients with diabetes and metabolic acidosis. Furthermore, SGLT2i was not discontinued in both of our cases. Because case 1 was an emergency, ongoing medications could not be terminated, while in case 2, canagliflozin was discontinued the day before the surgery. Generally, elimination from the body takes about 5 times as long as the half-life of the drug. The average half-life time of canagliflozin is reported to be 10.2 h, and 5 times the half-time is 51 h. The U.S. Food and Drug Administration in 2020 announced the approval of a change in the prescription of SGLT2i diabetes medicines, thereby recommending them to be terminated temporarily 3 or 4 days before scheduled surgery to prevent perioperative SGLT2i-associated ketoacidosis [26]. In our case 2, glycosuria was still detected on day 6 (7 days after the last oral administration of canagliflozin). We believed that the effect of canagliflozin remained at least until that time. In SGLT2i-associated DKA, glycosuria persisted for 3 to 10 days after the discontinuation of SGLT2is [27]. In case 2, canagliflozin may have required a washout period longer than 3 days.
Conclusions
We reported 2 cases of life-threatening complications that were caused or worsened by SGLT2i-associated eu-DKA. Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delayed diagnosis due to lack of evidence of hyperglycemia may have contributed to the development and worsening of these life-threatening complications. In situations in which SGLT2i is expected to become increasingly widespread owing to its effectiveness, the number of SGLT2i-associated DKA is expected to increase. It is imperative to assess the existing medication history of patients with diabetes and consider eu-DKA as an important differential diagnosis of patients with high anion gap metabolic acidosis to ensure early intervention. Additionally, SGLT2i-associated DKA is likely to develop perioperatively; therefore, clinicians should pay attention to the discontinuation period of SGLT2i prior to any surgical intervention.
We would like to thank Editage (www.editage.com) for English language editing.
Department and Institution Where the Work Was Performed
Department of Intensive Care Medicine, Tokyo Women’s Medical University, Tokyo, Japan
Conflict of Interest
None. | 51 kg. | Weight | CC BY-NC-ND | 33723205 | 19,780,336 | 2021-03-16 |
What was the dosage of drug 'EMPAGLIFLOZIN'? | Life-Threatening Complications Related to Delayed Diagnosis of Euglycemic Diabetic Ketoacidosis Associated with Sodium-Glucose Cotransporter-2 Inhibitors: A Report of 2 Cases.
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are widely used owing to their effective glycemic control and protective effects against heart and kidney failure. Euglycemic diabetic ketoacidosis (eu-DKA) is a complication of treatment with SGLT2is. Eu-DKA often leads to delayed diagnosis and results in life-threatening complications. We report 2 critical cases of SGLT2i-associated eu-DKA. CASE REPORT Case 1 was 52-year-old woman with unstable angina scheduled for elective coronary artery bypass grafting surgery. Preoperatively, she underwent tooth extraction which led to poor food intake because of pain. Three days before surgery, the patient had SGLT2i-associated eu-DKA and myocardial infraction, requiring percutaneous coronary intervention and peripheral venoarterial extracorporeal membrane oxygenation. The patient had taken SGLT2i until the morning of admission to the intensive care unit. Case 2 was a 76-year-old woman experiencing SGLT2i-associated eu-DKA and sinus arrest, necessitating a temporary pacemaker, followed by elective gastrojejunal bypass surgery. The SGLT2i was discontinued the day before surgery. On day 3 following surgery, the patient's metabolic acidosis improved, and sinus arrest resolved. CONCLUSIONS Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delay in diagnosis because of a lack of evidence of hyperglycemia could contribute to the development and worsening of life-threatening complications. This reiterates the importance of reviewing ongoing medications of patients with diabetes and considering eu-DKA as a differential diagnosis for patients with high anion gap metabolic acidosis to ensure early intervention. SGLT2i-associated DKA likely develops perioperatively; therefore, clinicians should pay attention to the discontinuation period of SGLT2i before any surgical intervention.
Background
Sodium-glucose cotransporter-transporter-2 inhibitors (SGLT2is) are used widely owing to their protective effects against heart and kidney failure and effective glycemic control [1–6]. SGLT2is decrease glycated hemoglobin, body weight, and blood pressure [1,2]. Recent randomized control trials have demonstrated that SGLT2is reduce the risk of heart failure, cardiovascular death, and serious renal outcomes in patients with or without diabetes [4–6]. However, diabetic ketoacidosis (DKA) has been reported as a complication of SGLT2is [7,8]. It was reported that, compared with dipeptidyl peptidase-4 inhibitors, SGLT2is have a higher risk of DKA (hazard ratio, 2.85) [7]. Caloric restriction, surgical stress, acute illness, risk of dehydration, and medication changes have been reported as precipitating factors of SGLT2i-associated DKA, and nausea and vomiting have been reported as its clinical presentation [9–11]. The incidence of SGLT2i-associated DKA perioperatively has been reported to be as high as 19% to 28% [12,13]. In a review of 47 cases of perioperative SGLT2i-associated DKA, 4 cases of severe acidemia or metabolic acidosis were reported (pH <7.0 in 2 cases; bicarbonate [HCO3–] level <5 mEq/L in 2 cases) [10]. Unlike with typical DKA, some patients have a normal blood glucose level. This type of DKA is known as euglycemic DKA (eu-DKA). Eu-DKA sometimes leads to delayed diagnosis and results in life-threatening complications [8,9]. Because the use of SGLT2i is expected to become increasingly widespread owing to its effectiveness, it is important to report this adverse drug reaction that can delay diagnosis.
We encountered 2 severe cases of SGLT2i-associated eu-DKA caused by delayed diagnosis in the intensive care unit (ICU). Both patients consented to the publication of this case report.
Case Reports
Case 1
A 52-year-old woman weighing 51 kg and receiving medications for type 2 diabetes mellitus (empagliflozin 10 mg daily and sitagliptin 50 mg daily), dyslipidemia (ezetimibe 10 mg daily and rosuvastatin 20 mg daily), and an old cerebral infarction (clopidogrel 75 mg daily) was diagnosed with unstable angina. She was scheduled for elective coronary artery bypass grafting surgery. Following hospital admission, the patient underwent a preoperative examination for the surgery. On days 12 and 15 of admission, she underwent tooth extraction for perioperative management. Subsequently, her oral food intake decreased because of pain. On day 22 of hospitalization, 3 days before the scheduled elective coronary artery bypass grafting surgery, she developed tachypnea, vomiting, and decreased blood pressure. She had high anion gap metabolic acidosis (pH, 6.84; HCO3– level, 2.1 mEq/L; base excess, −20.0 mmol/L; anion gap, 31.9 mmol/L; and lactate level, 2.4 mmol/L), while her blood glucose remained at normal levels (178 mg/dL). Empagliflozin was administered until the morning of that day. Although elevated cardiac troponin levels (serum troponin I, 324.5 pg/mL) were detected, no ST-segment elevation was observed on the electrocardiogram. Supportive therapy to manage metabolic acidosis was initiated. She was intubated for hypotension (systolic artery pressure, 78 mmHg; infusion with noradrenaline 0.06 μg/kg/h), severe acidemia, and tachypnea. The oral administration of empagliflozin was discontinued. Despite sodium bicarbonate infusion and continuous renal replacement therapy instituted for the life-threatening acidemia, the patient’s metabolic acidosis did not improve. On day 2 of ICU admission, based on elevated blood β-hydroxybutyrate levels (12.9 mmol/L), dextrose and insulin were administered to manage the eu-DKA. The acidosis was resolved within 24 h of treatment initiation; in addition, blood β-hydroxybutyrate levels decreased (4.3 mmol/L). On day 3 of ICU admission, she developed pulmonary edema but still required large doses of inotropes and vasopressors. As the metabolic acidosis improved, the status of her coronary arteries was evaluated. Following insertion of a percutaneous mechanical circulatory support device (Impella 2.5; Abiomed, Danvers, MA, USA) to ensure left ventricular unloading, percutaneous coronary intervention was performed. Stents were placed at 3 points, including the left anterior descending artery. Subsequently, there was a need for peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) owing to the prevailing potentially life-threatening poor oxygenation (ratio of arterial oxygen partial pressure to fractional inspired oxygen was 57.5 under 10 cmH2O positive end-expiratory pressure) and low output syndrome. VA-ECMO, continuous renal replacement therapy, Impella 2.5, and mechanical ventilation were required for 6, 6, 7, and 13 days, respectively. In addition, she had a hemorrhagic cerebral infarction on day 10 of ICU admission. She was discharged from the ICU on day 15 and transferred to a rehabilitation hospital on day 51 of admission.
Case 2
A 76-year-old woman weighing 63 kg and receiving medications for type 2 diabetes mellitus (canagliflozin 100 mg daily and metformin 500 mg daily), hypertension (cilnidipine 20 mg daily), and dyslipidemia (fenofibrate 80 mg daily) was diagnosed with duodenal cancer and scheduled for elective gastrojejunal bypass surgery. Canagliflozin was administered until the day before the surgery. After surgery, she was admitted to the ICU for postoperative management. On arrival, she had euglycemia (100 mg/dL), but with metabolic acidosis (pH, 7.25; HCO3– level, −17.3 mEq/L; base excess, −9.1; anion gap, 16.2 mmol/L; and lactate level, 0.8 mmol/L). Sodium bicarbonate infusion was initiated; however, the patient’s metabolic acidosis continued to worsen. On day 2 of ICU admission, she had cardiac sinus arrest and experienced loss of consciousness with metabolic acidosis (pH, 7.27; HCO3– level, 13.5 mEq/L; base excess, −12.1; anion gap, 23.7 mmol/L; and lactate level, 1.1 mmol/L). Elevated blood β-hydroxybutyrate (18.6 mmol/L) levels were noted, and an infusion of dextrose and insulin was initiated for the management of eu-DKA. Within 2 h of initiating eu-DKA treatment, she had another cardiac sinus arrest, lost consciousness, and continued to experience metabolic acidosis (pH, 7.30; HCO3– level, 16.0 mEq/L; base excess, −9.3; anion gap, 18.0 mmol/L; and lactate level, 1.0 mmol/L). Coronary angiography showed no myocardial ischemia, and a temporary pacemaker was intravenously inserted as an emergency intervention. On day 3 of ICU admission, the patient’s metabolic acidosis improved, her blood β-hydroxybutyrate level decreased (3.2 mmol/L), and sinus arrest resolved. The patient was discharged from the ICU on day 5. Glycosuria was also observed on day 6 (blood glucose level, 140 mg/dL) but was not observed on day 12 (blood glucose level, 163 mg/dL). The temporary pacemaker was removed on day 11, and no signs of sinus arrest were detected using a 24-h Holter monitor on day 14. She was discharged from the hospital on day 18.
Discussion
We encountered 2 cases of life-threatening complications caused by SGLT2i-associated eu-DKA. Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delay in diagnosis due to lack of evidence of hyperglycemia could have contributed to the development and deterioration of the life-threatening complications in our patients.
The underlying condition leading to eu-DKA was a caloric restriction in case 1 and surgical stress in case 2, and these conditions might have contributed to the development and worsening of life-threatening complications. Preoperative fasting, very low-calorie diets, and surgical stress are reported as precipitating factors of SGLT2i-associated DKA [10,11]. In case 1, tooth extraction resulted in poor food intake, whereas in case 2, DKA developed after surgery. Persistent glycosuria induced by SGLT2i lowers the amount of the body glucose pool [14], and in this situation, when caloric intake decreases, the blood glucose level cannot be increased, insulin secretion is suppressed, and ketone body production is induced. Surgical stress increases counter-regulatory hormones such as adrenaline and cortisol, and these hormones induce increased insulin resistance [10]. Increased insulin resistance causes impaired sugar utilization and ketogenesis. Additionally, surgical stress induces glucagon secretion [10]. Glucagon promotes lipolysis and fatty acid oxidation in the liver and increases ketogenesis [15].
In case 1, it remained unclear whether DKA or myocardial ischemia occurred first. In this patient, tooth extraction resulted in poor food intake; therefore, DKA might have developed before the myocardial ischemia. Several studies have illustrated that acute metabolic acidosis can have critical effects on the cardiovascular system [16,17]. The cardiovascular effects of acidosis include arterial vasodilatation contributing to hypotension [18], a decrease of contractility and cardiac output [19,20], sinus dysfunction [21], and a predisposition to cardiac arrhythmias associated with sudden death [22]. The patient in case 1 had severe coronary artery disease requiring coronary artery bypass grafting. Acidemia due to eu-DKA caused peripheral vasodilation, resulting in hypotension and decreased cardiac contractility due to increased left ventricular end-diastolic pressure. This potentially reduced coronary perfusion pressure and led to the myocardial infarction. Another possible association with DKA and acute coronary syndrome includes the supply-demand mismatch caused by an increased oxygen demand in the myocardium by counter-regulatory hormones, such as adrenaline, cortisol, and glucagon, released during DKA [23].
The patient in case 2 underwent major surgery, and the surgical stress resulted in SGLT2i-associated eu-DKA. A few cases of life-threatening complications due to SGLT2i-associated DKA in the postoperative period have been reported [24,25]. A postoperative gastric bypass case of SGLT2i-associated DKA requiring mechanical ventilation and hemodialysis was reported [24]. A patient that developed SGLT2i-associated DKA 2 days after laparoscopic appendectomy also developed encephalopathy and required mechanical ventilation and hemo-dialysis [25]; however, there are few reports on patients with severe complications requiring urgent pacemaker insertion for sinus arrest, as in our case 2. Sinus dysfunction and sudden death have been reported to be associated with metabolic acidosis [18,21]. Additionally, in case 2, coronary artery stenosis was not detected on coronary angiography. Once the acidemia improved, the sinus arrest resolved, with a Holter electrocardiogram reaffirming this result. Therefore, we believe that acidemia was the probable cause of the sinus arrest.
Delayed diagnosis due to lack of evidence of hyperglycemia may have contributed to the development of life-threatening complications in our patients. Although SGLT2i has become widely used in recent years, its complication, eu-DKA, appears to be under-recognized, especially by surgeons. Furthermore, eu-DKA often results in blood glucose levels below 200 mg/dL, which may delay its detection [8,9]. Even our cases were followed up with supportive therapy without an accurate diagnosis of metabolic acidosis. Therefore, SGLT2i-associated eu-DKA should be considered a probable differential diagnosis in patients with diabetes and metabolic acidosis. Furthermore, SGLT2i was not discontinued in both of our cases. Because case 1 was an emergency, ongoing medications could not be terminated, while in case 2, canagliflozin was discontinued the day before the surgery. Generally, elimination from the body takes about 5 times as long as the half-life of the drug. The average half-life time of canagliflozin is reported to be 10.2 h, and 5 times the half-time is 51 h. The U.S. Food and Drug Administration in 2020 announced the approval of a change in the prescription of SGLT2i diabetes medicines, thereby recommending them to be terminated temporarily 3 or 4 days before scheduled surgery to prevent perioperative SGLT2i-associated ketoacidosis [26]. In our case 2, glycosuria was still detected on day 6 (7 days after the last oral administration of canagliflozin). We believed that the effect of canagliflozin remained at least until that time. In SGLT2i-associated DKA, glycosuria persisted for 3 to 10 days after the discontinuation of SGLT2is [27]. In case 2, canagliflozin may have required a washout period longer than 3 days.
Conclusions
We reported 2 cases of life-threatening complications that were caused or worsened by SGLT2i-associated eu-DKA. Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delayed diagnosis due to lack of evidence of hyperglycemia may have contributed to the development and worsening of these life-threatening complications. In situations in which SGLT2i is expected to become increasingly widespread owing to its effectiveness, the number of SGLT2i-associated DKA is expected to increase. It is imperative to assess the existing medication history of patients with diabetes and consider eu-DKA as an important differential diagnosis of patients with high anion gap metabolic acidosis to ensure early intervention. Additionally, SGLT2i-associated DKA is likely to develop perioperatively; therefore, clinicians should pay attention to the discontinuation period of SGLT2i prior to any surgical intervention.
We would like to thank Editage (www.editage.com) for English language editing.
Department and Institution Where the Work Was Performed
Department of Intensive Care Medicine, Tokyo Women’s Medical University, Tokyo, Japan
Conflict of Interest
None. | 10 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33723205 | 19,780,336 | 2021-03-16 |
What was the outcome of reaction 'Euglycaemic diabetic ketoacidosis'? | Life-Threatening Complications Related to Delayed Diagnosis of Euglycemic Diabetic Ketoacidosis Associated with Sodium-Glucose Cotransporter-2 Inhibitors: A Report of 2 Cases.
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are widely used owing to their effective glycemic control and protective effects against heart and kidney failure. Euglycemic diabetic ketoacidosis (eu-DKA) is a complication of treatment with SGLT2is. Eu-DKA often leads to delayed diagnosis and results in life-threatening complications. We report 2 critical cases of SGLT2i-associated eu-DKA. CASE REPORT Case 1 was 52-year-old woman with unstable angina scheduled for elective coronary artery bypass grafting surgery. Preoperatively, she underwent tooth extraction which led to poor food intake because of pain. Three days before surgery, the patient had SGLT2i-associated eu-DKA and myocardial infraction, requiring percutaneous coronary intervention and peripheral venoarterial extracorporeal membrane oxygenation. The patient had taken SGLT2i until the morning of admission to the intensive care unit. Case 2 was a 76-year-old woman experiencing SGLT2i-associated eu-DKA and sinus arrest, necessitating a temporary pacemaker, followed by elective gastrojejunal bypass surgery. The SGLT2i was discontinued the day before surgery. On day 3 following surgery, the patient's metabolic acidosis improved, and sinus arrest resolved. CONCLUSIONS Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delay in diagnosis because of a lack of evidence of hyperglycemia could contribute to the development and worsening of life-threatening complications. This reiterates the importance of reviewing ongoing medications of patients with diabetes and considering eu-DKA as a differential diagnosis for patients with high anion gap metabolic acidosis to ensure early intervention. SGLT2i-associated DKA likely develops perioperatively; therefore, clinicians should pay attention to the discontinuation period of SGLT2i before any surgical intervention.
Background
Sodium-glucose cotransporter-transporter-2 inhibitors (SGLT2is) are used widely owing to their protective effects against heart and kidney failure and effective glycemic control [1–6]. SGLT2is decrease glycated hemoglobin, body weight, and blood pressure [1,2]. Recent randomized control trials have demonstrated that SGLT2is reduce the risk of heart failure, cardiovascular death, and serious renal outcomes in patients with or without diabetes [4–6]. However, diabetic ketoacidosis (DKA) has been reported as a complication of SGLT2is [7,8]. It was reported that, compared with dipeptidyl peptidase-4 inhibitors, SGLT2is have a higher risk of DKA (hazard ratio, 2.85) [7]. Caloric restriction, surgical stress, acute illness, risk of dehydration, and medication changes have been reported as precipitating factors of SGLT2i-associated DKA, and nausea and vomiting have been reported as its clinical presentation [9–11]. The incidence of SGLT2i-associated DKA perioperatively has been reported to be as high as 19% to 28% [12,13]. In a review of 47 cases of perioperative SGLT2i-associated DKA, 4 cases of severe acidemia or metabolic acidosis were reported (pH <7.0 in 2 cases; bicarbonate [HCO3–] level <5 mEq/L in 2 cases) [10]. Unlike with typical DKA, some patients have a normal blood glucose level. This type of DKA is known as euglycemic DKA (eu-DKA). Eu-DKA sometimes leads to delayed diagnosis and results in life-threatening complications [8,9]. Because the use of SGLT2i is expected to become increasingly widespread owing to its effectiveness, it is important to report this adverse drug reaction that can delay diagnosis.
We encountered 2 severe cases of SGLT2i-associated eu-DKA caused by delayed diagnosis in the intensive care unit (ICU). Both patients consented to the publication of this case report.
Case Reports
Case 1
A 52-year-old woman weighing 51 kg and receiving medications for type 2 diabetes mellitus (empagliflozin 10 mg daily and sitagliptin 50 mg daily), dyslipidemia (ezetimibe 10 mg daily and rosuvastatin 20 mg daily), and an old cerebral infarction (clopidogrel 75 mg daily) was diagnosed with unstable angina. She was scheduled for elective coronary artery bypass grafting surgery. Following hospital admission, the patient underwent a preoperative examination for the surgery. On days 12 and 15 of admission, she underwent tooth extraction for perioperative management. Subsequently, her oral food intake decreased because of pain. On day 22 of hospitalization, 3 days before the scheduled elective coronary artery bypass grafting surgery, she developed tachypnea, vomiting, and decreased blood pressure. She had high anion gap metabolic acidosis (pH, 6.84; HCO3– level, 2.1 mEq/L; base excess, −20.0 mmol/L; anion gap, 31.9 mmol/L; and lactate level, 2.4 mmol/L), while her blood glucose remained at normal levels (178 mg/dL). Empagliflozin was administered until the morning of that day. Although elevated cardiac troponin levels (serum troponin I, 324.5 pg/mL) were detected, no ST-segment elevation was observed on the electrocardiogram. Supportive therapy to manage metabolic acidosis was initiated. She was intubated for hypotension (systolic artery pressure, 78 mmHg; infusion with noradrenaline 0.06 μg/kg/h), severe acidemia, and tachypnea. The oral administration of empagliflozin was discontinued. Despite sodium bicarbonate infusion and continuous renal replacement therapy instituted for the life-threatening acidemia, the patient’s metabolic acidosis did not improve. On day 2 of ICU admission, based on elevated blood β-hydroxybutyrate levels (12.9 mmol/L), dextrose and insulin were administered to manage the eu-DKA. The acidosis was resolved within 24 h of treatment initiation; in addition, blood β-hydroxybutyrate levels decreased (4.3 mmol/L). On day 3 of ICU admission, she developed pulmonary edema but still required large doses of inotropes and vasopressors. As the metabolic acidosis improved, the status of her coronary arteries was evaluated. Following insertion of a percutaneous mechanical circulatory support device (Impella 2.5; Abiomed, Danvers, MA, USA) to ensure left ventricular unloading, percutaneous coronary intervention was performed. Stents were placed at 3 points, including the left anterior descending artery. Subsequently, there was a need for peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) owing to the prevailing potentially life-threatening poor oxygenation (ratio of arterial oxygen partial pressure to fractional inspired oxygen was 57.5 under 10 cmH2O positive end-expiratory pressure) and low output syndrome. VA-ECMO, continuous renal replacement therapy, Impella 2.5, and mechanical ventilation were required for 6, 6, 7, and 13 days, respectively. In addition, she had a hemorrhagic cerebral infarction on day 10 of ICU admission. She was discharged from the ICU on day 15 and transferred to a rehabilitation hospital on day 51 of admission.
Case 2
A 76-year-old woman weighing 63 kg and receiving medications for type 2 diabetes mellitus (canagliflozin 100 mg daily and metformin 500 mg daily), hypertension (cilnidipine 20 mg daily), and dyslipidemia (fenofibrate 80 mg daily) was diagnosed with duodenal cancer and scheduled for elective gastrojejunal bypass surgery. Canagliflozin was administered until the day before the surgery. After surgery, she was admitted to the ICU for postoperative management. On arrival, she had euglycemia (100 mg/dL), but with metabolic acidosis (pH, 7.25; HCO3– level, −17.3 mEq/L; base excess, −9.1; anion gap, 16.2 mmol/L; and lactate level, 0.8 mmol/L). Sodium bicarbonate infusion was initiated; however, the patient’s metabolic acidosis continued to worsen. On day 2 of ICU admission, she had cardiac sinus arrest and experienced loss of consciousness with metabolic acidosis (pH, 7.27; HCO3– level, 13.5 mEq/L; base excess, −12.1; anion gap, 23.7 mmol/L; and lactate level, 1.1 mmol/L). Elevated blood β-hydroxybutyrate (18.6 mmol/L) levels were noted, and an infusion of dextrose and insulin was initiated for the management of eu-DKA. Within 2 h of initiating eu-DKA treatment, she had another cardiac sinus arrest, lost consciousness, and continued to experience metabolic acidosis (pH, 7.30; HCO3– level, 16.0 mEq/L; base excess, −9.3; anion gap, 18.0 mmol/L; and lactate level, 1.0 mmol/L). Coronary angiography showed no myocardial ischemia, and a temporary pacemaker was intravenously inserted as an emergency intervention. On day 3 of ICU admission, the patient’s metabolic acidosis improved, her blood β-hydroxybutyrate level decreased (3.2 mmol/L), and sinus arrest resolved. The patient was discharged from the ICU on day 5. Glycosuria was also observed on day 6 (blood glucose level, 140 mg/dL) but was not observed on day 12 (blood glucose level, 163 mg/dL). The temporary pacemaker was removed on day 11, and no signs of sinus arrest were detected using a 24-h Holter monitor on day 14. She was discharged from the hospital on day 18.
Discussion
We encountered 2 cases of life-threatening complications caused by SGLT2i-associated eu-DKA. Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delay in diagnosis due to lack of evidence of hyperglycemia could have contributed to the development and deterioration of the life-threatening complications in our patients.
The underlying condition leading to eu-DKA was a caloric restriction in case 1 and surgical stress in case 2, and these conditions might have contributed to the development and worsening of life-threatening complications. Preoperative fasting, very low-calorie diets, and surgical stress are reported as precipitating factors of SGLT2i-associated DKA [10,11]. In case 1, tooth extraction resulted in poor food intake, whereas in case 2, DKA developed after surgery. Persistent glycosuria induced by SGLT2i lowers the amount of the body glucose pool [14], and in this situation, when caloric intake decreases, the blood glucose level cannot be increased, insulin secretion is suppressed, and ketone body production is induced. Surgical stress increases counter-regulatory hormones such as adrenaline and cortisol, and these hormones induce increased insulin resistance [10]. Increased insulin resistance causes impaired sugar utilization and ketogenesis. Additionally, surgical stress induces glucagon secretion [10]. Glucagon promotes lipolysis and fatty acid oxidation in the liver and increases ketogenesis [15].
In case 1, it remained unclear whether DKA or myocardial ischemia occurred first. In this patient, tooth extraction resulted in poor food intake; therefore, DKA might have developed before the myocardial ischemia. Several studies have illustrated that acute metabolic acidosis can have critical effects on the cardiovascular system [16,17]. The cardiovascular effects of acidosis include arterial vasodilatation contributing to hypotension [18], a decrease of contractility and cardiac output [19,20], sinus dysfunction [21], and a predisposition to cardiac arrhythmias associated with sudden death [22]. The patient in case 1 had severe coronary artery disease requiring coronary artery bypass grafting. Acidemia due to eu-DKA caused peripheral vasodilation, resulting in hypotension and decreased cardiac contractility due to increased left ventricular end-diastolic pressure. This potentially reduced coronary perfusion pressure and led to the myocardial infarction. Another possible association with DKA and acute coronary syndrome includes the supply-demand mismatch caused by an increased oxygen demand in the myocardium by counter-regulatory hormones, such as adrenaline, cortisol, and glucagon, released during DKA [23].
The patient in case 2 underwent major surgery, and the surgical stress resulted in SGLT2i-associated eu-DKA. A few cases of life-threatening complications due to SGLT2i-associated DKA in the postoperative period have been reported [24,25]. A postoperative gastric bypass case of SGLT2i-associated DKA requiring mechanical ventilation and hemodialysis was reported [24]. A patient that developed SGLT2i-associated DKA 2 days after laparoscopic appendectomy also developed encephalopathy and required mechanical ventilation and hemo-dialysis [25]; however, there are few reports on patients with severe complications requiring urgent pacemaker insertion for sinus arrest, as in our case 2. Sinus dysfunction and sudden death have been reported to be associated with metabolic acidosis [18,21]. Additionally, in case 2, coronary artery stenosis was not detected on coronary angiography. Once the acidemia improved, the sinus arrest resolved, with a Holter electrocardiogram reaffirming this result. Therefore, we believe that acidemia was the probable cause of the sinus arrest.
Delayed diagnosis due to lack of evidence of hyperglycemia may have contributed to the development of life-threatening complications in our patients. Although SGLT2i has become widely used in recent years, its complication, eu-DKA, appears to be under-recognized, especially by surgeons. Furthermore, eu-DKA often results in blood glucose levels below 200 mg/dL, which may delay its detection [8,9]. Even our cases were followed up with supportive therapy without an accurate diagnosis of metabolic acidosis. Therefore, SGLT2i-associated eu-DKA should be considered a probable differential diagnosis in patients with diabetes and metabolic acidosis. Furthermore, SGLT2i was not discontinued in both of our cases. Because case 1 was an emergency, ongoing medications could not be terminated, while in case 2, canagliflozin was discontinued the day before the surgery. Generally, elimination from the body takes about 5 times as long as the half-life of the drug. The average half-life time of canagliflozin is reported to be 10.2 h, and 5 times the half-time is 51 h. The U.S. Food and Drug Administration in 2020 announced the approval of a change in the prescription of SGLT2i diabetes medicines, thereby recommending them to be terminated temporarily 3 or 4 days before scheduled surgery to prevent perioperative SGLT2i-associated ketoacidosis [26]. In our case 2, glycosuria was still detected on day 6 (7 days after the last oral administration of canagliflozin). We believed that the effect of canagliflozin remained at least until that time. In SGLT2i-associated DKA, glycosuria persisted for 3 to 10 days after the discontinuation of SGLT2is [27]. In case 2, canagliflozin may have required a washout period longer than 3 days.
Conclusions
We reported 2 cases of life-threatening complications that were caused or worsened by SGLT2i-associated eu-DKA. Precipitating factors of eu-DKA (caloric restriction and surgical stress) and delayed diagnosis due to lack of evidence of hyperglycemia may have contributed to the development and worsening of these life-threatening complications. In situations in which SGLT2i is expected to become increasingly widespread owing to its effectiveness, the number of SGLT2i-associated DKA is expected to increase. It is imperative to assess the existing medication history of patients with diabetes and consider eu-DKA as an important differential diagnosis of patients with high anion gap metabolic acidosis to ensure early intervention. Additionally, SGLT2i-associated DKA is likely to develop perioperatively; therefore, clinicians should pay attention to the discontinuation period of SGLT2i prior to any surgical intervention.
We would like to thank Editage (www.editage.com) for English language editing.
Department and Institution Where the Work Was Performed
Department of Intensive Care Medicine, Tokyo Women’s Medical University, Tokyo, Japan
Conflict of Interest
None. | Recovering | ReactionOutcome | CC BY-NC-ND | 33723205 | 19,780,336 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective for unapproved indication'. | Long-Haul Post-COVID-19 Symptoms Presenting as a Variant of Postural Orthostatic Tachycardia Syndrome: The Swedish Experience.
Major clinical centers in Sweden have witnessed an inflow of patients with chronic symptoms following initial outpatient care for coronavirus disease-2019 (COVID-19) infection, suggestive of postural orthostatic tachycardia syndrome. This report presents the first case series of 3 Swedish patients diagnosed with postural orthostatic tachycardia syndrome more than 3 months after the primary COVID-2019 infections. (Level of Difficulty: Intermediate.).
INTRODUCTION
Postural orthostatic tachycardia syndrome (POTS) is the most prevalent chronic cardiovascular dysautonomia among young and middle-age individuals, predominantly women. It is characterized by chronic orthostatic intolerance, abnormal heart rate (HR) increase on standing, and deconditioning (1,2) (Table 1). The syndrome has been postulated to have post-viral autoimmune activation as a possible etiology (3).Learning Objectives
• To raise awareness of POTS as a possible long-term complication following COVID-19 infection.
• To present diagnostic principles for an accurate POTS diagnosis.
• To propose treatment regimens in patient with persistent POTS symptoms.
Table 1 Diagnostic Criteria of POTS
Sustained heart rate increment of not <30 beats/min or above 120 beats/min within 10 min of active standing or head-up tilt.
For individuals who are younger than 19 yrs the required increment is at least 40 beats/min.
Absence of orthostatic hypotension (i.e., sustained systolic blood pressure drop of not <20 mm Hg).
Reproduction of spontaneous symptoms such as light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, and fatigue. In some patients, tachycardia may evoke vasovagal syncope corresponding to spontaneous attacks from patient’s history.
History of chronic orthostatic intolerance and other typical POTS-associated symptoms (for at least 6 months [1]).
Absence of other conditions provoking sinus tachycardia such as anxiety disorders, hyperventilation, anemia, fever, pain, infection, dehydration, hyperthyroidism, pheochromocytoma, use of cardioactive drugs (sympathomimetics, anticholinergics).
This table has been endorsed by the American Academy of Neurology, the American Autonomic Society, the American College of Cardiology, the American Heart Association, the European Federation of Autonomic Societies, the European Heart Rhythm Association, the European Society of Cardiology, and the Heart Rhythm Society.
Adopted with permission from Fedorowski (1).
POTS = postural orthostatic tachycardia syndrome.
In the acute phase, coronavirus disease-2019 (COVID-19) causes multiple complications including pneumonia, respiratory distress syndrome, liver injury, cardiac injury, and prothrombotic coagulopathy. Long-term consequences remain unknown (4). Recently, chronic (“long-haul”) symptoms following COVID-19 infections have been consistent with a POTS-like presentation (4). Here we present a series of 3 patients with chronic post-COVID-19 symptoms diagnosed as POTS.
Patient #1
In March 2020, a 42-year-old woman with history of allergic rhinitis and conjunctivitis developed flu-like symptoms including malaise, cough, fever, weakness, loss of appetite, myalgia, and loss of smell and taste. She did not seek medical attention and her condition improved progressively but, in May, symptoms recurred with the addition of abdominal pain and odynophagia. Chest computed tomography and laboratory testing were normal. A nasopharyngeal swab showed no evidence of COVID-19.
In July, debilitating symptoms of profound exhaustion with associated sinus tachycardia followed. Telemetry showed HR of 70 to 160 beats/min. Echocardiography was normal. Serology tests for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) were considered borderline. By September, she was found unable to stand more than 5 min. Additionally, she complained of palpitations, dizziness, heat, and exercise intolerance (Figure 1). During a head-up tilt test, her HR increased from 85 beats/min supine to 135 beats/min upright within 10 min (Figure 2). Active standing showed initial orthostatic hypotension (Figure 3), whereas Valsalva maneuver showed a hyperadrenergic response characteristic for POTS (Figure 4).Figure 1 POTS Symptom Scoring in 42-Year-Old Woman
Patient #1 self-reported symptoms using a dedicated postural orthostatic tachycardia syndrome (POTS) symptom scoring questionnaire composed of 12 most commonly reported symptoms in POTS. Patients were asked to grade their symptoms using a visual analogue scale (VAS) ranging from 0 (no symptom) to 10 (worst possible). The maximum score is 120 points. A score >40 points likely indicates pathology.
Figure 2 HUT Testing in 42-Year-Old Woman
Head-up tilt (HUT) test revealing post–coronavirus disease-2019 POTS in a 42-year-old woman (Patient #1), with red arrows indicating the marked increase in heart rate (HR) during orthostasis. bpm = beats/min; Diz = dizziness; POTS = postural orthostatic tachycardia syndrome.
Figure 3 Active Standing in 42-Year-Old Woman
Active standing test demonstrating initial orthostatic hypotension and POTS in a 42-year-old woman (Patient #1) with long-haul post–coronavirus disease-2019 symptoms, with red arrow indicating the marked increase in heart rate during orthostasis. Abbreviations as in Figures 1 and2.
Figure 4 Valsalva Response in 42-Year-Old Woman
Hyperadrenergic Valsalva maneuver in a 42-year-old woman (Patient #1) with long-haul post–coronavirus disease 2019 symptoms, with red arrows indicating the marked increase in heart rate and blood pressure (hyperadrenergic response). Abbreviations as in Figure 2.
Ambulatory monitoring demonstrated a mean HR of 89 beats/min with episodic sinus tachycardia, maximum rate of 153 beats/min, while standing. Spirometry and cardiac magnetic resonance were normal. Autoimmunological screening of antiphospholipid antibodies, antinuclear antibodies, antineutrophil cytoplasmic antibody was normal. Twenty-four–hour blood pressure (BP) monitoring showed average BP of 112/74 mm Hg, preserved circadian profile, and lowest BP during daytime of 79/46 mm Hg.
Nonpharmacological measures including increased fluid intake, compression stockings, and avoidance of orthostatic triggers were recommended. She did not tolerate beta-blockers due to worsened orthostatic intolerance, and ivabradine 7.5 mg twice a day was started (Table 2) with substantial improvement, although the patient remains on sick leave.Table 2 Proposed Treatment of POTS
Drugs Dosage Side Effects Precautions
Nonpharmacological treatments
Withdraw exacerbating medications Stop drugs that decrease blood volume or directly increase heart rate
Increased oral water intake Target 2–3 l/day Frequent urination
Increased oral NaCl intake Target 8–10 g/day Hypertension, peripheral edema Buffered NaCl tablets can be used if this cannot be done with diet alone
Lower body compression garments 20–40 mm Hg compression; focus on abdomen ± legs Can be hot, tight, and itchy
Exercise training Aerobic: 30+ min 4 days/week with some leg resistance training Will initially feel poorly and/or worse for up to 6 weeks Initial recumbent exercise, such as a rowing machine, recumbent cycle, or swimming are preferred
Pharmacological treatments
Blood volume expanders
Fludrocortisone 0.1–0.2 mg daily Hypokalemia, edema, headache Electrolytes should be monitored
Desmopressin (DDAVP) 0.1–0.2 mg as needed Hyponatremia, edema Electrolytes should be monitored if used chronically
Acute IV saline 2 l IV over 2–3 h Venous thrombosis, infection
Chronic IV saline 2 l given IV once weekly Infection risk of central venous catheters Avoid long-term use and placement of central catheters
Erythropoietin 10,000 IU weekly Increased risk of cardiovascular death Hematocrit should be monitored
Heart rate inhibitors
Propranolol 10–20 mg orally up to 4× daily Hypotension, bradycardia, bronchospasm Can worsen asthma or exercise tolerance
Ivabradine 2.5–7.5 mg orally twice daily Headaches, palpitations, hypertension, visual disturbances
Pyridostigmine 30–60 mg orally up to 3× daily Abdominal cramps, diarrhea Can worsen asthma
Vasoconstrictors
Midodrine 2.5–15 mg orally 3× daily Headache, scalp tingling, hypertension
Octreotide Long-acting intramuscular injection 10–30 mg Nausea, stomach cramps, diarrhea
Methylphenidate 10 mg orally 2× to 3× a day. Last dose should be avoided before bed Tachycardia, insomnia, nausea, headache, dizziness
Droxidopa 100–600 mg 3× daily Headache, nausea, hypertension, and tachycardia Off-label use only
Sympatholytic drugs
Alpha2 adrenergic agonists, such as clonidine 0.1–0.2 mg orally 2× to 3× daily or long-acting patch Hypotension, fatigue, brain fog
Methyldopa 125–250 mg orally twice daily Hypotension, fatigue, brain fog
Other
Modafinil 50–200 mg orally once or twice daily Tachycardia
Adapted with permission from Miller and Raj (9).
DDAVP = desmopressin; IU = international units; IV = intravenous(ly); POTS = postural orthostatic tachycardia syndrome.
Patient #2
A 28-year-old woman developed COVID-19 symptoms in May 2020 with fever, dyspnea, chest pain, lightheadedness, and headache. Polymerase chain reaction testing was positive for SARS-CoV-2. Previous medical history included arthroscopic meniscectomy, tonsillectomy, and discectomy.
Due to persistent and progressive symptoms (chest pain, fatigue, vertigo, headache), she was hospitalized twice. Blood tests were normal except slight leukocytosis. Chest computed tomography excluded pulmonary embolism and viral pneumonia but revealed pericardial effusion. As pericarditis was suspected, prednisolone was started, and subsequently changed to colchicine and ibuprofen, with no effect on symptoms. Due to headache, nausea, and photophobia, viral meningitis was suspected. However, lumbar puncture and spine and brain magnetic resonance imaging scan were normal.
An active standing test demonstrated HR increase from 75 to 128 beats/min with concomitant slight increase in systolic BP (10 mm Hg) and pronounced orthostatic intolerance (dizziness, lightheadedness, tremor) (Figure 5).Figure 5 POTS Symptom Scoring in 28-Year-Old Woman
Patient #2 self-reported symptoms using a dedicated POTS symptom scoring questionnaire composed of 12 most commonly reported symptoms in POTS. Patients were asked to grade their symptoms using a VAS ranging from 0 (no symptom) to 10 (worst possible). The maximum score is 120 points. A score >40 points likely indicates pathology. Abbreviations as in Figure 1.
In September, she was referred to a tertiary center for post–COVID-19 follow-up and tested positive for SARS-CoV-2 immunoglobulin G antibodies. During a 6-min walking test peripheral oxygen desaturation was noted (from 99% to 89%) without any other findings.
Further evaluation with perfusion stress cardiac magnetic resonance, antinuclear antibodies, antineutrophil cytoplasmic antibody, metoxycatecholamines, and antiphospholipid autoantibodies was normal. POTS was confirmed by both active standing test and head-up tilt (symptomatic sinus tachycardia >130 beats/min).
Nonpharmacological recommendations included increased daily fluid and salt intake, as well as use of compression socks. She was prescribed propranolol 10 mg ×3 times a day (Table 2). After several weeks, she developed gastrointestinal symptoms, itching, and orbital edema. Because concomitant mast cell activation syndrome was suspected, she received H1 and H2 antihistamines but remains highly symptomatic and is on sick leave.
Patient #3
In May 2020, a 37-year-old man developed sore throat, fever, fatigue, muscle weakness, dry cough, and palpitations. He had a history of childhood sepsis and migraine. Polymerase chain reaction testing for SARS-CoV-2 and antibodies was negative on multiple occasions. Although not initially hospitalized, the patient was later admitted twice during the summer due to severe and persistent symptoms of extreme fatigue, muscle weakness, insomnia, palpitations, and “brain fog” with trouble concentrating.
A chest computed tomography revealed no signs of viral pneumonia. Myositis and neurological complications were initially suspected; however, the full-body magnetic resonance imaging (including brain and neck) was normal. Lumbar puncture, echocardiography, and laboratory work-up were normal. Skeletal muscle biopsy revealed minimal enrichment of inflammatory cells with unclear significance. Marked fluctuations in sinus rate (periodic increases >140 beats/min with minimal effort) were noted on telemetry. An active standing test demonstrated increase in sinus rate from 98 to 142 beats/min, whereas BP remained stable. POTS was confirmed.
He was referred to a tertiary center for post–COVID-19 follow-up. Additional tests were negative for antinuclear antibodies, antineutrophil cytoplasmic antibody, and metoxycatecholamines. Anticardiolipin and anti-beta-2-glycoprotein-2 immunoglobulin M were slightly elevated (9 E/ml, with values >30 diagnostic for antiphospholipid syndrome).
Recommendations were given to increase fluid and salt intake and use compression socks (Table 2). The patient received propranolol 10 mg ×3 times a day and pyridostigmine 10 mg ×3, the latter due to severe fatigue and muscle weakness. In addition to typical POTS symptoms he developed nausea, orbital edema, and gastrointestinal symptoms (Figure 6). Empirical treatment with H1 and H2 antihistamines was initiated due to suspected mast cell activation syndrome, with moderate clinical improvement. Despite up-titration of propranolol and pyridostigmine, he is still highly symptomatic and on sick leave.Figure 6 POTS Symptom Scoring in 37-Year-Old Man
Patient #3 self-reported symptoms using a dedicated POTS symptom scoring questionnaire composed of 12 most commonly reported symptoms in POTS. Patients were asked to grade their symptoms using a VAS ranging from 0 (no symptom) to 10 (worst possible). The maximum score is 120 points. A score >40 points likely indicates pathology. Abbreviations as in Figure 1.
Discussion
We describe 3 Swedish patients diagnosed with POTS-like symptoms following probable COVID-19 infections. Patients were diagnosed on the grounds of characteristic orthostatic tachycardia and chronic symptoms of orthostatic intolerance after exclusion of competing etiologies (Table 1).
POTS affects primarily women (≈80%) and is manifested by orthostatic tachycardia, in association with various symptoms including palpitations, dizziness, headache, fatigue, and blurred vision (1,2) (Table 3). The syndrome can be precipitated by viral illness or severe infection (5) in 30% to 50% of all patients. The mechanism of POTS is generally undetermined. Similarly, the mechanism of post–COVID-19 POTS remains unknown, although a chronic inflammatory or autoimmune response may be at play. Whereas few reports have been published (6,7), the number of patients affected by long-haul post–COVID-19 will likely grow.Table 3 Typical Clinical Presentation of POTS
Cardiovascular symptoms (pathognomonic)
Cardiovascular system Main: orthostatic intolerance, orthostatic tachycardia, palpitations, dizziness, lightheadedness, (pre-)syncope, exercise intolerance
Other frequent symptoms: dyspnea, chest pain/discomfort, acrocyanosis, Raynaud phenomenon, venous pooling, limb edema
Noncardiovascular symptoms (accompanying)
General symptoms General deconditioning, chronic fatigue, exhaustion, heat intolerance, fever, debility, bedridden
Nervous system Headache/migraine, mental clouding (“brain fog”), cognitive impairment, concentration problems, anxiety, tremulousness, light and sound sensitivity, blurred/tunnel vision, neuropathic pain (regional), sleeping disorders, involuntary movements
Musculoskeletal system Muscle fatigue, weakness, muscle pain
Gastrointestinal system Nausea, dysmotility, gastroparesis, constipation, diarrhea, abdominal pain, weight loss
Respiratory system Hyperventilation, bronchial asthma, shortness of breath
Urogenital system Bladder dysfunction, nocturia, polyuria
Skin Petechiae, rashes, erythema, telangiectasias, abnormal sudomotor regulation, diaphoresis, pallor, flushing
Adapted with permission from Fedorowski (1).
POTS = postural orthostatic tachycardia syndrome.
Negative SARS-CoV-2 test results do not exclude SARS-CoV-2 infection and ought to be interpreted with caution in the context of typical symptoms (8). In the differential diagnosis of POTS, it is important to consider and exclude other identifiable causes of sinus tachycardia such as dehydration, other infections, hyperthyroidism, cardiac disease, anxiety, anemia, metabolic disorders, chronic fatigue syndrome, or deconditioning (5) (Table 1).
Available management protocols for POTS (Table 2) aim at increasing intake of fluids (water) and salt, physical countermaneuvers, and individually adapted aerobic exercise in recumbent position (1,5,9) to help correct the physiological abnormalities. Pharmacotherapy includes volume expanders, vasoconstrictors, and HR regulators but patients may remain symptomatic and incapable of work.
Much remains unknown about the specific mechanisms responsible for the POTS-like symptoms in post–COVID-19 patients or how long these symptoms will last but chronic symptoms are expected in a subset of patients based on this initial clinical experience.
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center. | COLCHICINE, IBUPROFEN, PREDNISOLONE | DrugsGivenReaction | CC BY-NC-ND | 33723532 | 19,315,527 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Long-Haul Post-COVID-19 Symptoms Presenting as a Variant of Postural Orthostatic Tachycardia Syndrome: The Swedish Experience.
Major clinical centers in Sweden have witnessed an inflow of patients with chronic symptoms following initial outpatient care for coronavirus disease-2019 (COVID-19) infection, suggestive of postural orthostatic tachycardia syndrome. This report presents the first case series of 3 Swedish patients diagnosed with postural orthostatic tachycardia syndrome more than 3 months after the primary COVID-2019 infections. (Level of Difficulty: Intermediate.).
INTRODUCTION
Postural orthostatic tachycardia syndrome (POTS) is the most prevalent chronic cardiovascular dysautonomia among young and middle-age individuals, predominantly women. It is characterized by chronic orthostatic intolerance, abnormal heart rate (HR) increase on standing, and deconditioning (1,2) (Table 1). The syndrome has been postulated to have post-viral autoimmune activation as a possible etiology (3).Learning Objectives
• To raise awareness of POTS as a possible long-term complication following COVID-19 infection.
• To present diagnostic principles for an accurate POTS diagnosis.
• To propose treatment regimens in patient with persistent POTS symptoms.
Table 1 Diagnostic Criteria of POTS
Sustained heart rate increment of not <30 beats/min or above 120 beats/min within 10 min of active standing or head-up tilt.
For individuals who are younger than 19 yrs the required increment is at least 40 beats/min.
Absence of orthostatic hypotension (i.e., sustained systolic blood pressure drop of not <20 mm Hg).
Reproduction of spontaneous symptoms such as light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, and fatigue. In some patients, tachycardia may evoke vasovagal syncope corresponding to spontaneous attacks from patient’s history.
History of chronic orthostatic intolerance and other typical POTS-associated symptoms (for at least 6 months [1]).
Absence of other conditions provoking sinus tachycardia such as anxiety disorders, hyperventilation, anemia, fever, pain, infection, dehydration, hyperthyroidism, pheochromocytoma, use of cardioactive drugs (sympathomimetics, anticholinergics).
This table has been endorsed by the American Academy of Neurology, the American Autonomic Society, the American College of Cardiology, the American Heart Association, the European Federation of Autonomic Societies, the European Heart Rhythm Association, the European Society of Cardiology, and the Heart Rhythm Society.
Adopted with permission from Fedorowski (1).
POTS = postural orthostatic tachycardia syndrome.
In the acute phase, coronavirus disease-2019 (COVID-19) causes multiple complications including pneumonia, respiratory distress syndrome, liver injury, cardiac injury, and prothrombotic coagulopathy. Long-term consequences remain unknown (4). Recently, chronic (“long-haul”) symptoms following COVID-19 infections have been consistent with a POTS-like presentation (4). Here we present a series of 3 patients with chronic post-COVID-19 symptoms diagnosed as POTS.
Patient #1
In March 2020, a 42-year-old woman with history of allergic rhinitis and conjunctivitis developed flu-like symptoms including malaise, cough, fever, weakness, loss of appetite, myalgia, and loss of smell and taste. She did not seek medical attention and her condition improved progressively but, in May, symptoms recurred with the addition of abdominal pain and odynophagia. Chest computed tomography and laboratory testing were normal. A nasopharyngeal swab showed no evidence of COVID-19.
In July, debilitating symptoms of profound exhaustion with associated sinus tachycardia followed. Telemetry showed HR of 70 to 160 beats/min. Echocardiography was normal. Serology tests for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) were considered borderline. By September, she was found unable to stand more than 5 min. Additionally, she complained of palpitations, dizziness, heat, and exercise intolerance (Figure 1). During a head-up tilt test, her HR increased from 85 beats/min supine to 135 beats/min upright within 10 min (Figure 2). Active standing showed initial orthostatic hypotension (Figure 3), whereas Valsalva maneuver showed a hyperadrenergic response characteristic for POTS (Figure 4).Figure 1 POTS Symptom Scoring in 42-Year-Old Woman
Patient #1 self-reported symptoms using a dedicated postural orthostatic tachycardia syndrome (POTS) symptom scoring questionnaire composed of 12 most commonly reported symptoms in POTS. Patients were asked to grade their symptoms using a visual analogue scale (VAS) ranging from 0 (no symptom) to 10 (worst possible). The maximum score is 120 points. A score >40 points likely indicates pathology.
Figure 2 HUT Testing in 42-Year-Old Woman
Head-up tilt (HUT) test revealing post–coronavirus disease-2019 POTS in a 42-year-old woman (Patient #1), with red arrows indicating the marked increase in heart rate (HR) during orthostasis. bpm = beats/min; Diz = dizziness; POTS = postural orthostatic tachycardia syndrome.
Figure 3 Active Standing in 42-Year-Old Woman
Active standing test demonstrating initial orthostatic hypotension and POTS in a 42-year-old woman (Patient #1) with long-haul post–coronavirus disease-2019 symptoms, with red arrow indicating the marked increase in heart rate during orthostasis. Abbreviations as in Figures 1 and2.
Figure 4 Valsalva Response in 42-Year-Old Woman
Hyperadrenergic Valsalva maneuver in a 42-year-old woman (Patient #1) with long-haul post–coronavirus disease 2019 symptoms, with red arrows indicating the marked increase in heart rate and blood pressure (hyperadrenergic response). Abbreviations as in Figure 2.
Ambulatory monitoring demonstrated a mean HR of 89 beats/min with episodic sinus tachycardia, maximum rate of 153 beats/min, while standing. Spirometry and cardiac magnetic resonance were normal. Autoimmunological screening of antiphospholipid antibodies, antinuclear antibodies, antineutrophil cytoplasmic antibody was normal. Twenty-four–hour blood pressure (BP) monitoring showed average BP of 112/74 mm Hg, preserved circadian profile, and lowest BP during daytime of 79/46 mm Hg.
Nonpharmacological measures including increased fluid intake, compression stockings, and avoidance of orthostatic triggers were recommended. She did not tolerate beta-blockers due to worsened orthostatic intolerance, and ivabradine 7.5 mg twice a day was started (Table 2) with substantial improvement, although the patient remains on sick leave.Table 2 Proposed Treatment of POTS
Drugs Dosage Side Effects Precautions
Nonpharmacological treatments
Withdraw exacerbating medications Stop drugs that decrease blood volume or directly increase heart rate
Increased oral water intake Target 2–3 l/day Frequent urination
Increased oral NaCl intake Target 8–10 g/day Hypertension, peripheral edema Buffered NaCl tablets can be used if this cannot be done with diet alone
Lower body compression garments 20–40 mm Hg compression; focus on abdomen ± legs Can be hot, tight, and itchy
Exercise training Aerobic: 30+ min 4 days/week with some leg resistance training Will initially feel poorly and/or worse for up to 6 weeks Initial recumbent exercise, such as a rowing machine, recumbent cycle, or swimming are preferred
Pharmacological treatments
Blood volume expanders
Fludrocortisone 0.1–0.2 mg daily Hypokalemia, edema, headache Electrolytes should be monitored
Desmopressin (DDAVP) 0.1–0.2 mg as needed Hyponatremia, edema Electrolytes should be monitored if used chronically
Acute IV saline 2 l IV over 2–3 h Venous thrombosis, infection
Chronic IV saline 2 l given IV once weekly Infection risk of central venous catheters Avoid long-term use and placement of central catheters
Erythropoietin 10,000 IU weekly Increased risk of cardiovascular death Hematocrit should be monitored
Heart rate inhibitors
Propranolol 10–20 mg orally up to 4× daily Hypotension, bradycardia, bronchospasm Can worsen asthma or exercise tolerance
Ivabradine 2.5–7.5 mg orally twice daily Headaches, palpitations, hypertension, visual disturbances
Pyridostigmine 30–60 mg orally up to 3× daily Abdominal cramps, diarrhea Can worsen asthma
Vasoconstrictors
Midodrine 2.5–15 mg orally 3× daily Headache, scalp tingling, hypertension
Octreotide Long-acting intramuscular injection 10–30 mg Nausea, stomach cramps, diarrhea
Methylphenidate 10 mg orally 2× to 3× a day. Last dose should be avoided before bed Tachycardia, insomnia, nausea, headache, dizziness
Droxidopa 100–600 mg 3× daily Headache, nausea, hypertension, and tachycardia Off-label use only
Sympatholytic drugs
Alpha2 adrenergic agonists, such as clonidine 0.1–0.2 mg orally 2× to 3× daily or long-acting patch Hypotension, fatigue, brain fog
Methyldopa 125–250 mg orally twice daily Hypotension, fatigue, brain fog
Other
Modafinil 50–200 mg orally once or twice daily Tachycardia
Adapted with permission from Miller and Raj (9).
DDAVP = desmopressin; IU = international units; IV = intravenous(ly); POTS = postural orthostatic tachycardia syndrome.
Patient #2
A 28-year-old woman developed COVID-19 symptoms in May 2020 with fever, dyspnea, chest pain, lightheadedness, and headache. Polymerase chain reaction testing was positive for SARS-CoV-2. Previous medical history included arthroscopic meniscectomy, tonsillectomy, and discectomy.
Due to persistent and progressive symptoms (chest pain, fatigue, vertigo, headache), she was hospitalized twice. Blood tests were normal except slight leukocytosis. Chest computed tomography excluded pulmonary embolism and viral pneumonia but revealed pericardial effusion. As pericarditis was suspected, prednisolone was started, and subsequently changed to colchicine and ibuprofen, with no effect on symptoms. Due to headache, nausea, and photophobia, viral meningitis was suspected. However, lumbar puncture and spine and brain magnetic resonance imaging scan were normal.
An active standing test demonstrated HR increase from 75 to 128 beats/min with concomitant slight increase in systolic BP (10 mm Hg) and pronounced orthostatic intolerance (dizziness, lightheadedness, tremor) (Figure 5).Figure 5 POTS Symptom Scoring in 28-Year-Old Woman
Patient #2 self-reported symptoms using a dedicated POTS symptom scoring questionnaire composed of 12 most commonly reported symptoms in POTS. Patients were asked to grade their symptoms using a VAS ranging from 0 (no symptom) to 10 (worst possible). The maximum score is 120 points. A score >40 points likely indicates pathology. Abbreviations as in Figure 1.
In September, she was referred to a tertiary center for post–COVID-19 follow-up and tested positive for SARS-CoV-2 immunoglobulin G antibodies. During a 6-min walking test peripheral oxygen desaturation was noted (from 99% to 89%) without any other findings.
Further evaluation with perfusion stress cardiac magnetic resonance, antinuclear antibodies, antineutrophil cytoplasmic antibody, metoxycatecholamines, and antiphospholipid autoantibodies was normal. POTS was confirmed by both active standing test and head-up tilt (symptomatic sinus tachycardia >130 beats/min).
Nonpharmacological recommendations included increased daily fluid and salt intake, as well as use of compression socks. She was prescribed propranolol 10 mg ×3 times a day (Table 2). After several weeks, she developed gastrointestinal symptoms, itching, and orbital edema. Because concomitant mast cell activation syndrome was suspected, she received H1 and H2 antihistamines but remains highly symptomatic and is on sick leave.
Patient #3
In May 2020, a 37-year-old man developed sore throat, fever, fatigue, muscle weakness, dry cough, and palpitations. He had a history of childhood sepsis and migraine. Polymerase chain reaction testing for SARS-CoV-2 and antibodies was negative on multiple occasions. Although not initially hospitalized, the patient was later admitted twice during the summer due to severe and persistent symptoms of extreme fatigue, muscle weakness, insomnia, palpitations, and “brain fog” with trouble concentrating.
A chest computed tomography revealed no signs of viral pneumonia. Myositis and neurological complications were initially suspected; however, the full-body magnetic resonance imaging (including brain and neck) was normal. Lumbar puncture, echocardiography, and laboratory work-up were normal. Skeletal muscle biopsy revealed minimal enrichment of inflammatory cells with unclear significance. Marked fluctuations in sinus rate (periodic increases >140 beats/min with minimal effort) were noted on telemetry. An active standing test demonstrated increase in sinus rate from 98 to 142 beats/min, whereas BP remained stable. POTS was confirmed.
He was referred to a tertiary center for post–COVID-19 follow-up. Additional tests were negative for antinuclear antibodies, antineutrophil cytoplasmic antibody, and metoxycatecholamines. Anticardiolipin and anti-beta-2-glycoprotein-2 immunoglobulin M were slightly elevated (9 E/ml, with values >30 diagnostic for antiphospholipid syndrome).
Recommendations were given to increase fluid and salt intake and use compression socks (Table 2). The patient received propranolol 10 mg ×3 times a day and pyridostigmine 10 mg ×3, the latter due to severe fatigue and muscle weakness. In addition to typical POTS symptoms he developed nausea, orbital edema, and gastrointestinal symptoms (Figure 6). Empirical treatment with H1 and H2 antihistamines was initiated due to suspected mast cell activation syndrome, with moderate clinical improvement. Despite up-titration of propranolol and pyridostigmine, he is still highly symptomatic and on sick leave.Figure 6 POTS Symptom Scoring in 37-Year-Old Man
Patient #3 self-reported symptoms using a dedicated POTS symptom scoring questionnaire composed of 12 most commonly reported symptoms in POTS. Patients were asked to grade their symptoms using a VAS ranging from 0 (no symptom) to 10 (worst possible). The maximum score is 120 points. A score >40 points likely indicates pathology. Abbreviations as in Figure 1.
Discussion
We describe 3 Swedish patients diagnosed with POTS-like symptoms following probable COVID-19 infections. Patients were diagnosed on the grounds of characteristic orthostatic tachycardia and chronic symptoms of orthostatic intolerance after exclusion of competing etiologies (Table 1).
POTS affects primarily women (≈80%) and is manifested by orthostatic tachycardia, in association with various symptoms including palpitations, dizziness, headache, fatigue, and blurred vision (1,2) (Table 3). The syndrome can be precipitated by viral illness or severe infection (5) in 30% to 50% of all patients. The mechanism of POTS is generally undetermined. Similarly, the mechanism of post–COVID-19 POTS remains unknown, although a chronic inflammatory or autoimmune response may be at play. Whereas few reports have been published (6,7), the number of patients affected by long-haul post–COVID-19 will likely grow.Table 3 Typical Clinical Presentation of POTS
Cardiovascular symptoms (pathognomonic)
Cardiovascular system Main: orthostatic intolerance, orthostatic tachycardia, palpitations, dizziness, lightheadedness, (pre-)syncope, exercise intolerance
Other frequent symptoms: dyspnea, chest pain/discomfort, acrocyanosis, Raynaud phenomenon, venous pooling, limb edema
Noncardiovascular symptoms (accompanying)
General symptoms General deconditioning, chronic fatigue, exhaustion, heat intolerance, fever, debility, bedridden
Nervous system Headache/migraine, mental clouding (“brain fog”), cognitive impairment, concentration problems, anxiety, tremulousness, light and sound sensitivity, blurred/tunnel vision, neuropathic pain (regional), sleeping disorders, involuntary movements
Musculoskeletal system Muscle fatigue, weakness, muscle pain
Gastrointestinal system Nausea, dysmotility, gastroparesis, constipation, diarrhea, abdominal pain, weight loss
Respiratory system Hyperventilation, bronchial asthma, shortness of breath
Urogenital system Bladder dysfunction, nocturia, polyuria
Skin Petechiae, rashes, erythema, telangiectasias, abnormal sudomotor regulation, diaphoresis, pallor, flushing
Adapted with permission from Fedorowski (1).
POTS = postural orthostatic tachycardia syndrome.
Negative SARS-CoV-2 test results do not exclude SARS-CoV-2 infection and ought to be interpreted with caution in the context of typical symptoms (8). In the differential diagnosis of POTS, it is important to consider and exclude other identifiable causes of sinus tachycardia such as dehydration, other infections, hyperthyroidism, cardiac disease, anxiety, anemia, metabolic disorders, chronic fatigue syndrome, or deconditioning (5) (Table 1).
Available management protocols for POTS (Table 2) aim at increasing intake of fluids (water) and salt, physical countermaneuvers, and individually adapted aerobic exercise in recumbent position (1,5,9) to help correct the physiological abnormalities. Pharmacotherapy includes volume expanders, vasoconstrictors, and HR regulators but patients may remain symptomatic and incapable of work.
Much remains unknown about the specific mechanisms responsible for the POTS-like symptoms in post–COVID-19 patients or how long these symptoms will last but chronic symptoms are expected in a subset of patients based on this initial clinical experience.
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center. | COLCHICINE, IBUPROFEN, PREDNISOLONE | DrugsGivenReaction | CC BY-NC-ND | 33723532 | 19,315,527 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac disorder'. | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
Click here for additional data file.
Supplement 2. Data Sharing Statement
Click here for additional data file. | BUPIVACAINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33724391 | 19,062,341 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'. | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
Click here for additional data file.
Supplement 2. Data Sharing Statement
Click here for additional data file. | BUPIVACAINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33724391 | 19,062,343 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Endotracheal intubation'. | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
Click here for additional data file.
Supplement 2. Data Sharing Statement
Click here for additional data file. | BUPIVACAINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33724391 | 19,062,343 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal procedural complication'. | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
Click here for additional data file.
Supplement 2. Data Sharing Statement
Click here for additional data file. | BUPIVACAINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33724391 | 19,062,341 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemorrhage'. | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
Click here for additional data file.
Supplement 2. Data Sharing Statement
Click here for additional data file. | BUPIVACAINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33724391 | 19,062,341 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypotension'. | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
Click here for additional data file.
Supplement 2. Data Sharing Statement
Click here for additional data file. | BUPIVACAINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33724391 | 19,062,341 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Incorrect dose administered'. | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
Click here for additional data file.
Supplement 2. Data Sharing Statement
Click here for additional data file. | BUPIVACAINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33724391 | 19,062,343 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infection'. | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
Click here for additional data file.
Supplement 2. Data Sharing Statement
Click here for additional data file. | BUPIVACAINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33724391 | 19,062,341 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
Click here for additional data file.
Supplement 2. Data Sharing Statement
Click here for additional data file. | BUPIVACAINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33724391 | 19,062,341 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal disorder'. | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
Click here for additional data file.
Supplement 2. Data Sharing Statement
Click here for additional data file. | BUPIVACAINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33724391 | 19,062,341 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Surgery'. | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
Click here for additional data file.
Supplement 2. Data Sharing Statement
Click here for additional data file. | BUPIVACAINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33724391 | 19,062,343 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vomiting'. | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
Click here for additional data file.
Supplement 2. Data Sharing Statement
Click here for additional data file. | BUPIVACAINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33724391 | 19,062,341 | 2021-03-01 |
What was the administration route of drug 'BUPIVACAINE'? | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
Click here for additional data file.
Supplement 2. Data Sharing Statement
Click here for additional data file. | Other | DrugAdministrationRoute | CC BY | 33724391 | 19,062,341 | 2021-03-01 |
What was the administration route of drug 'SODIUM CHLORIDE'? | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
Click here for additional data file.
Supplement 2. Data Sharing Statement
Click here for additional data file. | Other | DrugAdministrationRoute | CC BY | 33724391 | 19,062,341 | 2021-03-01 |
What was the dosage of drug 'BUPIVACAINE'? | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
Click here for additional data file.
Supplement 2. Data Sharing Statement
Click here for additional data file. | 266 MG PREPARED AS ONE 1.3% 20ML VIAL IN 60 ML OF PRESERVATIVE?FREE NORMAL (0.9%) STERILE SALINE | DrugDosageText | CC BY | 33724391 | 19,062,341 | 2021-03-01 |
What was the dosage of drug 'SODIUM CHLORIDE'? | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
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Supplement 2. Data Sharing Statement
Click here for additional data file. | 60 ML WITH 266 MG (20 ML) OF EXPAREL FOR A TOTAL VOLUME OF 80 ML | DrugDosageText | CC BY | 33724391 | 19,062,341 | 2021-03-01 |
What was the outcome of reaction 'Death'? | Effectiveness of Standard Local Anesthetic Bupivacaine and Liposomal Bupivacaine for Postoperative Pain Control in Patients Undergoing Truncal Incisions: A Randomized Clinical Trial.
Liposomal bupivacaine for pain relief is purported to last 3 days compared with 8 hours with standard bupivacaine. However, its effectiveness is unknown in truncal incisions for cardiothoracic or vascular operations.
To compare the effectiveness of single-administration standard bupivacaine vs liposomal bupivacaine in patients undergoing truncal incisions.
This randomized clinical trial enrolled patients undergoing sternotomy, thoracotomy, minithoracotomy, and laparotomy from a single cardiovascular surgery department in an academic medical center between November 2012 and June 2018. The study was powered to detect a Cohen effect size of 0.35 with a power of greater than 80%. Data analysis was performed from July to December 2018.
Patients were randomized to standard bupivacaine or liposomal bupivacaine.
Pain was assessed over 3 postoperative days by the Numeric Rating Scale (NRS). Adjunctive opioids were converted to morphine equivalents units (MEU). NRS scores were compared using Wilcoxon rank-sum (3-day area under the curve) and 2-way nonparametric mixed models (daily scale score) to assess time-by-group interaction. Secondary outcomes included cumulative opioid consumption.
A total of 280 patients were analyzed, with 140 in each group (single-administration standard bupivacaine vs liposomal bupivacaine). Mean (SD) age was 60.2 (14.4) years, and 101 of 280 patients (36%) were women. Irrespective of treatment assignment, pain decreased by a mean of approximately 1 point per day over 3 days (β = -0.87; SE = 0.11; mixed model regression P < .001). Incision type was associated with pain with patients undergoing thoracotomy (including minithoracotomy) reporting highest median (interquartile range [IQR]) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (liposomal vs standard bupivacaine, 3 [2-6] vs 3 [1-5]; P = .10, Wilcoxon rank-sum), irrespective of treatment group. Median (IQR) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum) Furthermore, use of opioids was greater following liposomal bupivacaine compared with standard bupivacaine (median [IQR], 41.5 [21.3-73.8] MEU vs 33.0 [17.8-62.5] MEU; P = .03, Wilcoxon rank-sum). On multivariable analysis, no interaction by incision type was observed for mean pain scores or opioid use.
In this randomized clinical trial involving truncal incisions for cardiovascular procedures, liposomal bupivacaine did not provide improved pain control and did not reduce adjunctive opioid use compared with conventional bupivacaine formulation over 3 postoperative days.
ClinicalTrials.gov Identifier: NCT02111746.
Introduction
More than 80% of patients undergoing surgical procedures report acute postoperative pain, with less than half achieving adequate postoperative pain control, and nearly 75% of those reporting the severity as moderate, severe, or extreme.1,2,3,4 This is especially true in open heart, aortic, and lung surgical procedures, where painful truncal incisions are required. Adequate postoperative pain management improves the functional recovery and healing period but also contributes to reduction in postsurgical complication risk and faster patient mobilization, thereby reducing the hospital length of stay and health care costs.5,6
Short duration of action is a common drawback of most perioperative pain management regimens, including local anesthetic infiltrations lasting for less than 8 hours.6,7 An injectable extended-release bupivacaine formulation lasting up to 72 hours has gained popularity. Several studies8,9,10,11,12 on various surgical procedures, including hemorrhoidectomy, bunionectomy, mastectomy, and orthopedic surgery, reported a reduction in postoperative pain (up to 30%) and opioid use following intraoperative use of liposomal bupivacaine compared with placebo and active control. One study13 integrated the data from 10 randomized, double-blind studies using liposomal bupivacaine via local wound infiltration to assess the efficacy in postoperative pain control and demonstrated substantially prolonged reduction of postsurgical pain, with a greater proportion of patients avoiding use of opioid rescue medication and a lower total opioid consumption over 72 hours in 5 surgical models. A more recent trial14 showed no difference in opioid use within 48 hours after laparotomy for gynecologic surgery.
Few studies analyze liposomal bupivacaine efficacy in postoperative pain management for major truncal procedures, including vascular, cardiac, laparotomy, and/or thoracic surgical wounds. One trial15 evaluated parasternal nerve blockade and found minimal differences between liposomal bupivacaine vs saline. Most studies using long-acting local anesthesia were done for smaller incisions that did not penetrate the chest or abdominal cavities. We conducted a masked, randomized clinical trial to evaluate the effectiveness of liposomal bupivacaine for postoperative pain control following truncal incisions.
Methods
Study Design
The study was designed as a randomized, masked, active-controlled, parallel-group clinical trial performed at a single institution between November 2012 and June 2018. The study was approved by the University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects. The study conduct and safety was monitored by an independent data safety monitoring board, composed of 2 surgeons with clinical research master’s degrees, an anesthesiologist, and a chaplain, that met periodically during the course of the trial. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline (Figure 1).16 The trial protocol is shown in Supplement 1.
Figure 1. CONSORT Diagram of Participant Flow Through Study
Because both drug formulations are labeled for use in surgical wound pain control and are in common use for this indication, this was considered to be a comparative effectiveness study, and no support from industry was sought or obtained. Treatment allocation was masked to the patient, the postoperative nursing staff, and the research coordinator conducting the pain and quality of life assessments. Because the appearance of the study drug is different between the liposomal and standard formulations, we did not attempt to mask the treatment group to the surgeon administering the treatment. Most often this was a fellow who had been specifically trained to infiltrate the treatment in a standardized fashion, rather than the attending surgeon. Two separate study coordinators were involved in each case: an unmasked coordinator who obtained the randomization code, consulted with the treating physician, and arranged for the order from the pharmacy, and a masked coordinator who saw the patient daily after surgery and made the postoperative pain scale assessments. Supplemental opioid use was abstracted from the electronic medical record by research personnel masked to group assignment and included all supplemental analgesics delivered by patient-controlled analgesia pump, parenteral injection, or oral route of administration.
Eligibility and Enrollment
Patients aged 18 years or older who required surgery involving 1 of 4 eligible incisions (median sternotomy, laparotomy, thoracotomy, or minithoracotomy) were eligible to participate. Patients were excluded if they had known allergy to bupivacaine or any opioid, or had long-term opioid exposure or a chronic pain disorder that would make them difficult to evaluate for effectiveness of pain control. Conditions that conferred high probability of postoperative morbidity that could interfere with communication of pain status, such as expectation of intubation for more than 24 hours or altered mental status, were also exclusionary. Signed triplicate consent documents were obtained preoperatively, and adequate time was given to allow for patient and family deliberation. Original documents were included in the physical paper record during the admission. Active participation (assessment of pain and opioid use) was continued for 3 postoperative days. Complication occurrence was monitored for the entire period of hospitalization.
Administration of Study Drug
Surgery was performed according to routine practice in our group, and no alterations other than treatment with the study drug were made. The 2 treatments were the standard form of bupivacaine hydrochloride (HCl) suspension and a liposomal bupivacaine suspension. Patients in both groups received the same injected volume, 80 mL, divided into 4 20-mL syringes using 22-gauge needles. The liposomal bupivacaine group received a total dose of 266 mg prepared as one 1.3% 20-mL vial of liposomal bupivacaine diluted in 60 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. The nonliposomal bupivacaine group received a total dose of 125 mg of bupivacaine HCl prepared as one 0.25% 50 mL or five 0.25% 10-mL vials, diluted in 30 mL of preservative-free normal (0.9%) sterile saline for a total volume of 80 mL. At the time of wound closure, the assigned treatment was infiltrated by injection into the tissue surrounding the wound.
Statistical Analysis
Sample size determination was based on a Cohen effect size of 0.35, which is considered the lower end of the medium effect size range, and for the primary end point would translate to a between-treatment difference of roughly 2.5 scale points for the area under the curve (AUC).17 A previous randomized, placebo-controlled trial12 for pain management following hemorrhoidectomy demonstrated a Cohen effect size of 0.54, considered a large-medium effect, so we used a smaller hypothesized effect size for our active-controlled trial to ensure adequate power.17 We planned 2 interim analyses using the α spending function of O’Brien and Fleming18 and determined that a total sample size of 280 evaluable participants would require a final α of 0.0462 to return β = 0.17. The study was not powered to identify differences between incision types, although the randomization was stratified by incision type to ensure balanced treatment allocation within each incision. The randomization schedule was developed using a computer program in blocks of 4 to 6.
Stopping rules were prespecified, with P < .0002 required at the first interim analysis and P < .012 at the second to stop for efficacy. Sample size was calculated using PASS statistical software version 13 (NCSS, LLC). Stopping for safety, had it been necessary, would have been a determination made by the data safety monitoring board.
The primary end point was incisional pain over the first 3 postoperative days as recorded on the Numeric Rating Scale (NRS), an 11-point ordinal scale ranging from 0 (no pain) to 10 (worst pain imaginable).19,20,21,22 We considered an NRS score greater than 4 as poorly controlled pain and a change in 2 points to be clinically meaningful.23 Participants were asked to self-aggregate their pain during the previous 24 hours using the NRS. Secondary end points were scores on the Brief Pain Inventory (BPI),24,25 patient satisfaction with postoperative pain ratings (using a 5-point Likert scale, where 1 = extremely dissatisfied, 2 = somewhat dissatisfied, 3 = neutral, 4 = somewhat satisfied, and 5 = extremely satisfied), and cumulative opioid analgesic consumption over the first 3 postoperative days. We also evaluated postoperative length of stay, postoperative complications, and mortality. The pain scales are all ordinal and so were compared in univariate analysis using the Wilcoxon rank-sum statistic. NRS was collected at predetermined intervals at least 4 times in the first 8 hours after surgery. Nursing staff recorded hourly NRS in the cardiovascular intensive care units and every 4 hours in the cardiovascular intermediate care unit. Masked study coordinators queried participants on aggregated daily NRS and administered the BPI and 5-point satisfaction questionnaires once a day. Comparisons were made each day, and the AUC for the NRS over the cumulative 3-day period was also computed using the trapezoidal rule. If pain assessments were missed or patients were discharged before postoperative day 3, imputation of the nonmissing value nearest in time was used (last carried forward method). All supplementary analgesics, including both intravenous and oral opioids, were converted to standard morphine equivalent units (MEU) using a software tool developed in Oregon under a CDC cooperative agreement.39 Our service generally did not use nonsteroidal anti-inflammatory medications postoperatively because of the prevalence of kidney insufficiency in our patient population. We encouraged Dilaudid as our preferred opioid for breakthrough pain to simplify the analysis, but other opioids were not withheld if prescribed. Daily measures were compared using Wilcoxon rank-sum test and were further assessed for treatment-by-day interaction using nonparametric longitudinal mixed models with unstructured error terms. Main effects of day, treatment, and treatment-by-day interaction were modeled using fixed effects, with a random subject effect to account for within-subject clustering. For these models, P values are computed on ranked dependent variable data, and estimates are modeled using untransformed continuous values. The association between 72-hour pain score and opioid use was analyzed by fixed-effects generalized linear model with interaction. Lengths of stay for intensive care unit and total hospitalization were log-transformed for regression-based analysis but were analyzed by Wilcoxon rank-sum test for univariate comparisons, as were analgesics. If patients could not be assessed for pain because of prolonged intubation and sedation, they were excluded from the length-of-stay analysis. Complication frequencies were compared using contingency table tests, including the χ2 test where expected value assumptions were met and Fisher exact tests where expected cell frequencies were less than 5. P < .05 was considered significant and all tests were 2-sided. Data were analyzed using SAS statistical software version 9.4 (SAS Institute) from July to December 2018.
Results
We randomized 338 individuals to reach 280 evaluable patients, with 140 assigned to each treatment, standard vs liposomal bupivacaine (Figure 1). Mean (SD) age was 60.2 (14.4) years, and 36% (101 of 280) were women. Mean (SD) incision length was 194.3 (96.4) mm. Pretreatment characteristics are presented in the Table.
Table. Characteristics and Results of Liposomal Bupivacaine Group vs Standard Bupivacaine Groupa
Variable Patients, No. (%) RR (95% CI)c P valuec
Liposomal bupivacaine (n = 140)b Standard bupivacaine (n = 140)b
Preoperative and baseline characteristics
Age, mean (SD), y 60.3 (14.6) 60.1 (14.2) NA NA
Incision length, mean (SD), mm 201 (102.9) 187.7 (89.4) NA NA
Women 44 (31) 57 (41) NA NA
Prior
Laparotomy 20 (14) 20 (14) NA NA
Thoracotomy 3 (2) 3 (2) NA NA
Sternotomy 18 (13) 10 (7) NA NA
Congestive heart failure 22 (16) 22 (16) NA NA
Known kidney disease 15 (11) 21 (15) NA NA
Coronary artery disease 77 (55) 80 (57) NA NA
Chronic obstructive pulmonary disease 22 (16) 18 (13) NA NA
Dyslipidemia 92 (66) 86 (61) NA NA
Hypertension 118 (84) 118 (84) NA NA
Diabetes 47 (34) 44 (31) NA NA
Body mass index, mean (SD)d 34.5 (45.0) 29.8 (9.4) NA NA
Baseline glomerular filtration rate, mL/min/1.73 m2 99.0 (50.2) 90.4 (40.4) NA NA
Chronic kidney disease stage NA NA
1 71 (51) 61 (43)
2 39 (28) 50 (36)
3 16 (11) 14 (10)
3b 6 (4) 5 (4)
4 3 (2) 3 (2)
5 5 (4) 7 (5)
Intraoperative and clinical outcomes
Type of incision laparotomy 8 (6) 10 (7) NA NA
Minithoracotomy 19 (14) 18 (13)
Sternotomy 98 (70) 99 (71)
Thoracotomy 15 (11) 13 (9)
Redo 15 (11) 9 (6) 1.39 (0.82-2.36) NA
Extubated in OR 16 (11) 18 (13) 0.93 (0.67-1.32) NA
Postoperation
Kidney complications 16 (11) 17 (12) 0.97 (0.68-1.38) .85
Cardiac complications 56 (40) 46 (33) 1.17 (0.91-1.51) .21
Hypotension 70 (50) 66 (47) 1.06 (0.84-1.34) .63
Infective complications 17 (12) 25 (18) 0.82 (0.61-1.08) .18
Bleeding complications 34 (24) 33 (24) 1.02 (0.77-1.35) .89
Vomiting 11 (8) 10 (7) 1.05 (0.66-1.68) .82
Nausea 9 (6) 9 (6) 1.00 (0.62-1.61) >.99
Gastrointestinal complications 19 (14) 20 (14) 0.97 (0.70-1.35) .86
Wound complications 0 2 (1) 0.50 (0.44-0.56) .50
ICU length of stay, d 3 (2-4) 3 (2-5) NA .91
Hospital length of stay, d 8 (6-13) 8 (6-12) NA .45
Postoperative pain scores
NRS
POD 1 5 (3-8) 5 (3.5-7) NA .70
POD 2 5 (3-6) 4 (2-6) NA .04
POD 3 3 (2-5) 3 (1-4.5) NA .08
Cumulative NRS (POD 1-3) 13.5 (9-17) 12 (8-16.5) NA .15
BPI: worst pain
POD 1 9 (6-10) 8 (6-10) NA .54
POD 2 8 (5-9) 7 (5-9) NA .21
POD 3 6 (4-8) 5 (3-8) NA .11
BPI: least pain
POD 1 3 (1-5) 3 (1-5) NA .38
POD 2 2 (0-4) 2 (0-4) NA .10
POD 3 1.5 (0-3) 0 (0-3) NA .07
BPI: average pain
POD 1 5 (4-7) 5 (4-7) NA .97
POD 2 5 (3-6) 4 (2-6) NA .15
POD 3 4 (2-6) 3 (1-5) NA .049
BPI: pain right now
POD 1 4 (2-7) 5 (2-7) NA .35
POD 2 4 (1-6) 3 (1-5) NA .12
POD 3 2 (0-5) 1 (0-4) NA .08
5-point satisfaction
POD 1 4.5 (4-5) 5 (4-5) NA .93
POD 2 5 (4-5) 5 (4-5) NA .80
POD 3 5 (4-5) 5 (4-5) NA .21
Postoperative opioid consumption
MEU, POD1 16.9 (8.3-33.4) 11.7 (5-25.7) NA .04
Dilaudid, mg, POD 1 0 (0-3.2) 0 (0-2.6) NA .63
Fentanyl, μg, POD 1 75 (25-175) 50 (25-137.5) NA .23
Morphine, mg, POD 1 0 (0-0.3) 0 (0-0.6) NA .86
Acetaminophen, mg, POD 1 1000 (0-3000) 1000 (0-2000) NA .26
MEU, POD 2 11.3 (3.4-20.9) 10.7 (2.9-22.5) NA .87
Dilaudid, mg, POD 2 0 (0-3.6) 0 (0-3.5) NA .53
Fentanyl, μg,POD 2 0 (0-0) 0 (0-0) NA .82
Morphine, mg, POD 2 10 (0-37.5) 10 (0-30) NA .51
Acetaminophen, mg, POD 2 1625 (650-3000) 1000 (325-2600) NA .01
MEU, POD 3 7.5 (1.9-13.5) 6.3 (1.9-11.7) NA .29
Dilaudid, mg, POD 3 0 (0-0.1) 0 (0-0) NA .07
Fentanyl, μg, POD 3 0 (0-0) 0 (0-0) NA .95
Morphine, mg, POD 3 15 (0-36.8) 20 (0-34.5) NA .70
Acetaminophen, mg, POD 3 1000 (0-2350) 1300 (325-1975) NA .56
MEU total 41.5 (21.3-73.8) 33 (17.8-62.5) NA .03
Abbreviations: BPI, brief pain inventory; ICU, intensive care unit; MEU, morphine equivalent units; NRS, numeric rating scale; OR, operating room; POD, postoperative day.
a Continuous variables, including age, baseline glomerular filtration rate, body mass index, and incision length, are reported as mean (SD). Pain scores and opioid drug doses and morphine equivalent units are reported as median (interquartile range: 25th percentile to 75th percentile) with P values reporting nonparametric (Wilcoxon rank-sum) tests.
b Categorical variables are reported as No. (%).
c Measure of association refers to Wilcoxon P values for ordinal or nonnormally distributed variables, and risk ratio with 95% CIs is shown for categorical variables.
d Body mass index is calculated as weight in kilograms divided by the square of height in meters.
All patients received their allocated treatment, and there were no follow-up losses in this hospital-based study. The most common reason for exclusion after randomization was prolonged intubation or reintubation after surgery; these patients were sedated such that pain scores could not be obtained. We paused enrollment at the end of 2013 because of staffing turnovers and began recruiting again in 2015 when staffing levels stabilized. The majority of patient recruitment was obtained from 2015 to 2017.
Six patients in the standard bupivacaine group and 3 in the liposomal bupivacaine group had a missing primary end point pain assessment (NRS) on 1 of the postoperative days, and those data points were imputed—a total of 9 data points imputed in 840 measurements (280 patients with 3 postoperative pain measurements each), for an imputation rate of approximately 1%. Two of those imputed were day 2 discharges, and the imputed day 3 score for the bupivacaine patient was 2 and for the liposomal bupivacaine patient was 0 (last observation carried forward). The median (interquartile range [IQR]) 3-day cumulative NRS was 12.0 (8.0-16.5) for bupivacaine and 13.5 (9.0-17.0) for liposomal bupivacaine (P = .15, Wilcoxon rank-sum). Daily values for the pain scales are shown in the Table. In general, according to unpaired daily comparisons, pain scale scores did not differ between groups over the 3-day time period. There was also no difference in satisfaction with pain control on the basis of the 5-point satisfaction questionnaire (Table). Nonparametric mixed models showed no significant main effect for standard vs liposomal (β = –0.46; SE = 0.29; P = .23) and a significant main effect for postoperative day (β = –0.87; SE = 0.11; P < .001), indicating that the treatments did not differ overall but that pain scores decreased significantly over the 3-day observation period. The term for treatment-by-day interaction was significant (P = .03), indicating that the decline in postoperative pain scores was more rapid in the standard bupivacaine group (Figure 2).
Figure 2. Numeric Rating Scale (NRS) Mixed Model
NRS scores are shown by group over 3 days. No main effect of treatment (P = .23) was observed, but significant main effect of day (P < .001) and significant treatment-by-day interaction (P = .03) were present, indicating that rate of pain reduction was greater in the standard bupivacaine group over three postoperative days. Models shown are pain scores; P values are from mixed models of ranked data with unstructured error terms. Lines denotes regression function and shaded areas denote 95% CIs.
Median (IQR) total opioid use was 33.0 (17.8-62.5) MEU in the standard bupivacaine group and 41.5 (21.3-73.8) MEU in the liposomal bupivacaine group (P = .03, Wilcoxon rank-sum) during 3 postoperative days. Daily values for supplemental opioid use are shown in the Table. In general, opioid use was not different between groups during the study period, although total opioid use and opioid use on postoperative day 1 was higher in the liposomal bupivacaine group (median [IQR], 16.9 [8.3-33.4] MEU vs 11.7 [5-25.7] MEU; P = .04, Wilcoxon rank-sum]. This effect faded by postoperative day 2 (11.3 [3.4-20.9] MEU vs 10.7 [2.9-22.5] MEU; P = .87, Wilcoxon rank-sum) and postoperative day 3 (7.5 [1.9-13.5] MEU vs 6.3 [1.9-11.7] MEU; P = .29, Wilcoxon rank-sum). In nonparametric mixed model analysis, the main effect of drug was not significant (standard vs liposomal, β = –2.62; SE = 1.45; P = .12), but the main effect of postoperative day was significant (β = –17.8; SE = 2.4; P < .001) and treatment-by-day interaction was not significant (P = .29). This indicates that treatment effects of supplemental opioid use did not differ between groups overall, that it did decline significantly over the 3 postoperative day observation period, and that the rate of decline between the treatment groups did not differ (Figure 3). One patient in each treatment group was discharged on postoperative day 2, but both were not taking any opioid pain medications at the time of discharge.
Figure 3. Opioid Use Mixed Model
Opioid dose (parenteral morphine equivalents) is shown by group over 3 days postoperatively. No main effect of treatment (P = .12) or treatment-by-day interaction (P = .29) was observed, but a significant effect of day (P < .001) was. Hence, reduction in supplemental opioid use over 3 days is significant but does not depend on formulation of bupivacaine. Models shown are opioid doses; P values are from mixed models of ranked data with unstructured error terms. A pairwise contrast at day 1 is statistically significant (P = .04, Wilcoxon rank-sum). Lines denotes regression function and shaded areas denote 95% CIs.
Pain score was associated with supplemental opioid use at all time points and accounted for slightly more than 10% of the variance overall. In general, linear model regression analysis, model terms for effect of pain score (SE) were significant (β = 2.56 [0.55] MEU/NRS unit; P < .001), but treatment group (β = 6.02 [11.12] MEU increase in standard vs liposomal; P = .59) and treatment-by-pain interaction (P = .08) were not statistically significant. This indicates that, although opioid use depended on perceived pain, the formulation of bupivacaine administered did not modify this association. In other words, liposomal bupivacaine did not significantly reduce opioid use for a given level of pain compared with standard bupivacaine (Figure 4).
Figure 4. Effect of Cumulative Pain Rating on Cumulative Opioid Use—General Linear Model
Opioid consumption is positively correlated with pain (P < .001), with pain accounting for approximately 10% of the variance in opioid use (multiple R2 = 0.109). Main effect of treatment is not significant. No modification of the effect by liposomal bupivacaine relative to standard bupivacaine is evident (P for interaction P = .08). Lines denotes regression function and shaded areas denote 95% CIs.
Incision length did not differ between groups, and no incision length-by-treatment interaction was observed. Total NRS-reported pain was higher for thoracotomy incisions (thoracotomy and minithoracotomy combined) than the other incision types (14 [12-17] for thoracotomy vs 12 [8-17] for other incisions; P = .006, Wilcoxon rank-sum). Total opioid use was not different (38.8 [15.8-66.3] for thoracotomy vs 38.4 [20.0-68.1] for other incisions; P = .73, Wilcoxon rank-sum). Incision type was associated with pain with thoracotomy group reporting highest median (IQR) pain scores on postoperative days 1 (liposomal vs standard bupivacaine, 6 [4-8] vs 5 [3-7]; P = .049, Wilcoxon rank-sum) and 2 (liposomal vs standard bupivacaine, 5 [4-7] vs 4 [2-6]; P = .003, Wilcoxon rank-sum) but not day 3 (3 [2-6] vs 3 [1-5], P = .10, Wilcoxon rank-sum), irrespective of treatment group. No thoracotomy-by-treatment interaction was identified for pain (P for interaction = .06) or opioid use (P for interaction = .71). Because 70% of the incisions were sternotomies, we also performed a subgroup analysis within sternotomy and nonsternotomy groups. The findings were consistent with the overall findings of significant reduction in pain across the 3 postoperative days, but there were no differences in drug effect. In the nonsternotomy group (thoracotomy, minithoracotomy, and laparotomy), liposomal formulation was associated with less pain control than standard formulation (β = –1.14; SE = 0.57; P = .01), but no treatment-by-day interaction was identified.
No differences were observed in postoperative complications between the groups (Table). Neither intensive care unit length of stay nor hospital length of stay was significantly different between groups. There was 1 hospital death, which occurred in the standard formulation group.
Discussion
Effective surgical pain control is an important treatment goal, reduces morbidity, and improves return to activity and to work.26,27,28 It is also a major patient-centered outcome and an important factor in patient satisfaction and quality of life. Increasingly, development and implementation of opioid-reducing pain management strategies is a substantial public health issue given the scope and scale of the opioid abuse crisis in the US. This is of particular concern for major truncal procedures. Several recent studies demonstrated that many patients are still using opioids many months after surgery.29,30 Studies have also shown that postsurgical exposure may increase addiction risk and that even family members of long-term opioid users may be at increased risk for long-term use after their own surgical procedures.29,30,31,32,33 Improved methods for controlling pain that can minimize opioid use in the postoperative setting are needed, and multimodal nonopioid pain control, including local analgesia, is an important element in a comprehensive pain management strategy.27,34
Epidural anesthesia can also play a role in certain truncal incisions, but it is not useful for sternotomies or superiorly placed thoracotomy incisions. Epidural anesthesia adversely affects neurological examination after open aortic surgery. Nevertheless, although our service does not routinely use epidural anesthesia, it can be a useful pain control adjunct in selected cases. Placement of thoracic epidural catheters typically does not reside with the surgical team. The advantage of surgeon-administered local anesthesia is that it is fast, easy, and available. We use local anesthesia as part of a successful multimodal regimen that includes nonopioid oral pain medications, gabapentin, locoregional nerve blocks, and dexmedetomidine infusion.34
Our goal was to determine whether liposomal bupivacaine would improve the intensity and duration of postoperative pain in major truncal surgery as it has been reported to do in other nontruncal orthopedic, cosmetic, and colorectal indications,8,9,10,11,12,13,15,35 and whether it could also reduce reliance on opioid medications. In this randomized clinical trial involving 280 patients with 4 different types of chest and abdominal incisions, which, to our knowledge, is the largest study of its kind yet to be reported, we were unable to identify any clinically important difference in pain, supplemental opioid use, morbidity, or length of stay between liposomal and standard formulations of bupivacaine. We did observe significant reductions in pain and opioid use in both groups over 3 postoperative days, and also found that the NRS scores were reduced at a more rapid rate in the bupivacaine HCl group (Figure 2). For major truncal surgery in the setting of a large academic medical center, the findings of this study do not support the hypothesized superiority of liposomal bupivacaine over standard bupivacaine HCl.
The literature on the efficacy of liposomal bupivacaine vs conventionally formulated bupivacaine is equivocal, with multiple publications concluding that liposomal bupivacaine is superior to standard bupivacaine, and others that it is no better. In one case, liposomal bupivacaine was no better even than placebo for the sternotomy indication with respect to supplemental opioid sparing.15 Reviews in the orthopedic surgery literature36,37 also concluded that liposomal bupivacaine performed no better than controls. A recent Cochrane review38 concluded that the quality of the literature was poor, and that the limited evidence available does not demonstrate superiority of liposomal bupivacaine over standard bupivacaine HCl. Our project was designed to be a clinical comparative effectiveness study, performed under typical surgical conditions in an academic medical center, and without industry support. The Cochrane review authors38 downgraded their assessment of evidence quality in assessment of liposomal bupivacaine relative to standard bupivacaine because of the small-sample treatment sets in most of the published studies and also the unclear risk of bias attributable to the financial ties of the research teams and the editorial process to the manufacturer. The Cochrane review authors38 also highlighted the disagreement between their review and two other previously published reviews13,35 and point out that this can be attributed to heterogeneity in research designs, surgical procedures and, again, financial relationships.
Limitations
There were several limitations in the study. First, in the study design, we anticipated approximately equivalent numbers of incision types. In practice, we performed more sternotomies and fewer thoracotomies and laparotomies. This reflected a global trend toward increasing endovascular repair for thoracic and thoracoabdominal aortic aneurysms with fewer open aortic surgical procedures. Second, there is variability in technique, speed, and surgeon skill that may make our single-center results not fully replicable in other centers. The absolute pain scores are likely not generalizable because of different pain management regimens used by different groups. However, the comparison and effect size differences will still be useful. Third, although we attempted to standardize the administration of local anesthesia, there may be small differences between surgeons who performed more sternotomies compared with those who performed thoracotomies and laparotomies. Randomization and stratification by incision type should mitigate these limitations. Fourth, the postoperative pain assessments were done by coordinators masked to treatment assignment, but we could not blind the surgical team administering the local anesthesia. Liposomal bupivacaine has a white, milky appearance whereas standard bupivacaine is clear. Our institutional review board would not allow blinding of the operating room team because of concerns about confusing the study drugs and other drugs with the same appearance, such as propofol. Furthermore, local anesthesia was given at the conclusion of the operation. Some investigators preferred to administer local anesthesia prior to incision. We decided that this would complicate cases where the incision required lengthening for greater exposure. This should not affect the comparison because both groups received anesthesia in the same manner. This study did take longer than anticipated to conduct given the 2-year enrollment hiatus previously described. However, randomization was balanced by blocking every 4 to 6 participants, so any secular trends in pain management would have been absorbed equally into the treatment groups by design.
Fifth, some patients could not be evaluated after randomization because of unanticipated events such as prolonged intubation, so this is not strictly speaking an intent-to-treat analysis. The only randomized patients excluded from the analysis were those who did not have evaluable data, for example, because of prolonged intubation and inability to elicit pain scores. We would have included data for these patients if they existed. As a practical matter, a per protocol analysis is less conservative and, hence, reduces the likelihood of making a type 2 error, which in a negative study such as this would be the greater concern than the type 1 error intent-to-treat protocols are meant to guard against.
Conclusions
The heterogeneity of the findings reported in the literature, and the low quality of the evidence either for or against the use of liposomal vs conventional formulations of bupivacaine, underscores the importance of independent comparative effectiveness research, performed with high methodological standards (randomized, masked designs with large enough samples to control small-sample bias) by independent teams of investigators. The results of this study do not support the use of the more expensive liposomal formulation over the standard formulation of bupivacaine for postoperative pain control in major truncal surgery.
Supplement 1. Trial Protocol
Click here for additional data file.
Supplement 2. Data Sharing Statement
Click here for additional data file. | Fatal | ReactionOutcome | CC BY | 33724391 | 19,062,343 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug resistance'. | Improvement of Somatic Delusions with Altered Regional Cerebral Blood Flow Following Electroconvulsive Therapy in a Patient with Schizoaffective Disorder.
BACKGROUND Somatic delusions are false and fixed beliefs about health and organ function, which are observed in various psychiatric disorders. Psychotropic drugs such as antipsychotics and antidepressants are effective for some patients, while the efficacy of electroconvulsive therapy (ECT) for pharmacotherapy-resistant cases has been reported. Previous reports suggest that somatic delusions in delusional disorder somatic type are associated with reduced regional cerebral blood flow (rCBF), but it remains unclear whether this association is also observed in other psychiatric disorders. We report the case of a patient with schizoaffective disorder whose drug-resistant somatic delusions showed remarkable improvement accompanied by altered rCBF after successful ECT. CASE REPORT The patient was a Japanese man aged 52 years with a diagnosis of schizoaffective disorder. He was suffering from severe and persistent somatic delusions such as "There is a thick stick or bowl in my head" and "Something like a film stretches over my head and face", which were resistant to several antipsychotics and antidepressants. In our hospital, he received bitemporal ECT 8 times. His somatic delusions started to improve from the third administration, and they disappeared by the eighth administration. In parallel with this clinical improvement, reduction of rCBF in the bilateral parietal and occipital lobes observed before ECT disappeared. CONCLUSIONS The present study suggests that ECT is a useful choice for drug-resistant somatic delusions. Reduction of rCBF in the bilateral parietal and occipital lobes may be associated with manifestation of somatic delusions in schizoaffective disorder.
Background
Somatic delusions are false and fixed beliefs focusing on health and organ function, and are observed most often in schizophrenia, schizoaffective disorder, and delusional disorder somatic type (DDST) [1]. These delusions cause enormous anguish, and sometimes lead to suicide [2]. Psychotropics such as antipsychotics [2–4] and antidepressants [5,6] are efficacious for some patients. For pharmacotherapy-resistant cases in DDST [7], bipolar disorder [8], and schizophrenia [9], electroconvulsive therapy (ECT) has been reported to be effective.
In several reports on DDST, changes in regional cerebral blood flow (rCBF) after successful treatments with psychotropics [4-6] or ECT [7] have been presented. These reports consistently suggest that somatic delusions in DDST are associated with reduced rCBF. However, it remains unclear whether this association between somatic delusions and reduced rCBF is also observed in other psychiatric disorders.
Here, we report the case of a patient with schizoaffective disorder whose drug- resistant somatic delusions showed remarkable improvement accompanied by altered rCBF after successful ECT.
Case Report
The patient was a Japanese man aged 52 years at the time of presentation to our clinic. Written consent for the publication of this report was obtained from the patient. After graduating from a university, he had been working as a public servant. In April 2018, at the age of 51, he developed depressed mood, diminished pleasure, decrease in appetite, insomnia, anxiety, and loss of energy. He visited a psychiatric clinic, and was diagnosed with major depressive disorder. Treatment with mirtazapine 15–45 mg/day was partly effective. In September 2018, he developed somatic delusions, such as “There is a thick stick or bowl in my head which goes up and down or turns around” and “Something like a film stretches over my head and face and moves like gills of a fish”. Switching from mirtazapine to paroxetine 40 mg/day was not effective. Addition of aripiprazole 9 mg/day was ineffective and caused bradykinesia.
In June 2019, at the age of 52, he was referred to our clinic. In addition to the somatic delusions mentioned above, affective flattening and avolition were observed. Although he complained of diminished interest and mild concentration difficulty, he did not have depressed mood, decreased appetite, insomnia, guilt feelings, or suicidal ideation. No abnormalities were found on brain magnetic resonance imaging and blood tests. Because of the presence somatic delusions for 2 or more weeks in the absence of a major depressive episode, he was diagnosed with schizoaffective disorder according to the DSM-5 criteria [1]. Addition of olanzapine 20 mg/day or brexpiprazole 2 mg/day to paroxetine had no effect and caused body weight gain. Therefore, additional antipsychotics were discontinued.
In November 2019, he was admitted to our hospital to receive ECT because of drug resistance. He complained of marked somatic delusions, but again there were no depressive symptoms. Therefore, paroxetine was gradually reduced to 20 mg/day. Then, he received 8 sessions of bitemporal ECT administered using a Thymatron® system IV machine (Somatics, LLC, Venice, FL, USA). His somatic delusions gradually improved from the third administration of ECT, and disappeared by the eighth administration. In December 2019, he was discharged with residual affective flattening and avolition, but without depressive symptoms. The final diagnosis was schizoaffective disorder [1]. After discharge, paroxetine was gradually switched to risperidone 1 mg/day. As of December 2020, he was still in remission.
Figure 1 shows single-photon emission computed tomography (SPECT) with 99mTc-ethylcysteinate dimer images obtained in November of 2019 before ECT (A) and in December of 2019 after ECT (B). rCBF was reduced in the bilateral cerebral hemispheres when somatic delusions were prominent. After improvement of these by ECT, reduction of rCBF disappeared in the parietal and occipital lobes, but not in the frontal and temporal lobes.
Discussion
In our patient with schizoaffective disorder, ECT induced marked improvement of somatic delusions, which were refractory to extensive pharmacotherapy with antidepressants and antipsychotics. The present report together with other reports for DDST [7], bipolar disorder [8] and schizophrenia [9] suggest that ECT is a useful choice for treatment of drug-resistant somatic delusions.
In line with previous reports on SPECT images before and after treatment [4–7], reduced rCBF was associated with manifestation of somatic delusions. However, in contrast to DDST [4–7] in which the left temporal and parietal lobes are implicated, in the present case of schizoaffective disorder the bilateral parietal and occipital lobes were implicated. On the other hand, a recent study [9] showed hypometabolism in bilateral frontal-parietal-temporal association cortex in a patient of schizophrenia with Cotard’s delusions, which is a cluster of somatic delusions. Therefore, the brain regions responsible for somatic delusions may be different in various psychiatric disorders. Incidentally, our patient’s reduced rCBF in the bilateral frontal and temporal lobes remained after ECT and may be associated with residual affective flattening and avolition, as in schizophrenia [8].
One may wonder if the altered rCBF in the present case was attributable to paroxetine treatment. However, this possibility is unlikely, since the patient was taking paroxetine both before (40 mg/day) and after (20 mg/day) ECT.
There are 2 limitations in this report. Firstly, the absence of a major depressive episode was not confirmed by use of a depression scale such as the Montgomery Asberg Depression Rating Scale [10]. Secondly, the changes in somatic delusions were not evaluated by a specific scale like the Positive and Negative Syndrome Scale [11].
Conclusions
The present report suggests that ECT is a useful choice for treatment of drug-resistant somatic delusions. Reduction of rCBF in the bilateral parietal and occipital lobes may be associated with manifestation of somatic delusions in schizoaffective disorder.
Figure 1. Single-photon emission computed tomography with 99mTc-ethylcysteinate dimer images obtained in November of 2019 (A) and in December of 2019 (B). OM – orbitomeatal plane.
Conflict of Interest
None. | ARIPIPRAZOLE, BREXPIPRAZOLE, MIRTAZAPINE, OLANZAPINE, PAROXETINE | DrugsGivenReaction | CC BY-NC-ND | 33724980 | 19,962,325 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Somatic delusion'. | Improvement of Somatic Delusions with Altered Regional Cerebral Blood Flow Following Electroconvulsive Therapy in a Patient with Schizoaffective Disorder.
BACKGROUND Somatic delusions are false and fixed beliefs about health and organ function, which are observed in various psychiatric disorders. Psychotropic drugs such as antipsychotics and antidepressants are effective for some patients, while the efficacy of electroconvulsive therapy (ECT) for pharmacotherapy-resistant cases has been reported. Previous reports suggest that somatic delusions in delusional disorder somatic type are associated with reduced regional cerebral blood flow (rCBF), but it remains unclear whether this association is also observed in other psychiatric disorders. We report the case of a patient with schizoaffective disorder whose drug-resistant somatic delusions showed remarkable improvement accompanied by altered rCBF after successful ECT. CASE REPORT The patient was a Japanese man aged 52 years with a diagnosis of schizoaffective disorder. He was suffering from severe and persistent somatic delusions such as "There is a thick stick or bowl in my head" and "Something like a film stretches over my head and face", which were resistant to several antipsychotics and antidepressants. In our hospital, he received bitemporal ECT 8 times. His somatic delusions started to improve from the third administration, and they disappeared by the eighth administration. In parallel with this clinical improvement, reduction of rCBF in the bilateral parietal and occipital lobes observed before ECT disappeared. CONCLUSIONS The present study suggests that ECT is a useful choice for drug-resistant somatic delusions. Reduction of rCBF in the bilateral parietal and occipital lobes may be associated with manifestation of somatic delusions in schizoaffective disorder.
Background
Somatic delusions are false and fixed beliefs focusing on health and organ function, and are observed most often in schizophrenia, schizoaffective disorder, and delusional disorder somatic type (DDST) [1]. These delusions cause enormous anguish, and sometimes lead to suicide [2]. Psychotropics such as antipsychotics [2–4] and antidepressants [5,6] are efficacious for some patients. For pharmacotherapy-resistant cases in DDST [7], bipolar disorder [8], and schizophrenia [9], electroconvulsive therapy (ECT) has been reported to be effective.
In several reports on DDST, changes in regional cerebral blood flow (rCBF) after successful treatments with psychotropics [4-6] or ECT [7] have been presented. These reports consistently suggest that somatic delusions in DDST are associated with reduced rCBF. However, it remains unclear whether this association between somatic delusions and reduced rCBF is also observed in other psychiatric disorders.
Here, we report the case of a patient with schizoaffective disorder whose drug- resistant somatic delusions showed remarkable improvement accompanied by altered rCBF after successful ECT.
Case Report
The patient was a Japanese man aged 52 years at the time of presentation to our clinic. Written consent for the publication of this report was obtained from the patient. After graduating from a university, he had been working as a public servant. In April 2018, at the age of 51, he developed depressed mood, diminished pleasure, decrease in appetite, insomnia, anxiety, and loss of energy. He visited a psychiatric clinic, and was diagnosed with major depressive disorder. Treatment with mirtazapine 15–45 mg/day was partly effective. In September 2018, he developed somatic delusions, such as “There is a thick stick or bowl in my head which goes up and down or turns around” and “Something like a film stretches over my head and face and moves like gills of a fish”. Switching from mirtazapine to paroxetine 40 mg/day was not effective. Addition of aripiprazole 9 mg/day was ineffective and caused bradykinesia.
In June 2019, at the age of 52, he was referred to our clinic. In addition to the somatic delusions mentioned above, affective flattening and avolition were observed. Although he complained of diminished interest and mild concentration difficulty, he did not have depressed mood, decreased appetite, insomnia, guilt feelings, or suicidal ideation. No abnormalities were found on brain magnetic resonance imaging and blood tests. Because of the presence somatic delusions for 2 or more weeks in the absence of a major depressive episode, he was diagnosed with schizoaffective disorder according to the DSM-5 criteria [1]. Addition of olanzapine 20 mg/day or brexpiprazole 2 mg/day to paroxetine had no effect and caused body weight gain. Therefore, additional antipsychotics were discontinued.
In November 2019, he was admitted to our hospital to receive ECT because of drug resistance. He complained of marked somatic delusions, but again there were no depressive symptoms. Therefore, paroxetine was gradually reduced to 20 mg/day. Then, he received 8 sessions of bitemporal ECT administered using a Thymatron® system IV machine (Somatics, LLC, Venice, FL, USA). His somatic delusions gradually improved from the third administration of ECT, and disappeared by the eighth administration. In December 2019, he was discharged with residual affective flattening and avolition, but without depressive symptoms. The final diagnosis was schizoaffective disorder [1]. After discharge, paroxetine was gradually switched to risperidone 1 mg/day. As of December 2020, he was still in remission.
Figure 1 shows single-photon emission computed tomography (SPECT) with 99mTc-ethylcysteinate dimer images obtained in November of 2019 before ECT (A) and in December of 2019 after ECT (B). rCBF was reduced in the bilateral cerebral hemispheres when somatic delusions were prominent. After improvement of these by ECT, reduction of rCBF disappeared in the parietal and occipital lobes, but not in the frontal and temporal lobes.
Discussion
In our patient with schizoaffective disorder, ECT induced marked improvement of somatic delusions, which were refractory to extensive pharmacotherapy with antidepressants and antipsychotics. The present report together with other reports for DDST [7], bipolar disorder [8] and schizophrenia [9] suggest that ECT is a useful choice for treatment of drug-resistant somatic delusions.
In line with previous reports on SPECT images before and after treatment [4–7], reduced rCBF was associated with manifestation of somatic delusions. However, in contrast to DDST [4–7] in which the left temporal and parietal lobes are implicated, in the present case of schizoaffective disorder the bilateral parietal and occipital lobes were implicated. On the other hand, a recent study [9] showed hypometabolism in bilateral frontal-parietal-temporal association cortex in a patient of schizophrenia with Cotard’s delusions, which is a cluster of somatic delusions. Therefore, the brain regions responsible for somatic delusions may be different in various psychiatric disorders. Incidentally, our patient’s reduced rCBF in the bilateral frontal and temporal lobes remained after ECT and may be associated with residual affective flattening and avolition, as in schizophrenia [8].
One may wonder if the altered rCBF in the present case was attributable to paroxetine treatment. However, this possibility is unlikely, since the patient was taking paroxetine both before (40 mg/day) and after (20 mg/day) ECT.
There are 2 limitations in this report. Firstly, the absence of a major depressive episode was not confirmed by use of a depression scale such as the Montgomery Asberg Depression Rating Scale [10]. Secondly, the changes in somatic delusions were not evaluated by a specific scale like the Positive and Negative Syndrome Scale [11].
Conclusions
The present report suggests that ECT is a useful choice for treatment of drug-resistant somatic delusions. Reduction of rCBF in the bilateral parietal and occipital lobes may be associated with manifestation of somatic delusions in schizoaffective disorder.
Figure 1. Single-photon emission computed tomography with 99mTc-ethylcysteinate dimer images obtained in November of 2019 (A) and in December of 2019 (B). OM – orbitomeatal plane.
Conflict of Interest
None. | ARIPIPRAZOLE, BREXPIPRAZOLE, MIRTAZAPINE, OLANZAPINE, PAROXETINE | DrugsGivenReaction | CC BY-NC-ND | 33724980 | 19,962,325 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Improvement of Somatic Delusions with Altered Regional Cerebral Blood Flow Following Electroconvulsive Therapy in a Patient with Schizoaffective Disorder.
BACKGROUND Somatic delusions are false and fixed beliefs about health and organ function, which are observed in various psychiatric disorders. Psychotropic drugs such as antipsychotics and antidepressants are effective for some patients, while the efficacy of electroconvulsive therapy (ECT) for pharmacotherapy-resistant cases has been reported. Previous reports suggest that somatic delusions in delusional disorder somatic type are associated with reduced regional cerebral blood flow (rCBF), but it remains unclear whether this association is also observed in other psychiatric disorders. We report the case of a patient with schizoaffective disorder whose drug-resistant somatic delusions showed remarkable improvement accompanied by altered rCBF after successful ECT. CASE REPORT The patient was a Japanese man aged 52 years with a diagnosis of schizoaffective disorder. He was suffering from severe and persistent somatic delusions such as "There is a thick stick or bowl in my head" and "Something like a film stretches over my head and face", which were resistant to several antipsychotics and antidepressants. In our hospital, he received bitemporal ECT 8 times. His somatic delusions started to improve from the third administration, and they disappeared by the eighth administration. In parallel with this clinical improvement, reduction of rCBF in the bilateral parietal and occipital lobes observed before ECT disappeared. CONCLUSIONS The present study suggests that ECT is a useful choice for drug-resistant somatic delusions. Reduction of rCBF in the bilateral parietal and occipital lobes may be associated with manifestation of somatic delusions in schizoaffective disorder.
Background
Somatic delusions are false and fixed beliefs focusing on health and organ function, and are observed most often in schizophrenia, schizoaffective disorder, and delusional disorder somatic type (DDST) [1]. These delusions cause enormous anguish, and sometimes lead to suicide [2]. Psychotropics such as antipsychotics [2–4] and antidepressants [5,6] are efficacious for some patients. For pharmacotherapy-resistant cases in DDST [7], bipolar disorder [8], and schizophrenia [9], electroconvulsive therapy (ECT) has been reported to be effective.
In several reports on DDST, changes in regional cerebral blood flow (rCBF) after successful treatments with psychotropics [4-6] or ECT [7] have been presented. These reports consistently suggest that somatic delusions in DDST are associated with reduced rCBF. However, it remains unclear whether this association between somatic delusions and reduced rCBF is also observed in other psychiatric disorders.
Here, we report the case of a patient with schizoaffective disorder whose drug- resistant somatic delusions showed remarkable improvement accompanied by altered rCBF after successful ECT.
Case Report
The patient was a Japanese man aged 52 years at the time of presentation to our clinic. Written consent for the publication of this report was obtained from the patient. After graduating from a university, he had been working as a public servant. In April 2018, at the age of 51, he developed depressed mood, diminished pleasure, decrease in appetite, insomnia, anxiety, and loss of energy. He visited a psychiatric clinic, and was diagnosed with major depressive disorder. Treatment with mirtazapine 15–45 mg/day was partly effective. In September 2018, he developed somatic delusions, such as “There is a thick stick or bowl in my head which goes up and down or turns around” and “Something like a film stretches over my head and face and moves like gills of a fish”. Switching from mirtazapine to paroxetine 40 mg/day was not effective. Addition of aripiprazole 9 mg/day was ineffective and caused bradykinesia.
In June 2019, at the age of 52, he was referred to our clinic. In addition to the somatic delusions mentioned above, affective flattening and avolition were observed. Although he complained of diminished interest and mild concentration difficulty, he did not have depressed mood, decreased appetite, insomnia, guilt feelings, or suicidal ideation. No abnormalities were found on brain magnetic resonance imaging and blood tests. Because of the presence somatic delusions for 2 or more weeks in the absence of a major depressive episode, he was diagnosed with schizoaffective disorder according to the DSM-5 criteria [1]. Addition of olanzapine 20 mg/day or brexpiprazole 2 mg/day to paroxetine had no effect and caused body weight gain. Therefore, additional antipsychotics were discontinued.
In November 2019, he was admitted to our hospital to receive ECT because of drug resistance. He complained of marked somatic delusions, but again there were no depressive symptoms. Therefore, paroxetine was gradually reduced to 20 mg/day. Then, he received 8 sessions of bitemporal ECT administered using a Thymatron® system IV machine (Somatics, LLC, Venice, FL, USA). His somatic delusions gradually improved from the third administration of ECT, and disappeared by the eighth administration. In December 2019, he was discharged with residual affective flattening and avolition, but without depressive symptoms. The final diagnosis was schizoaffective disorder [1]. After discharge, paroxetine was gradually switched to risperidone 1 mg/day. As of December 2020, he was still in remission.
Figure 1 shows single-photon emission computed tomography (SPECT) with 99mTc-ethylcysteinate dimer images obtained in November of 2019 before ECT (A) and in December of 2019 after ECT (B). rCBF was reduced in the bilateral cerebral hemispheres when somatic delusions were prominent. After improvement of these by ECT, reduction of rCBF disappeared in the parietal and occipital lobes, but not in the frontal and temporal lobes.
Discussion
In our patient with schizoaffective disorder, ECT induced marked improvement of somatic delusions, which were refractory to extensive pharmacotherapy with antidepressants and antipsychotics. The present report together with other reports for DDST [7], bipolar disorder [8] and schizophrenia [9] suggest that ECT is a useful choice for treatment of drug-resistant somatic delusions.
In line with previous reports on SPECT images before and after treatment [4–7], reduced rCBF was associated with manifestation of somatic delusions. However, in contrast to DDST [4–7] in which the left temporal and parietal lobes are implicated, in the present case of schizoaffective disorder the bilateral parietal and occipital lobes were implicated. On the other hand, a recent study [9] showed hypometabolism in bilateral frontal-parietal-temporal association cortex in a patient of schizophrenia with Cotard’s delusions, which is a cluster of somatic delusions. Therefore, the brain regions responsible for somatic delusions may be different in various psychiatric disorders. Incidentally, our patient’s reduced rCBF in the bilateral frontal and temporal lobes remained after ECT and may be associated with residual affective flattening and avolition, as in schizophrenia [8].
One may wonder if the altered rCBF in the present case was attributable to paroxetine treatment. However, this possibility is unlikely, since the patient was taking paroxetine both before (40 mg/day) and after (20 mg/day) ECT.
There are 2 limitations in this report. Firstly, the absence of a major depressive episode was not confirmed by use of a depression scale such as the Montgomery Asberg Depression Rating Scale [10]. Secondly, the changes in somatic delusions were not evaluated by a specific scale like the Positive and Negative Syndrome Scale [11].
Conclusions
The present report suggests that ECT is a useful choice for treatment of drug-resistant somatic delusions. Reduction of rCBF in the bilateral parietal and occipital lobes may be associated with manifestation of somatic delusions in schizoaffective disorder.
Figure 1. Single-photon emission computed tomography with 99mTc-ethylcysteinate dimer images obtained in November of 2019 (A) and in December of 2019 (B). OM – orbitomeatal plane.
Conflict of Interest
None. | ARIPIPRAZOLE, BREXPIPRAZOLE, MIRTAZAPINE, OLANZAPINE, PAROXETINE | DrugsGivenReaction | CC BY-NC-ND | 33724980 | 19,919,515 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Antibiotic susceptibility guided reuse of levofloxacin-based therapy in a penicillin-allergic patient for Helicobacter pylori infection: A case report.
BACKGROUND
Antibiotic resistance poses a challenge for Helicobacter pylori eradication treatment. Current guidelines strongly recommend avoiding repeated treatments with the same antibiotic to prevent the emergence of drug resistance. However, for penicillin-allergic patients with recurrent H. pylori eradication failures, avoiding repeated treatments with the same antibiotic severely limits the choice of treatment.
A 47-year-old woman with a penicillin allergy for whom 2 previous levofloxacin and bismuth-based therapies had failed.
METHODS
H. pylori infection.
METHODS
Agar dilution susceptibility testing and gene sequence analysis was performed to confirm levofloxacin susceptibility again. Therefore, we treated her with a 14-day regimen consisting of levofloxacin (500 mg once daily), furazolidone (100 mg twice daily), colloidal bismuth pectin (220 mg twice daily), and esomeprazole (20 mg twice daily).
RESULTS
The patient was successfully treated with a third levofloxacin and bismuth-based regimen.
CONCLUSIONS
Antibiotics included in previous failed therapies need not be eliminated if no antibiotic resistance is found on antimicrobial susceptibility testing.
1 Introduction
Levofloxacin is a third-generation fluoroquinolone that is widely used in clinical practice. The rate of Helicobacter pylori resistance to levofloxacin has increased with the widespread use of fluoroquinolone antibiotics.[1] A recent review of 66,142 H. pylori isolates from 65 countries demonstrated that the rate of primary and secondary resistance to levofloxacin was more than 15% in all World Health Organization regions.[2] Therefore, consensus reports have suggested that for patients with previous antibiotic exposure, repeated treatment with the same antibiotic should be avoided in order to reduce resistance rates.[1,3,4] However, a retrospective study of 293 patients with a history of 2 failed H. pylori treatments found that clarithromycin-based therapies were repeated in 178 (60.8%) patients, and levofloxacin-based therapies were repeated in 88 (30.0%) patients.[5] Thus, in clinical practice, repeated treatment with the same antibiotic is common among patients with H. pylori treatment failure. However, in patients with several treatment failures, the fourth treatment option is worthy of careful consideration. For penicillin-allergic patients in particular, the choices for H. pylori eradication therapy are limited after the failure of several eradication regimens, due to the necessity of avoiding amoxicillin and the high prevalence of clarithromycin and metronidazole resistance (70.4% and 82.4%, respectively, in the United States).[6] Although fluoroquinolone consumption has been associated with levofloxacin resistance, repeated treatment with levofloxacin still carries a 50% chance of drug sensitivity.[7–10] Hence, the reuse of levofloxacin-based quadruple therapy as the fourth treatment is worthy of consideration, especially, for penicillin-allergic patients.
Here, we report a case of H. pylori infection that was successfully treated with levofloxacin and bismuth-based therapy after the failure of 2 previous levofloxacin and bismuth-based treatments. This case shows that antibiotics included in previous failed treatment regimens need not be eliminated if susceptibility is confirmed on antimicrobial susceptibility testing, and that it may be possible to reuse the same antibiotic in an appropriate rescue therapy regimen.
2 Case report
During a routine clinical visit, a 47-year-old woman presented with an approximately 2-year history of recurrent epigastric pain and dyspepsia. The patient reported that she had previously undergone eradication therapies for H. pylori infection 3 times, and that her 13C-urea breath test (13C-UBT) remained positive at the last follow-up. A review of her medical history showed that she was strongly positive for penicillin allergy on allergy testing. Therefore, she had initially been prescribed an eradication therapy regimen consisting of rabeprazole, bismuth, clarithromycin, and levofloxacin. After 6 months, she still tested positive for H. pylori on 13C-UBT. She then received another 2 rounds of rescue therapies for H. pylori eradication within the following year (Table 1), but all these treatments failed and produced no significant improvement in her symptoms.
Table 1 History of Helicobacter pylori eradication treatments in our patient.
Start date Regimen, dose, and frequency Duration
Feb 8, 2017 Rabeprazole (10 mg bid), colloidal bismuth pectin (220 mg bid), clarithromycin (500 mg bid), levofloxacin (500 mg qd) 14 days
July 5, 2017 Esomeprazole (20 mg bid), colloidal bismuth pectin (220 mg bid), clarithromycin (500 mg bid), bifidobacterium (420 mg bid) 14 days
Mar 8, 2018 Esomeprazole (20 mg bid), colloidal bismuth pectin (220 mg bid), clarithromycin (500 mg bid), levofloxacin (500 mg qd) 14 days
One month before the present visit, she underwent esophagogastroduodenoscopy with biopsy, and was histologically diagnosed with mild-to-moderate atrophic gastritis and intestinal metaplasia (Fig. 1). Additionally, a western blotting test was strongly positive for serum antibodies to the cytotoxin-associated gene A and vacuolating cytotoxin A.
Figure 1 Histopathological examination of a gastric angle biopsy shows atrophic gastritis and intestinal metaplasia.
The patient agreed to undergo antibiotic susceptibility testing to minimize the risk of eradication failure. Written informed consent was obtained from the patient for all invasive treatments, and oral informed consent was obtained for the use of her medical data for scientific research, with her private information protected. The study protocol was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University. She subsequently underwent gastroduodenoscopy, and biopsy specimens were collected from the gastric antrum and body for H. pylori isolation. H. pylori culture-based antimicrobial sensitivity testing was conducted by the laboratory at Zhiyuan Inspection Medical Institute (Hangzhou, China), according to a previously described method.[11] The results of agar dilution susceptibility testing showed susceptibility to amoxicillin, levofloxacin, and furazolidone and resistance to clarithromycin and metronidazole. The minimum inhibitory concentrations of the above drugs were as follows: amoxicillin, ≥2 μg/ml; levofloxacin, ≥2 μg/ml; furazolidone, ≥2 μg/ml; clarithromycin, ≥1 μg/ml; and metronidazole, ≥8 μg/ml. However, since the patient had twice received levofloxacin-containing regimens, gene sequence analysis was also performed to confirm levofloxacin susceptibility again. The molecular antimicrobial sensitivity test analyzed the sequence of the DNA gyrase A (gyrA) gene at Asn-87 and Asp-91 to determine levofloxacin sensitivity, and the sequence of the 23S rRNA gene at site 2143 to determine clarithromycin sensitivity. In the case of the 23S rRNA gene, we found the mutation genotype “G” instead of the wild-type genotype “A,” which indicated clarithromycin resistance (Fig. 2). In the case of the gyrA gene, the wild-type genotypes “C” at Asn-87 and “A” at Asp-91 were found, which indicated sensitivity to levofloxacin (Fig. 3). These results indicated that the patient's H. pylori strains were indeed sensitive to levofloxacin and resistant to clarithromycin, which was in accordance with the results of culture-based antimicrobial sensitivity testing. Therefore, we treated her with a 14-day regimen consisting of levofloxacin (500 mg once daily), furazolidone (100 mg twice daily), colloidal bismuth pectin (220 mg twice daily), and esomeprazole (20 mg twice daily). Two months after this therapy had ended, a 13C-UBT returned a result of 0.1 units; a result of <2.5 units was deemed to indicate successful treatment. Moreover, the symptoms of epigastric pain and dyspepsia had also significantly improved. Six months after ending the therapy, the 13C-UBT yielded a result of 0.7 units. Thus, finally, the eradication of H. pylori was successful.
Figure 2 Sequencing results of the 2143 site of the 23S rRNA gene.
Figure 3 Sequencing results of Asn-87 and Asp-91 in the gyrA gene.
3 Discussion
In this case, both the first and third treatment regimens contained clarithromycin and levofloxacin. Although both regimens had failed, antibiotic susceptibility testing demonstrated levofloxacin susceptibility and clarithromycin resistance. This indicated that clarithromycin resistance may be the most important determinant of eradication failure. Interestingly, the patient's H. pylori strains remained sensitive to levofloxacin even after 2 failed levofloxacin-containing regimens. This indicated that levofloxacin-sensitive H. pylori strains may not easily develop levofloxacin resistance. Indeed, levofloxacin was included in the patient's latest tailored therapy, which successfully eradicated the H. pylori infection.
Gram-negative bacteria, such as H. pylori, develop antibiotic resistance due to the transfer of antibiotic-resistance genes via mobile DNA elements such as plasmids, transposons, and integrons.[12,13] In H. pylori, the main mechanism of fluoroquinolone resistance involves point mutations in the quinolone resistance-determining regions of the gyrA and gyrB genes,[14] which change the effects of DNA gyrases (gyrA and gyrB) and topoisomerase IV.[15] GyrA mutations at Asn-87 may confer a higher level of resistance to levofloxacin than mutations at Asn-91.[16] In addition, gyrB mutations and several other gyrA mutations are not clinically important, and have a steady relationship with the gyrA 87 and gyrA 91 mutations.[16,17] Our patient had no gyrA mutations at Asn-87 or Asp-91 after 3 eradication failures. A study of 28 patients with H. pylori infection and any prior fluoroquinolone use over the past 10 years found that 17 (61%) patients continued to have levofloxacin-sensitive H. pylori infection.[18] Another study reported that suitable antibiotic exposure may not strongly contribute to the development of resistance.[19] Considering these results and our present findings, we can confirm that if H. pylori isolates are found to be sensitive to levofloxacin, repeated treatment with levofloxacin may be justifiable, even for patients with a history of multiple treatment failures.
4 Conclusions
Although the American College of Gastroenterology guidelines recommend that in patients with H. pylori treatment failure, the same regimen should not be repeated,[1] and the Toronto Consensus recommends against reusing levofloxacin for patients who have already failed to respond to a levofloxacin-containing regimen,[4] this practice severely limits the choice of treatment for penicillin-allergic patients with recurrent H. pylori eradication failures. Antimicrobial sensitivity testing is a better guide for the selection of appropriate antibiotics for such patients. The present case provides additional evidence that the clinician can reuse antibiotics if susceptibility is confirmed, which is in accordance with the Maastricht V/Florence Consensus Report.[3] Finally, the mechanisms underlying the development of levofloxacin resistance in H. pylori strains need to be further explored.
Author contributions
Data curation: Feng Ye.
Investigation: Siya Kong, Han Chen, Duochen Jin, Feng Ye.
Methodology: Keting Huang.
Supervision: Keting Huang, Duochen Jin, Guoxin Zhang, Feng Ye.
Writing – original draft: Siya Kong.
Writing – review & editing: Han Chen, Guoxin Zhang, Feng Ye.
Abbreviations: 13C-UBT = 13C-urea breath test, gyrA = gyrase A, H. pylori = Helicobacter pylori.
How to cite this article: Kong S, Chen H, Huang K, Jin D, Zhang G, Ye F. Antibiotic susceptibility guided reuse of levofloxacin-based therapy in a penicillin-allergic patient for Helicobacter pylori infection: a case report. Medicine. 2021;100:10(e24915).
This study was supported in part by the National Natural Science Foundation of China (no.81500431, no.81770561, and no.81970499), Natural Science Foundation of Jiangsu Province (no. BK20151039), Six Talent Peaks Project in Jiangsu Province (no.2018-WSW-003), and Jiangsu Province Leading Talents and Innovation Team (CXTDA2017033).
The funding body did not have a role in the design of the study or the collection, analysis, and interpretation of data.
A written informed consent was obtained from the patient for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. Its protocol was reviewed and approved by the ethics committee of the First Affiliated Hospital of Nanjing Medical University.
The authors have no conflicts of interests to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | CLARITHROMYCIN, ESOMEPRAZOLE MAGNESIUM, LEVOFLOXACIN, RABEPRAZOLE | DrugsGivenReaction | CC BY | 33725850 | 20,138,550 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Aphasia'. | Pituitary tumor apoplexy associated with extrapontine myelinolysis during pregnancy: A case report.
BACKGROUND
Pituitary tumor apoplexy (PTA) is a rare clinical syndrome which requires urgent diagnosis and treatment due to its life-threatening consequences. Management of undiagnosed pituitary tumor before pregnancy is a problem during pregnancy.
We reported a case with PTA which was not diagnosed before pregnancy presenting with vomiting associated with hyponatremia during the third trimester. After supplying the sodium the patient presented with dysarthria and hemiplegia.
MRI examination showed PTA accompanied with extrapontine myelinolysis (EPM).
METHODS
The patient was given hydrocortisone according to the symptoms gradually to taper off dose, at the same times oral levothyroxine therapy (25μg/day) was given.
RESULTS
The patient delivered a healthy baby via cesarean section at hospital at 38 + 1 week of gestation. We performed MRI examination regularly and the tumor regressed significantly 8 months postpartum.
CONCLUSIONS
We reported a case as PTA associated with EPM. Headache during pregnancy is often nonspecific, so careful medical history inquiry is very important.
1 Introduction
Pituitary tumor apoplexy (PTA) is a rare clinical syndrome with an estimated prevalence of 6.2 cases per 100,000 persons, which requires urgent diagnosis and treatment due to its life-threatening consequences.[1] Management of undiagnosed pituitary tumors before pregnancy is a problem during pregnancy and faces some safety issues including potential tumor growth and apoplexy which are very low and will be confronted with a major concern by the clinical doctors.[2] Pregnancy is one of the risk factors for pituitary apoplexy (PA) because the enlarged size of the pituitary gland, increased blood flow in the gland and increased hormones which stimulate the gland and pituitary tumor.[3,4] The PA occurrence rate during pregnancy is rare so that the diagnosis and treatment is sometimes neglected or delayed.
PTA is characterized by some acute clinical syndrome including headache, nausea, vomiting, visual abnormity, and/or decreased consciousness because of the result of a pituitary tumor infarction or hemorrhage.[5] Nausea and vomiting, as one of the most common symptoms of PTA, is very common during pregnancy and it does not get much attention from the patients and clinicians. Vomiting could cause pregnant women to develop severe electrolyte disorders, among which hypokalemia and hyponatremia occur most frequently. Hyponatremia refers to the serum sodium concentration less than 135 mmol/L, which is one of the most common kinds of water and salt imbalance in clinical practice, accounting for most of hospitalized patients. Hyponatremia can increase the complexity of symptoms and lead to misdiagnosis by the clinicians. There are different treatment principles about of hyponatremia of different degree, and inappropriate treatment such as rapid correction of hyponatraemia in patients may cause demyelination disease of nerve permeability.[6,7] Central pontine myelinolysis (CPM) and extrapontine myelinolysis (EMP) belong to osmotic demyelination syndrome (ODS) which can be caused in the treatment of hyponatremia associated with poor prognosis.[8] The patients with ODS present differently, including acute paralysis, dysarthria and dysphagia.
We report a case with PTA who was not diagnosed before pregnancy presenting with vomiting associated with hyponatremia during the third trimester. After supplying the sodium the patient presented with dysarthria and hemiplegia, MRI examination showed PTA accompanied with EPM and the patient was managed conservatively with a successful outcome. We performed MRI examination regularly and the tumor regressed significantly 8 months postpartum.
2 Case report
A 24-year-old woman with a history of vomiting for 3 days was admitted at emergency ward during the 32th week on December 11th, 2018. She complained that she had a history of low fever without measuring body temperature, no abdominal pain, no diarrhea and other discomfort and she did not take it seriously at first because she thought it was common flue or upper respiratory tract infection. But 1 day before, she began to vomit severely associated with fatigue.
Urgent blood arterial gas analysis for the patient showed that serum sodium concentration as high as 111.6 mmol/L, chlorine as 91.3 mmol/L, plasmatic osmolality as 226 m Osm 226/kg. Blood electrolyte test showed that serum sodium concentration was as 116.7 mmol/L, chlorine concentration as 87.3 mmol/L and potassium as 4.52 mmol/L in emergency ward. The patient was given 3% NaCl 400 ml by intravenous infusion. The next day, blood electrolyte retest showed that serum sodium concentration was 126.0 mmol/L (Table 1), so 3% NaCl 400 ml was given by intravenous infusion in the morning again. The patient developed aphasia and hemiplegia with no movement of the right limb in the afternoon suddenly, so she was admitted to the obstetric department for further treatment.
Table 1 Clinical detailed results of blood biochemistry measurements.
value Date Result (mmol/l) normal range Annotation
Osmolality 2018-12-11 226 Osm/kg 280–310mOsm/kg 3%Nacl 400 ml was given
2018-12-13 252 Osm/kg
2018-12-13 280 Osm/kg
Sodium 2018-12-11 116.7g mmol/l 137–147 mmol/l 3%Nacl 400 ml was given
2018-12-12 126 mmol/l 3%Nacl 400 ml was given
2018-12-13 132.7 mmol/l
2019-01-01 135.8 mmol/l
2019-01-15 132.8 mmol/l
Potassium 2018-12-11 4.52 mmol/l 3.5–5.3 mmol/l
2018-12-12 4.67 mmol/l
2018-12-13 4.49 mmol/l
2019-01-01 4.4 mmol/l
2019-01-15 3.6 mmol/l
Chloride 2018-12-11 87.3 mmol/l 98–110 mmol/l 3%Nacl 400 ml was given
2018-12-12 101.6 mmol/l 3%Nacl 400 ml was given
2018-12-13 107.7 mmol/l
2019-01-01 105.7 mmol/l
2019-01-15 105 mmol/l
Fibrinogen 2018-12-13 6.76 g/l 2–4 g/l Heparin was given
2018-12-15 3.77 g/l
After admission at the obstetric department, she was afebrile with 36.6°C on examination, with a heart rate of 101bpm and blood pressure of 122/77 mm Hg. Physical examination revealed that the patient's right nasolabial groove became shallow and her tongue extended to the right direction. Her visual field detection was normal. She was retarded with aphasia associated with hemiplegia in right arms and legs. Her right upper limb power was grade 0/5, right lower limb power was grade 3/5 and the left limb power was 4/5. Her pain sensitivity was lower in the right than that in the left. All her deep tendon reflexes were positive. Her plantar response was positive in the right. The rest of her physical examination was unremarkable. Obstetrical examinations showed a gravid uterus at around 32 weeks of gestation with normal fetal heart rate.
An emergency cerebral magnetic resonance imaging (MRI) was performed and a sellar abnormal signal with size about 15 × 14 × 14 mm was revealed, which indicated the PTA. Abnormal signals in corpus callosum, bilateral basal ganglia, and centrum semiovale were seen. There were no obvious abnormalities in magnetic resonance angiography and venography (Fig. 1). Immediate laboratory testing revealed as follow: PH 7.31, blood oxygen saturation 98.8%, CO2 partial pressure 23.10 mm Hg, plasmatic osmolality 252 Osm 226/kg, blood glucose 2.8 mmol/l, lactic acid <1 mmol/L by blood arterial gas analysis. Blood routine showed hemoglobin of 11.5 mg/dl, PLT of 248 × 109/L. Biochemistry test showed Na of 131.6 mmol/L, CO2 of 12.3 mmol/L, BUN of 1.0 mmol/L, creatinine of 45U mol/L, blood amylase of 63μ/L, blood lipase of 119μ/L, fibrinogen of 6.01 g/L (Table 1).
Figure 1 Brain Magnetic resonance imaging of the patient. (A) sagittal T1-weighted images shows a sellar and suprasellar high signal with the size of 15mm × 14mm × 14 mm, in which stratification was demonstrated, (B) coronal FLAIR images shows the high signal appeared as an hourglass, (C) axial T2-weighted images shows hyperintensity in bilateral basal ganglia region and corpus callosum, (D) (E) axial DWI images shows hyperintensity in corpus callosum and bilateral centrum semiovale (picture A–E, during 32 + 1 gestational week on December 12th,2018), (F) (G) shows the size of sellar and suprasellar high signal is reduced to 13mm × 12mm × 13 mm, compared with the previous examination (picture 1, 2),(H) shows the lesion in corpus callosum was slightly smaller, compared with picture 3,(I) (J) the signal of the lesion in corpus callosum and bilateral centrum semiovale was weaker, compared with picture 4, 5 (picture F–J, on December 20th,2018), (K)(L)shows the size of sellar and suprasellar high signal was reduced to 10mm × 11mm × 12 mm, (M)shows the abnormally high signal in bilateral basal ganglia region basically disappeared (picture K–M, on January 18th,2019), (N)(O)(P)shows the size of sellar and suprasellar high signal was further reduced to 8mm × 5mm × 9mm (on April 27th,2019),(Q)(R)contrast enhanced images shows the pituitary gland was almost normal in size, with homogeneous enhancement after enhancement, and pituitary stem was slightly shifted to the left, (S) coronal T2-weighed images shows the pituitary gland appeared as heterogeneous signal (on September 24th,2019).
Further hormonal examination results after admission were as follows: plasma prolactin (PRL) level of 104.71 ng/ml (3.34–26.72 ng/ml), TSH level of 1.49 mIU/ml (0.3–5.5 mIU/ml), fT4 level of 11.26 pmol/L (11.46–23.17 pmol/L), fT3 level of 3.25 pmol/L (2.8–7.1 pmol/L), ACTH level (8AM) of 9.53 pg/ml (6–40 pg/ml), ACTH level (4PM) of 7.12 pg/ml (3–30 pg/ml), and cortisol level (8AM):15.46 μg/dl (6.7–22.8), cortisol level (4PM) of >61.4 μg/dl (0–10 μg/dl), growth hormone of 0.65 ng/ml (0.06–5ng/ml) (Table 2). High cortisol level of 4PM was associated with hydrocortisone taking.
Table 2 Clinical detailed results of hormonal measurements.
value Date Result (mmol/l) normal range Annotation
TSH 2018-12-13 1.49 UIU/ml 0.3–5.5 UIU/ml 2019-01-23 delivery
2018-12-18 3.03 UIU/ml
2019-01-08 3.67 UIU/ml
2019-01-25 6.97 UIU/ml
2019-02-13 1.39 UIU/ml
2019-09-18 4.06 UIU/ml
2019-11-17 2.88 UIU/ml
FT4 2018-12-13 11.26 pmol/l 11.46–23.17pmol/l
2018-12-18 11.68 pmol/l
2019-01-08 12.5pmol/l
2019-01-25 13.09 pmol/l
2019-02-13 14.99 pmol/l
2019-09-18 11.7 pmol/l 12–22 pmol/l
2019-11-17 11.57 pmol/l
FT3 2018-12-13 3.25 pmol/l 2.8–7.1pmol/l
2018-12-18 3.11 pmol/l
2019-01-08 3.27 pmol/l
2019-01-25 3.03 pmol/l
2019-02-13 4.6 pmol/l
2019-09-18 4.46 pmol/l 3.1–6.8pmol/l
2019-11-17 4.22 pmol/l
Cortisol 2018-12-14 8AM:15.46μg/dl 6.7–22.8 μg/dl Cortisol 4PM (2018-12-14) after hydrocortisone using
2018-12-14 4PM:>61.4μg/dl 0–10 μg/dl
2019-01-25 8AM:8.87μg/dl 6.7–22.8 μg/dl
2019-01-25 4PM:5.58μg/dl 0-10 μg/dl
2019-09-18 8AM:7.37μg/dl 6.7–22.8 μg/dl
2019-09-18 4PM:2.2μg/dl 0–10 μg/dl
ACTH 2018-12-14 8AM:9.53 pg/ml 6–40 pg/ml
2018-12-14 4PM:7.12 pg/ml 3–30 pg/ml
2019-01-26 8AM:16.6 pg/ml 6–40 pg/ml
2019-01-26 4PM:7.36 pg/ml 3–30 pg/ml
2019-09-18 8AM:19.95pg/ml 6–40 pg/ml
2019-09-18 4PM:11.66pg/ml 3–30 pg/ml
Prolactin 2018-12-13 104.71 ng/ml 3.34–26.72 ng/ml Postpartum no breastfeeding
2018-12-18 108.40 ng/ml
2019-01-25 110.55 ng/ml
2019-02-13 59.06 ng/ml
2019-07-19 50.76 ng/ml
2019-09-18 48.80 ng/ml
2020-01-17 44.59 ng/ml
Growth hormone 2018-12-13 0.65 ng/ml 0.06–5 ng/ml
2019-02-13 0.06 ng/ml
2019-09-18 0.87 ng/ml
Insulin-like growth factor 2019-02-13 195.5 ng/ml 60–350 ng/ml
2019-09-18 176 ng/ml
A multidisciplinary team was organized including neurology, neurosurgery, endocrinology, ICU and obstetric department. PA with pituitary insufficiency were considered which caused hyponatremia and sodium supplied rapidly for EPM induction with hemiplegia and aphasia. The patient was given hydrocortisone according to the symptoms gradually to taper off dose, at the same times oral levothyroxine therapy (25μg/day) was given. The symptoms improved after 2 days and the patient could speak and recovered the movement of limbs. Her medical history was got which included that she had been irregular menstruation from the menarche at 14-year-old. In 2 years before pregnancy (August 23, 2016) she had taken hormone test and results were nearly normal. After that she had not gone to the hospital until she was pregnancy. She complained severe headache for the entire pregnancy and got the drug for painkiller at the early pregnancy. After taking medications, her symptoms did not improve and because of worrying about the outcomes of drugs on fetal, so she stopped the drug. After using hydrocortisone and levothyroxine, the symptoms including headache and vomiting disappear, MRI after 8 days at admission showed that abnormal signal in the splenium of the corpus callosum, bilateral basal ganglia, and centrum semiovale were weaker significantly. She delivered a healthy baby via cesarean section at hospital at 38 + 1 week of gestation (January 23, 2019). The baby birth weight was 2850 grams. The Apgar score was 9’ and 9’at first and fifth minutes, respectively. The blood volume during operation was 1000 ml. The patient did not have breastfeeding after delivery.
Postpartum, the patient did not have headache and vomiting except her irregular menstruation. The pituitary tumor was significantly regressive by MRI (Fig. 1). Meanwhile the blood hormone examination showed that PRL was decreased gradually of 44.59ng/ml (January 17, 2020). Thyroid function tests, serum cortisol, ACTH, growth hormone, and IGF-1 level showed normally. This study was approved by the Ethics Committee of Soochow University. The patient agreed to authorize us to share the figures and the experiences during the treatment procedure in our department. Informed consent was obtained.
3 Discuss
Gestational pituitary tumor apoplexy is a rare disease. Considering the situation of lack of consensus, it is difficult to manage the PA cases. So, every patient should be assessed and managed carefully. Especially for some cases with pituitary tumor which was not found before pregnancy it is difficult for timely treatment.
4 Clinical signs and diagnosis
PA occurs in patients which are asymptomatic previously in 60% to 80% of cases.[9] The main symptoms of PTA include headache, nausea, visual impairment among which headache occurs in 95% of cases and vomiting in 69% of that.[10,11] Due to the atypical symptoms, misdiagnosis is often caused and serious clinical complications are resulted in.[12]
Before pregnancy most of the patients with pituitary tumor have the history of irregular menstruation because of the elevated sexual hormones such as prolactin. Headache is one of the most common symptoms of PTA during pregnancy. Our patient complained of headache, but there was no effect after taking painkiller drugs. This symptom provided us with certain signals, but the clinician did not pay enough attention to it, because headache is common during pregnancy, associated with emotion such as stress, lack of sleep, depression, and malnutrition. In addition pregnant women themselves often fear that drugs for painkiller might affect the fetus, so simple headaches are not taken seriously.[13] Vomiting is one of the symptoms of PTA during pregnancy. The case complained of vomiting for 3 days, but emergency department only routinely conducted blood electrolyte examination, and immediately gave a large amount of sodium supplement treatment after the discovery of hyponatremia. Only the patient had symptoms with aphasia and hemiplegia on the next day, the attention was aroused by the clinicians. Similarly there are many reasons for simple vomiting during pregnancy and clinicians often pay more attention to electrolyte disorders than the reason of hyperemesis. The symptoms including headache and vomiting are caused by the increased intracranial pressure due to PTA and meningeal irritation.[9,10]
MRI examination is necessary for the diagnosis of PA and EPM. The precise mechanism underlying EPM and CPM remains elusive. It involves a patient with hyponatremia, in whom compensatory cellular expansion offsets the reduced plasma osmotic pressure. Thereafter, any rapid change in osmosis in the opposite direction, usually caused by hypertonic fluid, causes the swollen cells to shrink, leading to osmotic demyelination. The mechanism of cellular expansion relies upon the generation of osmoses such as taurine, glycine, glutamine, sorbitol, and inositol.[14] Our patient was given the rapid sodium treatment to correct hyponatremia which resulted in transient hemiplegia and aphasia. MRI examination may reveal abnormal signal, which could be considered the acute cerebral infarction if not combined with clinical history or lack of understanding of EMP and may lead to misdiagnosis of clinical doctors.
Traditional CPM was thought as pathological features about pons base symmetrical demyelination of nerve fibers, later it was found that outside parts of the pons also could appear the same change, known as the EPM. Generally, both of them have a history of rapid correction of hyponatremia. EPM without CPM was rare, which could result in misdiagnosis. The hallmark of EPM has the striking T2 signal abnormalities with lesions most commonly occurrence in the cerebellum, the lateral geniculate body, the external and extreme capsule, basal ganglia, thalamus, gray-white junction of the cerebral cortex, and the hippocampi.[15] Although rare, lesions have been described in the spinal cord, amygdala, anterior commissure, optic tracts, and the subthalamic nuclei.[6,8]
5 Treatment
Management of PA has 2 choices: surgery and conservative medication. When pregnancy is confirmed, most of the women with pre-existing pituitary tumor choose to stop dopamine agonist generally,[16] although the knowledge about pregnancy outcomes for women who have become pregnant while taking bromocriptine or cabergoline is widening. Large adenoma size, pregnancy, and cessation of cabergoline could lead to PA. There are no clear guidelines for the management of PA during pregnancy. In the case of prolactioma and non-stroke symptomatic tumor growth, most of them are recommended reactivating dopamine agonist as first-line therapy, as this is generally considered to be less risky to the mother and fetus than surgical intervention. Half of the patients were treated conservatively with pituitary hormone replacement therapy when necessary, few cases were treated with dopamine agonists.[17,18]
There are no randomized controlled trials comparing the effects of surgical and conservative treatment in pregnant women with PA. However, surgery seems appropriate for patients who fail to respond to conservative treatment or cannot tolerate dopamine agonists.[16] Neurosurgical intervention should be considered in cases with persistent visual field defects or deteriorating level of consciousness. If operation, it is emphasized that surgical excision should be performed by experienced neurosurgeons, not by on-call surgeons.
The main conservative treatment with PTA during pregnancy is to provide fluid and electrolyte balance and high dose glucocorticoid for emergency condition. Glucocorticoid is the most commonly used hormonal drug. In addition, if combined with thyroid insufficiency and adrenal insufficiency, it can be supplemented according to the examination results and clinical symptoms. About the CPM and EPM caused by fast natrium replenishment, sodium supplementation must be controlled. After the treatment, the symptoms of aphasia and hemiplegia of this case were rapidly improved and the effect of conservative treatment was obvious. Hypopituitarism is an important complication of apoplexy including hypothyroidism, hypoadrenalism and hyperprolactinaemia and may be missed if not carefully investigated.[5] Therefore, clinicians must pay attention to the occurrence of hypophysis dysfunction and give related hormone therapy in time.
6 Prognosis
The risk of pituitary tumor development will increase during pregnancy. The prognosis of PA during pregnancy depends on the timely diagnosis and clinical management. In general, early symptoms such as headache and vomiting should be pay attention. Careful medical history inquiry by the clinician, timely physical examination, MRI application and hormone replacement therapy as soon as possible can significantly improve the therapeutic effect.
7 Conclusion
In general, in the case of pregnancy, the diagnosis of PTA can be challenging and confused with other complex situations, such as preeclampsia. MRI is one of the most sensitive examination, revealing to confirm diagnosis of PTA and/or necrosis of part of adrenocorticotropic hormone deficiency and adrenal insufficiency. If not treated, it is a potentially life-threatening disease for both mother and fetus. Headache during pregnancy is often nonspecific, so it is easy to be omitted by clinicians. Therefore, careful medical history inquiry is very important. The patients need to be re-evaluated if chronic headaches do not ease. A multidisciplinary team consisting of neurology, neurosurgery, endocrinology, ICU, and obstetric department is important in deciding the optimal treatment. At the same time, maternal desires should be taking into consideration.
Author contributions
Conceptualization: Wenfeng Ye, Linlin Chen.
Data curation: Shiying Sheng, Zhengyu Liu.
Investigation: Wenfeng Ye, Linlin Chen, Changfang Yao, Chunyan Xue.
Project administration: Wenfeng Ye, Chunyan Xue, Wei Xing.
Supervision: Wei Xing.
Validation: Changfang Yao, Shiying Sheng, Zhengyu Liu, Chunyan Xue, Wei Xing.
Visualization: Wenjie Huang, Linlin Chen, Changfang Yao, Zhengyu Liu, Wei Xing.
Writing – original draft: Wenfeng Ye, Wenjie Huang.
Writing – review & editing: Wei Xing.
Abbreviations: CPM = central pontine myelinolysis, EPM = extrapontine myelinolysis, MRI = magnetic resonance imaging, ODS = osmotic demyelination syndrome, PA = pituitary apoplex, PTA = pituitary tumor apoplex.
How to cite this article: Ye W, Huang W, Chen L, Yao C, Sheng S, Liu Z, Xue C, Xing W. Pituitary tumor apoplexy associated with extrapontine myelinolysis during pregnancy: a case report. Medicine. 2021;100:10(e25075).
WY and WH contributed equally to this work.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33725898 | 19,197,894 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hemiplegia'. | Pituitary tumor apoplexy associated with extrapontine myelinolysis during pregnancy: A case report.
BACKGROUND
Pituitary tumor apoplexy (PTA) is a rare clinical syndrome which requires urgent diagnosis and treatment due to its life-threatening consequences. Management of undiagnosed pituitary tumor before pregnancy is a problem during pregnancy.
We reported a case with PTA which was not diagnosed before pregnancy presenting with vomiting associated with hyponatremia during the third trimester. After supplying the sodium the patient presented with dysarthria and hemiplegia.
MRI examination showed PTA accompanied with extrapontine myelinolysis (EPM).
METHODS
The patient was given hydrocortisone according to the symptoms gradually to taper off dose, at the same times oral levothyroxine therapy (25μg/day) was given.
RESULTS
The patient delivered a healthy baby via cesarean section at hospital at 38 + 1 week of gestation. We performed MRI examination regularly and the tumor regressed significantly 8 months postpartum.
CONCLUSIONS
We reported a case as PTA associated with EPM. Headache during pregnancy is often nonspecific, so careful medical history inquiry is very important.
1 Introduction
Pituitary tumor apoplexy (PTA) is a rare clinical syndrome with an estimated prevalence of 6.2 cases per 100,000 persons, which requires urgent diagnosis and treatment due to its life-threatening consequences.[1] Management of undiagnosed pituitary tumors before pregnancy is a problem during pregnancy and faces some safety issues including potential tumor growth and apoplexy which are very low and will be confronted with a major concern by the clinical doctors.[2] Pregnancy is one of the risk factors for pituitary apoplexy (PA) because the enlarged size of the pituitary gland, increased blood flow in the gland and increased hormones which stimulate the gland and pituitary tumor.[3,4] The PA occurrence rate during pregnancy is rare so that the diagnosis and treatment is sometimes neglected or delayed.
PTA is characterized by some acute clinical syndrome including headache, nausea, vomiting, visual abnormity, and/or decreased consciousness because of the result of a pituitary tumor infarction or hemorrhage.[5] Nausea and vomiting, as one of the most common symptoms of PTA, is very common during pregnancy and it does not get much attention from the patients and clinicians. Vomiting could cause pregnant women to develop severe electrolyte disorders, among which hypokalemia and hyponatremia occur most frequently. Hyponatremia refers to the serum sodium concentration less than 135 mmol/L, which is one of the most common kinds of water and salt imbalance in clinical practice, accounting for most of hospitalized patients. Hyponatremia can increase the complexity of symptoms and lead to misdiagnosis by the clinicians. There are different treatment principles about of hyponatremia of different degree, and inappropriate treatment such as rapid correction of hyponatraemia in patients may cause demyelination disease of nerve permeability.[6,7] Central pontine myelinolysis (CPM) and extrapontine myelinolysis (EMP) belong to osmotic demyelination syndrome (ODS) which can be caused in the treatment of hyponatremia associated with poor prognosis.[8] The patients with ODS present differently, including acute paralysis, dysarthria and dysphagia.
We report a case with PTA who was not diagnosed before pregnancy presenting with vomiting associated with hyponatremia during the third trimester. After supplying the sodium the patient presented with dysarthria and hemiplegia, MRI examination showed PTA accompanied with EPM and the patient was managed conservatively with a successful outcome. We performed MRI examination regularly and the tumor regressed significantly 8 months postpartum.
2 Case report
A 24-year-old woman with a history of vomiting for 3 days was admitted at emergency ward during the 32th week on December 11th, 2018. She complained that she had a history of low fever without measuring body temperature, no abdominal pain, no diarrhea and other discomfort and she did not take it seriously at first because she thought it was common flue or upper respiratory tract infection. But 1 day before, she began to vomit severely associated with fatigue.
Urgent blood arterial gas analysis for the patient showed that serum sodium concentration as high as 111.6 mmol/L, chlorine as 91.3 mmol/L, plasmatic osmolality as 226 m Osm 226/kg. Blood electrolyte test showed that serum sodium concentration was as 116.7 mmol/L, chlorine concentration as 87.3 mmol/L and potassium as 4.52 mmol/L in emergency ward. The patient was given 3% NaCl 400 ml by intravenous infusion. The next day, blood electrolyte retest showed that serum sodium concentration was 126.0 mmol/L (Table 1), so 3% NaCl 400 ml was given by intravenous infusion in the morning again. The patient developed aphasia and hemiplegia with no movement of the right limb in the afternoon suddenly, so she was admitted to the obstetric department for further treatment.
Table 1 Clinical detailed results of blood biochemistry measurements.
value Date Result (mmol/l) normal range Annotation
Osmolality 2018-12-11 226 Osm/kg 280–310mOsm/kg 3%Nacl 400 ml was given
2018-12-13 252 Osm/kg
2018-12-13 280 Osm/kg
Sodium 2018-12-11 116.7g mmol/l 137–147 mmol/l 3%Nacl 400 ml was given
2018-12-12 126 mmol/l 3%Nacl 400 ml was given
2018-12-13 132.7 mmol/l
2019-01-01 135.8 mmol/l
2019-01-15 132.8 mmol/l
Potassium 2018-12-11 4.52 mmol/l 3.5–5.3 mmol/l
2018-12-12 4.67 mmol/l
2018-12-13 4.49 mmol/l
2019-01-01 4.4 mmol/l
2019-01-15 3.6 mmol/l
Chloride 2018-12-11 87.3 mmol/l 98–110 mmol/l 3%Nacl 400 ml was given
2018-12-12 101.6 mmol/l 3%Nacl 400 ml was given
2018-12-13 107.7 mmol/l
2019-01-01 105.7 mmol/l
2019-01-15 105 mmol/l
Fibrinogen 2018-12-13 6.76 g/l 2–4 g/l Heparin was given
2018-12-15 3.77 g/l
After admission at the obstetric department, she was afebrile with 36.6°C on examination, with a heart rate of 101bpm and blood pressure of 122/77 mm Hg. Physical examination revealed that the patient's right nasolabial groove became shallow and her tongue extended to the right direction. Her visual field detection was normal. She was retarded with aphasia associated with hemiplegia in right arms and legs. Her right upper limb power was grade 0/5, right lower limb power was grade 3/5 and the left limb power was 4/5. Her pain sensitivity was lower in the right than that in the left. All her deep tendon reflexes were positive. Her plantar response was positive in the right. The rest of her physical examination was unremarkable. Obstetrical examinations showed a gravid uterus at around 32 weeks of gestation with normal fetal heart rate.
An emergency cerebral magnetic resonance imaging (MRI) was performed and a sellar abnormal signal with size about 15 × 14 × 14 mm was revealed, which indicated the PTA. Abnormal signals in corpus callosum, bilateral basal ganglia, and centrum semiovale were seen. There were no obvious abnormalities in magnetic resonance angiography and venography (Fig. 1). Immediate laboratory testing revealed as follow: PH 7.31, blood oxygen saturation 98.8%, CO2 partial pressure 23.10 mm Hg, plasmatic osmolality 252 Osm 226/kg, blood glucose 2.8 mmol/l, lactic acid <1 mmol/L by blood arterial gas analysis. Blood routine showed hemoglobin of 11.5 mg/dl, PLT of 248 × 109/L. Biochemistry test showed Na of 131.6 mmol/L, CO2 of 12.3 mmol/L, BUN of 1.0 mmol/L, creatinine of 45U mol/L, blood amylase of 63μ/L, blood lipase of 119μ/L, fibrinogen of 6.01 g/L (Table 1).
Figure 1 Brain Magnetic resonance imaging of the patient. (A) sagittal T1-weighted images shows a sellar and suprasellar high signal with the size of 15mm × 14mm × 14 mm, in which stratification was demonstrated, (B) coronal FLAIR images shows the high signal appeared as an hourglass, (C) axial T2-weighted images shows hyperintensity in bilateral basal ganglia region and corpus callosum, (D) (E) axial DWI images shows hyperintensity in corpus callosum and bilateral centrum semiovale (picture A–E, during 32 + 1 gestational week on December 12th,2018), (F) (G) shows the size of sellar and suprasellar high signal is reduced to 13mm × 12mm × 13 mm, compared with the previous examination (picture 1, 2),(H) shows the lesion in corpus callosum was slightly smaller, compared with picture 3,(I) (J) the signal of the lesion in corpus callosum and bilateral centrum semiovale was weaker, compared with picture 4, 5 (picture F–J, on December 20th,2018), (K)(L)shows the size of sellar and suprasellar high signal was reduced to 10mm × 11mm × 12 mm, (M)shows the abnormally high signal in bilateral basal ganglia region basically disappeared (picture K–M, on January 18th,2019), (N)(O)(P)shows the size of sellar and suprasellar high signal was further reduced to 8mm × 5mm × 9mm (on April 27th,2019),(Q)(R)contrast enhanced images shows the pituitary gland was almost normal in size, with homogeneous enhancement after enhancement, and pituitary stem was slightly shifted to the left, (S) coronal T2-weighed images shows the pituitary gland appeared as heterogeneous signal (on September 24th,2019).
Further hormonal examination results after admission were as follows: plasma prolactin (PRL) level of 104.71 ng/ml (3.34–26.72 ng/ml), TSH level of 1.49 mIU/ml (0.3–5.5 mIU/ml), fT4 level of 11.26 pmol/L (11.46–23.17 pmol/L), fT3 level of 3.25 pmol/L (2.8–7.1 pmol/L), ACTH level (8AM) of 9.53 pg/ml (6–40 pg/ml), ACTH level (4PM) of 7.12 pg/ml (3–30 pg/ml), and cortisol level (8AM):15.46 μg/dl (6.7–22.8), cortisol level (4PM) of >61.4 μg/dl (0–10 μg/dl), growth hormone of 0.65 ng/ml (0.06–5ng/ml) (Table 2). High cortisol level of 4PM was associated with hydrocortisone taking.
Table 2 Clinical detailed results of hormonal measurements.
value Date Result (mmol/l) normal range Annotation
TSH 2018-12-13 1.49 UIU/ml 0.3–5.5 UIU/ml 2019-01-23 delivery
2018-12-18 3.03 UIU/ml
2019-01-08 3.67 UIU/ml
2019-01-25 6.97 UIU/ml
2019-02-13 1.39 UIU/ml
2019-09-18 4.06 UIU/ml
2019-11-17 2.88 UIU/ml
FT4 2018-12-13 11.26 pmol/l 11.46–23.17pmol/l
2018-12-18 11.68 pmol/l
2019-01-08 12.5pmol/l
2019-01-25 13.09 pmol/l
2019-02-13 14.99 pmol/l
2019-09-18 11.7 pmol/l 12–22 pmol/l
2019-11-17 11.57 pmol/l
FT3 2018-12-13 3.25 pmol/l 2.8–7.1pmol/l
2018-12-18 3.11 pmol/l
2019-01-08 3.27 pmol/l
2019-01-25 3.03 pmol/l
2019-02-13 4.6 pmol/l
2019-09-18 4.46 pmol/l 3.1–6.8pmol/l
2019-11-17 4.22 pmol/l
Cortisol 2018-12-14 8AM:15.46μg/dl 6.7–22.8 μg/dl Cortisol 4PM (2018-12-14) after hydrocortisone using
2018-12-14 4PM:>61.4μg/dl 0–10 μg/dl
2019-01-25 8AM:8.87μg/dl 6.7–22.8 μg/dl
2019-01-25 4PM:5.58μg/dl 0-10 μg/dl
2019-09-18 8AM:7.37μg/dl 6.7–22.8 μg/dl
2019-09-18 4PM:2.2μg/dl 0–10 μg/dl
ACTH 2018-12-14 8AM:9.53 pg/ml 6–40 pg/ml
2018-12-14 4PM:7.12 pg/ml 3–30 pg/ml
2019-01-26 8AM:16.6 pg/ml 6–40 pg/ml
2019-01-26 4PM:7.36 pg/ml 3–30 pg/ml
2019-09-18 8AM:19.95pg/ml 6–40 pg/ml
2019-09-18 4PM:11.66pg/ml 3–30 pg/ml
Prolactin 2018-12-13 104.71 ng/ml 3.34–26.72 ng/ml Postpartum no breastfeeding
2018-12-18 108.40 ng/ml
2019-01-25 110.55 ng/ml
2019-02-13 59.06 ng/ml
2019-07-19 50.76 ng/ml
2019-09-18 48.80 ng/ml
2020-01-17 44.59 ng/ml
Growth hormone 2018-12-13 0.65 ng/ml 0.06–5 ng/ml
2019-02-13 0.06 ng/ml
2019-09-18 0.87 ng/ml
Insulin-like growth factor 2019-02-13 195.5 ng/ml 60–350 ng/ml
2019-09-18 176 ng/ml
A multidisciplinary team was organized including neurology, neurosurgery, endocrinology, ICU and obstetric department. PA with pituitary insufficiency were considered which caused hyponatremia and sodium supplied rapidly for EPM induction with hemiplegia and aphasia. The patient was given hydrocortisone according to the symptoms gradually to taper off dose, at the same times oral levothyroxine therapy (25μg/day) was given. The symptoms improved after 2 days and the patient could speak and recovered the movement of limbs. Her medical history was got which included that she had been irregular menstruation from the menarche at 14-year-old. In 2 years before pregnancy (August 23, 2016) she had taken hormone test and results were nearly normal. After that she had not gone to the hospital until she was pregnancy. She complained severe headache for the entire pregnancy and got the drug for painkiller at the early pregnancy. After taking medications, her symptoms did not improve and because of worrying about the outcomes of drugs on fetal, so she stopped the drug. After using hydrocortisone and levothyroxine, the symptoms including headache and vomiting disappear, MRI after 8 days at admission showed that abnormal signal in the splenium of the corpus callosum, bilateral basal ganglia, and centrum semiovale were weaker significantly. She delivered a healthy baby via cesarean section at hospital at 38 + 1 week of gestation (January 23, 2019). The baby birth weight was 2850 grams. The Apgar score was 9’ and 9’at first and fifth minutes, respectively. The blood volume during operation was 1000 ml. The patient did not have breastfeeding after delivery.
Postpartum, the patient did not have headache and vomiting except her irregular menstruation. The pituitary tumor was significantly regressive by MRI (Fig. 1). Meanwhile the blood hormone examination showed that PRL was decreased gradually of 44.59ng/ml (January 17, 2020). Thyroid function tests, serum cortisol, ACTH, growth hormone, and IGF-1 level showed normally. This study was approved by the Ethics Committee of Soochow University. The patient agreed to authorize us to share the figures and the experiences during the treatment procedure in our department. Informed consent was obtained.
3 Discuss
Gestational pituitary tumor apoplexy is a rare disease. Considering the situation of lack of consensus, it is difficult to manage the PA cases. So, every patient should be assessed and managed carefully. Especially for some cases with pituitary tumor which was not found before pregnancy it is difficult for timely treatment.
4 Clinical signs and diagnosis
PA occurs in patients which are asymptomatic previously in 60% to 80% of cases.[9] The main symptoms of PTA include headache, nausea, visual impairment among which headache occurs in 95% of cases and vomiting in 69% of that.[10,11] Due to the atypical symptoms, misdiagnosis is often caused and serious clinical complications are resulted in.[12]
Before pregnancy most of the patients with pituitary tumor have the history of irregular menstruation because of the elevated sexual hormones such as prolactin. Headache is one of the most common symptoms of PTA during pregnancy. Our patient complained of headache, but there was no effect after taking painkiller drugs. This symptom provided us with certain signals, but the clinician did not pay enough attention to it, because headache is common during pregnancy, associated with emotion such as stress, lack of sleep, depression, and malnutrition. In addition pregnant women themselves often fear that drugs for painkiller might affect the fetus, so simple headaches are not taken seriously.[13] Vomiting is one of the symptoms of PTA during pregnancy. The case complained of vomiting for 3 days, but emergency department only routinely conducted blood electrolyte examination, and immediately gave a large amount of sodium supplement treatment after the discovery of hyponatremia. Only the patient had symptoms with aphasia and hemiplegia on the next day, the attention was aroused by the clinicians. Similarly there are many reasons for simple vomiting during pregnancy and clinicians often pay more attention to electrolyte disorders than the reason of hyperemesis. The symptoms including headache and vomiting are caused by the increased intracranial pressure due to PTA and meningeal irritation.[9,10]
MRI examination is necessary for the diagnosis of PA and EPM. The precise mechanism underlying EPM and CPM remains elusive. It involves a patient with hyponatremia, in whom compensatory cellular expansion offsets the reduced plasma osmotic pressure. Thereafter, any rapid change in osmosis in the opposite direction, usually caused by hypertonic fluid, causes the swollen cells to shrink, leading to osmotic demyelination. The mechanism of cellular expansion relies upon the generation of osmoses such as taurine, glycine, glutamine, sorbitol, and inositol.[14] Our patient was given the rapid sodium treatment to correct hyponatremia which resulted in transient hemiplegia and aphasia. MRI examination may reveal abnormal signal, which could be considered the acute cerebral infarction if not combined with clinical history or lack of understanding of EMP and may lead to misdiagnosis of clinical doctors.
Traditional CPM was thought as pathological features about pons base symmetrical demyelination of nerve fibers, later it was found that outside parts of the pons also could appear the same change, known as the EPM. Generally, both of them have a history of rapid correction of hyponatremia. EPM without CPM was rare, which could result in misdiagnosis. The hallmark of EPM has the striking T2 signal abnormalities with lesions most commonly occurrence in the cerebellum, the lateral geniculate body, the external and extreme capsule, basal ganglia, thalamus, gray-white junction of the cerebral cortex, and the hippocampi.[15] Although rare, lesions have been described in the spinal cord, amygdala, anterior commissure, optic tracts, and the subthalamic nuclei.[6,8]
5 Treatment
Management of PA has 2 choices: surgery and conservative medication. When pregnancy is confirmed, most of the women with pre-existing pituitary tumor choose to stop dopamine agonist generally,[16] although the knowledge about pregnancy outcomes for women who have become pregnant while taking bromocriptine or cabergoline is widening. Large adenoma size, pregnancy, and cessation of cabergoline could lead to PA. There are no clear guidelines for the management of PA during pregnancy. In the case of prolactioma and non-stroke symptomatic tumor growth, most of them are recommended reactivating dopamine agonist as first-line therapy, as this is generally considered to be less risky to the mother and fetus than surgical intervention. Half of the patients were treated conservatively with pituitary hormone replacement therapy when necessary, few cases were treated with dopamine agonists.[17,18]
There are no randomized controlled trials comparing the effects of surgical and conservative treatment in pregnant women with PA. However, surgery seems appropriate for patients who fail to respond to conservative treatment or cannot tolerate dopamine agonists.[16] Neurosurgical intervention should be considered in cases with persistent visual field defects or deteriorating level of consciousness. If operation, it is emphasized that surgical excision should be performed by experienced neurosurgeons, not by on-call surgeons.
The main conservative treatment with PTA during pregnancy is to provide fluid and electrolyte balance and high dose glucocorticoid for emergency condition. Glucocorticoid is the most commonly used hormonal drug. In addition, if combined with thyroid insufficiency and adrenal insufficiency, it can be supplemented according to the examination results and clinical symptoms. About the CPM and EPM caused by fast natrium replenishment, sodium supplementation must be controlled. After the treatment, the symptoms of aphasia and hemiplegia of this case were rapidly improved and the effect of conservative treatment was obvious. Hypopituitarism is an important complication of apoplexy including hypothyroidism, hypoadrenalism and hyperprolactinaemia and may be missed if not carefully investigated.[5] Therefore, clinicians must pay attention to the occurrence of hypophysis dysfunction and give related hormone therapy in time.
6 Prognosis
The risk of pituitary tumor development will increase during pregnancy. The prognosis of PA during pregnancy depends on the timely diagnosis and clinical management. In general, early symptoms such as headache and vomiting should be pay attention. Careful medical history inquiry by the clinician, timely physical examination, MRI application and hormone replacement therapy as soon as possible can significantly improve the therapeutic effect.
7 Conclusion
In general, in the case of pregnancy, the diagnosis of PTA can be challenging and confused with other complex situations, such as preeclampsia. MRI is one of the most sensitive examination, revealing to confirm diagnosis of PTA and/or necrosis of part of adrenocorticotropic hormone deficiency and adrenal insufficiency. If not treated, it is a potentially life-threatening disease for both mother and fetus. Headache during pregnancy is often nonspecific, so it is easy to be omitted by clinicians. Therefore, careful medical history inquiry is very important. The patients need to be re-evaluated if chronic headaches do not ease. A multidisciplinary team consisting of neurology, neurosurgery, endocrinology, ICU, and obstetric department is important in deciding the optimal treatment. At the same time, maternal desires should be taking into consideration.
Author contributions
Conceptualization: Wenfeng Ye, Linlin Chen.
Data curation: Shiying Sheng, Zhengyu Liu.
Investigation: Wenfeng Ye, Linlin Chen, Changfang Yao, Chunyan Xue.
Project administration: Wenfeng Ye, Chunyan Xue, Wei Xing.
Supervision: Wei Xing.
Validation: Changfang Yao, Shiying Sheng, Zhengyu Liu, Chunyan Xue, Wei Xing.
Visualization: Wenjie Huang, Linlin Chen, Changfang Yao, Zhengyu Liu, Wei Xing.
Writing – original draft: Wenfeng Ye, Wenjie Huang.
Writing – review & editing: Wei Xing.
Abbreviations: CPM = central pontine myelinolysis, EPM = extrapontine myelinolysis, MRI = magnetic resonance imaging, ODS = osmotic demyelination syndrome, PA = pituitary apoplex, PTA = pituitary tumor apoplex.
How to cite this article: Ye W, Huang W, Chen L, Yao C, Sheng S, Liu Z, Xue C, Xing W. Pituitary tumor apoplexy associated with extrapontine myelinolysis during pregnancy: a case report. Medicine. 2021;100:10(e25075).
WY and WH contributed equally to this work.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33725898 | 19,197,894 | 2021-03-12 |
What was the administration route of drug 'SODIUM CHLORIDE'? | Pituitary tumor apoplexy associated with extrapontine myelinolysis during pregnancy: A case report.
BACKGROUND
Pituitary tumor apoplexy (PTA) is a rare clinical syndrome which requires urgent diagnosis and treatment due to its life-threatening consequences. Management of undiagnosed pituitary tumor before pregnancy is a problem during pregnancy.
We reported a case with PTA which was not diagnosed before pregnancy presenting with vomiting associated with hyponatremia during the third trimester. After supplying the sodium the patient presented with dysarthria and hemiplegia.
MRI examination showed PTA accompanied with extrapontine myelinolysis (EPM).
METHODS
The patient was given hydrocortisone according to the symptoms gradually to taper off dose, at the same times oral levothyroxine therapy (25μg/day) was given.
RESULTS
The patient delivered a healthy baby via cesarean section at hospital at 38 + 1 week of gestation. We performed MRI examination regularly and the tumor regressed significantly 8 months postpartum.
CONCLUSIONS
We reported a case as PTA associated with EPM. Headache during pregnancy is often nonspecific, so careful medical history inquiry is very important.
1 Introduction
Pituitary tumor apoplexy (PTA) is a rare clinical syndrome with an estimated prevalence of 6.2 cases per 100,000 persons, which requires urgent diagnosis and treatment due to its life-threatening consequences.[1] Management of undiagnosed pituitary tumors before pregnancy is a problem during pregnancy and faces some safety issues including potential tumor growth and apoplexy which are very low and will be confronted with a major concern by the clinical doctors.[2] Pregnancy is one of the risk factors for pituitary apoplexy (PA) because the enlarged size of the pituitary gland, increased blood flow in the gland and increased hormones which stimulate the gland and pituitary tumor.[3,4] The PA occurrence rate during pregnancy is rare so that the diagnosis and treatment is sometimes neglected or delayed.
PTA is characterized by some acute clinical syndrome including headache, nausea, vomiting, visual abnormity, and/or decreased consciousness because of the result of a pituitary tumor infarction or hemorrhage.[5] Nausea and vomiting, as one of the most common symptoms of PTA, is very common during pregnancy and it does not get much attention from the patients and clinicians. Vomiting could cause pregnant women to develop severe electrolyte disorders, among which hypokalemia and hyponatremia occur most frequently. Hyponatremia refers to the serum sodium concentration less than 135 mmol/L, which is one of the most common kinds of water and salt imbalance in clinical practice, accounting for most of hospitalized patients. Hyponatremia can increase the complexity of symptoms and lead to misdiagnosis by the clinicians. There are different treatment principles about of hyponatremia of different degree, and inappropriate treatment such as rapid correction of hyponatraemia in patients may cause demyelination disease of nerve permeability.[6,7] Central pontine myelinolysis (CPM) and extrapontine myelinolysis (EMP) belong to osmotic demyelination syndrome (ODS) which can be caused in the treatment of hyponatremia associated with poor prognosis.[8] The patients with ODS present differently, including acute paralysis, dysarthria and dysphagia.
We report a case with PTA who was not diagnosed before pregnancy presenting with vomiting associated with hyponatremia during the third trimester. After supplying the sodium the patient presented with dysarthria and hemiplegia, MRI examination showed PTA accompanied with EPM and the patient was managed conservatively with a successful outcome. We performed MRI examination regularly and the tumor regressed significantly 8 months postpartum.
2 Case report
A 24-year-old woman with a history of vomiting for 3 days was admitted at emergency ward during the 32th week on December 11th, 2018. She complained that she had a history of low fever without measuring body temperature, no abdominal pain, no diarrhea and other discomfort and she did not take it seriously at first because she thought it was common flue or upper respiratory tract infection. But 1 day before, she began to vomit severely associated with fatigue.
Urgent blood arterial gas analysis for the patient showed that serum sodium concentration as high as 111.6 mmol/L, chlorine as 91.3 mmol/L, plasmatic osmolality as 226 m Osm 226/kg. Blood electrolyte test showed that serum sodium concentration was as 116.7 mmol/L, chlorine concentration as 87.3 mmol/L and potassium as 4.52 mmol/L in emergency ward. The patient was given 3% NaCl 400 ml by intravenous infusion. The next day, blood electrolyte retest showed that serum sodium concentration was 126.0 mmol/L (Table 1), so 3% NaCl 400 ml was given by intravenous infusion in the morning again. The patient developed aphasia and hemiplegia with no movement of the right limb in the afternoon suddenly, so she was admitted to the obstetric department for further treatment.
Table 1 Clinical detailed results of blood biochemistry measurements.
value Date Result (mmol/l) normal range Annotation
Osmolality 2018-12-11 226 Osm/kg 280–310mOsm/kg 3%Nacl 400 ml was given
2018-12-13 252 Osm/kg
2018-12-13 280 Osm/kg
Sodium 2018-12-11 116.7g mmol/l 137–147 mmol/l 3%Nacl 400 ml was given
2018-12-12 126 mmol/l 3%Nacl 400 ml was given
2018-12-13 132.7 mmol/l
2019-01-01 135.8 mmol/l
2019-01-15 132.8 mmol/l
Potassium 2018-12-11 4.52 mmol/l 3.5–5.3 mmol/l
2018-12-12 4.67 mmol/l
2018-12-13 4.49 mmol/l
2019-01-01 4.4 mmol/l
2019-01-15 3.6 mmol/l
Chloride 2018-12-11 87.3 mmol/l 98–110 mmol/l 3%Nacl 400 ml was given
2018-12-12 101.6 mmol/l 3%Nacl 400 ml was given
2018-12-13 107.7 mmol/l
2019-01-01 105.7 mmol/l
2019-01-15 105 mmol/l
Fibrinogen 2018-12-13 6.76 g/l 2–4 g/l Heparin was given
2018-12-15 3.77 g/l
After admission at the obstetric department, she was afebrile with 36.6°C on examination, with a heart rate of 101bpm and blood pressure of 122/77 mm Hg. Physical examination revealed that the patient's right nasolabial groove became shallow and her tongue extended to the right direction. Her visual field detection was normal. She was retarded with aphasia associated with hemiplegia in right arms and legs. Her right upper limb power was grade 0/5, right lower limb power was grade 3/5 and the left limb power was 4/5. Her pain sensitivity was lower in the right than that in the left. All her deep tendon reflexes were positive. Her plantar response was positive in the right. The rest of her physical examination was unremarkable. Obstetrical examinations showed a gravid uterus at around 32 weeks of gestation with normal fetal heart rate.
An emergency cerebral magnetic resonance imaging (MRI) was performed and a sellar abnormal signal with size about 15 × 14 × 14 mm was revealed, which indicated the PTA. Abnormal signals in corpus callosum, bilateral basal ganglia, and centrum semiovale were seen. There were no obvious abnormalities in magnetic resonance angiography and venography (Fig. 1). Immediate laboratory testing revealed as follow: PH 7.31, blood oxygen saturation 98.8%, CO2 partial pressure 23.10 mm Hg, plasmatic osmolality 252 Osm 226/kg, blood glucose 2.8 mmol/l, lactic acid <1 mmol/L by blood arterial gas analysis. Blood routine showed hemoglobin of 11.5 mg/dl, PLT of 248 × 109/L. Biochemistry test showed Na of 131.6 mmol/L, CO2 of 12.3 mmol/L, BUN of 1.0 mmol/L, creatinine of 45U mol/L, blood amylase of 63μ/L, blood lipase of 119μ/L, fibrinogen of 6.01 g/L (Table 1).
Figure 1 Brain Magnetic resonance imaging of the patient. (A) sagittal T1-weighted images shows a sellar and suprasellar high signal with the size of 15mm × 14mm × 14 mm, in which stratification was demonstrated, (B) coronal FLAIR images shows the high signal appeared as an hourglass, (C) axial T2-weighted images shows hyperintensity in bilateral basal ganglia region and corpus callosum, (D) (E) axial DWI images shows hyperintensity in corpus callosum and bilateral centrum semiovale (picture A–E, during 32 + 1 gestational week on December 12th,2018), (F) (G) shows the size of sellar and suprasellar high signal is reduced to 13mm × 12mm × 13 mm, compared with the previous examination (picture 1, 2),(H) shows the lesion in corpus callosum was slightly smaller, compared with picture 3,(I) (J) the signal of the lesion in corpus callosum and bilateral centrum semiovale was weaker, compared with picture 4, 5 (picture F–J, on December 20th,2018), (K)(L)shows the size of sellar and suprasellar high signal was reduced to 10mm × 11mm × 12 mm, (M)shows the abnormally high signal in bilateral basal ganglia region basically disappeared (picture K–M, on January 18th,2019), (N)(O)(P)shows the size of sellar and suprasellar high signal was further reduced to 8mm × 5mm × 9mm (on April 27th,2019),(Q)(R)contrast enhanced images shows the pituitary gland was almost normal in size, with homogeneous enhancement after enhancement, and pituitary stem was slightly shifted to the left, (S) coronal T2-weighed images shows the pituitary gland appeared as heterogeneous signal (on September 24th,2019).
Further hormonal examination results after admission were as follows: plasma prolactin (PRL) level of 104.71 ng/ml (3.34–26.72 ng/ml), TSH level of 1.49 mIU/ml (0.3–5.5 mIU/ml), fT4 level of 11.26 pmol/L (11.46–23.17 pmol/L), fT3 level of 3.25 pmol/L (2.8–7.1 pmol/L), ACTH level (8AM) of 9.53 pg/ml (6–40 pg/ml), ACTH level (4PM) of 7.12 pg/ml (3–30 pg/ml), and cortisol level (8AM):15.46 μg/dl (6.7–22.8), cortisol level (4PM) of >61.4 μg/dl (0–10 μg/dl), growth hormone of 0.65 ng/ml (0.06–5ng/ml) (Table 2). High cortisol level of 4PM was associated with hydrocortisone taking.
Table 2 Clinical detailed results of hormonal measurements.
value Date Result (mmol/l) normal range Annotation
TSH 2018-12-13 1.49 UIU/ml 0.3–5.5 UIU/ml 2019-01-23 delivery
2018-12-18 3.03 UIU/ml
2019-01-08 3.67 UIU/ml
2019-01-25 6.97 UIU/ml
2019-02-13 1.39 UIU/ml
2019-09-18 4.06 UIU/ml
2019-11-17 2.88 UIU/ml
FT4 2018-12-13 11.26 pmol/l 11.46–23.17pmol/l
2018-12-18 11.68 pmol/l
2019-01-08 12.5pmol/l
2019-01-25 13.09 pmol/l
2019-02-13 14.99 pmol/l
2019-09-18 11.7 pmol/l 12–22 pmol/l
2019-11-17 11.57 pmol/l
FT3 2018-12-13 3.25 pmol/l 2.8–7.1pmol/l
2018-12-18 3.11 pmol/l
2019-01-08 3.27 pmol/l
2019-01-25 3.03 pmol/l
2019-02-13 4.6 pmol/l
2019-09-18 4.46 pmol/l 3.1–6.8pmol/l
2019-11-17 4.22 pmol/l
Cortisol 2018-12-14 8AM:15.46μg/dl 6.7–22.8 μg/dl Cortisol 4PM (2018-12-14) after hydrocortisone using
2018-12-14 4PM:>61.4μg/dl 0–10 μg/dl
2019-01-25 8AM:8.87μg/dl 6.7–22.8 μg/dl
2019-01-25 4PM:5.58μg/dl 0-10 μg/dl
2019-09-18 8AM:7.37μg/dl 6.7–22.8 μg/dl
2019-09-18 4PM:2.2μg/dl 0–10 μg/dl
ACTH 2018-12-14 8AM:9.53 pg/ml 6–40 pg/ml
2018-12-14 4PM:7.12 pg/ml 3–30 pg/ml
2019-01-26 8AM:16.6 pg/ml 6–40 pg/ml
2019-01-26 4PM:7.36 pg/ml 3–30 pg/ml
2019-09-18 8AM:19.95pg/ml 6–40 pg/ml
2019-09-18 4PM:11.66pg/ml 3–30 pg/ml
Prolactin 2018-12-13 104.71 ng/ml 3.34–26.72 ng/ml Postpartum no breastfeeding
2018-12-18 108.40 ng/ml
2019-01-25 110.55 ng/ml
2019-02-13 59.06 ng/ml
2019-07-19 50.76 ng/ml
2019-09-18 48.80 ng/ml
2020-01-17 44.59 ng/ml
Growth hormone 2018-12-13 0.65 ng/ml 0.06–5 ng/ml
2019-02-13 0.06 ng/ml
2019-09-18 0.87 ng/ml
Insulin-like growth factor 2019-02-13 195.5 ng/ml 60–350 ng/ml
2019-09-18 176 ng/ml
A multidisciplinary team was organized including neurology, neurosurgery, endocrinology, ICU and obstetric department. PA with pituitary insufficiency were considered which caused hyponatremia and sodium supplied rapidly for EPM induction with hemiplegia and aphasia. The patient was given hydrocortisone according to the symptoms gradually to taper off dose, at the same times oral levothyroxine therapy (25μg/day) was given. The symptoms improved after 2 days and the patient could speak and recovered the movement of limbs. Her medical history was got which included that she had been irregular menstruation from the menarche at 14-year-old. In 2 years before pregnancy (August 23, 2016) she had taken hormone test and results were nearly normal. After that she had not gone to the hospital until she was pregnancy. She complained severe headache for the entire pregnancy and got the drug for painkiller at the early pregnancy. After taking medications, her symptoms did not improve and because of worrying about the outcomes of drugs on fetal, so she stopped the drug. After using hydrocortisone and levothyroxine, the symptoms including headache and vomiting disappear, MRI after 8 days at admission showed that abnormal signal in the splenium of the corpus callosum, bilateral basal ganglia, and centrum semiovale were weaker significantly. She delivered a healthy baby via cesarean section at hospital at 38 + 1 week of gestation (January 23, 2019). The baby birth weight was 2850 grams. The Apgar score was 9’ and 9’at first and fifth minutes, respectively. The blood volume during operation was 1000 ml. The patient did not have breastfeeding after delivery.
Postpartum, the patient did not have headache and vomiting except her irregular menstruation. The pituitary tumor was significantly regressive by MRI (Fig. 1). Meanwhile the blood hormone examination showed that PRL was decreased gradually of 44.59ng/ml (January 17, 2020). Thyroid function tests, serum cortisol, ACTH, growth hormone, and IGF-1 level showed normally. This study was approved by the Ethics Committee of Soochow University. The patient agreed to authorize us to share the figures and the experiences during the treatment procedure in our department. Informed consent was obtained.
3 Discuss
Gestational pituitary tumor apoplexy is a rare disease. Considering the situation of lack of consensus, it is difficult to manage the PA cases. So, every patient should be assessed and managed carefully. Especially for some cases with pituitary tumor which was not found before pregnancy it is difficult for timely treatment.
4 Clinical signs and diagnosis
PA occurs in patients which are asymptomatic previously in 60% to 80% of cases.[9] The main symptoms of PTA include headache, nausea, visual impairment among which headache occurs in 95% of cases and vomiting in 69% of that.[10,11] Due to the atypical symptoms, misdiagnosis is often caused and serious clinical complications are resulted in.[12]
Before pregnancy most of the patients with pituitary tumor have the history of irregular menstruation because of the elevated sexual hormones such as prolactin. Headache is one of the most common symptoms of PTA during pregnancy. Our patient complained of headache, but there was no effect after taking painkiller drugs. This symptom provided us with certain signals, but the clinician did not pay enough attention to it, because headache is common during pregnancy, associated with emotion such as stress, lack of sleep, depression, and malnutrition. In addition pregnant women themselves often fear that drugs for painkiller might affect the fetus, so simple headaches are not taken seriously.[13] Vomiting is one of the symptoms of PTA during pregnancy. The case complained of vomiting for 3 days, but emergency department only routinely conducted blood electrolyte examination, and immediately gave a large amount of sodium supplement treatment after the discovery of hyponatremia. Only the patient had symptoms with aphasia and hemiplegia on the next day, the attention was aroused by the clinicians. Similarly there are many reasons for simple vomiting during pregnancy and clinicians often pay more attention to electrolyte disorders than the reason of hyperemesis. The symptoms including headache and vomiting are caused by the increased intracranial pressure due to PTA and meningeal irritation.[9,10]
MRI examination is necessary for the diagnosis of PA and EPM. The precise mechanism underlying EPM and CPM remains elusive. It involves a patient with hyponatremia, in whom compensatory cellular expansion offsets the reduced plasma osmotic pressure. Thereafter, any rapid change in osmosis in the opposite direction, usually caused by hypertonic fluid, causes the swollen cells to shrink, leading to osmotic demyelination. The mechanism of cellular expansion relies upon the generation of osmoses such as taurine, glycine, glutamine, sorbitol, and inositol.[14] Our patient was given the rapid sodium treatment to correct hyponatremia which resulted in transient hemiplegia and aphasia. MRI examination may reveal abnormal signal, which could be considered the acute cerebral infarction if not combined with clinical history or lack of understanding of EMP and may lead to misdiagnosis of clinical doctors.
Traditional CPM was thought as pathological features about pons base symmetrical demyelination of nerve fibers, later it was found that outside parts of the pons also could appear the same change, known as the EPM. Generally, both of them have a history of rapid correction of hyponatremia. EPM without CPM was rare, which could result in misdiagnosis. The hallmark of EPM has the striking T2 signal abnormalities with lesions most commonly occurrence in the cerebellum, the lateral geniculate body, the external and extreme capsule, basal ganglia, thalamus, gray-white junction of the cerebral cortex, and the hippocampi.[15] Although rare, lesions have been described in the spinal cord, amygdala, anterior commissure, optic tracts, and the subthalamic nuclei.[6,8]
5 Treatment
Management of PA has 2 choices: surgery and conservative medication. When pregnancy is confirmed, most of the women with pre-existing pituitary tumor choose to stop dopamine agonist generally,[16] although the knowledge about pregnancy outcomes for women who have become pregnant while taking bromocriptine or cabergoline is widening. Large adenoma size, pregnancy, and cessation of cabergoline could lead to PA. There are no clear guidelines for the management of PA during pregnancy. In the case of prolactioma and non-stroke symptomatic tumor growth, most of them are recommended reactivating dopamine agonist as first-line therapy, as this is generally considered to be less risky to the mother and fetus than surgical intervention. Half of the patients were treated conservatively with pituitary hormone replacement therapy when necessary, few cases were treated with dopamine agonists.[17,18]
There are no randomized controlled trials comparing the effects of surgical and conservative treatment in pregnant women with PA. However, surgery seems appropriate for patients who fail to respond to conservative treatment or cannot tolerate dopamine agonists.[16] Neurosurgical intervention should be considered in cases with persistent visual field defects or deteriorating level of consciousness. If operation, it is emphasized that surgical excision should be performed by experienced neurosurgeons, not by on-call surgeons.
The main conservative treatment with PTA during pregnancy is to provide fluid and electrolyte balance and high dose glucocorticoid for emergency condition. Glucocorticoid is the most commonly used hormonal drug. In addition, if combined with thyroid insufficiency and adrenal insufficiency, it can be supplemented according to the examination results and clinical symptoms. About the CPM and EPM caused by fast natrium replenishment, sodium supplementation must be controlled. After the treatment, the symptoms of aphasia and hemiplegia of this case were rapidly improved and the effect of conservative treatment was obvious. Hypopituitarism is an important complication of apoplexy including hypothyroidism, hypoadrenalism and hyperprolactinaemia and may be missed if not carefully investigated.[5] Therefore, clinicians must pay attention to the occurrence of hypophysis dysfunction and give related hormone therapy in time.
6 Prognosis
The risk of pituitary tumor development will increase during pregnancy. The prognosis of PA during pregnancy depends on the timely diagnosis and clinical management. In general, early symptoms such as headache and vomiting should be pay attention. Careful medical history inquiry by the clinician, timely physical examination, MRI application and hormone replacement therapy as soon as possible can significantly improve the therapeutic effect.
7 Conclusion
In general, in the case of pregnancy, the diagnosis of PTA can be challenging and confused with other complex situations, such as preeclampsia. MRI is one of the most sensitive examination, revealing to confirm diagnosis of PTA and/or necrosis of part of adrenocorticotropic hormone deficiency and adrenal insufficiency. If not treated, it is a potentially life-threatening disease for both mother and fetus. Headache during pregnancy is often nonspecific, so it is easy to be omitted by clinicians. Therefore, careful medical history inquiry is very important. The patients need to be re-evaluated if chronic headaches do not ease. A multidisciplinary team consisting of neurology, neurosurgery, endocrinology, ICU, and obstetric department is important in deciding the optimal treatment. At the same time, maternal desires should be taking into consideration.
Author contributions
Conceptualization: Wenfeng Ye, Linlin Chen.
Data curation: Shiying Sheng, Zhengyu Liu.
Investigation: Wenfeng Ye, Linlin Chen, Changfang Yao, Chunyan Xue.
Project administration: Wenfeng Ye, Chunyan Xue, Wei Xing.
Supervision: Wei Xing.
Validation: Changfang Yao, Shiying Sheng, Zhengyu Liu, Chunyan Xue, Wei Xing.
Visualization: Wenjie Huang, Linlin Chen, Changfang Yao, Zhengyu Liu, Wei Xing.
Writing – original draft: Wenfeng Ye, Wenjie Huang.
Writing – review & editing: Wei Xing.
Abbreviations: CPM = central pontine myelinolysis, EPM = extrapontine myelinolysis, MRI = magnetic resonance imaging, ODS = osmotic demyelination syndrome, PA = pituitary apoplex, PTA = pituitary tumor apoplex.
How to cite this article: Ye W, Huang W, Chen L, Yao C, Sheng S, Liu Z, Xue C, Xing W. Pituitary tumor apoplexy associated with extrapontine myelinolysis during pregnancy: a case report. Medicine. 2021;100:10(e25075).
WY and WH contributed equally to this work.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33725898 | 19,197,894 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Difference in the efficacy of intravitreal dexamethasone implant before and after silicone oil removal: A case report.
BACKGROUND
An intravitreal dexamethasone (IV-DEX) implant is safe and effective for the treatment of macular edemas; however, the efficacy of IV-DEX implants in silicone oil (SO)-filled eyes remains controversial. There is no previous study comparing an IV-DEX implant in the same eye with and without intravitreal SO.
A 72-year-old man with proliferative diabetic retinopathy, macular edema, and rhegmatogenous retinal detachment, treated with pars plana vitrectomy with SO tamponade had refractory macular edema.
METHODS
Refractory macular edema.
METHODS
Subtenon triamcinolone injection, intravitreal anti-vascular endothelial growth factor injection, and IV-DEX implantation were performed; this was followed by intravitreal SO removal combined with IV-DEX implantation.
RESULTS
The macular edema did not decrease significantly with posterior subtenon triamcinolone injection, intravitreal anti-vascular endothelial growth factor injection, and IV-DEX implantation; however, the edema was relieved after SO removal and a new IV-DEX implantation.
CONCLUSIONS
IV-DEX implant may be less efficacious in the treatment of macular edema in an SO-filled eye than that in a normal vitreous cavity.
1 Introduction
An intravitreal dexamethasone implant (IV-DEX implant; Ozurdex, Allergan, Inc., CA, USA) for the sustained release of dexamethasone (700 μg) is safe and effective for the treatment of macular edemas in patients with various retinal conditions.[1,2] Eyes with silicone oil (SO) often have refractory macular edema, which is considered curable with a IV-DEX implant; however, the efficacy of IV-DEX implants in SO-filled eyes remains controversial.[3–5] To our best knowledge, no study has compared the efficacy of an IV-DEX implant in the same eye with and without SO. Here, we report the variable efficacy of an IV-DEX implant before and after SO removal.
2 Case report
A 72-year-old man with a history of diabetes and hypertension visited our hospital with a chief complaint of right vision deterioration. His left eye was diagnosed with postoperative endophthalmitis by pars plana vitrectomy (PPV) at a local ophthalmic clinic 1 month prior; therefore, he underwent an immediate PPV with SO tamponade at our hospital. Postoperatively, his best-corrected visual acuity (BCVA) ended with non-light perception. His right eye was pseudophakic with a BCVA of 20/400 (Snellen chart) and intraocular pressure of 13 mm Hg (applanation tonometry), and a history of PPV for proliferative diabetic retinopathy and diabetic macular edema. The macula of his right eye was edematous and detached with a 1/5 disc-diameter-sized retinal break, which was 3-disc-diameter temporal to the fovea on optical coherence tomography imaging and fundus examination. In addition, the vitreous cavity was filled with SO. After another PPV with SO tamponade, the retina was completely reattached; however, the macular edema persisted postoperatively. The macular edema did not decrease despite posterior subtenon triamcinolone injection and intravitreal anti-vascular endothelial growth factor injection (Fig. 1a); therefore, he was treated with an IV-DEX implant. One week later, the implant was identified at the far peripheral fundus. The central subfield macular thickness (CSMT) had decreased slightly from 860 μm to 786 μm over a month (Fig. 1b). Three months after the first IV-DEX implant, the SO was removed and another IV-DEX implant was placed at the end of the surgery. One month after the SO removal, the macular edema had relieved, and the CSMT was 301 μm. This decrease remained stable postoperatively even at 14-month follow-up without additional treatment except an additional IV-DEX implant 1-year postoperatively (CSMT at postoperative 14 months, 229 μm). Moreover, the patient's BCVA improved to 40/200 (Fig. 1c and d). There were no postoperative complications during the follow-up period.
Figure 1 Optical coherence tomography images of the horizontal line scans through the macula of the patient's right eye. (A) Before the implantation of the intravitreal dexamethasone (IV-DEX) implant (central subfield macular thickness [CSMT], 860 μm). (B) One month after the implantation of the IV-DEX implant in the silicone oil-filled vitreous cavity (CSMT, 786 μm) (C) One month after the implantation of the IV-DEX implant after silicone oil removal (CSMT, 301 μm). (D) Fourteen months after implantation of the second IV-DEX implant, which was 2 months after the third implantation (CSMT, 229 μm).
3 Discussion
This case report shows that macular edema refractory to posterior subtenon triamcinolone injection, intravitreal anti-vascular endothelial growth factor administration, and an IV-DEX implant in an eye with SO was effectively relieved with the IV-DEX implant only after SO removal.
Previous case studies have reported contrasting findings on the behavior and efficacy of IV-DEX implants in eyes with a SO-filled vitreous cavity. Flores Villalobos et al reported that in vitro, DEX implants had less anti-inflammatory effects and more irregularity in its levels in SO than those in saline solution, and suggested that relatively denser mediums alter the pharmacokinetics of the IV-DEX implant; therefore, the IV-DEX implant should not be used in dense SO-filled eyes.[3] However, Afshar et al and Esenulku et al reported that the IV-DEX implant trapped at the macula in an SO-filled eye could improve BCVA and relieve macular edema.[4,5] In light of these previous reports, the pharmacological effects of an IV-DEX implant is presumed to be more sensitive to its proximity to the target tissues. In contrast, Kim et al reported that an IV-DEX implant in an SO-filled eye with macular edema secondary to chronic non-infectious uveitis was efficacious in improving BCVA and CSMT, regardless of the implant's proximity to the macula; the efficacy in the previous study might have decreased because of inflammation and not by the direct effect of DEX on the macula.[6] An IV-DEX implant rarely localizes to the macula because of the buoyancy of SO, and moreover, its location hardly changes in SO-filled eyes until it disappears.
In this case, the first IV-DEX implant was not efficacious presumably because it was not sufficiently close to the macula to deliver a therapeutic level of DEX through the SO. However, after SO removal, the second IV-DEX implant may have stably delivered a therapeutic dose of DEX to the macula without any hindrance.
In conclusion, this case shows that the efficacy of IV-DEX implant differs before and after SO removal. Moreover, the IV-DEX implant is less efficacious in the treatment of a macular edema in a SO-filled eye than that in a normal vitreous cavity, and especially when the implant is not proximal to the macula.
Author contributions
Conceptualization: Yu Cheol Kim.
Data curation: Jae Hong An, Yu Cheol Kim.
Investigation: Jae Hong An.
Methodology: Jae Hong An, Yu Cheol Kim.
Supervision: Yu Cheol Kim.
Visualization: Yu Cheol Kim, Jae Hong An.
Writing – original draft: Jae Hong An.
Writing – review & editing: Yu Cheol Kim.
Abbreviations: BCVA = best-corrected visual acuity, CSMT = central subfield macular thickness, IV-DEX = intravitreal dexamethasone, PPV = pars plana vitrectomy, SO = silicone oil.
How to cite this article: An JH, Kim YC. Difference in the efficacy of intravitreal dexamethasone implant before and after silicone oil removal: a case report. Medicine. 2021;100:11(e25161).
This research was supported by the Bisa Research Grant of Keimyung University in 2020 and Keimyung University and National Research Foundation of Korea (NRF-2019R1G1A1011559).
A written informed consent was obtained from the patient for publication of this case report.
The authors have no conflicts of interests to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | TRIAMCINOLONE ACETONIDE | DrugsGivenReaction | CC BY | 33726001 | 20,473,288 | 2021-03-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac arrest'. | Ruxolitinib in conjunction with the HLH-94 protocol for Epstein-Barr virus-related hemophagocytic lymphohistiocytosis in the intensive care unit: A case report.
BACKGROUND
The HLH-94 protocol is a standard induction treatment for hemophagocytic lymphohistiocytosis. However, about 30% of patients may not respond. Ruxolitinib has been clinically proven to be an effective treatment for hemophagocytic lymphohistiocytosis (HLH).
A previously healthy 14-year-old girl presented to the local hospital with a 4-day history of persistent fever and sore throat.
METHODS
Clinical and laboratory tests revealed fever >38.5°C, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, and an elevated interleukin-2 receptor level.
METHODS
This patient was treated with ruxolitinib and the HLH-94 protocol.
RESULTS
The patient's clinical and some laboratory indices improved. Unfortunately, vital signs such as respiratory function and consciousness did not improve.
CONCLUSIONS
This case report highlights the effect of using ruxolitinib in conjunction with the HLH-94 protocol. However, safety evaluation of this regimen was not performed because critically ill patient died too fast.
1 Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder characterized by an excessive inflammatory response mediated by hyperactivation of T cells and antigen-presenting cells. Epstein-Barr virus (EBV) is a common triggering factor for HLH. EBV-associated HLH (EBV-HLH) can progress rapidly to multiorgan dysfunction. Symptoms of HLH include persistent pyrexia, pancytopenia, hepatosplenomegaly, elevated lactate dehydrogenase, serum ferritin, and triglyceride levels, and decreased fibrinogen.[1,2] The HLH-94 protocol is a standard induction treatment for HLH, consisting of dexamethasone and etoposide.[3] However, about 30% of patients may not respond.[4] Ruxolitinib has been clinically proven to be effective to treat HLH.[5–7] Thus, we use ruxolitinib in conjunction with the HLH-94 protocol as the first-line treatment.
Here we report a case of a patient with newly diagnosis EBV-triggered HLH who was critically ill and experienced improvement after ruxolitinib in conjunction with the HLH-94 protocol.
1.1 Consent statement
The patient's family had provided informed consent for the publication of this case report.
2 Case report
A previously healthy 14-year-old girl presented to the local hospital with a 4-day history of persistent fever and sore throat. After taking acetaminophen for 2 days, she felt worse and complained of extremity myalgia. Laboratory tests revealed pancytopenia (white blood cell [WBC] count, 2.69 × 109/L; neutrophil count, 1.96 × 109/L; hemoglobin, 93 g/L; platelet count, 34 × 109/L), abnormal liver function (aspartate aminotransferase, 300 units/L [normal: <40 units/L]; alanine aminotransferase, 111 units/L [normal: <35 units/L]; total bilirubin, 102 μmol/L [normal: <21 μmol/L]; albumin, 27.6 g/L [normal: 40–55 g/L], and creatinine, 247 μmol/L [normal: 41–73 μmol/L]). The patient was diagnosed with multiorgan failure and admitted to our hospital.
Meropenem and vancomycin treatment was initiated within 3 days of admission, and a chest computed tomography (CT) scan revealed pneumonia. On hospital day 2, thrombotic thrombocytopenic purpura was suspected. Dexamethasone 10 mg/day, intravenous immunoglobulin 0.4 g/kg/day, and plasmapheresis were administered. Her condition worsened, with a persistent fever of 38.5 to 39.8°C and rapid heart rate of >140 bpm. Her blood pressure was about 90/60 mm Hg, and she was supported with 1.6 mg/hour norepinephrine. She received mechanical ventilation because of respiratory failure. Platelets and fibrinogen were not elevated after an infusion. She had persistent epistaxis and coma on hospital day 3. Rheumatological, autoimmune, and oncological workups revealed no positive results (Table 1). EBV polymerase chain reaction revealed 1.03 × 106 copies/ml. Metagenomic next-generation sequencing (NGS) was positive for EBV but negative for bacteria, fungus, parasites, and Mycobacterium. Lactate dehydrogenase (LDH) was 3560 U/L. The patient met all 8 criteria for HLH, that is, fever >38.5°C, hepatosplenomegaly (based on Doppler ultrasound and abdominal CT), pancytopenia (WBC count, 0.67 × 109 /L, hemoglobin, 67 g/L; platelet count, 2 × 109 /L), hypertriglyceridemia (5.89 g/L), hypofibrinogenemia (0.72 g/L), hyperferritinemia (100,096 ng/ml), elevated interleukin-2 receptor level (40,740 U/ml), and hemophagocytosis observed on a bone marrow biopsy specimen. Genetic testing was performed and was negative for any known mutations causing HLH.
Table 1 The patient's laboratory results.
Infectious
Blood cultures: negative
COVID-19 PCR: negative
EBV PCR: 1.5 × 106 copies/ml
EBV NGS: positive
HIV antibody: negative
Hepatitis B surface antigen: negative
Hepatitis B surface IgG: positive
Hepatitis B core IgG: negative
Hepatitis C antibody: negative
Widal reaction: negative
Weil-Felix assay: negative
Immunologic
CD3+: 640/μl (normal: 770–2,860/μl)
CD4+: 308/μl (normal: 414–1,440/μl)
CD8+: 328/μl (normal: 238–1,250/μl)
CD4/CD8: 0.94 (normal: 0.7–2.87)
Rheumatologic
C3: 53.7 mg/dl (normal: 70–140 mg/dl)
C4: 38.2 mg/dl (normal: 10–40 mg/dl)
Rheumatoid factor:18.1 IU/ml (normal,: <25 IU/ml)
Antibody spectrum of anti-ENA peptide: negative
Antinuclear antibody: negative
ADAMTS13 activity: normal
Oncologic
CT chest, abdomen biopsy negative for malignancy
Bone marrow biopsy negative for leukemia
EBV = Epstein-Barr virus, NGS = next-generation sequencing, PCR = polymerase chain reaction.
After confirming the diagnosis on hospital day 4, ruxolitinib (10 mg twice per day) was administered in conjunction with the HLH-94 protocol (Fig. 1). Her temperature returned to normal and the heart rate dropped to about 105 bpm after 20 hours (Fig. 2A). Her blood pressure returned to normal after administering 0.2 mg/hour norepinephrine. Improvements were seen in several indices, including the WBC count (Fig. 2B), platelet count (Fig. 2C), and fibrinogen level (Fig. 2D). Her platelet count increased to 53 × 109 /L after infusion. Her fibrinogen level returned to normal, and there was a normal prothrombin time and activated partial thromboplastin. D-dimer decreased from 125 mg/L to 2.5 mg/L. EBV dropped to 2.35 × 104 copies/ml on hospital day 6. However, LDH and serum ferritin levels increased to 6,442 U/L and 42,897 ng/ml on hospital day 7, respectively. She remained in a coma on mechanical ventilation with high flow oxygen. On hospital day 8, her blood cell count decreased again (WBC count, 0.02 × 109 /L; hemoglobin, 80 g/L; platelet count, 2 × 109/L). On hospital day 10, we utilized the DEP protocol (20 mg liposomal doxorubicin, 100 mg etoposide, and 500 mg methylprednisone) rather than the HLH94 protocol. She died of cardiac arrest at 11 pm that day.
Figure 1 The treatment processes.
Figure 2 The patient's treatment response. The temperature returned to normal and the heart rate dropped to about 105 bpm after 20 hours (A). Improvements were seen in several indices, including the white blood cell count (B) platelet count (C), and fibrinogen level (D).
3 Discussion
HLH is a fatal clinical syndrome and no optimal treatment is available for HLH, the mortality rate for which exceeds 40% in children and adults even when following the standard HLH-94 protocol.[2,8] Clinicians have tried other combinations of agents. Ruxolitinib is a promising agent due to its powerful calming effect on the cytokine storm.[9] Ruxolitinib is a Janus kinase 1/2 inhibitor that suppresses the transmission of cytokine-induced signals. It suppresses cytokine signaling pathways, such as those of interferon (IFN)-γ and interleukin-2. In murine models of HLH, mice who received ruxolitinib had improved survival, due to reversal of pancytopenia and splenomegaly, and reductions in proinflammatory cytokines and the number of CD8+ T cells.[10,11] Ruxolitinib also reduces the severity of inflammation-associated anemia, and the number and activation status of T cells and neutrophils in primary and secondary HLH murine models, but only the IFN-γ-neutralizing antibody reduces anemia severity.[12] Ruxolitinib increased the apoptotic potential of CD8+ T cells in a murine model and primary patient samples, which were resistant to dexamethasone.[13]
In the human body, ruxolitinib has been demonstrated to exert a dramatic effect in some acute inflammatory syndromes, including acute graft-vs-host disease,[14] steroid-refractory cytokine release syndrome,[15] and COVID-19 with severe systemic hyperinflammation.[16] As a single drug, ruxolitinib has been used in salvage therapy for HLH, and exerted a powerful effect in several case reports.[17–21] Similar to what we observed in our case, the first reported case was a 38-year-old woman diagnosed as secondary HLH caused by an EBV infection. This patient exhibited improving disease markers but died eventually.[17] The improving markers included ferritin, fibrinogen, and LDH concentrations, but not pancytopenia. However, a 26-year-old woman diagnosed with treatment-refractory HLH caused by EBV and acute hepatitis C virus infection achieved completely recovery after the use of ruxolitinib.[19] In a series of children cases reported in China, the authors reported poor response to ruxolitinib alone in EBV-HLH when compared with other causes of HLH.[20] The authors suggested that ruxolitinib might not be able to eradicate EBV because EBV does not solely rely on JAK-STAT pathway to cause HLH. Therefore, combination with other drugs is needed.
Small series have reported improved clinical outcomes using ruxolitinib in conjunction with the HLH-94 protocol or chemotherapy.[6,22,23] In a multicenter, nonrandomized, phase II trial for refractory/relapsed HLH (NCT03533790), 54 patients received ruxolitinib combined with the doxorubicin-etoposide-methylprednisolone regimen for 2 weeks. Excitingly, in the patients who had previously received the DEP regimen but showed no improvement, 7 of 12 (58·3%) exhibited a partial response.[23] A pilot trial with first-line ruxolitinib as a single agent reported responses in 5 patients (NCT02400463), and the 2-month overall survival rate was 100%.[7] However, EBV-associated HLH was excluded from that trial. The most exciting outcome of ruxolitinib as a single agent for EBV-associated HLH was a 100% response rate (complete response, 75%, partial response, 25%) in a Chinese trial (ChiCTR2000029977).[5] Three cases treated with first-line ruxolitinib plus HLH-94 protocol showed rapid response and no obvious adverse effects.[6] For our patient who was treated with ruxolitinib plus HLH-94 protocol for the first line, clinical and some laboratory indices improved. Unfortunately, the vital signs, such as respiratory function and consciousness, did not improve.
Author contributions
Resources: Jiangbo Xie.
Writing – original draft: Zoufang Huang.
Writing – review & editing: Jiangbo Xie.
Abbreviations: CT = computed tomography, EBV = Epstein-Barr virus, HLH = hemophagocytic lymphohistiocytosis, IL-2 = interleukin-2, LDH = lactate dehydrogenase, NGS = next-generation sequencing, PCR = polymerase chain reaction, WBC = white blood cell.
How to cite this article: Huang Z, Xie J. Ruxolitinib in conjunction with the HLH-94 protocol for Epstein-Barr virus-related hemophagocytic lymphohistiocytosis in the intensive care unit: a case report. Medicine. 2021;100:11(e25188).
The authors have no conflicts of interests to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | DOXORUBICIN, ETOPOSIDE, METHYLPREDNISOLONE | DrugsGivenReaction | CC BY | 33726009 | 19,107,068 | 2021-03-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Ruxolitinib in conjunction with the HLH-94 protocol for Epstein-Barr virus-related hemophagocytic lymphohistiocytosis in the intensive care unit: A case report.
BACKGROUND
The HLH-94 protocol is a standard induction treatment for hemophagocytic lymphohistiocytosis. However, about 30% of patients may not respond. Ruxolitinib has been clinically proven to be an effective treatment for hemophagocytic lymphohistiocytosis (HLH).
A previously healthy 14-year-old girl presented to the local hospital with a 4-day history of persistent fever and sore throat.
METHODS
Clinical and laboratory tests revealed fever >38.5°C, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, and an elevated interleukin-2 receptor level.
METHODS
This patient was treated with ruxolitinib and the HLH-94 protocol.
RESULTS
The patient's clinical and some laboratory indices improved. Unfortunately, vital signs such as respiratory function and consciousness did not improve.
CONCLUSIONS
This case report highlights the effect of using ruxolitinib in conjunction with the HLH-94 protocol. However, safety evaluation of this regimen was not performed because critically ill patient died too fast.
1 Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder characterized by an excessive inflammatory response mediated by hyperactivation of T cells and antigen-presenting cells. Epstein-Barr virus (EBV) is a common triggering factor for HLH. EBV-associated HLH (EBV-HLH) can progress rapidly to multiorgan dysfunction. Symptoms of HLH include persistent pyrexia, pancytopenia, hepatosplenomegaly, elevated lactate dehydrogenase, serum ferritin, and triglyceride levels, and decreased fibrinogen.[1,2] The HLH-94 protocol is a standard induction treatment for HLH, consisting of dexamethasone and etoposide.[3] However, about 30% of patients may not respond.[4] Ruxolitinib has been clinically proven to be effective to treat HLH.[5–7] Thus, we use ruxolitinib in conjunction with the HLH-94 protocol as the first-line treatment.
Here we report a case of a patient with newly diagnosis EBV-triggered HLH who was critically ill and experienced improvement after ruxolitinib in conjunction with the HLH-94 protocol.
1.1 Consent statement
The patient's family had provided informed consent for the publication of this case report.
2 Case report
A previously healthy 14-year-old girl presented to the local hospital with a 4-day history of persistent fever and sore throat. After taking acetaminophen for 2 days, she felt worse and complained of extremity myalgia. Laboratory tests revealed pancytopenia (white blood cell [WBC] count, 2.69 × 109/L; neutrophil count, 1.96 × 109/L; hemoglobin, 93 g/L; platelet count, 34 × 109/L), abnormal liver function (aspartate aminotransferase, 300 units/L [normal: <40 units/L]; alanine aminotransferase, 111 units/L [normal: <35 units/L]; total bilirubin, 102 μmol/L [normal: <21 μmol/L]; albumin, 27.6 g/L [normal: 40–55 g/L], and creatinine, 247 μmol/L [normal: 41–73 μmol/L]). The patient was diagnosed with multiorgan failure and admitted to our hospital.
Meropenem and vancomycin treatment was initiated within 3 days of admission, and a chest computed tomography (CT) scan revealed pneumonia. On hospital day 2, thrombotic thrombocytopenic purpura was suspected. Dexamethasone 10 mg/day, intravenous immunoglobulin 0.4 g/kg/day, and plasmapheresis were administered. Her condition worsened, with a persistent fever of 38.5 to 39.8°C and rapid heart rate of >140 bpm. Her blood pressure was about 90/60 mm Hg, and she was supported with 1.6 mg/hour norepinephrine. She received mechanical ventilation because of respiratory failure. Platelets and fibrinogen were not elevated after an infusion. She had persistent epistaxis and coma on hospital day 3. Rheumatological, autoimmune, and oncological workups revealed no positive results (Table 1). EBV polymerase chain reaction revealed 1.03 × 106 copies/ml. Metagenomic next-generation sequencing (NGS) was positive for EBV but negative for bacteria, fungus, parasites, and Mycobacterium. Lactate dehydrogenase (LDH) was 3560 U/L. The patient met all 8 criteria for HLH, that is, fever >38.5°C, hepatosplenomegaly (based on Doppler ultrasound and abdominal CT), pancytopenia (WBC count, 0.67 × 109 /L, hemoglobin, 67 g/L; platelet count, 2 × 109 /L), hypertriglyceridemia (5.89 g/L), hypofibrinogenemia (0.72 g/L), hyperferritinemia (100,096 ng/ml), elevated interleukin-2 receptor level (40,740 U/ml), and hemophagocytosis observed on a bone marrow biopsy specimen. Genetic testing was performed and was negative for any known mutations causing HLH.
Table 1 The patient's laboratory results.
Infectious
Blood cultures: negative
COVID-19 PCR: negative
EBV PCR: 1.5 × 106 copies/ml
EBV NGS: positive
HIV antibody: negative
Hepatitis B surface antigen: negative
Hepatitis B surface IgG: positive
Hepatitis B core IgG: negative
Hepatitis C antibody: negative
Widal reaction: negative
Weil-Felix assay: negative
Immunologic
CD3+: 640/μl (normal: 770–2,860/μl)
CD4+: 308/μl (normal: 414–1,440/μl)
CD8+: 328/μl (normal: 238–1,250/μl)
CD4/CD8: 0.94 (normal: 0.7–2.87)
Rheumatologic
C3: 53.7 mg/dl (normal: 70–140 mg/dl)
C4: 38.2 mg/dl (normal: 10–40 mg/dl)
Rheumatoid factor:18.1 IU/ml (normal,: <25 IU/ml)
Antibody spectrum of anti-ENA peptide: negative
Antinuclear antibody: negative
ADAMTS13 activity: normal
Oncologic
CT chest, abdomen biopsy negative for malignancy
Bone marrow biopsy negative for leukemia
EBV = Epstein-Barr virus, NGS = next-generation sequencing, PCR = polymerase chain reaction.
After confirming the diagnosis on hospital day 4, ruxolitinib (10 mg twice per day) was administered in conjunction with the HLH-94 protocol (Fig. 1). Her temperature returned to normal and the heart rate dropped to about 105 bpm after 20 hours (Fig. 2A). Her blood pressure returned to normal after administering 0.2 mg/hour norepinephrine. Improvements were seen in several indices, including the WBC count (Fig. 2B), platelet count (Fig. 2C), and fibrinogen level (Fig. 2D). Her platelet count increased to 53 × 109 /L after infusion. Her fibrinogen level returned to normal, and there was a normal prothrombin time and activated partial thromboplastin. D-dimer decreased from 125 mg/L to 2.5 mg/L. EBV dropped to 2.35 × 104 copies/ml on hospital day 6. However, LDH and serum ferritin levels increased to 6,442 U/L and 42,897 ng/ml on hospital day 7, respectively. She remained in a coma on mechanical ventilation with high flow oxygen. On hospital day 8, her blood cell count decreased again (WBC count, 0.02 × 109 /L; hemoglobin, 80 g/L; platelet count, 2 × 109/L). On hospital day 10, we utilized the DEP protocol (20 mg liposomal doxorubicin, 100 mg etoposide, and 500 mg methylprednisone) rather than the HLH94 protocol. She died of cardiac arrest at 11 pm that day.
Figure 1 The treatment processes.
Figure 2 The patient's treatment response. The temperature returned to normal and the heart rate dropped to about 105 bpm after 20 hours (A). Improvements were seen in several indices, including the white blood cell count (B) platelet count (C), and fibrinogen level (D).
3 Discussion
HLH is a fatal clinical syndrome and no optimal treatment is available for HLH, the mortality rate for which exceeds 40% in children and adults even when following the standard HLH-94 protocol.[2,8] Clinicians have tried other combinations of agents. Ruxolitinib is a promising agent due to its powerful calming effect on the cytokine storm.[9] Ruxolitinib is a Janus kinase 1/2 inhibitor that suppresses the transmission of cytokine-induced signals. It suppresses cytokine signaling pathways, such as those of interferon (IFN)-γ and interleukin-2. In murine models of HLH, mice who received ruxolitinib had improved survival, due to reversal of pancytopenia and splenomegaly, and reductions in proinflammatory cytokines and the number of CD8+ T cells.[10,11] Ruxolitinib also reduces the severity of inflammation-associated anemia, and the number and activation status of T cells and neutrophils in primary and secondary HLH murine models, but only the IFN-γ-neutralizing antibody reduces anemia severity.[12] Ruxolitinib increased the apoptotic potential of CD8+ T cells in a murine model and primary patient samples, which were resistant to dexamethasone.[13]
In the human body, ruxolitinib has been demonstrated to exert a dramatic effect in some acute inflammatory syndromes, including acute graft-vs-host disease,[14] steroid-refractory cytokine release syndrome,[15] and COVID-19 with severe systemic hyperinflammation.[16] As a single drug, ruxolitinib has been used in salvage therapy for HLH, and exerted a powerful effect in several case reports.[17–21] Similar to what we observed in our case, the first reported case was a 38-year-old woman diagnosed as secondary HLH caused by an EBV infection. This patient exhibited improving disease markers but died eventually.[17] The improving markers included ferritin, fibrinogen, and LDH concentrations, but not pancytopenia. However, a 26-year-old woman diagnosed with treatment-refractory HLH caused by EBV and acute hepatitis C virus infection achieved completely recovery after the use of ruxolitinib.[19] In a series of children cases reported in China, the authors reported poor response to ruxolitinib alone in EBV-HLH when compared with other causes of HLH.[20] The authors suggested that ruxolitinib might not be able to eradicate EBV because EBV does not solely rely on JAK-STAT pathway to cause HLH. Therefore, combination with other drugs is needed.
Small series have reported improved clinical outcomes using ruxolitinib in conjunction with the HLH-94 protocol or chemotherapy.[6,22,23] In a multicenter, nonrandomized, phase II trial for refractory/relapsed HLH (NCT03533790), 54 patients received ruxolitinib combined with the doxorubicin-etoposide-methylprednisolone regimen for 2 weeks. Excitingly, in the patients who had previously received the DEP regimen but showed no improvement, 7 of 12 (58·3%) exhibited a partial response.[23] A pilot trial with first-line ruxolitinib as a single agent reported responses in 5 patients (NCT02400463), and the 2-month overall survival rate was 100%.[7] However, EBV-associated HLH was excluded from that trial. The most exciting outcome of ruxolitinib as a single agent for EBV-associated HLH was a 100% response rate (complete response, 75%, partial response, 25%) in a Chinese trial (ChiCTR2000029977).[5] Three cases treated with first-line ruxolitinib plus HLH-94 protocol showed rapid response and no obvious adverse effects.[6] For our patient who was treated with ruxolitinib plus HLH-94 protocol for the first line, clinical and some laboratory indices improved. Unfortunately, the vital signs, such as respiratory function and consciousness, did not improve.
Author contributions
Resources: Jiangbo Xie.
Writing – original draft: Zoufang Huang.
Writing – review & editing: Jiangbo Xie.
Abbreviations: CT = computed tomography, EBV = Epstein-Barr virus, HLH = hemophagocytic lymphohistiocytosis, IL-2 = interleukin-2, LDH = lactate dehydrogenase, NGS = next-generation sequencing, PCR = polymerase chain reaction, WBC = white blood cell.
How to cite this article: Huang Z, Xie J. Ruxolitinib in conjunction with the HLH-94 protocol for Epstein-Barr virus-related hemophagocytic lymphohistiocytosis in the intensive care unit: a case report. Medicine. 2021;100:11(e25188).
The authors have no conflicts of interests to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | DOXORUBICIN, ETOPOSIDE, METHYLPREDNISOLONE | DrugsGivenReaction | CC BY | 33726009 | 19,107,068 | 2021-03-19 |
What was the dosage of drug 'DOXORUBICIN'? | Ruxolitinib in conjunction with the HLH-94 protocol for Epstein-Barr virus-related hemophagocytic lymphohistiocytosis in the intensive care unit: A case report.
BACKGROUND
The HLH-94 protocol is a standard induction treatment for hemophagocytic lymphohistiocytosis. However, about 30% of patients may not respond. Ruxolitinib has been clinically proven to be an effective treatment for hemophagocytic lymphohistiocytosis (HLH).
A previously healthy 14-year-old girl presented to the local hospital with a 4-day history of persistent fever and sore throat.
METHODS
Clinical and laboratory tests revealed fever >38.5°C, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, and an elevated interleukin-2 receptor level.
METHODS
This patient was treated with ruxolitinib and the HLH-94 protocol.
RESULTS
The patient's clinical and some laboratory indices improved. Unfortunately, vital signs such as respiratory function and consciousness did not improve.
CONCLUSIONS
This case report highlights the effect of using ruxolitinib in conjunction with the HLH-94 protocol. However, safety evaluation of this regimen was not performed because critically ill patient died too fast.
1 Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder characterized by an excessive inflammatory response mediated by hyperactivation of T cells and antigen-presenting cells. Epstein-Barr virus (EBV) is a common triggering factor for HLH. EBV-associated HLH (EBV-HLH) can progress rapidly to multiorgan dysfunction. Symptoms of HLH include persistent pyrexia, pancytopenia, hepatosplenomegaly, elevated lactate dehydrogenase, serum ferritin, and triglyceride levels, and decreased fibrinogen.[1,2] The HLH-94 protocol is a standard induction treatment for HLH, consisting of dexamethasone and etoposide.[3] However, about 30% of patients may not respond.[4] Ruxolitinib has been clinically proven to be effective to treat HLH.[5–7] Thus, we use ruxolitinib in conjunction with the HLH-94 protocol as the first-line treatment.
Here we report a case of a patient with newly diagnosis EBV-triggered HLH who was critically ill and experienced improvement after ruxolitinib in conjunction with the HLH-94 protocol.
1.1 Consent statement
The patient's family had provided informed consent for the publication of this case report.
2 Case report
A previously healthy 14-year-old girl presented to the local hospital with a 4-day history of persistent fever and sore throat. After taking acetaminophen for 2 days, she felt worse and complained of extremity myalgia. Laboratory tests revealed pancytopenia (white blood cell [WBC] count, 2.69 × 109/L; neutrophil count, 1.96 × 109/L; hemoglobin, 93 g/L; platelet count, 34 × 109/L), abnormal liver function (aspartate aminotransferase, 300 units/L [normal: <40 units/L]; alanine aminotransferase, 111 units/L [normal: <35 units/L]; total bilirubin, 102 μmol/L [normal: <21 μmol/L]; albumin, 27.6 g/L [normal: 40–55 g/L], and creatinine, 247 μmol/L [normal: 41–73 μmol/L]). The patient was diagnosed with multiorgan failure and admitted to our hospital.
Meropenem and vancomycin treatment was initiated within 3 days of admission, and a chest computed tomography (CT) scan revealed pneumonia. On hospital day 2, thrombotic thrombocytopenic purpura was suspected. Dexamethasone 10 mg/day, intravenous immunoglobulin 0.4 g/kg/day, and plasmapheresis were administered. Her condition worsened, with a persistent fever of 38.5 to 39.8°C and rapid heart rate of >140 bpm. Her blood pressure was about 90/60 mm Hg, and she was supported with 1.6 mg/hour norepinephrine. She received mechanical ventilation because of respiratory failure. Platelets and fibrinogen were not elevated after an infusion. She had persistent epistaxis and coma on hospital day 3. Rheumatological, autoimmune, and oncological workups revealed no positive results (Table 1). EBV polymerase chain reaction revealed 1.03 × 106 copies/ml. Metagenomic next-generation sequencing (NGS) was positive for EBV but negative for bacteria, fungus, parasites, and Mycobacterium. Lactate dehydrogenase (LDH) was 3560 U/L. The patient met all 8 criteria for HLH, that is, fever >38.5°C, hepatosplenomegaly (based on Doppler ultrasound and abdominal CT), pancytopenia (WBC count, 0.67 × 109 /L, hemoglobin, 67 g/L; platelet count, 2 × 109 /L), hypertriglyceridemia (5.89 g/L), hypofibrinogenemia (0.72 g/L), hyperferritinemia (100,096 ng/ml), elevated interleukin-2 receptor level (40,740 U/ml), and hemophagocytosis observed on a bone marrow biopsy specimen. Genetic testing was performed and was negative for any known mutations causing HLH.
Table 1 The patient's laboratory results.
Infectious
Blood cultures: negative
COVID-19 PCR: negative
EBV PCR: 1.5 × 106 copies/ml
EBV NGS: positive
HIV antibody: negative
Hepatitis B surface antigen: negative
Hepatitis B surface IgG: positive
Hepatitis B core IgG: negative
Hepatitis C antibody: negative
Widal reaction: negative
Weil-Felix assay: negative
Immunologic
CD3+: 640/μl (normal: 770–2,860/μl)
CD4+: 308/μl (normal: 414–1,440/μl)
CD8+: 328/μl (normal: 238–1,250/μl)
CD4/CD8: 0.94 (normal: 0.7–2.87)
Rheumatologic
C3: 53.7 mg/dl (normal: 70–140 mg/dl)
C4: 38.2 mg/dl (normal: 10–40 mg/dl)
Rheumatoid factor:18.1 IU/ml (normal,: <25 IU/ml)
Antibody spectrum of anti-ENA peptide: negative
Antinuclear antibody: negative
ADAMTS13 activity: normal
Oncologic
CT chest, abdomen biopsy negative for malignancy
Bone marrow biopsy negative for leukemia
EBV = Epstein-Barr virus, NGS = next-generation sequencing, PCR = polymerase chain reaction.
After confirming the diagnosis on hospital day 4, ruxolitinib (10 mg twice per day) was administered in conjunction with the HLH-94 protocol (Fig. 1). Her temperature returned to normal and the heart rate dropped to about 105 bpm after 20 hours (Fig. 2A). Her blood pressure returned to normal after administering 0.2 mg/hour norepinephrine. Improvements were seen in several indices, including the WBC count (Fig. 2B), platelet count (Fig. 2C), and fibrinogen level (Fig. 2D). Her platelet count increased to 53 × 109 /L after infusion. Her fibrinogen level returned to normal, and there was a normal prothrombin time and activated partial thromboplastin. D-dimer decreased from 125 mg/L to 2.5 mg/L. EBV dropped to 2.35 × 104 copies/ml on hospital day 6. However, LDH and serum ferritin levels increased to 6,442 U/L and 42,897 ng/ml on hospital day 7, respectively. She remained in a coma on mechanical ventilation with high flow oxygen. On hospital day 8, her blood cell count decreased again (WBC count, 0.02 × 109 /L; hemoglobin, 80 g/L; platelet count, 2 × 109/L). On hospital day 10, we utilized the DEP protocol (20 mg liposomal doxorubicin, 100 mg etoposide, and 500 mg methylprednisone) rather than the HLH94 protocol. She died of cardiac arrest at 11 pm that day.
Figure 1 The treatment processes.
Figure 2 The patient's treatment response. The temperature returned to normal and the heart rate dropped to about 105 bpm after 20 hours (A). Improvements were seen in several indices, including the white blood cell count (B) platelet count (C), and fibrinogen level (D).
3 Discussion
HLH is a fatal clinical syndrome and no optimal treatment is available for HLH, the mortality rate for which exceeds 40% in children and adults even when following the standard HLH-94 protocol.[2,8] Clinicians have tried other combinations of agents. Ruxolitinib is a promising agent due to its powerful calming effect on the cytokine storm.[9] Ruxolitinib is a Janus kinase 1/2 inhibitor that suppresses the transmission of cytokine-induced signals. It suppresses cytokine signaling pathways, such as those of interferon (IFN)-γ and interleukin-2. In murine models of HLH, mice who received ruxolitinib had improved survival, due to reversal of pancytopenia and splenomegaly, and reductions in proinflammatory cytokines and the number of CD8+ T cells.[10,11] Ruxolitinib also reduces the severity of inflammation-associated anemia, and the number and activation status of T cells and neutrophils in primary and secondary HLH murine models, but only the IFN-γ-neutralizing antibody reduces anemia severity.[12] Ruxolitinib increased the apoptotic potential of CD8+ T cells in a murine model and primary patient samples, which were resistant to dexamethasone.[13]
In the human body, ruxolitinib has been demonstrated to exert a dramatic effect in some acute inflammatory syndromes, including acute graft-vs-host disease,[14] steroid-refractory cytokine release syndrome,[15] and COVID-19 with severe systemic hyperinflammation.[16] As a single drug, ruxolitinib has been used in salvage therapy for HLH, and exerted a powerful effect in several case reports.[17–21] Similar to what we observed in our case, the first reported case was a 38-year-old woman diagnosed as secondary HLH caused by an EBV infection. This patient exhibited improving disease markers but died eventually.[17] The improving markers included ferritin, fibrinogen, and LDH concentrations, but not pancytopenia. However, a 26-year-old woman diagnosed with treatment-refractory HLH caused by EBV and acute hepatitis C virus infection achieved completely recovery after the use of ruxolitinib.[19] In a series of children cases reported in China, the authors reported poor response to ruxolitinib alone in EBV-HLH when compared with other causes of HLH.[20] The authors suggested that ruxolitinib might not be able to eradicate EBV because EBV does not solely rely on JAK-STAT pathway to cause HLH. Therefore, combination with other drugs is needed.
Small series have reported improved clinical outcomes using ruxolitinib in conjunction with the HLH-94 protocol or chemotherapy.[6,22,23] In a multicenter, nonrandomized, phase II trial for refractory/relapsed HLH (NCT03533790), 54 patients received ruxolitinib combined with the doxorubicin-etoposide-methylprednisolone regimen for 2 weeks. Excitingly, in the patients who had previously received the DEP regimen but showed no improvement, 7 of 12 (58·3%) exhibited a partial response.[23] A pilot trial with first-line ruxolitinib as a single agent reported responses in 5 patients (NCT02400463), and the 2-month overall survival rate was 100%.[7] However, EBV-associated HLH was excluded from that trial. The most exciting outcome of ruxolitinib as a single agent for EBV-associated HLH was a 100% response rate (complete response, 75%, partial response, 25%) in a Chinese trial (ChiCTR2000029977).[5] Three cases treated with first-line ruxolitinib plus HLH-94 protocol showed rapid response and no obvious adverse effects.[6] For our patient who was treated with ruxolitinib plus HLH-94 protocol for the first line, clinical and some laboratory indices improved. Unfortunately, the vital signs, such as respiratory function and consciousness, did not improve.
Author contributions
Resources: Jiangbo Xie.
Writing – original draft: Zoufang Huang.
Writing – review & editing: Jiangbo Xie.
Abbreviations: CT = computed tomography, EBV = Epstein-Barr virus, HLH = hemophagocytic lymphohistiocytosis, IL-2 = interleukin-2, LDH = lactate dehydrogenase, NGS = next-generation sequencing, PCR = polymerase chain reaction, WBC = white blood cell.
How to cite this article: Huang Z, Xie J. Ruxolitinib in conjunction with the HLH-94 protocol for Epstein-Barr virus-related hemophagocytic lymphohistiocytosis in the intensive care unit: a case report. Medicine. 2021;100:11(e25188).
The authors have no conflicts of interests to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | 20 mg (milligrams). | DrugDosage | CC BY | 33726009 | 19,107,068 | 2021-03-19 |
What was the dosage of drug 'ETOPOSIDE'? | Ruxolitinib in conjunction with the HLH-94 protocol for Epstein-Barr virus-related hemophagocytic lymphohistiocytosis in the intensive care unit: A case report.
BACKGROUND
The HLH-94 protocol is a standard induction treatment for hemophagocytic lymphohistiocytosis. However, about 30% of patients may not respond. Ruxolitinib has been clinically proven to be an effective treatment for hemophagocytic lymphohistiocytosis (HLH).
A previously healthy 14-year-old girl presented to the local hospital with a 4-day history of persistent fever and sore throat.
METHODS
Clinical and laboratory tests revealed fever >38.5°C, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, and an elevated interleukin-2 receptor level.
METHODS
This patient was treated with ruxolitinib and the HLH-94 protocol.
RESULTS
The patient's clinical and some laboratory indices improved. Unfortunately, vital signs such as respiratory function and consciousness did not improve.
CONCLUSIONS
This case report highlights the effect of using ruxolitinib in conjunction with the HLH-94 protocol. However, safety evaluation of this regimen was not performed because critically ill patient died too fast.
1 Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder characterized by an excessive inflammatory response mediated by hyperactivation of T cells and antigen-presenting cells. Epstein-Barr virus (EBV) is a common triggering factor for HLH. EBV-associated HLH (EBV-HLH) can progress rapidly to multiorgan dysfunction. Symptoms of HLH include persistent pyrexia, pancytopenia, hepatosplenomegaly, elevated lactate dehydrogenase, serum ferritin, and triglyceride levels, and decreased fibrinogen.[1,2] The HLH-94 protocol is a standard induction treatment for HLH, consisting of dexamethasone and etoposide.[3] However, about 30% of patients may not respond.[4] Ruxolitinib has been clinically proven to be effective to treat HLH.[5–7] Thus, we use ruxolitinib in conjunction with the HLH-94 protocol as the first-line treatment.
Here we report a case of a patient with newly diagnosis EBV-triggered HLH who was critically ill and experienced improvement after ruxolitinib in conjunction with the HLH-94 protocol.
1.1 Consent statement
The patient's family had provided informed consent for the publication of this case report.
2 Case report
A previously healthy 14-year-old girl presented to the local hospital with a 4-day history of persistent fever and sore throat. After taking acetaminophen for 2 days, she felt worse and complained of extremity myalgia. Laboratory tests revealed pancytopenia (white blood cell [WBC] count, 2.69 × 109/L; neutrophil count, 1.96 × 109/L; hemoglobin, 93 g/L; platelet count, 34 × 109/L), abnormal liver function (aspartate aminotransferase, 300 units/L [normal: <40 units/L]; alanine aminotransferase, 111 units/L [normal: <35 units/L]; total bilirubin, 102 μmol/L [normal: <21 μmol/L]; albumin, 27.6 g/L [normal: 40–55 g/L], and creatinine, 247 μmol/L [normal: 41–73 μmol/L]). The patient was diagnosed with multiorgan failure and admitted to our hospital.
Meropenem and vancomycin treatment was initiated within 3 days of admission, and a chest computed tomography (CT) scan revealed pneumonia. On hospital day 2, thrombotic thrombocytopenic purpura was suspected. Dexamethasone 10 mg/day, intravenous immunoglobulin 0.4 g/kg/day, and plasmapheresis were administered. Her condition worsened, with a persistent fever of 38.5 to 39.8°C and rapid heart rate of >140 bpm. Her blood pressure was about 90/60 mm Hg, and she was supported with 1.6 mg/hour norepinephrine. She received mechanical ventilation because of respiratory failure. Platelets and fibrinogen were not elevated after an infusion. She had persistent epistaxis and coma on hospital day 3. Rheumatological, autoimmune, and oncological workups revealed no positive results (Table 1). EBV polymerase chain reaction revealed 1.03 × 106 copies/ml. Metagenomic next-generation sequencing (NGS) was positive for EBV but negative for bacteria, fungus, parasites, and Mycobacterium. Lactate dehydrogenase (LDH) was 3560 U/L. The patient met all 8 criteria for HLH, that is, fever >38.5°C, hepatosplenomegaly (based on Doppler ultrasound and abdominal CT), pancytopenia (WBC count, 0.67 × 109 /L, hemoglobin, 67 g/L; platelet count, 2 × 109 /L), hypertriglyceridemia (5.89 g/L), hypofibrinogenemia (0.72 g/L), hyperferritinemia (100,096 ng/ml), elevated interleukin-2 receptor level (40,740 U/ml), and hemophagocytosis observed on a bone marrow biopsy specimen. Genetic testing was performed and was negative for any known mutations causing HLH.
Table 1 The patient's laboratory results.
Infectious
Blood cultures: negative
COVID-19 PCR: negative
EBV PCR: 1.5 × 106 copies/ml
EBV NGS: positive
HIV antibody: negative
Hepatitis B surface antigen: negative
Hepatitis B surface IgG: positive
Hepatitis B core IgG: negative
Hepatitis C antibody: negative
Widal reaction: negative
Weil-Felix assay: negative
Immunologic
CD3+: 640/μl (normal: 770–2,860/μl)
CD4+: 308/μl (normal: 414–1,440/μl)
CD8+: 328/μl (normal: 238–1,250/μl)
CD4/CD8: 0.94 (normal: 0.7–2.87)
Rheumatologic
C3: 53.7 mg/dl (normal: 70–140 mg/dl)
C4: 38.2 mg/dl (normal: 10–40 mg/dl)
Rheumatoid factor:18.1 IU/ml (normal,: <25 IU/ml)
Antibody spectrum of anti-ENA peptide: negative
Antinuclear antibody: negative
ADAMTS13 activity: normal
Oncologic
CT chest, abdomen biopsy negative for malignancy
Bone marrow biopsy negative for leukemia
EBV = Epstein-Barr virus, NGS = next-generation sequencing, PCR = polymerase chain reaction.
After confirming the diagnosis on hospital day 4, ruxolitinib (10 mg twice per day) was administered in conjunction with the HLH-94 protocol (Fig. 1). Her temperature returned to normal and the heart rate dropped to about 105 bpm after 20 hours (Fig. 2A). Her blood pressure returned to normal after administering 0.2 mg/hour norepinephrine. Improvements were seen in several indices, including the WBC count (Fig. 2B), platelet count (Fig. 2C), and fibrinogen level (Fig. 2D). Her platelet count increased to 53 × 109 /L after infusion. Her fibrinogen level returned to normal, and there was a normal prothrombin time and activated partial thromboplastin. D-dimer decreased from 125 mg/L to 2.5 mg/L. EBV dropped to 2.35 × 104 copies/ml on hospital day 6. However, LDH and serum ferritin levels increased to 6,442 U/L and 42,897 ng/ml on hospital day 7, respectively. She remained in a coma on mechanical ventilation with high flow oxygen. On hospital day 8, her blood cell count decreased again (WBC count, 0.02 × 109 /L; hemoglobin, 80 g/L; platelet count, 2 × 109/L). On hospital day 10, we utilized the DEP protocol (20 mg liposomal doxorubicin, 100 mg etoposide, and 500 mg methylprednisone) rather than the HLH94 protocol. She died of cardiac arrest at 11 pm that day.
Figure 1 The treatment processes.
Figure 2 The patient's treatment response. The temperature returned to normal and the heart rate dropped to about 105 bpm after 20 hours (A). Improvements were seen in several indices, including the white blood cell count (B) platelet count (C), and fibrinogen level (D).
3 Discussion
HLH is a fatal clinical syndrome and no optimal treatment is available for HLH, the mortality rate for which exceeds 40% in children and adults even when following the standard HLH-94 protocol.[2,8] Clinicians have tried other combinations of agents. Ruxolitinib is a promising agent due to its powerful calming effect on the cytokine storm.[9] Ruxolitinib is a Janus kinase 1/2 inhibitor that suppresses the transmission of cytokine-induced signals. It suppresses cytokine signaling pathways, such as those of interferon (IFN)-γ and interleukin-2. In murine models of HLH, mice who received ruxolitinib had improved survival, due to reversal of pancytopenia and splenomegaly, and reductions in proinflammatory cytokines and the number of CD8+ T cells.[10,11] Ruxolitinib also reduces the severity of inflammation-associated anemia, and the number and activation status of T cells and neutrophils in primary and secondary HLH murine models, but only the IFN-γ-neutralizing antibody reduces anemia severity.[12] Ruxolitinib increased the apoptotic potential of CD8+ T cells in a murine model and primary patient samples, which were resistant to dexamethasone.[13]
In the human body, ruxolitinib has been demonstrated to exert a dramatic effect in some acute inflammatory syndromes, including acute graft-vs-host disease,[14] steroid-refractory cytokine release syndrome,[15] and COVID-19 with severe systemic hyperinflammation.[16] As a single drug, ruxolitinib has been used in salvage therapy for HLH, and exerted a powerful effect in several case reports.[17–21] Similar to what we observed in our case, the first reported case was a 38-year-old woman diagnosed as secondary HLH caused by an EBV infection. This patient exhibited improving disease markers but died eventually.[17] The improving markers included ferritin, fibrinogen, and LDH concentrations, but not pancytopenia. However, a 26-year-old woman diagnosed with treatment-refractory HLH caused by EBV and acute hepatitis C virus infection achieved completely recovery after the use of ruxolitinib.[19] In a series of children cases reported in China, the authors reported poor response to ruxolitinib alone in EBV-HLH when compared with other causes of HLH.[20] The authors suggested that ruxolitinib might not be able to eradicate EBV because EBV does not solely rely on JAK-STAT pathway to cause HLH. Therefore, combination with other drugs is needed.
Small series have reported improved clinical outcomes using ruxolitinib in conjunction with the HLH-94 protocol or chemotherapy.[6,22,23] In a multicenter, nonrandomized, phase II trial for refractory/relapsed HLH (NCT03533790), 54 patients received ruxolitinib combined with the doxorubicin-etoposide-methylprednisolone regimen for 2 weeks. Excitingly, in the patients who had previously received the DEP regimen but showed no improvement, 7 of 12 (58·3%) exhibited a partial response.[23] A pilot trial with first-line ruxolitinib as a single agent reported responses in 5 patients (NCT02400463), and the 2-month overall survival rate was 100%.[7] However, EBV-associated HLH was excluded from that trial. The most exciting outcome of ruxolitinib as a single agent for EBV-associated HLH was a 100% response rate (complete response, 75%, partial response, 25%) in a Chinese trial (ChiCTR2000029977).[5] Three cases treated with first-line ruxolitinib plus HLH-94 protocol showed rapid response and no obvious adverse effects.[6] For our patient who was treated with ruxolitinib plus HLH-94 protocol for the first line, clinical and some laboratory indices improved. Unfortunately, the vital signs, such as respiratory function and consciousness, did not improve.
Author contributions
Resources: Jiangbo Xie.
Writing – original draft: Zoufang Huang.
Writing – review & editing: Jiangbo Xie.
Abbreviations: CT = computed tomography, EBV = Epstein-Barr virus, HLH = hemophagocytic lymphohistiocytosis, IL-2 = interleukin-2, LDH = lactate dehydrogenase, NGS = next-generation sequencing, PCR = polymerase chain reaction, WBC = white blood cell.
How to cite this article: Huang Z, Xie J. Ruxolitinib in conjunction with the HLH-94 protocol for Epstein-Barr virus-related hemophagocytic lymphohistiocytosis in the intensive care unit: a case report. Medicine. 2021;100:11(e25188).
The authors have no conflicts of interests to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | 100 mg (milligrams). | DrugDosage | CC BY | 33726009 | 19,107,068 | 2021-03-19 |
What was the dosage of drug 'METHYLPREDNISOLONE'? | Ruxolitinib in conjunction with the HLH-94 protocol for Epstein-Barr virus-related hemophagocytic lymphohistiocytosis in the intensive care unit: A case report.
BACKGROUND
The HLH-94 protocol is a standard induction treatment for hemophagocytic lymphohistiocytosis. However, about 30% of patients may not respond. Ruxolitinib has been clinically proven to be an effective treatment for hemophagocytic lymphohistiocytosis (HLH).
A previously healthy 14-year-old girl presented to the local hospital with a 4-day history of persistent fever and sore throat.
METHODS
Clinical and laboratory tests revealed fever >38.5°C, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, and an elevated interleukin-2 receptor level.
METHODS
This patient was treated with ruxolitinib and the HLH-94 protocol.
RESULTS
The patient's clinical and some laboratory indices improved. Unfortunately, vital signs such as respiratory function and consciousness did not improve.
CONCLUSIONS
This case report highlights the effect of using ruxolitinib in conjunction with the HLH-94 protocol. However, safety evaluation of this regimen was not performed because critically ill patient died too fast.
1 Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder characterized by an excessive inflammatory response mediated by hyperactivation of T cells and antigen-presenting cells. Epstein-Barr virus (EBV) is a common triggering factor for HLH. EBV-associated HLH (EBV-HLH) can progress rapidly to multiorgan dysfunction. Symptoms of HLH include persistent pyrexia, pancytopenia, hepatosplenomegaly, elevated lactate dehydrogenase, serum ferritin, and triglyceride levels, and decreased fibrinogen.[1,2] The HLH-94 protocol is a standard induction treatment for HLH, consisting of dexamethasone and etoposide.[3] However, about 30% of patients may not respond.[4] Ruxolitinib has been clinically proven to be effective to treat HLH.[5–7] Thus, we use ruxolitinib in conjunction with the HLH-94 protocol as the first-line treatment.
Here we report a case of a patient with newly diagnosis EBV-triggered HLH who was critically ill and experienced improvement after ruxolitinib in conjunction with the HLH-94 protocol.
1.1 Consent statement
The patient's family had provided informed consent for the publication of this case report.
2 Case report
A previously healthy 14-year-old girl presented to the local hospital with a 4-day history of persistent fever and sore throat. After taking acetaminophen for 2 days, she felt worse and complained of extremity myalgia. Laboratory tests revealed pancytopenia (white blood cell [WBC] count, 2.69 × 109/L; neutrophil count, 1.96 × 109/L; hemoglobin, 93 g/L; platelet count, 34 × 109/L), abnormal liver function (aspartate aminotransferase, 300 units/L [normal: <40 units/L]; alanine aminotransferase, 111 units/L [normal: <35 units/L]; total bilirubin, 102 μmol/L [normal: <21 μmol/L]; albumin, 27.6 g/L [normal: 40–55 g/L], and creatinine, 247 μmol/L [normal: 41–73 μmol/L]). The patient was diagnosed with multiorgan failure and admitted to our hospital.
Meropenem and vancomycin treatment was initiated within 3 days of admission, and a chest computed tomography (CT) scan revealed pneumonia. On hospital day 2, thrombotic thrombocytopenic purpura was suspected. Dexamethasone 10 mg/day, intravenous immunoglobulin 0.4 g/kg/day, and plasmapheresis were administered. Her condition worsened, with a persistent fever of 38.5 to 39.8°C and rapid heart rate of >140 bpm. Her blood pressure was about 90/60 mm Hg, and she was supported with 1.6 mg/hour norepinephrine. She received mechanical ventilation because of respiratory failure. Platelets and fibrinogen were not elevated after an infusion. She had persistent epistaxis and coma on hospital day 3. Rheumatological, autoimmune, and oncological workups revealed no positive results (Table 1). EBV polymerase chain reaction revealed 1.03 × 106 copies/ml. Metagenomic next-generation sequencing (NGS) was positive for EBV but negative for bacteria, fungus, parasites, and Mycobacterium. Lactate dehydrogenase (LDH) was 3560 U/L. The patient met all 8 criteria for HLH, that is, fever >38.5°C, hepatosplenomegaly (based on Doppler ultrasound and abdominal CT), pancytopenia (WBC count, 0.67 × 109 /L, hemoglobin, 67 g/L; platelet count, 2 × 109 /L), hypertriglyceridemia (5.89 g/L), hypofibrinogenemia (0.72 g/L), hyperferritinemia (100,096 ng/ml), elevated interleukin-2 receptor level (40,740 U/ml), and hemophagocytosis observed on a bone marrow biopsy specimen. Genetic testing was performed and was negative for any known mutations causing HLH.
Table 1 The patient's laboratory results.
Infectious
Blood cultures: negative
COVID-19 PCR: negative
EBV PCR: 1.5 × 106 copies/ml
EBV NGS: positive
HIV antibody: negative
Hepatitis B surface antigen: negative
Hepatitis B surface IgG: positive
Hepatitis B core IgG: negative
Hepatitis C antibody: negative
Widal reaction: negative
Weil-Felix assay: negative
Immunologic
CD3+: 640/μl (normal: 770–2,860/μl)
CD4+: 308/μl (normal: 414–1,440/μl)
CD8+: 328/μl (normal: 238–1,250/μl)
CD4/CD8: 0.94 (normal: 0.7–2.87)
Rheumatologic
C3: 53.7 mg/dl (normal: 70–140 mg/dl)
C4: 38.2 mg/dl (normal: 10–40 mg/dl)
Rheumatoid factor:18.1 IU/ml (normal,: <25 IU/ml)
Antibody spectrum of anti-ENA peptide: negative
Antinuclear antibody: negative
ADAMTS13 activity: normal
Oncologic
CT chest, abdomen biopsy negative for malignancy
Bone marrow biopsy negative for leukemia
EBV = Epstein-Barr virus, NGS = next-generation sequencing, PCR = polymerase chain reaction.
After confirming the diagnosis on hospital day 4, ruxolitinib (10 mg twice per day) was administered in conjunction with the HLH-94 protocol (Fig. 1). Her temperature returned to normal and the heart rate dropped to about 105 bpm after 20 hours (Fig. 2A). Her blood pressure returned to normal after administering 0.2 mg/hour norepinephrine. Improvements were seen in several indices, including the WBC count (Fig. 2B), platelet count (Fig. 2C), and fibrinogen level (Fig. 2D). Her platelet count increased to 53 × 109 /L after infusion. Her fibrinogen level returned to normal, and there was a normal prothrombin time and activated partial thromboplastin. D-dimer decreased from 125 mg/L to 2.5 mg/L. EBV dropped to 2.35 × 104 copies/ml on hospital day 6. However, LDH and serum ferritin levels increased to 6,442 U/L and 42,897 ng/ml on hospital day 7, respectively. She remained in a coma on mechanical ventilation with high flow oxygen. On hospital day 8, her blood cell count decreased again (WBC count, 0.02 × 109 /L; hemoglobin, 80 g/L; platelet count, 2 × 109/L). On hospital day 10, we utilized the DEP protocol (20 mg liposomal doxorubicin, 100 mg etoposide, and 500 mg methylprednisone) rather than the HLH94 protocol. She died of cardiac arrest at 11 pm that day.
Figure 1 The treatment processes.
Figure 2 The patient's treatment response. The temperature returned to normal and the heart rate dropped to about 105 bpm after 20 hours (A). Improvements were seen in several indices, including the white blood cell count (B) platelet count (C), and fibrinogen level (D).
3 Discussion
HLH is a fatal clinical syndrome and no optimal treatment is available for HLH, the mortality rate for which exceeds 40% in children and adults even when following the standard HLH-94 protocol.[2,8] Clinicians have tried other combinations of agents. Ruxolitinib is a promising agent due to its powerful calming effect on the cytokine storm.[9] Ruxolitinib is a Janus kinase 1/2 inhibitor that suppresses the transmission of cytokine-induced signals. It suppresses cytokine signaling pathways, such as those of interferon (IFN)-γ and interleukin-2. In murine models of HLH, mice who received ruxolitinib had improved survival, due to reversal of pancytopenia and splenomegaly, and reductions in proinflammatory cytokines and the number of CD8+ T cells.[10,11] Ruxolitinib also reduces the severity of inflammation-associated anemia, and the number and activation status of T cells and neutrophils in primary and secondary HLH murine models, but only the IFN-γ-neutralizing antibody reduces anemia severity.[12] Ruxolitinib increased the apoptotic potential of CD8+ T cells in a murine model and primary patient samples, which were resistant to dexamethasone.[13]
In the human body, ruxolitinib has been demonstrated to exert a dramatic effect in some acute inflammatory syndromes, including acute graft-vs-host disease,[14] steroid-refractory cytokine release syndrome,[15] and COVID-19 with severe systemic hyperinflammation.[16] As a single drug, ruxolitinib has been used in salvage therapy for HLH, and exerted a powerful effect in several case reports.[17–21] Similar to what we observed in our case, the first reported case was a 38-year-old woman diagnosed as secondary HLH caused by an EBV infection. This patient exhibited improving disease markers but died eventually.[17] The improving markers included ferritin, fibrinogen, and LDH concentrations, but not pancytopenia. However, a 26-year-old woman diagnosed with treatment-refractory HLH caused by EBV and acute hepatitis C virus infection achieved completely recovery after the use of ruxolitinib.[19] In a series of children cases reported in China, the authors reported poor response to ruxolitinib alone in EBV-HLH when compared with other causes of HLH.[20] The authors suggested that ruxolitinib might not be able to eradicate EBV because EBV does not solely rely on JAK-STAT pathway to cause HLH. Therefore, combination with other drugs is needed.
Small series have reported improved clinical outcomes using ruxolitinib in conjunction with the HLH-94 protocol or chemotherapy.[6,22,23] In a multicenter, nonrandomized, phase II trial for refractory/relapsed HLH (NCT03533790), 54 patients received ruxolitinib combined with the doxorubicin-etoposide-methylprednisolone regimen for 2 weeks. Excitingly, in the patients who had previously received the DEP regimen but showed no improvement, 7 of 12 (58·3%) exhibited a partial response.[23] A pilot trial with first-line ruxolitinib as a single agent reported responses in 5 patients (NCT02400463), and the 2-month overall survival rate was 100%.[7] However, EBV-associated HLH was excluded from that trial. The most exciting outcome of ruxolitinib as a single agent for EBV-associated HLH was a 100% response rate (complete response, 75%, partial response, 25%) in a Chinese trial (ChiCTR2000029977).[5] Three cases treated with first-line ruxolitinib plus HLH-94 protocol showed rapid response and no obvious adverse effects.[6] For our patient who was treated with ruxolitinib plus HLH-94 protocol for the first line, clinical and some laboratory indices improved. Unfortunately, the vital signs, such as respiratory function and consciousness, did not improve.
Author contributions
Resources: Jiangbo Xie.
Writing – original draft: Zoufang Huang.
Writing – review & editing: Jiangbo Xie.
Abbreviations: CT = computed tomography, EBV = Epstein-Barr virus, HLH = hemophagocytic lymphohistiocytosis, IL-2 = interleukin-2, LDH = lactate dehydrogenase, NGS = next-generation sequencing, PCR = polymerase chain reaction, WBC = white blood cell.
How to cite this article: Huang Z, Xie J. Ruxolitinib in conjunction with the HLH-94 protocol for Epstein-Barr virus-related hemophagocytic lymphohistiocytosis in the intensive care unit: a case report. Medicine. 2021;100:11(e25188).
The authors have no conflicts of interests to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | 500 mg (milligrams). | DrugDosage | CC BY | 33726009 | 19,107,068 | 2021-03-19 |
What was the outcome of reaction 'Cardiac arrest'? | Ruxolitinib in conjunction with the HLH-94 protocol for Epstein-Barr virus-related hemophagocytic lymphohistiocytosis in the intensive care unit: A case report.
BACKGROUND
The HLH-94 protocol is a standard induction treatment for hemophagocytic lymphohistiocytosis. However, about 30% of patients may not respond. Ruxolitinib has been clinically proven to be an effective treatment for hemophagocytic lymphohistiocytosis (HLH).
A previously healthy 14-year-old girl presented to the local hospital with a 4-day history of persistent fever and sore throat.
METHODS
Clinical and laboratory tests revealed fever >38.5°C, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, and an elevated interleukin-2 receptor level.
METHODS
This patient was treated with ruxolitinib and the HLH-94 protocol.
RESULTS
The patient's clinical and some laboratory indices improved. Unfortunately, vital signs such as respiratory function and consciousness did not improve.
CONCLUSIONS
This case report highlights the effect of using ruxolitinib in conjunction with the HLH-94 protocol. However, safety evaluation of this regimen was not performed because critically ill patient died too fast.
1 Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder characterized by an excessive inflammatory response mediated by hyperactivation of T cells and antigen-presenting cells. Epstein-Barr virus (EBV) is a common triggering factor for HLH. EBV-associated HLH (EBV-HLH) can progress rapidly to multiorgan dysfunction. Symptoms of HLH include persistent pyrexia, pancytopenia, hepatosplenomegaly, elevated lactate dehydrogenase, serum ferritin, and triglyceride levels, and decreased fibrinogen.[1,2] The HLH-94 protocol is a standard induction treatment for HLH, consisting of dexamethasone and etoposide.[3] However, about 30% of patients may not respond.[4] Ruxolitinib has been clinically proven to be effective to treat HLH.[5–7] Thus, we use ruxolitinib in conjunction with the HLH-94 protocol as the first-line treatment.
Here we report a case of a patient with newly diagnosis EBV-triggered HLH who was critically ill and experienced improvement after ruxolitinib in conjunction with the HLH-94 protocol.
1.1 Consent statement
The patient's family had provided informed consent for the publication of this case report.
2 Case report
A previously healthy 14-year-old girl presented to the local hospital with a 4-day history of persistent fever and sore throat. After taking acetaminophen for 2 days, she felt worse and complained of extremity myalgia. Laboratory tests revealed pancytopenia (white blood cell [WBC] count, 2.69 × 109/L; neutrophil count, 1.96 × 109/L; hemoglobin, 93 g/L; platelet count, 34 × 109/L), abnormal liver function (aspartate aminotransferase, 300 units/L [normal: <40 units/L]; alanine aminotransferase, 111 units/L [normal: <35 units/L]; total bilirubin, 102 μmol/L [normal: <21 μmol/L]; albumin, 27.6 g/L [normal: 40–55 g/L], and creatinine, 247 μmol/L [normal: 41–73 μmol/L]). The patient was diagnosed with multiorgan failure and admitted to our hospital.
Meropenem and vancomycin treatment was initiated within 3 days of admission, and a chest computed tomography (CT) scan revealed pneumonia. On hospital day 2, thrombotic thrombocytopenic purpura was suspected. Dexamethasone 10 mg/day, intravenous immunoglobulin 0.4 g/kg/day, and plasmapheresis were administered. Her condition worsened, with a persistent fever of 38.5 to 39.8°C and rapid heart rate of >140 bpm. Her blood pressure was about 90/60 mm Hg, and she was supported with 1.6 mg/hour norepinephrine. She received mechanical ventilation because of respiratory failure. Platelets and fibrinogen were not elevated after an infusion. She had persistent epistaxis and coma on hospital day 3. Rheumatological, autoimmune, and oncological workups revealed no positive results (Table 1). EBV polymerase chain reaction revealed 1.03 × 106 copies/ml. Metagenomic next-generation sequencing (NGS) was positive for EBV but negative for bacteria, fungus, parasites, and Mycobacterium. Lactate dehydrogenase (LDH) was 3560 U/L. The patient met all 8 criteria for HLH, that is, fever >38.5°C, hepatosplenomegaly (based on Doppler ultrasound and abdominal CT), pancytopenia (WBC count, 0.67 × 109 /L, hemoglobin, 67 g/L; platelet count, 2 × 109 /L), hypertriglyceridemia (5.89 g/L), hypofibrinogenemia (0.72 g/L), hyperferritinemia (100,096 ng/ml), elevated interleukin-2 receptor level (40,740 U/ml), and hemophagocytosis observed on a bone marrow biopsy specimen. Genetic testing was performed and was negative for any known mutations causing HLH.
Table 1 The patient's laboratory results.
Infectious
Blood cultures: negative
COVID-19 PCR: negative
EBV PCR: 1.5 × 106 copies/ml
EBV NGS: positive
HIV antibody: negative
Hepatitis B surface antigen: negative
Hepatitis B surface IgG: positive
Hepatitis B core IgG: negative
Hepatitis C antibody: negative
Widal reaction: negative
Weil-Felix assay: negative
Immunologic
CD3+: 640/μl (normal: 770–2,860/μl)
CD4+: 308/μl (normal: 414–1,440/μl)
CD8+: 328/μl (normal: 238–1,250/μl)
CD4/CD8: 0.94 (normal: 0.7–2.87)
Rheumatologic
C3: 53.7 mg/dl (normal: 70–140 mg/dl)
C4: 38.2 mg/dl (normal: 10–40 mg/dl)
Rheumatoid factor:18.1 IU/ml (normal,: <25 IU/ml)
Antibody spectrum of anti-ENA peptide: negative
Antinuclear antibody: negative
ADAMTS13 activity: normal
Oncologic
CT chest, abdomen biopsy negative for malignancy
Bone marrow biopsy negative for leukemia
EBV = Epstein-Barr virus, NGS = next-generation sequencing, PCR = polymerase chain reaction.
After confirming the diagnosis on hospital day 4, ruxolitinib (10 mg twice per day) was administered in conjunction with the HLH-94 protocol (Fig. 1). Her temperature returned to normal and the heart rate dropped to about 105 bpm after 20 hours (Fig. 2A). Her blood pressure returned to normal after administering 0.2 mg/hour norepinephrine. Improvements were seen in several indices, including the WBC count (Fig. 2B), platelet count (Fig. 2C), and fibrinogen level (Fig. 2D). Her platelet count increased to 53 × 109 /L after infusion. Her fibrinogen level returned to normal, and there was a normal prothrombin time and activated partial thromboplastin. D-dimer decreased from 125 mg/L to 2.5 mg/L. EBV dropped to 2.35 × 104 copies/ml on hospital day 6. However, LDH and serum ferritin levels increased to 6,442 U/L and 42,897 ng/ml on hospital day 7, respectively. She remained in a coma on mechanical ventilation with high flow oxygen. On hospital day 8, her blood cell count decreased again (WBC count, 0.02 × 109 /L; hemoglobin, 80 g/L; platelet count, 2 × 109/L). On hospital day 10, we utilized the DEP protocol (20 mg liposomal doxorubicin, 100 mg etoposide, and 500 mg methylprednisone) rather than the HLH94 protocol. She died of cardiac arrest at 11 pm that day.
Figure 1 The treatment processes.
Figure 2 The patient's treatment response. The temperature returned to normal and the heart rate dropped to about 105 bpm after 20 hours (A). Improvements were seen in several indices, including the white blood cell count (B) platelet count (C), and fibrinogen level (D).
3 Discussion
HLH is a fatal clinical syndrome and no optimal treatment is available for HLH, the mortality rate for which exceeds 40% in children and adults even when following the standard HLH-94 protocol.[2,8] Clinicians have tried other combinations of agents. Ruxolitinib is a promising agent due to its powerful calming effect on the cytokine storm.[9] Ruxolitinib is a Janus kinase 1/2 inhibitor that suppresses the transmission of cytokine-induced signals. It suppresses cytokine signaling pathways, such as those of interferon (IFN)-γ and interleukin-2. In murine models of HLH, mice who received ruxolitinib had improved survival, due to reversal of pancytopenia and splenomegaly, and reductions in proinflammatory cytokines and the number of CD8+ T cells.[10,11] Ruxolitinib also reduces the severity of inflammation-associated anemia, and the number and activation status of T cells and neutrophils in primary and secondary HLH murine models, but only the IFN-γ-neutralizing antibody reduces anemia severity.[12] Ruxolitinib increased the apoptotic potential of CD8+ T cells in a murine model and primary patient samples, which were resistant to dexamethasone.[13]
In the human body, ruxolitinib has been demonstrated to exert a dramatic effect in some acute inflammatory syndromes, including acute graft-vs-host disease,[14] steroid-refractory cytokine release syndrome,[15] and COVID-19 with severe systemic hyperinflammation.[16] As a single drug, ruxolitinib has been used in salvage therapy for HLH, and exerted a powerful effect in several case reports.[17–21] Similar to what we observed in our case, the first reported case was a 38-year-old woman diagnosed as secondary HLH caused by an EBV infection. This patient exhibited improving disease markers but died eventually.[17] The improving markers included ferritin, fibrinogen, and LDH concentrations, but not pancytopenia. However, a 26-year-old woman diagnosed with treatment-refractory HLH caused by EBV and acute hepatitis C virus infection achieved completely recovery after the use of ruxolitinib.[19] In a series of children cases reported in China, the authors reported poor response to ruxolitinib alone in EBV-HLH when compared with other causes of HLH.[20] The authors suggested that ruxolitinib might not be able to eradicate EBV because EBV does not solely rely on JAK-STAT pathway to cause HLH. Therefore, combination with other drugs is needed.
Small series have reported improved clinical outcomes using ruxolitinib in conjunction with the HLH-94 protocol or chemotherapy.[6,22,23] In a multicenter, nonrandomized, phase II trial for refractory/relapsed HLH (NCT03533790), 54 patients received ruxolitinib combined with the doxorubicin-etoposide-methylprednisolone regimen for 2 weeks. Excitingly, in the patients who had previously received the DEP regimen but showed no improvement, 7 of 12 (58·3%) exhibited a partial response.[23] A pilot trial with first-line ruxolitinib as a single agent reported responses in 5 patients (NCT02400463), and the 2-month overall survival rate was 100%.[7] However, EBV-associated HLH was excluded from that trial. The most exciting outcome of ruxolitinib as a single agent for EBV-associated HLH was a 100% response rate (complete response, 75%, partial response, 25%) in a Chinese trial (ChiCTR2000029977).[5] Three cases treated with first-line ruxolitinib plus HLH-94 protocol showed rapid response and no obvious adverse effects.[6] For our patient who was treated with ruxolitinib plus HLH-94 protocol for the first line, clinical and some laboratory indices improved. Unfortunately, the vital signs, such as respiratory function and consciousness, did not improve.
Author contributions
Resources: Jiangbo Xie.
Writing – original draft: Zoufang Huang.
Writing – review & editing: Jiangbo Xie.
Abbreviations: CT = computed tomography, EBV = Epstein-Barr virus, HLH = hemophagocytic lymphohistiocytosis, IL-2 = interleukin-2, LDH = lactate dehydrogenase, NGS = next-generation sequencing, PCR = polymerase chain reaction, WBC = white blood cell.
How to cite this article: Huang Z, Xie J. Ruxolitinib in conjunction with the HLH-94 protocol for Epstein-Barr virus-related hemophagocytic lymphohistiocytosis in the intensive care unit: a case report. Medicine. 2021;100:11(e25188).
The authors have no conflicts of interests to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | Fatal | ReactionOutcome | CC BY | 33726009 | 19,107,068 | 2021-03-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Biliary tract disorder'. | The safety and efficacy of Glubran 2 as biliostatic agent in liver resection.
BACKGROUND
Biloma, an encapsulated collection of bile outside the biliary tree, supported by a predominantly iatrogenic biliary fistula, and bile likeage are two of the most important surgical complications after liver resection. We, hypothesized to conduct a project aimed to prevent, or reduce, the formation of biloma or biliary fistula applying on the hepatic resection area the cyanoacrylate glue (Glubran2).
METHODS
We searched in our surgical database all patients underwent liver resection for mCRC from January 2013 to December 2018 and we found a total of 510 patients. 205 patients for Group A (study population: included patients in which we have used Glubran2 during surgical procedure) and 113 patients for Group B (control group), were enrolled.
RESULTS
In both Groups no patients died during hospitalization and the 30-day mortality was 0 %. During follow-up in Group A, a biliary fistula was found in 2 patients (1 %) versus 3 patients in the Group B (2,6 %). In patients enrolled in Group A no adverse event were reported relate to the use of Glubran2.
CONCLUSIONS
It is possible to affirm that the use of Glubran2 as biliostatic agent after liver resection is useful to prevent bile leakage complication and biloma formation and its use demonstrated to be safe and feasible during liver surgery.
Background
The only curative option for patients with colorectal liver metastases (mCRC) enabling 5-year overall survival rates of 50 %, is hepatic resection [1, 2]. Effective oxaliplatin- and irinotecan-based chemotherapy protocols associated with targeted agents have significantly improved response rates, conversion to resectability and long-term survival in mCRC patients [1]. However, nevertheless the benefit of neoadjuvant chemotherapy, there are a number of chemotherapy-effects that have an influence on surgical morbidity. The chemotherapy-related complications, steatosis, chemotherapy-associated steatohepatitis (CASH) and sinusoidal obstruction syndrome (SOS), might impair the hepatic parenchyma, thus reducing the functionality and influencing the outcome following resection [1–3]. One of the most serious complication reported in Literature, related to liver surgery, are the biliary system iatrogenic injury with an important rate from 3.6 to 17 % depending on several clinical risk factor [3–7]. Due to an increase of postoperative mortality rates related to biliary complications the use of topical hemostatic agents have been recommended [4, 5, 8–10]. Nonetheless, in Literature, only few study focused attention on the use of these agents to prevent complication related to liver resection [11–15]. In this study, the topical hemostatic agent used was a new synthetic cyanoacrylate glue called Glubran2, tested in various surgery with promising results [16–18]. Our primary endpoint is to test the safety and feasibility of Glubran2 during surgical liver resection in patients with mCRC previously treated with chemotherapy; as secondary endpoint we selected the utility of this agent to prevent biloma or biliary fistula to assess its biliostatic effect.
Methods
Study population
We searched, in the surgical database of the National Cancer Institute of Naples, all patients who underwent liver resection for mCRC from January 2013 to December 2018 and we found a total of 510 patients. From this total number we divided patients in two groups: Group A (study population) included patients in which we have used Glubran2 after liver resection, and Group B (control group).
This retrospective study was approved by the Ethical Committee of the National Cancer Institute “G. Pascale Foundation - IRCCS” of Naples and the requirement for patient informed consent was waived.
The inclusion criteria for the study population and control group were: (a) patients who had pathologically proven mCRC; (b) patients who had undergone imaging studies within 1 month to surgical procedure; and (c) patients who had been subjected to the same neo-adjuvant treatments. The exclusion criteria were: (a) discrepancy between the pre-surgical diagnosis and the pathologically confirmed diagnosis, (b) no available follow-up imaging studies.
During the study period, 205 patients for Group A and 113 patients for Group B, were enrolled in the study that fulfilled the inclusion criteria.
Characteristics of patients from both groups are summarized in Table 1.
Table 1 Datation regarding the MR imaging pps
mCRC patients (no.=205) Control patients (no.=113) P value
Demographics
Gender Men 89 (43.4%) Men 64 (56.6%) 0.89
Women 116 (56.6%) Women 49 (43.4%) 0.89
Age Mean, 56 years Mean, 48 years 0.74
Range, 33-80 years Range, 35-78 years
Primary cancer site
Colon 94 (45.9%) 52 (46%) 0.92
Rectum 111 (54.1%) 61 (54%) 0.92
History of chemotherapy 205 (100 %) 113 (100%) 0.99
Chemotherapy protocol mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) plus bevacizumab 205 (100%) mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) plus bevacizumab 113 (100%)
Liver metastases
Number 1075 452
mean 4 per patient mean 5 per patient
range 1-7 per patient range 2-6 per patient
Largest diameter mean 32 mm mean 28 mm
range 8-64 mm range 10-54 mm
Complications
Biloma 27 (13%) 18 (16%) 0.054
Bile leakage 2 (1%) 3 (2.6%) 0.001
Chemotherapy protocol
Both groups of patients received neoadjuvant mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) plus bevacizumab. mFOLFOX6 was administered IV every 14 days with oxaliplatin 85 mg/m-2 by infusion on day1, followed by leucovorin 200 mg/m-2 infusion on day 1, followed by 5-fluorouracil 400 mg/m-2 bolus on day 1, and 5-fluorouracil 2400 mg/m− 2 46-h continuous infusion. The antiangiogenic drug Bevacizumab was administered every 14 day-sat 5 mg/kg by IV infusion over 90 min at the first cycle, and then, if adequately tolerated, over 60 min. The treatment of mFOLFOX6 plus bevacizumab was administered for a total of 6 cycles.
Surgical procedure
All resections were initiated with curative intent. Surgical exploration and intra-operative ultrasound were performed in all cases to detect occult tumors and to plan appropriate resections. Resections of all metastatic sites were executed as anatomic or non-anatomic resections with the goal of maximal parenchymal preservation by non-anatomic resection. Dissection was accomplished using SonaStar by Misonix, allowing precise, non-anatomic resections. Major hepatectomy was defined as resection of three or more liver segments. Patients with synchronous colorectal and liver tumor at the time of presentation were assessed for feasibility of single stage combined colon and liver resection by the multidisciplinary team. In general, younger patients in good general condition and no significant comorbidity conditions were deemed candidates for single stage combined liver and colon resections.
Haemostatic agents
Glubran2 is a synthetic surgical glue, (CE Mark) certificated for internal and external use, with haemostatic, adhesive, sealer, and bacteriostatic properties. When used in moist environment, it quickly polymerizes into a thin elastic film which has high tensile strength and firmly adheres to the anatomy of the tissue on which it is applied. Once it is polymerized, Glubran2 acts as a bio inert material. We used 1 package of 1mL Glubran2 for each patient.
Lesion confirmation: reference standard
Two pathologists, specialized in the liver, performed histopathologic analysis of resected specimens. Lesion confirmation was based on the pathologic diagnosis of surgically resected liver specimens. The resected specimens were processed and then sectioned with a 5-mm slice thickness. All tumor samples were stained with hematoxylin and eosin coloration. Immunohistochemistry stains were obtained to confirm the intestinal origin of the metastatic lesions. The panel of immunohistochemical markers included cytokeratin 7, cytokeratin 20, and CDX2. The histopathological report included the pushing or infiltrating growth and the presence or absence of tumor budding and/or fibrosis and necrosis.
Follow‐up
Al patients underwent to US and CT at 1 month post surgical resection. A MDCT study was performed at 3th, 6th and 12th month. MRI study was a problem-solving tool for patients with suspicious of recurrence disease or in which a complication was detected.
OS was defined as the interval (in months) from the date of partial hepatectomy to the date of death.
MDCT protocol
CT studies were performed with a 64-detector row scanner (Optima 660, GE Healthcare, USA), using the following scanning parameters: 120 kVp, 100–470 mAs (NI 16.36) and 2.5-mm slice thickness. Liver protocol study in our Cancer Center includes a quadruple phases contrast study with an unenhanced, an arterial, a portal/venous, and equilibrium phases. Images acquisition in the arterial phase is started after attenuation in the descending aorta reached 120 HUs, measured with the bolus tracking method. For the portal/venous phase, the images were acquired 33 s after the arterial phase. For the equilibrium phase, images were acquired 180 s after the contrast medium injection.
MR Imaging Protocol
MR studies were performed by using a 1.5T scanner (Magnetom Symphony, with Total Imaging Matrix Package, Siemens, Erlangen, Germany) with an 8-element body coil and a phased array coil. Detailed information regarding the MR study protocol is summarized in Table 2. A standard dose (0.025 mmol/kg) of gadoxetic acid (Primovist, Bayer Healthcare, Berlin, Germany) was injected at a rate of 1.0 mL/s by using a power injector (Spectris Solaris EP; Medrad, Warrendale, Pa) followed by a 30-mL saline flush. Arterial phase images were acquired 7 s after contrast medium arrival at the thoracic aorta by using an MR fluoroscopic monitoring system. Thereafter, portal venous phase, transitional phase, and hepatobiliary phase (HBP) were obtained 60 s, 3 min, and 20 min after contrast medium injection, respectively.
Table 2 Detailed information regarding the MR imaging parameters
Sequence Orientation TR/TE/FA
(ms/ms/deg.) AT
(min) Acquisition Matrix ST/Gap (mm) FS
Trufisp T2-W Coronal 4.30/2.15/80 0.46 512 × 512 4 / 0 without
HASTE T2-W Axial 1500/90/170 0.36 320 × 320 5 / 0 Without and with (SPAIR)
HASTE T2w Coronal 1500/92/170 0.38 320 × 320 5 / 0 without
In-Out phase T1-W Axial 160/2.35/70 0.33 256 × 192 5 / 0 without
DWI Axial 7500/91/90 7 192 × 192 3 / 0 without
Vibe
T1-W
Axial 4.80/1.76/12 0.18 320 × 260 3 / 0 with (SPAIR)
Note. TR Repetition time, TE Echo time, FA Flip angle, AT Acquisition time, ST Slice thickness, FS Fat suppression, SPAIR Spectral adiabatic inversion recovery
CEUS protocol
CEUS was always preceded by a careful US survey, assessing the size and appearance of the lesion/s. This baseline assessment was done to appropriately choose the liver area or areas to be particularly focused in the forthcoming contrast-enhanced part of the US study. In all cases, a separated injection was performed for each liver lobe. For both injections, the arterial phase assessment was focused on any known lesion at baseline US. CEUS was performed as a low- mechanical index, double-split mode, real-time modality. We employed a Technos MyLab 70 XVG and MyLab Twice scanner (Esaote, Genoa, Italy), injecting 2.4 ml of a sulfur hexafluoride-based contrast medium (SonoVue, Bracco, Milan, Italy) per each liver lobe. After the injection, the radiologist focused the sonographic field of view on the parenchymal area of interest, waiting for the microbubble’s arrival. Thereafter, he/she moved the transducer to explore the remaining parenchyma of each lobe, with special reference to the resected area.
Biloma and bile leakage definition, diagnosis and management
Following scientific Literature we considered biloma as an encapsulated collection of bile outside the biliary tree and within the abdominal cavity and bile leakage as a postoperative loss of fluid bile via abdominal drains after liver surgery [19, 20]. We diagnosed and divided bile leakage in grade A, B and C based on the impact of this complication on patients’ clinical management. [20]
Surgical complications
Surgical Complications were classified according to Clavien Dindo et al. [21].
Statistical analyses
Each continuous variable was expressed in terms of median value ± range while each variable categorical was summarized by frequencies and percentages. Chi square test was performed to assess statistically significant difference between percentage values. Mann Whitney non parametric test were used to compare a continuous variable between 2 groups. A p value < 0.05 was considered statistically significant.
All statistical analysis was performed with SPSS for Windows (Version 23.0; SPSS Inc, Chicago, Ill).
Results
We analyzed a total of 318 patients: Group A with 205 patients and 1036 pathologically proven lesions (mean tumor size: 32 mm; range 8–64 mm) and Group B with 113 patients and 452 mCRC pathologically proven lesions (mean tumor size: 36 mm; range 11–59 mm).
In the Group A we performed 60 lobectomy, 43 meso-hepatectomy, 48 bi-segmentectomy (73 % major hepatectomy) and 54 segmentectomy or other liver resection (wedge/metasasectomy) (2 in seg I, 3 in seg II, 4 in seg III, 10 in seg IV, 9 in seg V and 8 in seg VI, 18 in seg. VII). Twenty-five patients underwent single stage combined liver and colon resections.
The average hospitalization time was 8 days (7–16). No major complications occurred during surgical procedures. No patients died during hospitalization and the 30-day mortality was 0 %. During follow-up in 27 patients (13 %) was reported a Biloma and in 2 patients (1 %) a bile leakage grade B was detected. No adverse events were reported regarding the use of Glubran 2.
About Group B (113 patients), 56 patients underwent major hepatectomy (49,5 %), 40 liver segmentectomy (35.5 %), 17 wedge procedure or metasasectomy (5 in seg II, 2 in seg III, 3 in seg IV, 2 in seg V and 5 in seg VI). Seventeen patients underwent single stage combined liver and colon resections.
The average hospitalization time was 10 days (5–14). No major complications occurred during surgical procedures. No patients died during hospitalization and the 30-day mortality was 0 %.
During follow-up 18 patients (16 %) showed presence of biloma and in 3 patients (2,6 %) a bile leakage was detected (2 grade B, 1 grade C).
A new hepatic lesions were identified (mean time 5 months) in 32 patients (15,6 %), 13 in group A and 19 in group B.
Discussion
The rationale behind our study is the polymerization of cyanoacrylate glue when it is in contact with blood and tissues owing to the presence of ions and proteins. Nowadays the solid polymer created by this reaction, has demonstrated to be safe and useful in several use during surgical clinical practices.
In surgery for ventral hernia repair, Glubran2 permitted a suturless fixation mesh, in bariatric surgery showed to be effective to prevent gastric fistulas or suture line dehiscence (leaks), in endovascular surgery many scientific articles had described it’s use to stop bleeding in elective and in emergency and new applications are investigate in colorectal and thoracic surgery, to prevent anastomotic and air leak [22–28].
Our study is focused on biliostatic effect of cyanoacrylate glue but, in Literature, is possible to find articles that analyzed or compare hemostatic or sealant agent to prevent bile leakage and hemorrhagic events. López-Guerra D et al., in 2019, compare the use of two different fibrin sealant patches during liver surgery. Contrary to ours, this study included benign patients, patients without pre-operative chemotherapy, HCC and mCRC and concluded with no superiority between different fibrin patches in post-operative complications not focusing attentions on bile leakage [18].
Likewise others papers compare different agent both on prevent bleeding and bile leakage and, similarly to López-Guerra D et al., their population study included not only mCRC patients [29–31].
Also Briceño J et al., evaluating a fibrin sealant, concluded advising the use of this agent during liver surgery due to the decrease moderate and severe postoperative complications with no clarification on bile leakage impact [29].
Precisely for this, our study acquire relevance because this is the first study that assesses the safety and efficacy of Glubran2 as a biliostatic agent, at the best of our knowledge, focusing attention to prevent bile post-opertive complications.
This project was inspired by the evolution of neoadjuvant chemotherapy for colorectal liver metastases. Thanks to the use of new drugs, especially anti-angiogenetic monoclonal antibody added to usual chemotherapy, has become possible to treat surgically patients with more curative intent due an increase response rates conversion to resectability and long-term survival. This is a very important result considering that hepatic resection is the only curative option for patients with colorectal liver metastases (mCRC) [1]. However, we need to consider also the neoadjuvant chemotherapy influence on surgical morbidity. The chemotherapy-related complications, steatosis, chemotherapy-associated steatohepatitis (CASH) and sinusoidal obstruction syndrome (SOS), might impair the hepatic parenchyma, thus reducing the functionality and influencing the outcome following resection [1, 2]. Despite the results of same studies demonstrated that neoadjuvant chemotherapy did not impair outcomes of liver resections for mCRC, in our experience we reported an increase of complications rates in this type of patients [32]. The most peculiar and important complication after liver resection is bile leakage with an incidence that is reported between 3.6 and 17 % [33]. In our two groups, we evaluate and match age, sex, site of primary cancer, chemotherapy protocol, duration of chemotherapy and type of liver resection. All patients underwent to US and MDCT at one month post resection and MDCT at 3th, 6th and 12th month for the first post-operative year. In the Group A we performed major hepatectomy in 73 % of patients versus 49.5 % in Group B. Several researches have shown that risk of biliary complications increase with the complexity of surgical procedure [34]. Patients enrolled in Group A were compared with patients in Group B; biloma was reported in 13 % (group A) vs. 16 % (group B) and bile leakage in 1 % (Group A) vs. 2.6 % (group B) (P-value < 0,001). All patients underwent liver resection using the same surgical open or laparoscopic approach, uniform technique and energy devices. In literature is possible to find numerous study that compared different types of advanced energetic devices and their haemostatic effect, their lateral spread damage in many tissues and no one demonstrated better result over others [35]. In all our patients, in booth groups, we used only Harmonic Scalpel in order to minimizing the intraoperative bias.
During the follow up, no patients died but a new hepatic lesions were found in 32 patients (15,6 %): 13 in Group A and 19 in Group B.
We observed no adverse events regarding the use of Glubran2. Analyzing our results, we could state that Glubran2 is a safe and efficacy biliostatic agent useful to prevent bile leakage complication after liver resection. Our results are similar to others that have shown that Glubran2 is a safe and effective hemostatic agent [20, 34, 36, 37].
The current study had several limitations: data collected derived from only one cancer centre, and a small semple size enrolled in this study may have influence the conclusion. In addition, this is a retrospective study. Therefore, further perspective multicentre analyses including more patients were needed to validate the prognostic significance of these results.
Conclusions
Answering to our primary end-point, it is possible to affirm that Glubran2 is a safe and feasible biliostatic agent useful to prevent bile leakage complication and biloma formation after liver resection.
Abbreviations
mCRC Colorectal liver metastases
CASH Chemotherapy-associated steatohepatitis
MDCT Multiple detector computed tomography
CT Computed tomography
CEUS Contrast Enhanced Ultrasound
SOS Sinusoidal obstruction syndrome
Acknowledgements
The authors are grateful to Alessandra Trocino, librarian and Assunta Zazzaro data manager at the National Cancer Institute of Naples, Italy.
Informed consent
Each patient signed the informed consent.
Author contributions
RP1: Data curation, Writing - original draft. VG: Conceptualization, Supervision, Data curation, Writing - review &editing. AB: Supervision. RP2: Supervision. VA: Data curation; Formal analysis. MP: Data curation; Formal analysis. RF: Data curation; Formal analysis. FT: Data curation; Formal analysis. GN: Data curation; Formal analysis. AV: Supervision. FI: Conceptualization, Supervision, Writing - review & editing. The author(s) read and approved the final manuscript.
Funding
Authors have no receiving founds for this project.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This retrospective study was approved by the Ethical Committee of the National Cancer Institute “G. Pascale Foundation - IRCCS” of Naples and the requirement for patient informed consent was waived. All procedures performed in the study were in accordance with the ethical standards of the institutional and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Consent for publication
Each author give the consent for publication.
Competing interests
The authors declare that they have no competing interests
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BEVACIZUMAB, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY | 33726798 | 19,116,272 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Biloma'. | The safety and efficacy of Glubran 2 as biliostatic agent in liver resection.
BACKGROUND
Biloma, an encapsulated collection of bile outside the biliary tree, supported by a predominantly iatrogenic biliary fistula, and bile likeage are two of the most important surgical complications after liver resection. We, hypothesized to conduct a project aimed to prevent, or reduce, the formation of biloma or biliary fistula applying on the hepatic resection area the cyanoacrylate glue (Glubran2).
METHODS
We searched in our surgical database all patients underwent liver resection for mCRC from January 2013 to December 2018 and we found a total of 510 patients. 205 patients for Group A (study population: included patients in which we have used Glubran2 during surgical procedure) and 113 patients for Group B (control group), were enrolled.
RESULTS
In both Groups no patients died during hospitalization and the 30-day mortality was 0 %. During follow-up in Group A, a biliary fistula was found in 2 patients (1 %) versus 3 patients in the Group B (2,6 %). In patients enrolled in Group A no adverse event were reported relate to the use of Glubran2.
CONCLUSIONS
It is possible to affirm that the use of Glubran2 as biliostatic agent after liver resection is useful to prevent bile leakage complication and biloma formation and its use demonstrated to be safe and feasible during liver surgery.
Background
The only curative option for patients with colorectal liver metastases (mCRC) enabling 5-year overall survival rates of 50 %, is hepatic resection [1, 2]. Effective oxaliplatin- and irinotecan-based chemotherapy protocols associated with targeted agents have significantly improved response rates, conversion to resectability and long-term survival in mCRC patients [1]. However, nevertheless the benefit of neoadjuvant chemotherapy, there are a number of chemotherapy-effects that have an influence on surgical morbidity. The chemotherapy-related complications, steatosis, chemotherapy-associated steatohepatitis (CASH) and sinusoidal obstruction syndrome (SOS), might impair the hepatic parenchyma, thus reducing the functionality and influencing the outcome following resection [1–3]. One of the most serious complication reported in Literature, related to liver surgery, are the biliary system iatrogenic injury with an important rate from 3.6 to 17 % depending on several clinical risk factor [3–7]. Due to an increase of postoperative mortality rates related to biliary complications the use of topical hemostatic agents have been recommended [4, 5, 8–10]. Nonetheless, in Literature, only few study focused attention on the use of these agents to prevent complication related to liver resection [11–15]. In this study, the topical hemostatic agent used was a new synthetic cyanoacrylate glue called Glubran2, tested in various surgery with promising results [16–18]. Our primary endpoint is to test the safety and feasibility of Glubran2 during surgical liver resection in patients with mCRC previously treated with chemotherapy; as secondary endpoint we selected the utility of this agent to prevent biloma or biliary fistula to assess its biliostatic effect.
Methods
Study population
We searched, in the surgical database of the National Cancer Institute of Naples, all patients who underwent liver resection for mCRC from January 2013 to December 2018 and we found a total of 510 patients. From this total number we divided patients in two groups: Group A (study population) included patients in which we have used Glubran2 after liver resection, and Group B (control group).
This retrospective study was approved by the Ethical Committee of the National Cancer Institute “G. Pascale Foundation - IRCCS” of Naples and the requirement for patient informed consent was waived.
The inclusion criteria for the study population and control group were: (a) patients who had pathologically proven mCRC; (b) patients who had undergone imaging studies within 1 month to surgical procedure; and (c) patients who had been subjected to the same neo-adjuvant treatments. The exclusion criteria were: (a) discrepancy between the pre-surgical diagnosis and the pathologically confirmed diagnosis, (b) no available follow-up imaging studies.
During the study period, 205 patients for Group A and 113 patients for Group B, were enrolled in the study that fulfilled the inclusion criteria.
Characteristics of patients from both groups are summarized in Table 1.
Table 1 Datation regarding the MR imaging pps
mCRC patients (no.=205) Control patients (no.=113) P value
Demographics
Gender Men 89 (43.4%) Men 64 (56.6%) 0.89
Women 116 (56.6%) Women 49 (43.4%) 0.89
Age Mean, 56 years Mean, 48 years 0.74
Range, 33-80 years Range, 35-78 years
Primary cancer site
Colon 94 (45.9%) 52 (46%) 0.92
Rectum 111 (54.1%) 61 (54%) 0.92
History of chemotherapy 205 (100 %) 113 (100%) 0.99
Chemotherapy protocol mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) plus bevacizumab 205 (100%) mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) plus bevacizumab 113 (100%)
Liver metastases
Number 1075 452
mean 4 per patient mean 5 per patient
range 1-7 per patient range 2-6 per patient
Largest diameter mean 32 mm mean 28 mm
range 8-64 mm range 10-54 mm
Complications
Biloma 27 (13%) 18 (16%) 0.054
Bile leakage 2 (1%) 3 (2.6%) 0.001
Chemotherapy protocol
Both groups of patients received neoadjuvant mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) plus bevacizumab. mFOLFOX6 was administered IV every 14 days with oxaliplatin 85 mg/m-2 by infusion on day1, followed by leucovorin 200 mg/m-2 infusion on day 1, followed by 5-fluorouracil 400 mg/m-2 bolus on day 1, and 5-fluorouracil 2400 mg/m− 2 46-h continuous infusion. The antiangiogenic drug Bevacizumab was administered every 14 day-sat 5 mg/kg by IV infusion over 90 min at the first cycle, and then, if adequately tolerated, over 60 min. The treatment of mFOLFOX6 plus bevacizumab was administered for a total of 6 cycles.
Surgical procedure
All resections were initiated with curative intent. Surgical exploration and intra-operative ultrasound were performed in all cases to detect occult tumors and to plan appropriate resections. Resections of all metastatic sites were executed as anatomic or non-anatomic resections with the goal of maximal parenchymal preservation by non-anatomic resection. Dissection was accomplished using SonaStar by Misonix, allowing precise, non-anatomic resections. Major hepatectomy was defined as resection of three or more liver segments. Patients with synchronous colorectal and liver tumor at the time of presentation were assessed for feasibility of single stage combined colon and liver resection by the multidisciplinary team. In general, younger patients in good general condition and no significant comorbidity conditions were deemed candidates for single stage combined liver and colon resections.
Haemostatic agents
Glubran2 is a synthetic surgical glue, (CE Mark) certificated for internal and external use, with haemostatic, adhesive, sealer, and bacteriostatic properties. When used in moist environment, it quickly polymerizes into a thin elastic film which has high tensile strength and firmly adheres to the anatomy of the tissue on which it is applied. Once it is polymerized, Glubran2 acts as a bio inert material. We used 1 package of 1mL Glubran2 for each patient.
Lesion confirmation: reference standard
Two pathologists, specialized in the liver, performed histopathologic analysis of resected specimens. Lesion confirmation was based on the pathologic diagnosis of surgically resected liver specimens. The resected specimens were processed and then sectioned with a 5-mm slice thickness. All tumor samples were stained with hematoxylin and eosin coloration. Immunohistochemistry stains were obtained to confirm the intestinal origin of the metastatic lesions. The panel of immunohistochemical markers included cytokeratin 7, cytokeratin 20, and CDX2. The histopathological report included the pushing or infiltrating growth and the presence or absence of tumor budding and/or fibrosis and necrosis.
Follow‐up
Al patients underwent to US and CT at 1 month post surgical resection. A MDCT study was performed at 3th, 6th and 12th month. MRI study was a problem-solving tool for patients with suspicious of recurrence disease or in which a complication was detected.
OS was defined as the interval (in months) from the date of partial hepatectomy to the date of death.
MDCT protocol
CT studies were performed with a 64-detector row scanner (Optima 660, GE Healthcare, USA), using the following scanning parameters: 120 kVp, 100–470 mAs (NI 16.36) and 2.5-mm slice thickness. Liver protocol study in our Cancer Center includes a quadruple phases contrast study with an unenhanced, an arterial, a portal/venous, and equilibrium phases. Images acquisition in the arterial phase is started after attenuation in the descending aorta reached 120 HUs, measured with the bolus tracking method. For the portal/venous phase, the images were acquired 33 s after the arterial phase. For the equilibrium phase, images were acquired 180 s after the contrast medium injection.
MR Imaging Protocol
MR studies were performed by using a 1.5T scanner (Magnetom Symphony, with Total Imaging Matrix Package, Siemens, Erlangen, Germany) with an 8-element body coil and a phased array coil. Detailed information regarding the MR study protocol is summarized in Table 2. A standard dose (0.025 mmol/kg) of gadoxetic acid (Primovist, Bayer Healthcare, Berlin, Germany) was injected at a rate of 1.0 mL/s by using a power injector (Spectris Solaris EP; Medrad, Warrendale, Pa) followed by a 30-mL saline flush. Arterial phase images were acquired 7 s after contrast medium arrival at the thoracic aorta by using an MR fluoroscopic monitoring system. Thereafter, portal venous phase, transitional phase, and hepatobiliary phase (HBP) were obtained 60 s, 3 min, and 20 min after contrast medium injection, respectively.
Table 2 Detailed information regarding the MR imaging parameters
Sequence Orientation TR/TE/FA
(ms/ms/deg.) AT
(min) Acquisition Matrix ST/Gap (mm) FS
Trufisp T2-W Coronal 4.30/2.15/80 0.46 512 × 512 4 / 0 without
HASTE T2-W Axial 1500/90/170 0.36 320 × 320 5 / 0 Without and with (SPAIR)
HASTE T2w Coronal 1500/92/170 0.38 320 × 320 5 / 0 without
In-Out phase T1-W Axial 160/2.35/70 0.33 256 × 192 5 / 0 without
DWI Axial 7500/91/90 7 192 × 192 3 / 0 without
Vibe
T1-W
Axial 4.80/1.76/12 0.18 320 × 260 3 / 0 with (SPAIR)
Note. TR Repetition time, TE Echo time, FA Flip angle, AT Acquisition time, ST Slice thickness, FS Fat suppression, SPAIR Spectral adiabatic inversion recovery
CEUS protocol
CEUS was always preceded by a careful US survey, assessing the size and appearance of the lesion/s. This baseline assessment was done to appropriately choose the liver area or areas to be particularly focused in the forthcoming contrast-enhanced part of the US study. In all cases, a separated injection was performed for each liver lobe. For both injections, the arterial phase assessment was focused on any known lesion at baseline US. CEUS was performed as a low- mechanical index, double-split mode, real-time modality. We employed a Technos MyLab 70 XVG and MyLab Twice scanner (Esaote, Genoa, Italy), injecting 2.4 ml of a sulfur hexafluoride-based contrast medium (SonoVue, Bracco, Milan, Italy) per each liver lobe. After the injection, the radiologist focused the sonographic field of view on the parenchymal area of interest, waiting for the microbubble’s arrival. Thereafter, he/she moved the transducer to explore the remaining parenchyma of each lobe, with special reference to the resected area.
Biloma and bile leakage definition, diagnosis and management
Following scientific Literature we considered biloma as an encapsulated collection of bile outside the biliary tree and within the abdominal cavity and bile leakage as a postoperative loss of fluid bile via abdominal drains after liver surgery [19, 20]. We diagnosed and divided bile leakage in grade A, B and C based on the impact of this complication on patients’ clinical management. [20]
Surgical complications
Surgical Complications were classified according to Clavien Dindo et al. [21].
Statistical analyses
Each continuous variable was expressed in terms of median value ± range while each variable categorical was summarized by frequencies and percentages. Chi square test was performed to assess statistically significant difference between percentage values. Mann Whitney non parametric test were used to compare a continuous variable between 2 groups. A p value < 0.05 was considered statistically significant.
All statistical analysis was performed with SPSS for Windows (Version 23.0; SPSS Inc, Chicago, Ill).
Results
We analyzed a total of 318 patients: Group A with 205 patients and 1036 pathologically proven lesions (mean tumor size: 32 mm; range 8–64 mm) and Group B with 113 patients and 452 mCRC pathologically proven lesions (mean tumor size: 36 mm; range 11–59 mm).
In the Group A we performed 60 lobectomy, 43 meso-hepatectomy, 48 bi-segmentectomy (73 % major hepatectomy) and 54 segmentectomy or other liver resection (wedge/metasasectomy) (2 in seg I, 3 in seg II, 4 in seg III, 10 in seg IV, 9 in seg V and 8 in seg VI, 18 in seg. VII). Twenty-five patients underwent single stage combined liver and colon resections.
The average hospitalization time was 8 days (7–16). No major complications occurred during surgical procedures. No patients died during hospitalization and the 30-day mortality was 0 %. During follow-up in 27 patients (13 %) was reported a Biloma and in 2 patients (1 %) a bile leakage grade B was detected. No adverse events were reported regarding the use of Glubran 2.
About Group B (113 patients), 56 patients underwent major hepatectomy (49,5 %), 40 liver segmentectomy (35.5 %), 17 wedge procedure or metasasectomy (5 in seg II, 2 in seg III, 3 in seg IV, 2 in seg V and 5 in seg VI). Seventeen patients underwent single stage combined liver and colon resections.
The average hospitalization time was 10 days (5–14). No major complications occurred during surgical procedures. No patients died during hospitalization and the 30-day mortality was 0 %.
During follow-up 18 patients (16 %) showed presence of biloma and in 3 patients (2,6 %) a bile leakage was detected (2 grade B, 1 grade C).
A new hepatic lesions were identified (mean time 5 months) in 32 patients (15,6 %), 13 in group A and 19 in group B.
Discussion
The rationale behind our study is the polymerization of cyanoacrylate glue when it is in contact with blood and tissues owing to the presence of ions and proteins. Nowadays the solid polymer created by this reaction, has demonstrated to be safe and useful in several use during surgical clinical practices.
In surgery for ventral hernia repair, Glubran2 permitted a suturless fixation mesh, in bariatric surgery showed to be effective to prevent gastric fistulas or suture line dehiscence (leaks), in endovascular surgery many scientific articles had described it’s use to stop bleeding in elective and in emergency and new applications are investigate in colorectal and thoracic surgery, to prevent anastomotic and air leak [22–28].
Our study is focused on biliostatic effect of cyanoacrylate glue but, in Literature, is possible to find articles that analyzed or compare hemostatic or sealant agent to prevent bile leakage and hemorrhagic events. López-Guerra D et al., in 2019, compare the use of two different fibrin sealant patches during liver surgery. Contrary to ours, this study included benign patients, patients without pre-operative chemotherapy, HCC and mCRC and concluded with no superiority between different fibrin patches in post-operative complications not focusing attentions on bile leakage [18].
Likewise others papers compare different agent both on prevent bleeding and bile leakage and, similarly to López-Guerra D et al., their population study included not only mCRC patients [29–31].
Also Briceño J et al., evaluating a fibrin sealant, concluded advising the use of this agent during liver surgery due to the decrease moderate and severe postoperative complications with no clarification on bile leakage impact [29].
Precisely for this, our study acquire relevance because this is the first study that assesses the safety and efficacy of Glubran2 as a biliostatic agent, at the best of our knowledge, focusing attention to prevent bile post-opertive complications.
This project was inspired by the evolution of neoadjuvant chemotherapy for colorectal liver metastases. Thanks to the use of new drugs, especially anti-angiogenetic monoclonal antibody added to usual chemotherapy, has become possible to treat surgically patients with more curative intent due an increase response rates conversion to resectability and long-term survival. This is a very important result considering that hepatic resection is the only curative option for patients with colorectal liver metastases (mCRC) [1]. However, we need to consider also the neoadjuvant chemotherapy influence on surgical morbidity. The chemotherapy-related complications, steatosis, chemotherapy-associated steatohepatitis (CASH) and sinusoidal obstruction syndrome (SOS), might impair the hepatic parenchyma, thus reducing the functionality and influencing the outcome following resection [1, 2]. Despite the results of same studies demonstrated that neoadjuvant chemotherapy did not impair outcomes of liver resections for mCRC, in our experience we reported an increase of complications rates in this type of patients [32]. The most peculiar and important complication after liver resection is bile leakage with an incidence that is reported between 3.6 and 17 % [33]. In our two groups, we evaluate and match age, sex, site of primary cancer, chemotherapy protocol, duration of chemotherapy and type of liver resection. All patients underwent to US and MDCT at one month post resection and MDCT at 3th, 6th and 12th month for the first post-operative year. In the Group A we performed major hepatectomy in 73 % of patients versus 49.5 % in Group B. Several researches have shown that risk of biliary complications increase with the complexity of surgical procedure [34]. Patients enrolled in Group A were compared with patients in Group B; biloma was reported in 13 % (group A) vs. 16 % (group B) and bile leakage in 1 % (Group A) vs. 2.6 % (group B) (P-value < 0,001). All patients underwent liver resection using the same surgical open or laparoscopic approach, uniform technique and energy devices. In literature is possible to find numerous study that compared different types of advanced energetic devices and their haemostatic effect, their lateral spread damage in many tissues and no one demonstrated better result over others [35]. In all our patients, in booth groups, we used only Harmonic Scalpel in order to minimizing the intraoperative bias.
During the follow up, no patients died but a new hepatic lesions were found in 32 patients (15,6 %): 13 in Group A and 19 in Group B.
We observed no adverse events regarding the use of Glubran2. Analyzing our results, we could state that Glubran2 is a safe and efficacy biliostatic agent useful to prevent bile leakage complication after liver resection. Our results are similar to others that have shown that Glubran2 is a safe and effective hemostatic agent [20, 34, 36, 37].
The current study had several limitations: data collected derived from only one cancer centre, and a small semple size enrolled in this study may have influence the conclusion. In addition, this is a retrospective study. Therefore, further perspective multicentre analyses including more patients were needed to validate the prognostic significance of these results.
Conclusions
Answering to our primary end-point, it is possible to affirm that Glubran2 is a safe and feasible biliostatic agent useful to prevent bile leakage complication and biloma formation after liver resection.
Abbreviations
mCRC Colorectal liver metastases
CASH Chemotherapy-associated steatohepatitis
MDCT Multiple detector computed tomography
CT Computed tomography
CEUS Contrast Enhanced Ultrasound
SOS Sinusoidal obstruction syndrome
Acknowledgements
The authors are grateful to Alessandra Trocino, librarian and Assunta Zazzaro data manager at the National Cancer Institute of Naples, Italy.
Informed consent
Each patient signed the informed consent.
Author contributions
RP1: Data curation, Writing - original draft. VG: Conceptualization, Supervision, Data curation, Writing - review &editing. AB: Supervision. RP2: Supervision. VA: Data curation; Formal analysis. MP: Data curation; Formal analysis. RF: Data curation; Formal analysis. FT: Data curation; Formal analysis. GN: Data curation; Formal analysis. AV: Supervision. FI: Conceptualization, Supervision, Writing - review & editing. The author(s) read and approved the final manuscript.
Funding
Authors have no receiving founds for this project.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This retrospective study was approved by the Ethical Committee of the National Cancer Institute “G. Pascale Foundation - IRCCS” of Naples and the requirement for patient informed consent was waived. All procedures performed in the study were in accordance with the ethical standards of the institutional and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Consent for publication
Each author give the consent for publication.
Competing interests
The authors declare that they have no competing interests
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BEVACIZUMAB, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY | 33726798 | 19,116,272 | 2021-03-16 |
What was the administration route of drug 'BEVACIZUMAB'? | The safety and efficacy of Glubran 2 as biliostatic agent in liver resection.
BACKGROUND
Biloma, an encapsulated collection of bile outside the biliary tree, supported by a predominantly iatrogenic biliary fistula, and bile likeage are two of the most important surgical complications after liver resection. We, hypothesized to conduct a project aimed to prevent, or reduce, the formation of biloma or biliary fistula applying on the hepatic resection area the cyanoacrylate glue (Glubran2).
METHODS
We searched in our surgical database all patients underwent liver resection for mCRC from January 2013 to December 2018 and we found a total of 510 patients. 205 patients for Group A (study population: included patients in which we have used Glubran2 during surgical procedure) and 113 patients for Group B (control group), were enrolled.
RESULTS
In both Groups no patients died during hospitalization and the 30-day mortality was 0 %. During follow-up in Group A, a biliary fistula was found in 2 patients (1 %) versus 3 patients in the Group B (2,6 %). In patients enrolled in Group A no adverse event were reported relate to the use of Glubran2.
CONCLUSIONS
It is possible to affirm that the use of Glubran2 as biliostatic agent after liver resection is useful to prevent bile leakage complication and biloma formation and its use demonstrated to be safe and feasible during liver surgery.
Background
The only curative option for patients with colorectal liver metastases (mCRC) enabling 5-year overall survival rates of 50 %, is hepatic resection [1, 2]. Effective oxaliplatin- and irinotecan-based chemotherapy protocols associated with targeted agents have significantly improved response rates, conversion to resectability and long-term survival in mCRC patients [1]. However, nevertheless the benefit of neoadjuvant chemotherapy, there are a number of chemotherapy-effects that have an influence on surgical morbidity. The chemotherapy-related complications, steatosis, chemotherapy-associated steatohepatitis (CASH) and sinusoidal obstruction syndrome (SOS), might impair the hepatic parenchyma, thus reducing the functionality and influencing the outcome following resection [1–3]. One of the most serious complication reported in Literature, related to liver surgery, are the biliary system iatrogenic injury with an important rate from 3.6 to 17 % depending on several clinical risk factor [3–7]. Due to an increase of postoperative mortality rates related to biliary complications the use of topical hemostatic agents have been recommended [4, 5, 8–10]. Nonetheless, in Literature, only few study focused attention on the use of these agents to prevent complication related to liver resection [11–15]. In this study, the topical hemostatic agent used was a new synthetic cyanoacrylate glue called Glubran2, tested in various surgery with promising results [16–18]. Our primary endpoint is to test the safety and feasibility of Glubran2 during surgical liver resection in patients with mCRC previously treated with chemotherapy; as secondary endpoint we selected the utility of this agent to prevent biloma or biliary fistula to assess its biliostatic effect.
Methods
Study population
We searched, in the surgical database of the National Cancer Institute of Naples, all patients who underwent liver resection for mCRC from January 2013 to December 2018 and we found a total of 510 patients. From this total number we divided patients in two groups: Group A (study population) included patients in which we have used Glubran2 after liver resection, and Group B (control group).
This retrospective study was approved by the Ethical Committee of the National Cancer Institute “G. Pascale Foundation - IRCCS” of Naples and the requirement for patient informed consent was waived.
The inclusion criteria for the study population and control group were: (a) patients who had pathologically proven mCRC; (b) patients who had undergone imaging studies within 1 month to surgical procedure; and (c) patients who had been subjected to the same neo-adjuvant treatments. The exclusion criteria were: (a) discrepancy between the pre-surgical diagnosis and the pathologically confirmed diagnosis, (b) no available follow-up imaging studies.
During the study period, 205 patients for Group A and 113 patients for Group B, were enrolled in the study that fulfilled the inclusion criteria.
Characteristics of patients from both groups are summarized in Table 1.
Table 1 Datation regarding the MR imaging pps
mCRC patients (no.=205) Control patients (no.=113) P value
Demographics
Gender Men 89 (43.4%) Men 64 (56.6%) 0.89
Women 116 (56.6%) Women 49 (43.4%) 0.89
Age Mean, 56 years Mean, 48 years 0.74
Range, 33-80 years Range, 35-78 years
Primary cancer site
Colon 94 (45.9%) 52 (46%) 0.92
Rectum 111 (54.1%) 61 (54%) 0.92
History of chemotherapy 205 (100 %) 113 (100%) 0.99
Chemotherapy protocol mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) plus bevacizumab 205 (100%) mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) plus bevacizumab 113 (100%)
Liver metastases
Number 1075 452
mean 4 per patient mean 5 per patient
range 1-7 per patient range 2-6 per patient
Largest diameter mean 32 mm mean 28 mm
range 8-64 mm range 10-54 mm
Complications
Biloma 27 (13%) 18 (16%) 0.054
Bile leakage 2 (1%) 3 (2.6%) 0.001
Chemotherapy protocol
Both groups of patients received neoadjuvant mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) plus bevacizumab. mFOLFOX6 was administered IV every 14 days with oxaliplatin 85 mg/m-2 by infusion on day1, followed by leucovorin 200 mg/m-2 infusion on day 1, followed by 5-fluorouracil 400 mg/m-2 bolus on day 1, and 5-fluorouracil 2400 mg/m− 2 46-h continuous infusion. The antiangiogenic drug Bevacizumab was administered every 14 day-sat 5 mg/kg by IV infusion over 90 min at the first cycle, and then, if adequately tolerated, over 60 min. The treatment of mFOLFOX6 plus bevacizumab was administered for a total of 6 cycles.
Surgical procedure
All resections were initiated with curative intent. Surgical exploration and intra-operative ultrasound were performed in all cases to detect occult tumors and to plan appropriate resections. Resections of all metastatic sites were executed as anatomic or non-anatomic resections with the goal of maximal parenchymal preservation by non-anatomic resection. Dissection was accomplished using SonaStar by Misonix, allowing precise, non-anatomic resections. Major hepatectomy was defined as resection of three or more liver segments. Patients with synchronous colorectal and liver tumor at the time of presentation were assessed for feasibility of single stage combined colon and liver resection by the multidisciplinary team. In general, younger patients in good general condition and no significant comorbidity conditions were deemed candidates for single stage combined liver and colon resections.
Haemostatic agents
Glubran2 is a synthetic surgical glue, (CE Mark) certificated for internal and external use, with haemostatic, adhesive, sealer, and bacteriostatic properties. When used in moist environment, it quickly polymerizes into a thin elastic film which has high tensile strength and firmly adheres to the anatomy of the tissue on which it is applied. Once it is polymerized, Glubran2 acts as a bio inert material. We used 1 package of 1mL Glubran2 for each patient.
Lesion confirmation: reference standard
Two pathologists, specialized in the liver, performed histopathologic analysis of resected specimens. Lesion confirmation was based on the pathologic diagnosis of surgically resected liver specimens. The resected specimens were processed and then sectioned with a 5-mm slice thickness. All tumor samples were stained with hematoxylin and eosin coloration. Immunohistochemistry stains were obtained to confirm the intestinal origin of the metastatic lesions. The panel of immunohistochemical markers included cytokeratin 7, cytokeratin 20, and CDX2. The histopathological report included the pushing or infiltrating growth and the presence or absence of tumor budding and/or fibrosis and necrosis.
Follow‐up
Al patients underwent to US and CT at 1 month post surgical resection. A MDCT study was performed at 3th, 6th and 12th month. MRI study was a problem-solving tool for patients with suspicious of recurrence disease or in which a complication was detected.
OS was defined as the interval (in months) from the date of partial hepatectomy to the date of death.
MDCT protocol
CT studies were performed with a 64-detector row scanner (Optima 660, GE Healthcare, USA), using the following scanning parameters: 120 kVp, 100–470 mAs (NI 16.36) and 2.5-mm slice thickness. Liver protocol study in our Cancer Center includes a quadruple phases contrast study with an unenhanced, an arterial, a portal/venous, and equilibrium phases. Images acquisition in the arterial phase is started after attenuation in the descending aorta reached 120 HUs, measured with the bolus tracking method. For the portal/venous phase, the images were acquired 33 s after the arterial phase. For the equilibrium phase, images were acquired 180 s after the contrast medium injection.
MR Imaging Protocol
MR studies were performed by using a 1.5T scanner (Magnetom Symphony, with Total Imaging Matrix Package, Siemens, Erlangen, Germany) with an 8-element body coil and a phased array coil. Detailed information regarding the MR study protocol is summarized in Table 2. A standard dose (0.025 mmol/kg) of gadoxetic acid (Primovist, Bayer Healthcare, Berlin, Germany) was injected at a rate of 1.0 mL/s by using a power injector (Spectris Solaris EP; Medrad, Warrendale, Pa) followed by a 30-mL saline flush. Arterial phase images were acquired 7 s after contrast medium arrival at the thoracic aorta by using an MR fluoroscopic monitoring system. Thereafter, portal venous phase, transitional phase, and hepatobiliary phase (HBP) were obtained 60 s, 3 min, and 20 min after contrast medium injection, respectively.
Table 2 Detailed information regarding the MR imaging parameters
Sequence Orientation TR/TE/FA
(ms/ms/deg.) AT
(min) Acquisition Matrix ST/Gap (mm) FS
Trufisp T2-W Coronal 4.30/2.15/80 0.46 512 × 512 4 / 0 without
HASTE T2-W Axial 1500/90/170 0.36 320 × 320 5 / 0 Without and with (SPAIR)
HASTE T2w Coronal 1500/92/170 0.38 320 × 320 5 / 0 without
In-Out phase T1-W Axial 160/2.35/70 0.33 256 × 192 5 / 0 without
DWI Axial 7500/91/90 7 192 × 192 3 / 0 without
Vibe
T1-W
Axial 4.80/1.76/12 0.18 320 × 260 3 / 0 with (SPAIR)
Note. TR Repetition time, TE Echo time, FA Flip angle, AT Acquisition time, ST Slice thickness, FS Fat suppression, SPAIR Spectral adiabatic inversion recovery
CEUS protocol
CEUS was always preceded by a careful US survey, assessing the size and appearance of the lesion/s. This baseline assessment was done to appropriately choose the liver area or areas to be particularly focused in the forthcoming contrast-enhanced part of the US study. In all cases, a separated injection was performed for each liver lobe. For both injections, the arterial phase assessment was focused on any known lesion at baseline US. CEUS was performed as a low- mechanical index, double-split mode, real-time modality. We employed a Technos MyLab 70 XVG and MyLab Twice scanner (Esaote, Genoa, Italy), injecting 2.4 ml of a sulfur hexafluoride-based contrast medium (SonoVue, Bracco, Milan, Italy) per each liver lobe. After the injection, the radiologist focused the sonographic field of view on the parenchymal area of interest, waiting for the microbubble’s arrival. Thereafter, he/she moved the transducer to explore the remaining parenchyma of each lobe, with special reference to the resected area.
Biloma and bile leakage definition, diagnosis and management
Following scientific Literature we considered biloma as an encapsulated collection of bile outside the biliary tree and within the abdominal cavity and bile leakage as a postoperative loss of fluid bile via abdominal drains after liver surgery [19, 20]. We diagnosed and divided bile leakage in grade A, B and C based on the impact of this complication on patients’ clinical management. [20]
Surgical complications
Surgical Complications were classified according to Clavien Dindo et al. [21].
Statistical analyses
Each continuous variable was expressed in terms of median value ± range while each variable categorical was summarized by frequencies and percentages. Chi square test was performed to assess statistically significant difference between percentage values. Mann Whitney non parametric test were used to compare a continuous variable between 2 groups. A p value < 0.05 was considered statistically significant.
All statistical analysis was performed with SPSS for Windows (Version 23.0; SPSS Inc, Chicago, Ill).
Results
We analyzed a total of 318 patients: Group A with 205 patients and 1036 pathologically proven lesions (mean tumor size: 32 mm; range 8–64 mm) and Group B with 113 patients and 452 mCRC pathologically proven lesions (mean tumor size: 36 mm; range 11–59 mm).
In the Group A we performed 60 lobectomy, 43 meso-hepatectomy, 48 bi-segmentectomy (73 % major hepatectomy) and 54 segmentectomy or other liver resection (wedge/metasasectomy) (2 in seg I, 3 in seg II, 4 in seg III, 10 in seg IV, 9 in seg V and 8 in seg VI, 18 in seg. VII). Twenty-five patients underwent single stage combined liver and colon resections.
The average hospitalization time was 8 days (7–16). No major complications occurred during surgical procedures. No patients died during hospitalization and the 30-day mortality was 0 %. During follow-up in 27 patients (13 %) was reported a Biloma and in 2 patients (1 %) a bile leakage grade B was detected. No adverse events were reported regarding the use of Glubran 2.
About Group B (113 patients), 56 patients underwent major hepatectomy (49,5 %), 40 liver segmentectomy (35.5 %), 17 wedge procedure or metasasectomy (5 in seg II, 2 in seg III, 3 in seg IV, 2 in seg V and 5 in seg VI). Seventeen patients underwent single stage combined liver and colon resections.
The average hospitalization time was 10 days (5–14). No major complications occurred during surgical procedures. No patients died during hospitalization and the 30-day mortality was 0 %.
During follow-up 18 patients (16 %) showed presence of biloma and in 3 patients (2,6 %) a bile leakage was detected (2 grade B, 1 grade C).
A new hepatic lesions were identified (mean time 5 months) in 32 patients (15,6 %), 13 in group A and 19 in group B.
Discussion
The rationale behind our study is the polymerization of cyanoacrylate glue when it is in contact with blood and tissues owing to the presence of ions and proteins. Nowadays the solid polymer created by this reaction, has demonstrated to be safe and useful in several use during surgical clinical practices.
In surgery for ventral hernia repair, Glubran2 permitted a suturless fixation mesh, in bariatric surgery showed to be effective to prevent gastric fistulas or suture line dehiscence (leaks), in endovascular surgery many scientific articles had described it’s use to stop bleeding in elective and in emergency and new applications are investigate in colorectal and thoracic surgery, to prevent anastomotic and air leak [22–28].
Our study is focused on biliostatic effect of cyanoacrylate glue but, in Literature, is possible to find articles that analyzed or compare hemostatic or sealant agent to prevent bile leakage and hemorrhagic events. López-Guerra D et al., in 2019, compare the use of two different fibrin sealant patches during liver surgery. Contrary to ours, this study included benign patients, patients without pre-operative chemotherapy, HCC and mCRC and concluded with no superiority between different fibrin patches in post-operative complications not focusing attentions on bile leakage [18].
Likewise others papers compare different agent both on prevent bleeding and bile leakage and, similarly to López-Guerra D et al., their population study included not only mCRC patients [29–31].
Also Briceño J et al., evaluating a fibrin sealant, concluded advising the use of this agent during liver surgery due to the decrease moderate and severe postoperative complications with no clarification on bile leakage impact [29].
Precisely for this, our study acquire relevance because this is the first study that assesses the safety and efficacy of Glubran2 as a biliostatic agent, at the best of our knowledge, focusing attention to prevent bile post-opertive complications.
This project was inspired by the evolution of neoadjuvant chemotherapy for colorectal liver metastases. Thanks to the use of new drugs, especially anti-angiogenetic monoclonal antibody added to usual chemotherapy, has become possible to treat surgically patients with more curative intent due an increase response rates conversion to resectability and long-term survival. This is a very important result considering that hepatic resection is the only curative option for patients with colorectal liver metastases (mCRC) [1]. However, we need to consider also the neoadjuvant chemotherapy influence on surgical morbidity. The chemotherapy-related complications, steatosis, chemotherapy-associated steatohepatitis (CASH) and sinusoidal obstruction syndrome (SOS), might impair the hepatic parenchyma, thus reducing the functionality and influencing the outcome following resection [1, 2]. Despite the results of same studies demonstrated that neoadjuvant chemotherapy did not impair outcomes of liver resections for mCRC, in our experience we reported an increase of complications rates in this type of patients [32]. The most peculiar and important complication after liver resection is bile leakage with an incidence that is reported between 3.6 and 17 % [33]. In our two groups, we evaluate and match age, sex, site of primary cancer, chemotherapy protocol, duration of chemotherapy and type of liver resection. All patients underwent to US and MDCT at one month post resection and MDCT at 3th, 6th and 12th month for the first post-operative year. In the Group A we performed major hepatectomy in 73 % of patients versus 49.5 % in Group B. Several researches have shown that risk of biliary complications increase with the complexity of surgical procedure [34]. Patients enrolled in Group A were compared with patients in Group B; biloma was reported in 13 % (group A) vs. 16 % (group B) and bile leakage in 1 % (Group A) vs. 2.6 % (group B) (P-value < 0,001). All patients underwent liver resection using the same surgical open or laparoscopic approach, uniform technique and energy devices. In literature is possible to find numerous study that compared different types of advanced energetic devices and their haemostatic effect, their lateral spread damage in many tissues and no one demonstrated better result over others [35]. In all our patients, in booth groups, we used only Harmonic Scalpel in order to minimizing the intraoperative bias.
During the follow up, no patients died but a new hepatic lesions were found in 32 patients (15,6 %): 13 in Group A and 19 in Group B.
We observed no adverse events regarding the use of Glubran2. Analyzing our results, we could state that Glubran2 is a safe and efficacy biliostatic agent useful to prevent bile leakage complication after liver resection. Our results are similar to others that have shown that Glubran2 is a safe and effective hemostatic agent [20, 34, 36, 37].
The current study had several limitations: data collected derived from only one cancer centre, and a small semple size enrolled in this study may have influence the conclusion. In addition, this is a retrospective study. Therefore, further perspective multicentre analyses including more patients were needed to validate the prognostic significance of these results.
Conclusions
Answering to our primary end-point, it is possible to affirm that Glubran2 is a safe and feasible biliostatic agent useful to prevent bile leakage complication and biloma formation after liver resection.
Abbreviations
mCRC Colorectal liver metastases
CASH Chemotherapy-associated steatohepatitis
MDCT Multiple detector computed tomography
CT Computed tomography
CEUS Contrast Enhanced Ultrasound
SOS Sinusoidal obstruction syndrome
Acknowledgements
The authors are grateful to Alessandra Trocino, librarian and Assunta Zazzaro data manager at the National Cancer Institute of Naples, Italy.
Informed consent
Each patient signed the informed consent.
Author contributions
RP1: Data curation, Writing - original draft. VG: Conceptualization, Supervision, Data curation, Writing - review &editing. AB: Supervision. RP2: Supervision. VA: Data curation; Formal analysis. MP: Data curation; Formal analysis. RF: Data curation; Formal analysis. FT: Data curation; Formal analysis. GN: Data curation; Formal analysis. AV: Supervision. FI: Conceptualization, Supervision, Writing - review & editing. The author(s) read and approved the final manuscript.
Funding
Authors have no receiving founds for this project.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This retrospective study was approved by the Ethical Committee of the National Cancer Institute “G. Pascale Foundation - IRCCS” of Naples and the requirement for patient informed consent was waived. All procedures performed in the study were in accordance with the ethical standards of the institutional and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Consent for publication
Each author give the consent for publication.
Competing interests
The authors declare that they have no competing interests
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33726798 | 19,116,272 | 2021-03-16 |
What was the administration route of drug 'OXALIPLATIN'? | The safety and efficacy of Glubran 2 as biliostatic agent in liver resection.
BACKGROUND
Biloma, an encapsulated collection of bile outside the biliary tree, supported by a predominantly iatrogenic biliary fistula, and bile likeage are two of the most important surgical complications after liver resection. We, hypothesized to conduct a project aimed to prevent, or reduce, the formation of biloma or biliary fistula applying on the hepatic resection area the cyanoacrylate glue (Glubran2).
METHODS
We searched in our surgical database all patients underwent liver resection for mCRC from January 2013 to December 2018 and we found a total of 510 patients. 205 patients for Group A (study population: included patients in which we have used Glubran2 during surgical procedure) and 113 patients for Group B (control group), were enrolled.
RESULTS
In both Groups no patients died during hospitalization and the 30-day mortality was 0 %. During follow-up in Group A, a biliary fistula was found in 2 patients (1 %) versus 3 patients in the Group B (2,6 %). In patients enrolled in Group A no adverse event were reported relate to the use of Glubran2.
CONCLUSIONS
It is possible to affirm that the use of Glubran2 as biliostatic agent after liver resection is useful to prevent bile leakage complication and biloma formation and its use demonstrated to be safe and feasible during liver surgery.
Background
The only curative option for patients with colorectal liver metastases (mCRC) enabling 5-year overall survival rates of 50 %, is hepatic resection [1, 2]. Effective oxaliplatin- and irinotecan-based chemotherapy protocols associated with targeted agents have significantly improved response rates, conversion to resectability and long-term survival in mCRC patients [1]. However, nevertheless the benefit of neoadjuvant chemotherapy, there are a number of chemotherapy-effects that have an influence on surgical morbidity. The chemotherapy-related complications, steatosis, chemotherapy-associated steatohepatitis (CASH) and sinusoidal obstruction syndrome (SOS), might impair the hepatic parenchyma, thus reducing the functionality and influencing the outcome following resection [1–3]. One of the most serious complication reported in Literature, related to liver surgery, are the biliary system iatrogenic injury with an important rate from 3.6 to 17 % depending on several clinical risk factor [3–7]. Due to an increase of postoperative mortality rates related to biliary complications the use of topical hemostatic agents have been recommended [4, 5, 8–10]. Nonetheless, in Literature, only few study focused attention on the use of these agents to prevent complication related to liver resection [11–15]. In this study, the topical hemostatic agent used was a new synthetic cyanoacrylate glue called Glubran2, tested in various surgery with promising results [16–18]. Our primary endpoint is to test the safety and feasibility of Glubran2 during surgical liver resection in patients with mCRC previously treated with chemotherapy; as secondary endpoint we selected the utility of this agent to prevent biloma or biliary fistula to assess its biliostatic effect.
Methods
Study population
We searched, in the surgical database of the National Cancer Institute of Naples, all patients who underwent liver resection for mCRC from January 2013 to December 2018 and we found a total of 510 patients. From this total number we divided patients in two groups: Group A (study population) included patients in which we have used Glubran2 after liver resection, and Group B (control group).
This retrospective study was approved by the Ethical Committee of the National Cancer Institute “G. Pascale Foundation - IRCCS” of Naples and the requirement for patient informed consent was waived.
The inclusion criteria for the study population and control group were: (a) patients who had pathologically proven mCRC; (b) patients who had undergone imaging studies within 1 month to surgical procedure; and (c) patients who had been subjected to the same neo-adjuvant treatments. The exclusion criteria were: (a) discrepancy between the pre-surgical diagnosis and the pathologically confirmed diagnosis, (b) no available follow-up imaging studies.
During the study period, 205 patients for Group A and 113 patients for Group B, were enrolled in the study that fulfilled the inclusion criteria.
Characteristics of patients from both groups are summarized in Table 1.
Table 1 Datation regarding the MR imaging pps
mCRC patients (no.=205) Control patients (no.=113) P value
Demographics
Gender Men 89 (43.4%) Men 64 (56.6%) 0.89
Women 116 (56.6%) Women 49 (43.4%) 0.89
Age Mean, 56 years Mean, 48 years 0.74
Range, 33-80 years Range, 35-78 years
Primary cancer site
Colon 94 (45.9%) 52 (46%) 0.92
Rectum 111 (54.1%) 61 (54%) 0.92
History of chemotherapy 205 (100 %) 113 (100%) 0.99
Chemotherapy protocol mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) plus bevacizumab 205 (100%) mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) plus bevacizumab 113 (100%)
Liver metastases
Number 1075 452
mean 4 per patient mean 5 per patient
range 1-7 per patient range 2-6 per patient
Largest diameter mean 32 mm mean 28 mm
range 8-64 mm range 10-54 mm
Complications
Biloma 27 (13%) 18 (16%) 0.054
Bile leakage 2 (1%) 3 (2.6%) 0.001
Chemotherapy protocol
Both groups of patients received neoadjuvant mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) plus bevacizumab. mFOLFOX6 was administered IV every 14 days with oxaliplatin 85 mg/m-2 by infusion on day1, followed by leucovorin 200 mg/m-2 infusion on day 1, followed by 5-fluorouracil 400 mg/m-2 bolus on day 1, and 5-fluorouracil 2400 mg/m− 2 46-h continuous infusion. The antiangiogenic drug Bevacizumab was administered every 14 day-sat 5 mg/kg by IV infusion over 90 min at the first cycle, and then, if adequately tolerated, over 60 min. The treatment of mFOLFOX6 plus bevacizumab was administered for a total of 6 cycles.
Surgical procedure
All resections were initiated with curative intent. Surgical exploration and intra-operative ultrasound were performed in all cases to detect occult tumors and to plan appropriate resections. Resections of all metastatic sites were executed as anatomic or non-anatomic resections with the goal of maximal parenchymal preservation by non-anatomic resection. Dissection was accomplished using SonaStar by Misonix, allowing precise, non-anatomic resections. Major hepatectomy was defined as resection of three or more liver segments. Patients with synchronous colorectal and liver tumor at the time of presentation were assessed for feasibility of single stage combined colon and liver resection by the multidisciplinary team. In general, younger patients in good general condition and no significant comorbidity conditions were deemed candidates for single stage combined liver and colon resections.
Haemostatic agents
Glubran2 is a synthetic surgical glue, (CE Mark) certificated for internal and external use, with haemostatic, adhesive, sealer, and bacteriostatic properties. When used in moist environment, it quickly polymerizes into a thin elastic film which has high tensile strength and firmly adheres to the anatomy of the tissue on which it is applied. Once it is polymerized, Glubran2 acts as a bio inert material. We used 1 package of 1mL Glubran2 for each patient.
Lesion confirmation: reference standard
Two pathologists, specialized in the liver, performed histopathologic analysis of resected specimens. Lesion confirmation was based on the pathologic diagnosis of surgically resected liver specimens. The resected specimens were processed and then sectioned with a 5-mm slice thickness. All tumor samples were stained with hematoxylin and eosin coloration. Immunohistochemistry stains were obtained to confirm the intestinal origin of the metastatic lesions. The panel of immunohistochemical markers included cytokeratin 7, cytokeratin 20, and CDX2. The histopathological report included the pushing or infiltrating growth and the presence or absence of tumor budding and/or fibrosis and necrosis.
Follow‐up
Al patients underwent to US and CT at 1 month post surgical resection. A MDCT study was performed at 3th, 6th and 12th month. MRI study was a problem-solving tool for patients with suspicious of recurrence disease or in which a complication was detected.
OS was defined as the interval (in months) from the date of partial hepatectomy to the date of death.
MDCT protocol
CT studies were performed with a 64-detector row scanner (Optima 660, GE Healthcare, USA), using the following scanning parameters: 120 kVp, 100–470 mAs (NI 16.36) and 2.5-mm slice thickness. Liver protocol study in our Cancer Center includes a quadruple phases contrast study with an unenhanced, an arterial, a portal/venous, and equilibrium phases. Images acquisition in the arterial phase is started after attenuation in the descending aorta reached 120 HUs, measured with the bolus tracking method. For the portal/venous phase, the images were acquired 33 s after the arterial phase. For the equilibrium phase, images were acquired 180 s after the contrast medium injection.
MR Imaging Protocol
MR studies were performed by using a 1.5T scanner (Magnetom Symphony, with Total Imaging Matrix Package, Siemens, Erlangen, Germany) with an 8-element body coil and a phased array coil. Detailed information regarding the MR study protocol is summarized in Table 2. A standard dose (0.025 mmol/kg) of gadoxetic acid (Primovist, Bayer Healthcare, Berlin, Germany) was injected at a rate of 1.0 mL/s by using a power injector (Spectris Solaris EP; Medrad, Warrendale, Pa) followed by a 30-mL saline flush. Arterial phase images were acquired 7 s after contrast medium arrival at the thoracic aorta by using an MR fluoroscopic monitoring system. Thereafter, portal venous phase, transitional phase, and hepatobiliary phase (HBP) were obtained 60 s, 3 min, and 20 min after contrast medium injection, respectively.
Table 2 Detailed information regarding the MR imaging parameters
Sequence Orientation TR/TE/FA
(ms/ms/deg.) AT
(min) Acquisition Matrix ST/Gap (mm) FS
Trufisp T2-W Coronal 4.30/2.15/80 0.46 512 × 512 4 / 0 without
HASTE T2-W Axial 1500/90/170 0.36 320 × 320 5 / 0 Without and with (SPAIR)
HASTE T2w Coronal 1500/92/170 0.38 320 × 320 5 / 0 without
In-Out phase T1-W Axial 160/2.35/70 0.33 256 × 192 5 / 0 without
DWI Axial 7500/91/90 7 192 × 192 3 / 0 without
Vibe
T1-W
Axial 4.80/1.76/12 0.18 320 × 260 3 / 0 with (SPAIR)
Note. TR Repetition time, TE Echo time, FA Flip angle, AT Acquisition time, ST Slice thickness, FS Fat suppression, SPAIR Spectral adiabatic inversion recovery
CEUS protocol
CEUS was always preceded by a careful US survey, assessing the size and appearance of the lesion/s. This baseline assessment was done to appropriately choose the liver area or areas to be particularly focused in the forthcoming contrast-enhanced part of the US study. In all cases, a separated injection was performed for each liver lobe. For both injections, the arterial phase assessment was focused on any known lesion at baseline US. CEUS was performed as a low- mechanical index, double-split mode, real-time modality. We employed a Technos MyLab 70 XVG and MyLab Twice scanner (Esaote, Genoa, Italy), injecting 2.4 ml of a sulfur hexafluoride-based contrast medium (SonoVue, Bracco, Milan, Italy) per each liver lobe. After the injection, the radiologist focused the sonographic field of view on the parenchymal area of interest, waiting for the microbubble’s arrival. Thereafter, he/she moved the transducer to explore the remaining parenchyma of each lobe, with special reference to the resected area.
Biloma and bile leakage definition, diagnosis and management
Following scientific Literature we considered biloma as an encapsulated collection of bile outside the biliary tree and within the abdominal cavity and bile leakage as a postoperative loss of fluid bile via abdominal drains after liver surgery [19, 20]. We diagnosed and divided bile leakage in grade A, B and C based on the impact of this complication on patients’ clinical management. [20]
Surgical complications
Surgical Complications were classified according to Clavien Dindo et al. [21].
Statistical analyses
Each continuous variable was expressed in terms of median value ± range while each variable categorical was summarized by frequencies and percentages. Chi square test was performed to assess statistically significant difference between percentage values. Mann Whitney non parametric test were used to compare a continuous variable between 2 groups. A p value < 0.05 was considered statistically significant.
All statistical analysis was performed with SPSS for Windows (Version 23.0; SPSS Inc, Chicago, Ill).
Results
We analyzed a total of 318 patients: Group A with 205 patients and 1036 pathologically proven lesions (mean tumor size: 32 mm; range 8–64 mm) and Group B with 113 patients and 452 mCRC pathologically proven lesions (mean tumor size: 36 mm; range 11–59 mm).
In the Group A we performed 60 lobectomy, 43 meso-hepatectomy, 48 bi-segmentectomy (73 % major hepatectomy) and 54 segmentectomy or other liver resection (wedge/metasasectomy) (2 in seg I, 3 in seg II, 4 in seg III, 10 in seg IV, 9 in seg V and 8 in seg VI, 18 in seg. VII). Twenty-five patients underwent single stage combined liver and colon resections.
The average hospitalization time was 8 days (7–16). No major complications occurred during surgical procedures. No patients died during hospitalization and the 30-day mortality was 0 %. During follow-up in 27 patients (13 %) was reported a Biloma and in 2 patients (1 %) a bile leakage grade B was detected. No adverse events were reported regarding the use of Glubran 2.
About Group B (113 patients), 56 patients underwent major hepatectomy (49,5 %), 40 liver segmentectomy (35.5 %), 17 wedge procedure or metasasectomy (5 in seg II, 2 in seg III, 3 in seg IV, 2 in seg V and 5 in seg VI). Seventeen patients underwent single stage combined liver and colon resections.
The average hospitalization time was 10 days (5–14). No major complications occurred during surgical procedures. No patients died during hospitalization and the 30-day mortality was 0 %.
During follow-up 18 patients (16 %) showed presence of biloma and in 3 patients (2,6 %) a bile leakage was detected (2 grade B, 1 grade C).
A new hepatic lesions were identified (mean time 5 months) in 32 patients (15,6 %), 13 in group A and 19 in group B.
Discussion
The rationale behind our study is the polymerization of cyanoacrylate glue when it is in contact with blood and tissues owing to the presence of ions and proteins. Nowadays the solid polymer created by this reaction, has demonstrated to be safe and useful in several use during surgical clinical practices.
In surgery for ventral hernia repair, Glubran2 permitted a suturless fixation mesh, in bariatric surgery showed to be effective to prevent gastric fistulas or suture line dehiscence (leaks), in endovascular surgery many scientific articles had described it’s use to stop bleeding in elective and in emergency and new applications are investigate in colorectal and thoracic surgery, to prevent anastomotic and air leak [22–28].
Our study is focused on biliostatic effect of cyanoacrylate glue but, in Literature, is possible to find articles that analyzed or compare hemostatic or sealant agent to prevent bile leakage and hemorrhagic events. López-Guerra D et al., in 2019, compare the use of two different fibrin sealant patches during liver surgery. Contrary to ours, this study included benign patients, patients without pre-operative chemotherapy, HCC and mCRC and concluded with no superiority between different fibrin patches in post-operative complications not focusing attentions on bile leakage [18].
Likewise others papers compare different agent both on prevent bleeding and bile leakage and, similarly to López-Guerra D et al., their population study included not only mCRC patients [29–31].
Also Briceño J et al., evaluating a fibrin sealant, concluded advising the use of this agent during liver surgery due to the decrease moderate and severe postoperative complications with no clarification on bile leakage impact [29].
Precisely for this, our study acquire relevance because this is the first study that assesses the safety and efficacy of Glubran2 as a biliostatic agent, at the best of our knowledge, focusing attention to prevent bile post-opertive complications.
This project was inspired by the evolution of neoadjuvant chemotherapy for colorectal liver metastases. Thanks to the use of new drugs, especially anti-angiogenetic monoclonal antibody added to usual chemotherapy, has become possible to treat surgically patients with more curative intent due an increase response rates conversion to resectability and long-term survival. This is a very important result considering that hepatic resection is the only curative option for patients with colorectal liver metastases (mCRC) [1]. However, we need to consider also the neoadjuvant chemotherapy influence on surgical morbidity. The chemotherapy-related complications, steatosis, chemotherapy-associated steatohepatitis (CASH) and sinusoidal obstruction syndrome (SOS), might impair the hepatic parenchyma, thus reducing the functionality and influencing the outcome following resection [1, 2]. Despite the results of same studies demonstrated that neoadjuvant chemotherapy did not impair outcomes of liver resections for mCRC, in our experience we reported an increase of complications rates in this type of patients [32]. The most peculiar and important complication after liver resection is bile leakage with an incidence that is reported between 3.6 and 17 % [33]. In our two groups, we evaluate and match age, sex, site of primary cancer, chemotherapy protocol, duration of chemotherapy and type of liver resection. All patients underwent to US and MDCT at one month post resection and MDCT at 3th, 6th and 12th month for the first post-operative year. In the Group A we performed major hepatectomy in 73 % of patients versus 49.5 % in Group B. Several researches have shown that risk of biliary complications increase with the complexity of surgical procedure [34]. Patients enrolled in Group A were compared with patients in Group B; biloma was reported in 13 % (group A) vs. 16 % (group B) and bile leakage in 1 % (Group A) vs. 2.6 % (group B) (P-value < 0,001). All patients underwent liver resection using the same surgical open or laparoscopic approach, uniform technique and energy devices. In literature is possible to find numerous study that compared different types of advanced energetic devices and their haemostatic effect, their lateral spread damage in many tissues and no one demonstrated better result over others [35]. In all our patients, in booth groups, we used only Harmonic Scalpel in order to minimizing the intraoperative bias.
During the follow up, no patients died but a new hepatic lesions were found in 32 patients (15,6 %): 13 in Group A and 19 in Group B.
We observed no adverse events regarding the use of Glubran2. Analyzing our results, we could state that Glubran2 is a safe and efficacy biliostatic agent useful to prevent bile leakage complication after liver resection. Our results are similar to others that have shown that Glubran2 is a safe and effective hemostatic agent [20, 34, 36, 37].
The current study had several limitations: data collected derived from only one cancer centre, and a small semple size enrolled in this study may have influence the conclusion. In addition, this is a retrospective study. Therefore, further perspective multicentre analyses including more patients were needed to validate the prognostic significance of these results.
Conclusions
Answering to our primary end-point, it is possible to affirm that Glubran2 is a safe and feasible biliostatic agent useful to prevent bile leakage complication and biloma formation after liver resection.
Abbreviations
mCRC Colorectal liver metastases
CASH Chemotherapy-associated steatohepatitis
MDCT Multiple detector computed tomography
CT Computed tomography
CEUS Contrast Enhanced Ultrasound
SOS Sinusoidal obstruction syndrome
Acknowledgements
The authors are grateful to Alessandra Trocino, librarian and Assunta Zazzaro data manager at the National Cancer Institute of Naples, Italy.
Informed consent
Each patient signed the informed consent.
Author contributions
RP1: Data curation, Writing - original draft. VG: Conceptualization, Supervision, Data curation, Writing - review &editing. AB: Supervision. RP2: Supervision. VA: Data curation; Formal analysis. MP: Data curation; Formal analysis. RF: Data curation; Formal analysis. FT: Data curation; Formal analysis. GN: Data curation; Formal analysis. AV: Supervision. FI: Conceptualization, Supervision, Writing - review & editing. The author(s) read and approved the final manuscript.
Funding
Authors have no receiving founds for this project.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This retrospective study was approved by the Ethical Committee of the National Cancer Institute “G. Pascale Foundation - IRCCS” of Naples and the requirement for patient informed consent was waived. All procedures performed in the study were in accordance with the ethical standards of the institutional and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Consent for publication
Each author give the consent for publication.
Competing interests
The authors declare that they have no competing interests
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33726798 | 19,116,272 | 2021-03-16 |
What was the dosage of drug 'BEVACIZUMAB'? | The safety and efficacy of Glubran 2 as biliostatic agent in liver resection.
BACKGROUND
Biloma, an encapsulated collection of bile outside the biliary tree, supported by a predominantly iatrogenic biliary fistula, and bile likeage are two of the most important surgical complications after liver resection. We, hypothesized to conduct a project aimed to prevent, or reduce, the formation of biloma or biliary fistula applying on the hepatic resection area the cyanoacrylate glue (Glubran2).
METHODS
We searched in our surgical database all patients underwent liver resection for mCRC from January 2013 to December 2018 and we found a total of 510 patients. 205 patients for Group A (study population: included patients in which we have used Glubran2 during surgical procedure) and 113 patients for Group B (control group), were enrolled.
RESULTS
In both Groups no patients died during hospitalization and the 30-day mortality was 0 %. During follow-up in Group A, a biliary fistula was found in 2 patients (1 %) versus 3 patients in the Group B (2,6 %). In patients enrolled in Group A no adverse event were reported relate to the use of Glubran2.
CONCLUSIONS
It is possible to affirm that the use of Glubran2 as biliostatic agent after liver resection is useful to prevent bile leakage complication and biloma formation and its use demonstrated to be safe and feasible during liver surgery.
Background
The only curative option for patients with colorectal liver metastases (mCRC) enabling 5-year overall survival rates of 50 %, is hepatic resection [1, 2]. Effective oxaliplatin- and irinotecan-based chemotherapy protocols associated with targeted agents have significantly improved response rates, conversion to resectability and long-term survival in mCRC patients [1]. However, nevertheless the benefit of neoadjuvant chemotherapy, there are a number of chemotherapy-effects that have an influence on surgical morbidity. The chemotherapy-related complications, steatosis, chemotherapy-associated steatohepatitis (CASH) and sinusoidal obstruction syndrome (SOS), might impair the hepatic parenchyma, thus reducing the functionality and influencing the outcome following resection [1–3]. One of the most serious complication reported in Literature, related to liver surgery, are the biliary system iatrogenic injury with an important rate from 3.6 to 17 % depending on several clinical risk factor [3–7]. Due to an increase of postoperative mortality rates related to biliary complications the use of topical hemostatic agents have been recommended [4, 5, 8–10]. Nonetheless, in Literature, only few study focused attention on the use of these agents to prevent complication related to liver resection [11–15]. In this study, the topical hemostatic agent used was a new synthetic cyanoacrylate glue called Glubran2, tested in various surgery with promising results [16–18]. Our primary endpoint is to test the safety and feasibility of Glubran2 during surgical liver resection in patients with mCRC previously treated with chemotherapy; as secondary endpoint we selected the utility of this agent to prevent biloma or biliary fistula to assess its biliostatic effect.
Methods
Study population
We searched, in the surgical database of the National Cancer Institute of Naples, all patients who underwent liver resection for mCRC from January 2013 to December 2018 and we found a total of 510 patients. From this total number we divided patients in two groups: Group A (study population) included patients in which we have used Glubran2 after liver resection, and Group B (control group).
This retrospective study was approved by the Ethical Committee of the National Cancer Institute “G. Pascale Foundation - IRCCS” of Naples and the requirement for patient informed consent was waived.
The inclusion criteria for the study population and control group were: (a) patients who had pathologically proven mCRC; (b) patients who had undergone imaging studies within 1 month to surgical procedure; and (c) patients who had been subjected to the same neo-adjuvant treatments. The exclusion criteria were: (a) discrepancy between the pre-surgical diagnosis and the pathologically confirmed diagnosis, (b) no available follow-up imaging studies.
During the study period, 205 patients for Group A and 113 patients for Group B, were enrolled in the study that fulfilled the inclusion criteria.
Characteristics of patients from both groups are summarized in Table 1.
Table 1 Datation regarding the MR imaging pps
mCRC patients (no.=205) Control patients (no.=113) P value
Demographics
Gender Men 89 (43.4%) Men 64 (56.6%) 0.89
Women 116 (56.6%) Women 49 (43.4%) 0.89
Age Mean, 56 years Mean, 48 years 0.74
Range, 33-80 years Range, 35-78 years
Primary cancer site
Colon 94 (45.9%) 52 (46%) 0.92
Rectum 111 (54.1%) 61 (54%) 0.92
History of chemotherapy 205 (100 %) 113 (100%) 0.99
Chemotherapy protocol mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) plus bevacizumab 205 (100%) mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) plus bevacizumab 113 (100%)
Liver metastases
Number 1075 452
mean 4 per patient mean 5 per patient
range 1-7 per patient range 2-6 per patient
Largest diameter mean 32 mm mean 28 mm
range 8-64 mm range 10-54 mm
Complications
Biloma 27 (13%) 18 (16%) 0.054
Bile leakage 2 (1%) 3 (2.6%) 0.001
Chemotherapy protocol
Both groups of patients received neoadjuvant mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) plus bevacizumab. mFOLFOX6 was administered IV every 14 days with oxaliplatin 85 mg/m-2 by infusion on day1, followed by leucovorin 200 mg/m-2 infusion on day 1, followed by 5-fluorouracil 400 mg/m-2 bolus on day 1, and 5-fluorouracil 2400 mg/m− 2 46-h continuous infusion. The antiangiogenic drug Bevacizumab was administered every 14 day-sat 5 mg/kg by IV infusion over 90 min at the first cycle, and then, if adequately tolerated, over 60 min. The treatment of mFOLFOX6 plus bevacizumab was administered for a total of 6 cycles.
Surgical procedure
All resections were initiated with curative intent. Surgical exploration and intra-operative ultrasound were performed in all cases to detect occult tumors and to plan appropriate resections. Resections of all metastatic sites were executed as anatomic or non-anatomic resections with the goal of maximal parenchymal preservation by non-anatomic resection. Dissection was accomplished using SonaStar by Misonix, allowing precise, non-anatomic resections. Major hepatectomy was defined as resection of three or more liver segments. Patients with synchronous colorectal and liver tumor at the time of presentation were assessed for feasibility of single stage combined colon and liver resection by the multidisciplinary team. In general, younger patients in good general condition and no significant comorbidity conditions were deemed candidates for single stage combined liver and colon resections.
Haemostatic agents
Glubran2 is a synthetic surgical glue, (CE Mark) certificated for internal and external use, with haemostatic, adhesive, sealer, and bacteriostatic properties. When used in moist environment, it quickly polymerizes into a thin elastic film which has high tensile strength and firmly adheres to the anatomy of the tissue on which it is applied. Once it is polymerized, Glubran2 acts as a bio inert material. We used 1 package of 1mL Glubran2 for each patient.
Lesion confirmation: reference standard
Two pathologists, specialized in the liver, performed histopathologic analysis of resected specimens. Lesion confirmation was based on the pathologic diagnosis of surgically resected liver specimens. The resected specimens were processed and then sectioned with a 5-mm slice thickness. All tumor samples were stained with hematoxylin and eosin coloration. Immunohistochemistry stains were obtained to confirm the intestinal origin of the metastatic lesions. The panel of immunohistochemical markers included cytokeratin 7, cytokeratin 20, and CDX2. The histopathological report included the pushing or infiltrating growth and the presence or absence of tumor budding and/or fibrosis and necrosis.
Follow‐up
Al patients underwent to US and CT at 1 month post surgical resection. A MDCT study was performed at 3th, 6th and 12th month. MRI study was a problem-solving tool for patients with suspicious of recurrence disease or in which a complication was detected.
OS was defined as the interval (in months) from the date of partial hepatectomy to the date of death.
MDCT protocol
CT studies were performed with a 64-detector row scanner (Optima 660, GE Healthcare, USA), using the following scanning parameters: 120 kVp, 100–470 mAs (NI 16.36) and 2.5-mm slice thickness. Liver protocol study in our Cancer Center includes a quadruple phases contrast study with an unenhanced, an arterial, a portal/venous, and equilibrium phases. Images acquisition in the arterial phase is started after attenuation in the descending aorta reached 120 HUs, measured with the bolus tracking method. For the portal/venous phase, the images were acquired 33 s after the arterial phase. For the equilibrium phase, images were acquired 180 s after the contrast medium injection.
MR Imaging Protocol
MR studies were performed by using a 1.5T scanner (Magnetom Symphony, with Total Imaging Matrix Package, Siemens, Erlangen, Germany) with an 8-element body coil and a phased array coil. Detailed information regarding the MR study protocol is summarized in Table 2. A standard dose (0.025 mmol/kg) of gadoxetic acid (Primovist, Bayer Healthcare, Berlin, Germany) was injected at a rate of 1.0 mL/s by using a power injector (Spectris Solaris EP; Medrad, Warrendale, Pa) followed by a 30-mL saline flush. Arterial phase images were acquired 7 s after contrast medium arrival at the thoracic aorta by using an MR fluoroscopic monitoring system. Thereafter, portal venous phase, transitional phase, and hepatobiliary phase (HBP) were obtained 60 s, 3 min, and 20 min after contrast medium injection, respectively.
Table 2 Detailed information regarding the MR imaging parameters
Sequence Orientation TR/TE/FA
(ms/ms/deg.) AT
(min) Acquisition Matrix ST/Gap (mm) FS
Trufisp T2-W Coronal 4.30/2.15/80 0.46 512 × 512 4 / 0 without
HASTE T2-W Axial 1500/90/170 0.36 320 × 320 5 / 0 Without and with (SPAIR)
HASTE T2w Coronal 1500/92/170 0.38 320 × 320 5 / 0 without
In-Out phase T1-W Axial 160/2.35/70 0.33 256 × 192 5 / 0 without
DWI Axial 7500/91/90 7 192 × 192 3 / 0 without
Vibe
T1-W
Axial 4.80/1.76/12 0.18 320 × 260 3 / 0 with (SPAIR)
Note. TR Repetition time, TE Echo time, FA Flip angle, AT Acquisition time, ST Slice thickness, FS Fat suppression, SPAIR Spectral adiabatic inversion recovery
CEUS protocol
CEUS was always preceded by a careful US survey, assessing the size and appearance of the lesion/s. This baseline assessment was done to appropriately choose the liver area or areas to be particularly focused in the forthcoming contrast-enhanced part of the US study. In all cases, a separated injection was performed for each liver lobe. For both injections, the arterial phase assessment was focused on any known lesion at baseline US. CEUS was performed as a low- mechanical index, double-split mode, real-time modality. We employed a Technos MyLab 70 XVG and MyLab Twice scanner (Esaote, Genoa, Italy), injecting 2.4 ml of a sulfur hexafluoride-based contrast medium (SonoVue, Bracco, Milan, Italy) per each liver lobe. After the injection, the radiologist focused the sonographic field of view on the parenchymal area of interest, waiting for the microbubble’s arrival. Thereafter, he/she moved the transducer to explore the remaining parenchyma of each lobe, with special reference to the resected area.
Biloma and bile leakage definition, diagnosis and management
Following scientific Literature we considered biloma as an encapsulated collection of bile outside the biliary tree and within the abdominal cavity and bile leakage as a postoperative loss of fluid bile via abdominal drains after liver surgery [19, 20]. We diagnosed and divided bile leakage in grade A, B and C based on the impact of this complication on patients’ clinical management. [20]
Surgical complications
Surgical Complications were classified according to Clavien Dindo et al. [21].
Statistical analyses
Each continuous variable was expressed in terms of median value ± range while each variable categorical was summarized by frequencies and percentages. Chi square test was performed to assess statistically significant difference between percentage values. Mann Whitney non parametric test were used to compare a continuous variable between 2 groups. A p value < 0.05 was considered statistically significant.
All statistical analysis was performed with SPSS for Windows (Version 23.0; SPSS Inc, Chicago, Ill).
Results
We analyzed a total of 318 patients: Group A with 205 patients and 1036 pathologically proven lesions (mean tumor size: 32 mm; range 8–64 mm) and Group B with 113 patients and 452 mCRC pathologically proven lesions (mean tumor size: 36 mm; range 11–59 mm).
In the Group A we performed 60 lobectomy, 43 meso-hepatectomy, 48 bi-segmentectomy (73 % major hepatectomy) and 54 segmentectomy or other liver resection (wedge/metasasectomy) (2 in seg I, 3 in seg II, 4 in seg III, 10 in seg IV, 9 in seg V and 8 in seg VI, 18 in seg. VII). Twenty-five patients underwent single stage combined liver and colon resections.
The average hospitalization time was 8 days (7–16). No major complications occurred during surgical procedures. No patients died during hospitalization and the 30-day mortality was 0 %. During follow-up in 27 patients (13 %) was reported a Biloma and in 2 patients (1 %) a bile leakage grade B was detected. No adverse events were reported regarding the use of Glubran 2.
About Group B (113 patients), 56 patients underwent major hepatectomy (49,5 %), 40 liver segmentectomy (35.5 %), 17 wedge procedure or metasasectomy (5 in seg II, 2 in seg III, 3 in seg IV, 2 in seg V and 5 in seg VI). Seventeen patients underwent single stage combined liver and colon resections.
The average hospitalization time was 10 days (5–14). No major complications occurred during surgical procedures. No patients died during hospitalization and the 30-day mortality was 0 %.
During follow-up 18 patients (16 %) showed presence of biloma and in 3 patients (2,6 %) a bile leakage was detected (2 grade B, 1 grade C).
A new hepatic lesions were identified (mean time 5 months) in 32 patients (15,6 %), 13 in group A and 19 in group B.
Discussion
The rationale behind our study is the polymerization of cyanoacrylate glue when it is in contact with blood and tissues owing to the presence of ions and proteins. Nowadays the solid polymer created by this reaction, has demonstrated to be safe and useful in several use during surgical clinical practices.
In surgery for ventral hernia repair, Glubran2 permitted a suturless fixation mesh, in bariatric surgery showed to be effective to prevent gastric fistulas or suture line dehiscence (leaks), in endovascular surgery many scientific articles had described it’s use to stop bleeding in elective and in emergency and new applications are investigate in colorectal and thoracic surgery, to prevent anastomotic and air leak [22–28].
Our study is focused on biliostatic effect of cyanoacrylate glue but, in Literature, is possible to find articles that analyzed or compare hemostatic or sealant agent to prevent bile leakage and hemorrhagic events. López-Guerra D et al., in 2019, compare the use of two different fibrin sealant patches during liver surgery. Contrary to ours, this study included benign patients, patients without pre-operative chemotherapy, HCC and mCRC and concluded with no superiority between different fibrin patches in post-operative complications not focusing attentions on bile leakage [18].
Likewise others papers compare different agent both on prevent bleeding and bile leakage and, similarly to López-Guerra D et al., their population study included not only mCRC patients [29–31].
Also Briceño J et al., evaluating a fibrin sealant, concluded advising the use of this agent during liver surgery due to the decrease moderate and severe postoperative complications with no clarification on bile leakage impact [29].
Precisely for this, our study acquire relevance because this is the first study that assesses the safety and efficacy of Glubran2 as a biliostatic agent, at the best of our knowledge, focusing attention to prevent bile post-opertive complications.
This project was inspired by the evolution of neoadjuvant chemotherapy for colorectal liver metastases. Thanks to the use of new drugs, especially anti-angiogenetic monoclonal antibody added to usual chemotherapy, has become possible to treat surgically patients with more curative intent due an increase response rates conversion to resectability and long-term survival. This is a very important result considering that hepatic resection is the only curative option for patients with colorectal liver metastases (mCRC) [1]. However, we need to consider also the neoadjuvant chemotherapy influence on surgical morbidity. The chemotherapy-related complications, steatosis, chemotherapy-associated steatohepatitis (CASH) and sinusoidal obstruction syndrome (SOS), might impair the hepatic parenchyma, thus reducing the functionality and influencing the outcome following resection [1, 2]. Despite the results of same studies demonstrated that neoadjuvant chemotherapy did not impair outcomes of liver resections for mCRC, in our experience we reported an increase of complications rates in this type of patients [32]. The most peculiar and important complication after liver resection is bile leakage with an incidence that is reported between 3.6 and 17 % [33]. In our two groups, we evaluate and match age, sex, site of primary cancer, chemotherapy protocol, duration of chemotherapy and type of liver resection. All patients underwent to US and MDCT at one month post resection and MDCT at 3th, 6th and 12th month for the first post-operative year. In the Group A we performed major hepatectomy in 73 % of patients versus 49.5 % in Group B. Several researches have shown that risk of biliary complications increase with the complexity of surgical procedure [34]. Patients enrolled in Group A were compared with patients in Group B; biloma was reported in 13 % (group A) vs. 16 % (group B) and bile leakage in 1 % (Group A) vs. 2.6 % (group B) (P-value < 0,001). All patients underwent liver resection using the same surgical open or laparoscopic approach, uniform technique and energy devices. In literature is possible to find numerous study that compared different types of advanced energetic devices and their haemostatic effect, their lateral spread damage in many tissues and no one demonstrated better result over others [35]. In all our patients, in booth groups, we used only Harmonic Scalpel in order to minimizing the intraoperative bias.
During the follow up, no patients died but a new hepatic lesions were found in 32 patients (15,6 %): 13 in Group A and 19 in Group B.
We observed no adverse events regarding the use of Glubran2. Analyzing our results, we could state that Glubran2 is a safe and efficacy biliostatic agent useful to prevent bile leakage complication after liver resection. Our results are similar to others that have shown that Glubran2 is a safe and effective hemostatic agent [20, 34, 36, 37].
The current study had several limitations: data collected derived from only one cancer centre, and a small semple size enrolled in this study may have influence the conclusion. In addition, this is a retrospective study. Therefore, further perspective multicentre analyses including more patients were needed to validate the prognostic significance of these results.
Conclusions
Answering to our primary end-point, it is possible to affirm that Glubran2 is a safe and feasible biliostatic agent useful to prevent bile leakage complication and biloma formation after liver resection.
Abbreviations
mCRC Colorectal liver metastases
CASH Chemotherapy-associated steatohepatitis
MDCT Multiple detector computed tomography
CT Computed tomography
CEUS Contrast Enhanced Ultrasound
SOS Sinusoidal obstruction syndrome
Acknowledgements
The authors are grateful to Alessandra Trocino, librarian and Assunta Zazzaro data manager at the National Cancer Institute of Naples, Italy.
Informed consent
Each patient signed the informed consent.
Author contributions
RP1: Data curation, Writing - original draft. VG: Conceptualization, Supervision, Data curation, Writing - review &editing. AB: Supervision. RP2: Supervision. VA: Data curation; Formal analysis. MP: Data curation; Formal analysis. RF: Data curation; Formal analysis. FT: Data curation; Formal analysis. GN: Data curation; Formal analysis. AV: Supervision. FI: Conceptualization, Supervision, Writing - review & editing. The author(s) read and approved the final manuscript.
Funding
Authors have no receiving founds for this project.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This retrospective study was approved by the Ethical Committee of the National Cancer Institute “G. Pascale Foundation - IRCCS” of Naples and the requirement for patient informed consent was waived. All procedures performed in the study were in accordance with the ethical standards of the institutional and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Consent for publication
Each author give the consent for publication.
Competing interests
The authors declare that they have no competing interests
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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | THE ANTIANGIOGENIC DRUG BEVACIZUMAB WAS ADMINISTERED EVERY 14 DAY?SAT 5 MG/KG BY IV INFUSION OVER 90 | DrugDosageText | CC BY | 33726798 | 19,116,272 | 2021-03-16 |
What was the administration route of drug 'CYCLOPHOSPHAMIDE'? | Effectiveness and safety of mepolizumab in combination with corticosteroids in patients with eosinophilic granulomatosis with polyangiitis.
Mepolizumab (MPZ), an anti-interleukin-5 antibody, is effective for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). However, its effectiveness has not been adequately evaluated in real-world clinical practice. In this study, we assessed the effectiveness and safety of MPZ (300 mg) for relapsing/refractory EGPA resistant to corticosteroids (CS) for 1 year in real-world settings.
We administered MPZ (300 mg) to 16 patients with relapsing/refractory EGPA resistant to CS (Post-MPZ). We also retrospectively collected data from the same patients for the 12 months before the administration of MPZ (Pre-MPZ). The primary endpoint was the 12-month remission rate after MPZ administration and the secondary endpoints were the Birmingham vasculitis activity score (BVAS), vasculitis damage index (VDI), eosinophil counts, changes in concomitant CS doses/concomitant immunosuppressant use, MPZ retention rate, and incidence of adverse events. The clinical course was compared between Pre-MPZ and Post-MPZ.
The 12-month remission rate after the initiation of MPZ was 75%. No change was observed in BVAS, eosinophil count, or concomitant CS dose over time in the Pre-MPZ group, whereas all these parameters were significantly decreased over time in the Post-MPZ group. The number of patients using concomitant immunosuppressant also decreased over time in the Post-MPZ group. VDI did not increase in either group. The MPZ retention rate was 100% and only three patients (18.8%) had infections. Changes in BVAS, eosinophil count, and cumulative concomitant CS dose were significantly lower in the Post-MPZ group than in the Pre-MPZ group. There was no significant difference in the changes in VDI between the groups.
This study demonstrated that MPZ is effective and safe for EGPA. Furthermore, MPZ decreases disease activity, increases remission rate, and has a CS-sparing effect.
Key messages
MPZ is safe for the treatment of EGPA in real-world clinical practice.
Comparing to Pre-MPZ, MPZ possesses the high remission rate and CS sparing effect.
Background
Eosinophilic granulomatosis with polyangiitis (EGPA) is a disease that is preceded by asthma or allergic rhinitis. EGPA causes various symptoms owing to vasculitis, including fever and purpura, and increases peripheral eosinophil counts [1, 2]. Corticosteroids (CS) are used in remission induction therapy and maintenance therapy for EGPA. Patients with severe vasculitis symptoms and those who respond poorly to CS are treated with cyclophosphamide (CY), azathioprine (AZ), methotrexate (MTX), cyclosporine (CsA)/tacrolimus (TAC), or intravenous immunoglobulin (IVIG). However, EGPA often relapses during CS dose reduction; hence, CS dose reduction is often challenging [3–5].
In recent years, mepolizumab (MPZ), an anti-interleukin-5 (IL-5) monoclonal antibody, has been reported to extend the remission period of EGPA and reduce the CS dose required [6]. Although MPZ was listed in the National Health Insurance drug price list for the treatment of EGPA in Japan in 2018, its effectiveness and safety have not been adequately evaluated in real-world clinical practice. Although the dose of MPZ administered in previous studies was 100 mg/month, which is the same dose used for the treatment of bronchial asthma, an MPZ dose of 300 mg is used in some countries, including Japan. Thus, we investigated the effectiveness and safety of MPZ at a dose of 300 mg/month in a real-world setting.
Methods
Patients
In this study, MPZ (300 mg) was administered to 16 patients with relapsing or refractory EGPA who were receiving the standard of care, mainly CS [7, 8]. In Japan, the use of MPZ is allowed when the effect of CS therapy is insufficient. All patients used in this study met this criterion. All patients were diagnosed with EGPA according to the diagnostic criteria for EGPA, as proposed by the Japanese Ministry of Health, Labour and Welfare, and met the classification criteria of the American College of Rheumatology [9] (Table 1, Supplementary Table 1). Patients in remission and those with relapsing or refractory EGPA were defined as follows according to the criteria of the Mepolizumab Treatment in Relapsing or Refractory EGPA trial [6]: patients with remission had a Birmingham vasculitis activity score (BVAS) of 0 and were treated with oral CS at a dose of ≤ 4 mg/day; patients with relapsing EGPA had an increased oral CS dose, started concomitant immunosuppressive therapy, had an increased concomitant immunosuppressant dose, had an increased BVAS [10], or had a history of hospitalization; and patients with refractory EGPA experienced no relapse and achieved no remission within the last 1 year. Table 1 Baseline characteristic of 16 patients with eosinophilic granulomatosis with polyangiitis
Pre-MPZ (n = 16) Post–MPZ (n = 16) P value*
Clinical manifestations at diagnosis, n (%) Asthma 16 (100), general 10 (62.5), cutaneous 8 (50.0), ENT 5 (31.3), chest 8 (50.0), cardiomyopathy 3 (18.8), abdominal 1 (6.3), neuropathy 8 (50.0), ANCA positive status 5 (31.3), biopsy findings 12 (75)
Male/female/age at MPZ introduction 7/9/61.5 [53.3–70.5]
Disease duration (months) at MPZ introduction 54 [22–144]
Treatment history, n (%) CS pulse 2 (12.5), high-dose CS 14 (87.5), low-dose CS 2 (12.5), IVCY 9 (56.3), IVIG 6 (37.5), RTX 1 (6.3), MTX 6 (37.5), AZ 12 (75.0), TAC 1 (6.3)
Relapsing/refractory/remission, n (%) 4 (25.0)/11 (68.7)/1 (6.3) 10 (62.5)/6 (37.5)/0 (0) ND
Concomitant CS dose (PSL mg/day) 8.0 [5.0–11.5] 6.5 [2.6–10.0] 0.2012
Concomitant CS < 4 mg/day (PSL), n (%) 3 (18.8) 5 (31.3) 0.1573
Concomitant immunosuppressant, n (%) AZ 6 (37.5), MTX 5 (31.3), TAC 1 (6.3) AZ 6 (37.5), MTX 4 (25.0), TAC 1 (6.3)
Without immunosuppressant, n (%) 6 (37.5) 7 (43.8) 0.3173
BVAS 0 [0–2.0] 1.0 [0–3.8] 0.1084
BVAS > 0, n (%) 4 (25.0) 8 (50.0) 0.3173
BVAS items Asthma 2 (12.5), sinonasal 2 (12.5), chest 1 (6.3) Asthma 6 (37.5), general 1 (6.3), cutaneous 2 (12.5), sinonasal 2 (12.5), chest 3 (18.8),
VDI 3.5 [3.0–4.8] 4.0 [3.0–5.8] 0.5577
VDI items Chronic bronchial asthma 16 (100), chronic respiratory failure 1 (6.3), abnormal respiratory function 7 (43.8), old myocardial infarction 2 (12.5), cardiomyopathy 2 (12.5), low vision 1 (6.3), chronic sinusitis 6 (37.5), deafness 3 (18.8), peripheral neuropathy 8 (50.0), diabetes 4 (25), hypertension 4 (25), osteoporosis 5 (31.3), other 3 (18.8) Chronic bronchial asthma 16 (100), chronic respiratory failure 1 (6.3), abnormal respiratory function 8 (50.0), old myocardial infarction 2 (12.5), cardiomyopathy 2 (12.5), low vision 1 (6.3), chronic sinusitis 7 (43.8), deafness 3 (18.8), peripheral neuropathy 8 (50.0), diabetes 4 (25), hypertension 4 (25), osteoporosis 5 (31.3), other 5 (31.3)
ANCA-positive status, n (%) 0 (0) 1 (6.3) ND
Absolute eosinophil count (/μL) 178.6 [48.7–370.2] 183 [60.0–2479] 0.1591
CRP (mg/dL) 0.06 [0.03–0.09] 0.09 [0.05–0.24] 0.0593
CS corticosteroid (prednisolone or equivalent), IVCY cyclophosphamide pulse therapy i.v., RTX rituximab, MTX methotrexate, AZ azathioprine, TAC tacrolimus, BVAS Birmingham Vasculitis Activity Score, VDI vasculitis damage index, ND not detected by McNemar test. Data are shown by median [quartile] or n (%). P values were determined by McNemar test or Wilcoxon signed-rank test. *P < 0.05: Pre-MPZ (n = 16) vs. Post-MPZ (n = 16)
The patients were followed up for 12 months after the introduction of MPZ at our hospital and affiliated institutions, during the period between the domestic introduction of MPZ in May 2018 until August 2020 (Post-MPZ). Additionally, we retrospectively collected data from the same patients for the 12 months before the initiation of MPZ therapy (Pre-MPZ). All patients received maintenance therapy according to the standard of care. The standard of care in this study was defined as treatment with CS, intravenous CY, intravenous immunoglobulin, azathioprine, MTX, or CsA/TAC. The Human Ethics Review Committee of our university reviewed and approved this study (No. H27-014). We also complied with the Declaration of Helsinki. All participants provided informed consent prior to inclusion in the study. Details that might disclose the identity of the study subjects were omitted.
Clinical measurement
This study was a multicenter and ambispective cohort study in which MPZ at a dose of 300 mg/month was administered to 16 patients with relapsing or refractory EGPA to investigate the effectiveness and safety of MPZ over 1 year.
The primary endpoint was the remission rate. The secondary endpoints were the BVAS (overall and for each item), vasculitis damage index (VDI) (overall and for each item) [11, 12], eosinophil counts, daily and cumulative concomitant CS doses, presence or absence of changes/addition of immunosuppressant(s), MPZ retention rate, and incidence of adverse events. Additionally, the reduction in BVAS, change in VDI, reduction in peripheral eosinophil counts, and cumulative concomitant CS doses were compared between the 1-year period before the initiation of MPZ therapy (Pre-MPZ; month − 12 to month 0) and 1-year period after the initiation of MPZ (Post-MPZ; month 0 to month 12). To express the results of the two groups synchronously, the original timeframes Pre-MPZ (− 12 (baseline), − 11, − 9, and − 6 months) are represented as 0 (baseline), 1, 3, and 6 months, respectively.
Measurement of serum concentration of IL-5
The serum concentration of IL-5 at the baseline (before MPZ initiation) was measured using the enzyme-linked immunosorbent assay (ELISA) (R&D SYSTEMS Human IL-5 Duo Set ELISA, P249454) and compared with that of six age- and sex-matched healthy controls.
Statistical analysis
Data are expressed as the median (interquartile range). For statistical analysis, data from cases in which MPZ was discontinued or the disease relapsed were complemented using the last observation carried forward method. Differences between groups (Post-MPZ vs. Pre-MPZ) and between data measured at the baseline and each observation point (Post-MPZ: month 0 vs. month 1, 3, 6, 12) were compared using the Wilcoxon signed-rank test or McNemar test. Differences in the serum IL-5 concentration between the patients and healthy controls were compared using the Mann-Whitney U test.
The timeframes of both groups were represented synchronously and compared [− 12 months (baseline) in the Pre-MPZ corresponded to 0 months (baseline) in the Post-MPZ group]. All reported P values are two-sided. Remission was defined as a BVAS score of 0 and CS less than 4 mg/day. All analyses were conducted using JMP version 14.0.0 (SAS Institute Inc.). The post hoc power of this study for the comparison between month 0 and the other observation points in the Post-MPZ group was 0.37 for BVAS, 0.99 for VDI, 0.36 for absolute eosinophil count, and 0.76 for concomitant CS dose (α error, 0.05; 1-β error, post hoc power).
Results
Patient background
The characteristics of the patients are shown in Table 1. The characteristics of each patient at the time of EGPA diagnosis are shown in Supplementary Table 1 and those at the time of MPZ therapy initiation are shown in Supplementary Table 2. At the time of MPZ therapy initiation, the median age [interquartile range] of the 16 patients with EGPA was 61.5 [53.3–70.5] years and the disease duration was 54 [22–144] months. Regarding medical history, all patients were treated with CS. The Pre-MPZ group included four patients with relapsing EGPA, 11 with refractory EGPA, and one in remission, whereas the Post-MPZ group included 10 patients with relapsing EGPA and six with refractory EGPA. No statistically significant differences were observed in the concomitant CS dose or the rate of concomitant immunosuppressant use between the groups. There were also no statistically significant differences in BVAS, VDI, positivity rate for anti-neutrophil cytoplasmic antibody, eosinophil counts, or C-reactive protein level between the groups. The IL-5 concentration before MPZ therapy initiation was 1.88 [0.28–8.95] pg/mL, which was significantly higher than that in the six age- and sex-matched healthy controls (0.027 [0.003–0.55], P = *0.0063 using Mann-Whitney U test; Supplementary Fig. 1).
Effectiveness of MPZ
The remission rates (the primary endpoint) were 6.3% (1/16 patients) at month 1, 12.5% (2/16 patients) at month 3, 6.3% (1/16 patients) at month 6, and 0% at month 12 in the Pre-MPZ group. The corresponding rates in the Post-MPZ group were 12.5% (2/16 patients) at month 1, 31.3% (5/16 patients) at month 3, 50.0% (8/16 patients) at month 6, and 75.0% (12/16 patients) at month 12. In this group, the remission rate increased at month 12 (Fig. 1a). Fig. 1 Comparison of effectiveness between the Pre-MPZ and the Post-MPZ. a Remission rates. b BVAS. c VDI. d Eosinophil counts. e Concomitant CS doses. BVAS, Birmingham vasculitis activity score; CS, corticosteroid; VDI, vasculitis damage index. P values were determined by Wilcoxon signed-rank test. *P < 0.05: baseline (month 0) vs. each observation points (month 0,1, 3, 6, and 12)
In the Pre-MPZ group, the BVASs were 0 [0–2.0] at month 1, 0 [0–2.0] at month 3, 0 [0–2.0] at month 6, and 1.0 [0–3.8] at month 12. In the Post-MPZ group, the BVASs were 0 [0–2.8] at month 1, 0 [0–0] at month 3, 0 [0–0] at month 6, and 0 [0–0] at month 12. The BVASs at month 1 and afterward significantly decreased from the BVAS at month 0 (Fig. 1b). The decrease in BVAS during the 1-year period in the Post-MPZ group was 0.5 [0–3.5], which was significantly higher than that in the Pre-MPZ group (− 1.0 [− 3.0–0]; Fig. 2a). Fig. 2 Comparison of changes of each item between the 12-month period in Pre-MPZ and Post-MPZ. a Changes in BVAS, b increase in VDI, c reduction in peripheral eosinophil counts (/μL), and d accumulated concomitant CS dose (mg/year). BVAS, Birmingham vasculitis activity score; CS, corticosteroid; VDI, vasculitis damage index. P values were determined by Wilcoxon signed-rank test. *P < 0.05: Pre-MPZ vs. Post-MPZ
Based on the changes in BVASs for each item, respiratory symptoms were exacerbated in the Pre-MPZ group but improved immediately after the initiation of MPZ therapy. The number of patients with symptoms decreased from 11/16 to 2/16 after 1 year of treatment. Ear, nose, and throat symptoms also improved, as the number of patients with these symptoms decreased from 6/16 to 3/16 patients, 1 year after the initiation of MPZ therapy. In contrast, neuropathy did not improve in either the Post-MPZ or Pre-MPZ groups. In the Post-MPZ group, no organ dysfunction was exacerbated at month 12 (Table 2). Table 2 Changes in organ damage before and after the introduction of MPZ
Pre-MPZ Post-MPZ
-12 M -11 M -9 M -6 M 0 M 1 M 3 M 6 M 12 M
General symptoms 0 0 1 (6.3%) 1 (6.3%) 1 (6.3%) 1 (6.3%) 0 1 (6.3%) 0
Cutaneous manifestations 1 (6.3%) 1 (6.3%) 1 (6.3%) 1 (6.3%) 2 (12.5%) 2 (12.5%) 0 1 (6.3%) 0
ENT manifestations 6 (37.5%) 6 (37.5%) 6 (37.5%) 6 (37.5%) 6 (37.5%) 6 (37.5%) 6 (37.5%) 4 (25.0%) 3 (18.8%)
Chest manifestations 6 (37.5%) 6 (37.5%) 8 (50.0%) 8 (50.0%) 11 (68.8%) 5 (31.3%) 2 (12.5%) 2 (12.5%) 2 (12.5%)
Nervous system manifestations 7 (45.8%) 7 (45.8%) 7 (45.8%) 8 (50.0%) 8 (50.0%) 8 (50.0%) 7 (43.8%) 7 (43.8%) 7 (43.8%)
ENT ear, nose, throat
In the Pre-MPZ group, the VDI scores were 3.5 [3.0–4.8] at month 1, 4.0 [3.0–5.5] at month 3, 4.0 [3.0–5.5] at month 6, and 4.0 [3.0–5.5] at month 12. In the Post-MPZ group, the VDI scores were 4.0 [3.0–5.5] at month 1, 4.0 [3.0–5.5] at month 3, 4.0 [3.0–5.5] at month 6, and 4.0 [3.0–5.5] at month 12, with no significant changes (Fig. 1c). The increase in the VDI score during the 1-year period was 0 [0–0.8] in the Pre-MPZ and 0 [0–0] in the Post-MPZ groups, with no significant difference between the groups (Fig. 2b).
In the Pre-MPZ group, the eosinophil counts were 280.4 [63.2–426.8]/μL at month 1, 217.8 [93.3–1354.2]/μL at month 3, and 293.9 [39.1–880.7]/μL at month 6. In the Post-MPZ group, the eosinophil counts were 54.8 [10.6–99.8]/μL at month 1, 25.2 [12.8–53.9]/μL at month 3, 29.4 [9.63–42.5]/μL at month 6, and 28.8 [20.5–68.0] at month 12, with a significant reduction from month 1 onwards (Fig. 1d). The reduction in the eosinophil counts during the 1-year period in the Post-MPZ group was 146.2 [9.88–2449.9], which was significantly higher than that in the Pre-MPZ group (− 8.8 [− 2927.4–175.4]; Fig. 2c).
The changes in the concomitant CS dose in each patient are shown in Table 3. In the Pre-MPZ group, the concomitant CS doses were 8.0 [5.0–10.0] mg/day at month 1, 7.0 [3.5–10.0] mg/day at month 3, 6.5 [2.6–10.0] mg/day at month 6, and 6.0 [2.6–10.0] mg/day at month 12. In the Post-MPZ group, the concomitant CS doses were 6.5 [2.6–10.0] mg/day at month 1, 5.0 [2.3–7.4] mg/day at month 3, 4.5 [0.5–5.0] mg/day at month 6, and 2.5 [0.1–3.8] mg/day at month 12, with a significant reduction from month 3 onwards (Fig. 1e). The concomitant CS dose was significantly lower in the Post-MPZ group (1655 [570.0–2190.0] mg/year) than in the Pre-MPZ group (2665 [1473.8–3993.8] mg/year; Fig. 2d). The changes in the use of immunosuppressants are shown in Table 4. The number of patients using concomitant immunosuppressant(s) reduced from 10 to nine patients at 1 year in the Pre-MPZ group and from nine to five patients in the Post-MPZ group. Table 3 Changes in the concomitant corticosteroids use before and after the introduction of MPZ (PSL mg/day)
Case No. Pre-MPZ Post-MPZ
− 12 months − 11 months − 9 months − 6 months 0 months 1 months 3 months 6 months 12 months
1 5 mg 5 mg 30 mg 15 mg 15 mg 15 mg 10 mg 10 mg 5 mg
2 5 mg 5 mg 7.5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg
3 8 mg 8 mg 3.5 mg 2.5 mg 2.5 mg 2.5 mg 2 mg 2 mg 1.5 mg
4 12 mg 12 mg 12 mg 12 mg 12 mg 10 mg 8 mg 9 mg 4 mg
5 8 mg 8 mg 7 mg 7 mg 7 mg 7 mg 5 mg 5 mg 3 mg
6 1 mg 1 mg 1 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg
7 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg
8 10 mg 9 mg 7 mg 6 mg 6 mg 6 mg 5 mg 3 mg 0.5 mg
9 5 mg 5 mg 4 mg 3 mg 3 mg 3 mg 3 mg 0 mg 0 mg
10 15 mg 10 mg 5 mg 35 mg 20 mg 15 mg 7.5 mg 5 mg 3 mg
11 8 mg 8 mg 7 mg 7 mg 7 mg 7 mg 5 mg 5 mg 2 mg
12 20 mg 15 mg 10 mg 10 mg 10 mg 10 mg 7 mg 5 mg 2 mg
13 10 mg 10 mg 10 mg 10 mg 10 mg 10 mg 8 mg 6 mg 5 mg
14 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 3 mg 3 mg
15 20 mg 15 mg 8 mg 7 mg 7 mg 7 mg 5 mg 4 mg 3 mg
16 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg
Table 4 Changes in the concomitant immunosuppressants use before and after the introduction of MPZ
Case No. Pre-MPZ Post-MPZ
− 12 months − 11 months − 9 months − 6 months 0 months 1 months 3 months 6 months 12 months
1 MTX 8 mg MTX 8 mg None None None None None None None
2 MTX 8 mg+AZ 125 mg MTX 8 mg+AZ 125 mg MTX 8 mg+AZ 125 mg MTX 8 mg+AZ 125 mg MTX 8 mg+AZ 125 mg AZ125 mg AZ125 mg AZ125 mg AZ100 mg
3 AZ50 mg AZ50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg
4 None None AZ 50 mg None None None None MTX 8 mg MTX 8 mg
5 MTX 6 mg+AZ 50 mg MTX 6 mg+AZ 50 mg MTX 6 mg+AZ 50 mg MTX 6 mg+AZ 50 mg MTX 6 mg+AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg
6 MTX 16 mg MTX 16 mg MTX 16 mg MTX 16 mg MTX 16 mg MTX 16 mg MTX 10 mg MTX 4 mg None
7 None None None None None None None None None
8 MTX 12 mg MTX 12 mg MTX 12 mg MTX 12 mg MTX 12 mg None None None None
9 AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg None None None None
10 None None IVCY None None None None None None
11 TAC 3 mg TAC 3 mg TAC 3 mg TAC 3 mg TAC 3 mg None None None None
12 None None None None None None None None None
13 AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg
14 None None None None None None None None None
15 AZ 100 mg AZ 100 mg AZ 100 mg AZ 100 mg AZ 100 mg None None None None
16 None None None None None None None None None
IVCY cyclophosphamide pulse therapy i.v., MTX methotrexate, AZ azathioprine, TAC tacrolimus
MPZ retention rate and safety
The 1-year MPZ retention rate was 100%. Although three patients had an infection, all patients continued MPZ. Adverse events before and after the initiation of MPZ therapy are shown in Table 5. After MPZ therapy initiation, cases 1 and 11 developed bacterial pneumonia that required hospitalization. Sputum culture identified Moraxella catarrhalis in case 1 and Pseudomonas aeruginosa in case 11. In both patients, a drip infusion of antibiotics improved their condition. Case 15 also developed bacterial pneumonia. Because the general and respiratory conditions were favorable, the patient received oral antibiotic therapy at the outpatient clinic and improved. All three patients who had an infection after the initiation of MPZ therapy had the same infection within 1 year before initiation. None of the patients had a new infection after the initiation of therapy. Table 5 Adverse events before and after introduction of MPZ
Case No. Pre-MPZ Post-MPZ
1 Bacterial pneumonia (hospitalization) Bacterial pneumonia (hospitalization)
Bacterial species: Moraxella catarrhalis
2 None None
3 None None
4 Drug-induced liver injury None
5 Sinusitis surgery, bacterial bronchitis None
6 Bacterial bronchitis, infectious otitis media None
7 None None
8 None None
9 None None
10 None None
11 Bacterial pneumonia (hospitalization) Bacterial pneumonia (hospitalization)
Bacterial species: Pseudomonas aeruginosa
12 None None
13 Bacterial pneumonia (hospitalization) None
14 Bacterial bronchitis None
15 Bacterial pneumonia Bacterial pneumonia
16 None None
Discussion
The results of this study demonstrated the effectiveness and safety of MPZ for relapsing or refractory EGPA in a real-world setting by comparing the clinical courses before and after the initiation of MPZ therapy. During the 1-year period before MPZ therapy initiation, BVASs increased as CS doses were tapered, although the effectiveness of immunosuppressants in controlling disease activity was inadequate to allow CS dose reduction. Although many patients used AZ as a concomitant immunosuppressant before MPZ therapy initiation in this study, it has been previously reported that AZ is not useful for maintenance therapy [13]. In this study, BVASs and eosinophil counts significantly decreased 1 month after MPZ therapy initiation. The doses of CS and immunosuppressants were also successfully reduced (Figs. 2a, c, d). MPZ was a useful drug for maintenance therapy that exerted a more consistent effect in controlling disease activity than existing immunosuppressants.
Although the 16 patients included in this study had relatively low eosinophil counts (Table 1), the IL-5 levels before MPZ initiation were significantly higher than those of healthy controls. However, MPZ was effective even in patients whose serum concentration of IL-5 was comparable to that of healthy controls. We believe that these results indicate that MPZ is an effective treatment option in patients with relapsing or refractory EGPA, regardless of IL-5 concentration.
The MPZ retention rate was 100%, and the incidence of infections tended to decrease after MPZ initiation (Table 2). These results confirm the safety of MPZ. In particular, a severe infection that required hospitalization was noted only in two patients with a history of infection, and there was no occurrence of a new serious infection. These results can be considered useful. The reduced incidence of infection might be attributable to the significant reduction in concomitant CS doses and the reduced number of patients using concomitant immunosuppressant after MPZ therapy initiation (Fig. 2d; Tables 3 and 4). The long-term oral administration of CS induces infections and various complications, including osteoporosis, diabetes, hypertension, dyslipidemia, and femoral head necrosis. We did not observe a significant increase in VDI scores nor an increased incidence of complications owing to CS after MPZ therapy initiation. Thus, we demonstrated that MPZ therapy was sufficiently effective in controlling disease activity and prevented adverse events induced by CS and immunosuppressants. In the future, it is important that a long-term investigation is conducted to determine whether long-term MPZ therapy allows the dose reduction or discontinuation of CS without relapse and whether VDI increases.
However, this study has important limitations. For example, this study had limited statistical power owing to the small sample size. Additionally, because the Pre-MPZ group was set as the control group to compare the effects of MPZ therapy with, the control group might be inadequate. Moreover, few countries recommend subcutaneous MPZ injection at a dose of 300 mg for EGPA, such as Japan. A strength of this study is that although there are some case reports of the use of MPZ at a dose of 300 mg [14] and a case series of the use of MPZ at 100 mg for the treatment of comorbid asthma [15], no studies have investigated the safety and effectiveness of MPZ at 300 mg in real-world clinical practice. To the best of our knowledge, this is the first study to demonstrate the safety and effectiveness of MPZ at 300 mg in a real-world setting.
Supplementary Information
Additional file 1: Supplementary Table 1. Clinical manifestations, Japanese Ministry of Health, Labor and Welfare criteria items and classification criteria of the American College of Rheumatology criteria at diagnosis.
Additional file 2: Supplementary Table 2. Baseline characteristic of 16 Patients with Eosinophilic Granulomatosis with Polyangiitis.
Additional file 3: Supplementary Fig. 1. Serum IL-5 concentration of 16 Patients with EGPA before initiating MPZ and health controls (HC group). P values were determined by Mann-Whitney’s U test. p* < 0.01: EGPA group (n = 16) vs. HC (n = 6).
Abbreviations
MPZ Mepolizumab
EGPA Eosinophilic granulomatosis with polyangiitis
CS Corticosteroids
BVAS Birmingham vasculitis activity score
VDI Vasculitis damage index
CY Cyclophosphamide
IVCY Intravenous cyclophosphamide
AZ Azathioprine
MTX Methotrexate
CsA Cyclosporine
TAC Tacrolimus
IVIG Intravenous immunoglobulin
Pre-MPZ 1-Year period before initiating MPZ therapy
Post-MPZ 1-Year period after initiating MPZ
Supplementary information
Supplementary information accompanies this paper at 10.1186/s13075-021-02462-6.
Acknowledgements
The authors thank the study participants, without whom this study would never have been accomplished as well as the investigators for their participation in the study, especially those in Kitakyushu General Hospital, Tobata General Hospital, Saiseikai Shimonoseki General Hospital, Fukuoka Yutaka Central Hospital, Nakama Municipal Hospital, and Steel Memorial Yahata Hospital.
Authors’ contributions
MU contributed to the study design, overall review, writing of the manuscript, and the other authors were involved in the performance of the study and review of the manuscript. YT, MI, KN, SI, and SN participated in the study design and coordination. All authors read and approved the final manuscript.
Funding
No specific funding was received from any bodies in the public, commercial, or not-for-profit sectors to carry out the work described in this article.
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
Ethical approval was obtained from the University of Occupational and Environmental Health Japan Ethics Committee following the Helsinki Declaration. This retrospective study was approved by the institutional review board, and the requirement to obtain informed consent was waived.
Consent for publication
Not applicable.
Competing interests
Y. Tanaka has received speaking fees and/or honoraria from Daiichi-Sankyo, Astellas, Eli Lilly, Chugai, Sanofi, Abbvie, Pfizer, YL Biologics, Bristol-Myers, Glaxo-Smithkline, UCB, Mitsubishi-Tanabe, Novartis, Eisai, Takeda, Janssen, and Asahi-kasei and has received research grants from Mitsubishi-Tanabe, Bristol-Myers, Eisai, Chugai, Takeda, Abbvie, Astellas, Daiichi-Sankyo, Ono, MSD, and Taisho-Toyama.
K. Nakano has received speaking fees from Astellas, UCB, Mitsubishi-Tanabe, and Eisai and has received research grants from Mitsubishi-Tanabe, Eisai, and Eli Lilly.
S. Nakayamada received speaking fees and/or honoraria from Bristol-Myers, Sanofi, Abbvie, Eisai, Eli Lilly, Chugai, Asahi-kasei, and Pfizer (less than $10,000 each) and also research grants from Mitsubishi-Tanabe, Takeda, Novartis, and MSD.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33726827 | 20,033,098 | 2021-03-16 |
What was the administration route of drug 'HUMAN IMMUNOGLOBULIN G'? | Effectiveness and safety of mepolizumab in combination with corticosteroids in patients with eosinophilic granulomatosis with polyangiitis.
Mepolizumab (MPZ), an anti-interleukin-5 antibody, is effective for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). However, its effectiveness has not been adequately evaluated in real-world clinical practice. In this study, we assessed the effectiveness and safety of MPZ (300 mg) for relapsing/refractory EGPA resistant to corticosteroids (CS) for 1 year in real-world settings.
We administered MPZ (300 mg) to 16 patients with relapsing/refractory EGPA resistant to CS (Post-MPZ). We also retrospectively collected data from the same patients for the 12 months before the administration of MPZ (Pre-MPZ). The primary endpoint was the 12-month remission rate after MPZ administration and the secondary endpoints were the Birmingham vasculitis activity score (BVAS), vasculitis damage index (VDI), eosinophil counts, changes in concomitant CS doses/concomitant immunosuppressant use, MPZ retention rate, and incidence of adverse events. The clinical course was compared between Pre-MPZ and Post-MPZ.
The 12-month remission rate after the initiation of MPZ was 75%. No change was observed in BVAS, eosinophil count, or concomitant CS dose over time in the Pre-MPZ group, whereas all these parameters were significantly decreased over time in the Post-MPZ group. The number of patients using concomitant immunosuppressant also decreased over time in the Post-MPZ group. VDI did not increase in either group. The MPZ retention rate was 100% and only three patients (18.8%) had infections. Changes in BVAS, eosinophil count, and cumulative concomitant CS dose were significantly lower in the Post-MPZ group than in the Pre-MPZ group. There was no significant difference in the changes in VDI between the groups.
This study demonstrated that MPZ is effective and safe for EGPA. Furthermore, MPZ decreases disease activity, increases remission rate, and has a CS-sparing effect.
Key messages
MPZ is safe for the treatment of EGPA in real-world clinical practice.
Comparing to Pre-MPZ, MPZ possesses the high remission rate and CS sparing effect.
Background
Eosinophilic granulomatosis with polyangiitis (EGPA) is a disease that is preceded by asthma or allergic rhinitis. EGPA causes various symptoms owing to vasculitis, including fever and purpura, and increases peripheral eosinophil counts [1, 2]. Corticosteroids (CS) are used in remission induction therapy and maintenance therapy for EGPA. Patients with severe vasculitis symptoms and those who respond poorly to CS are treated with cyclophosphamide (CY), azathioprine (AZ), methotrexate (MTX), cyclosporine (CsA)/tacrolimus (TAC), or intravenous immunoglobulin (IVIG). However, EGPA often relapses during CS dose reduction; hence, CS dose reduction is often challenging [3–5].
In recent years, mepolizumab (MPZ), an anti-interleukin-5 (IL-5) monoclonal antibody, has been reported to extend the remission period of EGPA and reduce the CS dose required [6]. Although MPZ was listed in the National Health Insurance drug price list for the treatment of EGPA in Japan in 2018, its effectiveness and safety have not been adequately evaluated in real-world clinical practice. Although the dose of MPZ administered in previous studies was 100 mg/month, which is the same dose used for the treatment of bronchial asthma, an MPZ dose of 300 mg is used in some countries, including Japan. Thus, we investigated the effectiveness and safety of MPZ at a dose of 300 mg/month in a real-world setting.
Methods
Patients
In this study, MPZ (300 mg) was administered to 16 patients with relapsing or refractory EGPA who were receiving the standard of care, mainly CS [7, 8]. In Japan, the use of MPZ is allowed when the effect of CS therapy is insufficient. All patients used in this study met this criterion. All patients were diagnosed with EGPA according to the diagnostic criteria for EGPA, as proposed by the Japanese Ministry of Health, Labour and Welfare, and met the classification criteria of the American College of Rheumatology [9] (Table 1, Supplementary Table 1). Patients in remission and those with relapsing or refractory EGPA were defined as follows according to the criteria of the Mepolizumab Treatment in Relapsing or Refractory EGPA trial [6]: patients with remission had a Birmingham vasculitis activity score (BVAS) of 0 and were treated with oral CS at a dose of ≤ 4 mg/day; patients with relapsing EGPA had an increased oral CS dose, started concomitant immunosuppressive therapy, had an increased concomitant immunosuppressant dose, had an increased BVAS [10], or had a history of hospitalization; and patients with refractory EGPA experienced no relapse and achieved no remission within the last 1 year. Table 1 Baseline characteristic of 16 patients with eosinophilic granulomatosis with polyangiitis
Pre-MPZ (n = 16) Post–MPZ (n = 16) P value*
Clinical manifestations at diagnosis, n (%) Asthma 16 (100), general 10 (62.5), cutaneous 8 (50.0), ENT 5 (31.3), chest 8 (50.0), cardiomyopathy 3 (18.8), abdominal 1 (6.3), neuropathy 8 (50.0), ANCA positive status 5 (31.3), biopsy findings 12 (75)
Male/female/age at MPZ introduction 7/9/61.5 [53.3–70.5]
Disease duration (months) at MPZ introduction 54 [22–144]
Treatment history, n (%) CS pulse 2 (12.5), high-dose CS 14 (87.5), low-dose CS 2 (12.5), IVCY 9 (56.3), IVIG 6 (37.5), RTX 1 (6.3), MTX 6 (37.5), AZ 12 (75.0), TAC 1 (6.3)
Relapsing/refractory/remission, n (%) 4 (25.0)/11 (68.7)/1 (6.3) 10 (62.5)/6 (37.5)/0 (0) ND
Concomitant CS dose (PSL mg/day) 8.0 [5.0–11.5] 6.5 [2.6–10.0] 0.2012
Concomitant CS < 4 mg/day (PSL), n (%) 3 (18.8) 5 (31.3) 0.1573
Concomitant immunosuppressant, n (%) AZ 6 (37.5), MTX 5 (31.3), TAC 1 (6.3) AZ 6 (37.5), MTX 4 (25.0), TAC 1 (6.3)
Without immunosuppressant, n (%) 6 (37.5) 7 (43.8) 0.3173
BVAS 0 [0–2.0] 1.0 [0–3.8] 0.1084
BVAS > 0, n (%) 4 (25.0) 8 (50.0) 0.3173
BVAS items Asthma 2 (12.5), sinonasal 2 (12.5), chest 1 (6.3) Asthma 6 (37.5), general 1 (6.3), cutaneous 2 (12.5), sinonasal 2 (12.5), chest 3 (18.8),
VDI 3.5 [3.0–4.8] 4.0 [3.0–5.8] 0.5577
VDI items Chronic bronchial asthma 16 (100), chronic respiratory failure 1 (6.3), abnormal respiratory function 7 (43.8), old myocardial infarction 2 (12.5), cardiomyopathy 2 (12.5), low vision 1 (6.3), chronic sinusitis 6 (37.5), deafness 3 (18.8), peripheral neuropathy 8 (50.0), diabetes 4 (25), hypertension 4 (25), osteoporosis 5 (31.3), other 3 (18.8) Chronic bronchial asthma 16 (100), chronic respiratory failure 1 (6.3), abnormal respiratory function 8 (50.0), old myocardial infarction 2 (12.5), cardiomyopathy 2 (12.5), low vision 1 (6.3), chronic sinusitis 7 (43.8), deafness 3 (18.8), peripheral neuropathy 8 (50.0), diabetes 4 (25), hypertension 4 (25), osteoporosis 5 (31.3), other 5 (31.3)
ANCA-positive status, n (%) 0 (0) 1 (6.3) ND
Absolute eosinophil count (/μL) 178.6 [48.7–370.2] 183 [60.0–2479] 0.1591
CRP (mg/dL) 0.06 [0.03–0.09] 0.09 [0.05–0.24] 0.0593
CS corticosteroid (prednisolone or equivalent), IVCY cyclophosphamide pulse therapy i.v., RTX rituximab, MTX methotrexate, AZ azathioprine, TAC tacrolimus, BVAS Birmingham Vasculitis Activity Score, VDI vasculitis damage index, ND not detected by McNemar test. Data are shown by median [quartile] or n (%). P values were determined by McNemar test or Wilcoxon signed-rank test. *P < 0.05: Pre-MPZ (n = 16) vs. Post-MPZ (n = 16)
The patients were followed up for 12 months after the introduction of MPZ at our hospital and affiliated institutions, during the period between the domestic introduction of MPZ in May 2018 until August 2020 (Post-MPZ). Additionally, we retrospectively collected data from the same patients for the 12 months before the initiation of MPZ therapy (Pre-MPZ). All patients received maintenance therapy according to the standard of care. The standard of care in this study was defined as treatment with CS, intravenous CY, intravenous immunoglobulin, azathioprine, MTX, or CsA/TAC. The Human Ethics Review Committee of our university reviewed and approved this study (No. H27-014). We also complied with the Declaration of Helsinki. All participants provided informed consent prior to inclusion in the study. Details that might disclose the identity of the study subjects were omitted.
Clinical measurement
This study was a multicenter and ambispective cohort study in which MPZ at a dose of 300 mg/month was administered to 16 patients with relapsing or refractory EGPA to investigate the effectiveness and safety of MPZ over 1 year.
The primary endpoint was the remission rate. The secondary endpoints were the BVAS (overall and for each item), vasculitis damage index (VDI) (overall and for each item) [11, 12], eosinophil counts, daily and cumulative concomitant CS doses, presence or absence of changes/addition of immunosuppressant(s), MPZ retention rate, and incidence of adverse events. Additionally, the reduction in BVAS, change in VDI, reduction in peripheral eosinophil counts, and cumulative concomitant CS doses were compared between the 1-year period before the initiation of MPZ therapy (Pre-MPZ; month − 12 to month 0) and 1-year period after the initiation of MPZ (Post-MPZ; month 0 to month 12). To express the results of the two groups synchronously, the original timeframes Pre-MPZ (− 12 (baseline), − 11, − 9, and − 6 months) are represented as 0 (baseline), 1, 3, and 6 months, respectively.
Measurement of serum concentration of IL-5
The serum concentration of IL-5 at the baseline (before MPZ initiation) was measured using the enzyme-linked immunosorbent assay (ELISA) (R&D SYSTEMS Human IL-5 Duo Set ELISA, P249454) and compared with that of six age- and sex-matched healthy controls.
Statistical analysis
Data are expressed as the median (interquartile range). For statistical analysis, data from cases in which MPZ was discontinued or the disease relapsed were complemented using the last observation carried forward method. Differences between groups (Post-MPZ vs. Pre-MPZ) and between data measured at the baseline and each observation point (Post-MPZ: month 0 vs. month 1, 3, 6, 12) were compared using the Wilcoxon signed-rank test or McNemar test. Differences in the serum IL-5 concentration between the patients and healthy controls were compared using the Mann-Whitney U test.
The timeframes of both groups were represented synchronously and compared [− 12 months (baseline) in the Pre-MPZ corresponded to 0 months (baseline) in the Post-MPZ group]. All reported P values are two-sided. Remission was defined as a BVAS score of 0 and CS less than 4 mg/day. All analyses were conducted using JMP version 14.0.0 (SAS Institute Inc.). The post hoc power of this study for the comparison between month 0 and the other observation points in the Post-MPZ group was 0.37 for BVAS, 0.99 for VDI, 0.36 for absolute eosinophil count, and 0.76 for concomitant CS dose (α error, 0.05; 1-β error, post hoc power).
Results
Patient background
The characteristics of the patients are shown in Table 1. The characteristics of each patient at the time of EGPA diagnosis are shown in Supplementary Table 1 and those at the time of MPZ therapy initiation are shown in Supplementary Table 2. At the time of MPZ therapy initiation, the median age [interquartile range] of the 16 patients with EGPA was 61.5 [53.3–70.5] years and the disease duration was 54 [22–144] months. Regarding medical history, all patients were treated with CS. The Pre-MPZ group included four patients with relapsing EGPA, 11 with refractory EGPA, and one in remission, whereas the Post-MPZ group included 10 patients with relapsing EGPA and six with refractory EGPA. No statistically significant differences were observed in the concomitant CS dose or the rate of concomitant immunosuppressant use between the groups. There were also no statistically significant differences in BVAS, VDI, positivity rate for anti-neutrophil cytoplasmic antibody, eosinophil counts, or C-reactive protein level between the groups. The IL-5 concentration before MPZ therapy initiation was 1.88 [0.28–8.95] pg/mL, which was significantly higher than that in the six age- and sex-matched healthy controls (0.027 [0.003–0.55], P = *0.0063 using Mann-Whitney U test; Supplementary Fig. 1).
Effectiveness of MPZ
The remission rates (the primary endpoint) were 6.3% (1/16 patients) at month 1, 12.5% (2/16 patients) at month 3, 6.3% (1/16 patients) at month 6, and 0% at month 12 in the Pre-MPZ group. The corresponding rates in the Post-MPZ group were 12.5% (2/16 patients) at month 1, 31.3% (5/16 patients) at month 3, 50.0% (8/16 patients) at month 6, and 75.0% (12/16 patients) at month 12. In this group, the remission rate increased at month 12 (Fig. 1a). Fig. 1 Comparison of effectiveness between the Pre-MPZ and the Post-MPZ. a Remission rates. b BVAS. c VDI. d Eosinophil counts. e Concomitant CS doses. BVAS, Birmingham vasculitis activity score; CS, corticosteroid; VDI, vasculitis damage index. P values were determined by Wilcoxon signed-rank test. *P < 0.05: baseline (month 0) vs. each observation points (month 0,1, 3, 6, and 12)
In the Pre-MPZ group, the BVASs were 0 [0–2.0] at month 1, 0 [0–2.0] at month 3, 0 [0–2.0] at month 6, and 1.0 [0–3.8] at month 12. In the Post-MPZ group, the BVASs were 0 [0–2.8] at month 1, 0 [0–0] at month 3, 0 [0–0] at month 6, and 0 [0–0] at month 12. The BVASs at month 1 and afterward significantly decreased from the BVAS at month 0 (Fig. 1b). The decrease in BVAS during the 1-year period in the Post-MPZ group was 0.5 [0–3.5], which was significantly higher than that in the Pre-MPZ group (− 1.0 [− 3.0–0]; Fig. 2a). Fig. 2 Comparison of changes of each item between the 12-month period in Pre-MPZ and Post-MPZ. a Changes in BVAS, b increase in VDI, c reduction in peripheral eosinophil counts (/μL), and d accumulated concomitant CS dose (mg/year). BVAS, Birmingham vasculitis activity score; CS, corticosteroid; VDI, vasculitis damage index. P values were determined by Wilcoxon signed-rank test. *P < 0.05: Pre-MPZ vs. Post-MPZ
Based on the changes in BVASs for each item, respiratory symptoms were exacerbated in the Pre-MPZ group but improved immediately after the initiation of MPZ therapy. The number of patients with symptoms decreased from 11/16 to 2/16 after 1 year of treatment. Ear, nose, and throat symptoms also improved, as the number of patients with these symptoms decreased from 6/16 to 3/16 patients, 1 year after the initiation of MPZ therapy. In contrast, neuropathy did not improve in either the Post-MPZ or Pre-MPZ groups. In the Post-MPZ group, no organ dysfunction was exacerbated at month 12 (Table 2). Table 2 Changes in organ damage before and after the introduction of MPZ
Pre-MPZ Post-MPZ
-12 M -11 M -9 M -6 M 0 M 1 M 3 M 6 M 12 M
General symptoms 0 0 1 (6.3%) 1 (6.3%) 1 (6.3%) 1 (6.3%) 0 1 (6.3%) 0
Cutaneous manifestations 1 (6.3%) 1 (6.3%) 1 (6.3%) 1 (6.3%) 2 (12.5%) 2 (12.5%) 0 1 (6.3%) 0
ENT manifestations 6 (37.5%) 6 (37.5%) 6 (37.5%) 6 (37.5%) 6 (37.5%) 6 (37.5%) 6 (37.5%) 4 (25.0%) 3 (18.8%)
Chest manifestations 6 (37.5%) 6 (37.5%) 8 (50.0%) 8 (50.0%) 11 (68.8%) 5 (31.3%) 2 (12.5%) 2 (12.5%) 2 (12.5%)
Nervous system manifestations 7 (45.8%) 7 (45.8%) 7 (45.8%) 8 (50.0%) 8 (50.0%) 8 (50.0%) 7 (43.8%) 7 (43.8%) 7 (43.8%)
ENT ear, nose, throat
In the Pre-MPZ group, the VDI scores were 3.5 [3.0–4.8] at month 1, 4.0 [3.0–5.5] at month 3, 4.0 [3.0–5.5] at month 6, and 4.0 [3.0–5.5] at month 12. In the Post-MPZ group, the VDI scores were 4.0 [3.0–5.5] at month 1, 4.0 [3.0–5.5] at month 3, 4.0 [3.0–5.5] at month 6, and 4.0 [3.0–5.5] at month 12, with no significant changes (Fig. 1c). The increase in the VDI score during the 1-year period was 0 [0–0.8] in the Pre-MPZ and 0 [0–0] in the Post-MPZ groups, with no significant difference between the groups (Fig. 2b).
In the Pre-MPZ group, the eosinophil counts were 280.4 [63.2–426.8]/μL at month 1, 217.8 [93.3–1354.2]/μL at month 3, and 293.9 [39.1–880.7]/μL at month 6. In the Post-MPZ group, the eosinophil counts were 54.8 [10.6–99.8]/μL at month 1, 25.2 [12.8–53.9]/μL at month 3, 29.4 [9.63–42.5]/μL at month 6, and 28.8 [20.5–68.0] at month 12, with a significant reduction from month 1 onwards (Fig. 1d). The reduction in the eosinophil counts during the 1-year period in the Post-MPZ group was 146.2 [9.88–2449.9], which was significantly higher than that in the Pre-MPZ group (− 8.8 [− 2927.4–175.4]; Fig. 2c).
The changes in the concomitant CS dose in each patient are shown in Table 3. In the Pre-MPZ group, the concomitant CS doses were 8.0 [5.0–10.0] mg/day at month 1, 7.0 [3.5–10.0] mg/day at month 3, 6.5 [2.6–10.0] mg/day at month 6, and 6.0 [2.6–10.0] mg/day at month 12. In the Post-MPZ group, the concomitant CS doses were 6.5 [2.6–10.0] mg/day at month 1, 5.0 [2.3–7.4] mg/day at month 3, 4.5 [0.5–5.0] mg/day at month 6, and 2.5 [0.1–3.8] mg/day at month 12, with a significant reduction from month 3 onwards (Fig. 1e). The concomitant CS dose was significantly lower in the Post-MPZ group (1655 [570.0–2190.0] mg/year) than in the Pre-MPZ group (2665 [1473.8–3993.8] mg/year; Fig. 2d). The changes in the use of immunosuppressants are shown in Table 4. The number of patients using concomitant immunosuppressant(s) reduced from 10 to nine patients at 1 year in the Pre-MPZ group and from nine to five patients in the Post-MPZ group. Table 3 Changes in the concomitant corticosteroids use before and after the introduction of MPZ (PSL mg/day)
Case No. Pre-MPZ Post-MPZ
− 12 months − 11 months − 9 months − 6 months 0 months 1 months 3 months 6 months 12 months
1 5 mg 5 mg 30 mg 15 mg 15 mg 15 mg 10 mg 10 mg 5 mg
2 5 mg 5 mg 7.5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg
3 8 mg 8 mg 3.5 mg 2.5 mg 2.5 mg 2.5 mg 2 mg 2 mg 1.5 mg
4 12 mg 12 mg 12 mg 12 mg 12 mg 10 mg 8 mg 9 mg 4 mg
5 8 mg 8 mg 7 mg 7 mg 7 mg 7 mg 5 mg 5 mg 3 mg
6 1 mg 1 mg 1 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg
7 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg
8 10 mg 9 mg 7 mg 6 mg 6 mg 6 mg 5 mg 3 mg 0.5 mg
9 5 mg 5 mg 4 mg 3 mg 3 mg 3 mg 3 mg 0 mg 0 mg
10 15 mg 10 mg 5 mg 35 mg 20 mg 15 mg 7.5 mg 5 mg 3 mg
11 8 mg 8 mg 7 mg 7 mg 7 mg 7 mg 5 mg 5 mg 2 mg
12 20 mg 15 mg 10 mg 10 mg 10 mg 10 mg 7 mg 5 mg 2 mg
13 10 mg 10 mg 10 mg 10 mg 10 mg 10 mg 8 mg 6 mg 5 mg
14 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 3 mg 3 mg
15 20 mg 15 mg 8 mg 7 mg 7 mg 7 mg 5 mg 4 mg 3 mg
16 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg
Table 4 Changes in the concomitant immunosuppressants use before and after the introduction of MPZ
Case No. Pre-MPZ Post-MPZ
− 12 months − 11 months − 9 months − 6 months 0 months 1 months 3 months 6 months 12 months
1 MTX 8 mg MTX 8 mg None None None None None None None
2 MTX 8 mg+AZ 125 mg MTX 8 mg+AZ 125 mg MTX 8 mg+AZ 125 mg MTX 8 mg+AZ 125 mg MTX 8 mg+AZ 125 mg AZ125 mg AZ125 mg AZ125 mg AZ100 mg
3 AZ50 mg AZ50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg
4 None None AZ 50 mg None None None None MTX 8 mg MTX 8 mg
5 MTX 6 mg+AZ 50 mg MTX 6 mg+AZ 50 mg MTX 6 mg+AZ 50 mg MTX 6 mg+AZ 50 mg MTX 6 mg+AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg
6 MTX 16 mg MTX 16 mg MTX 16 mg MTX 16 mg MTX 16 mg MTX 16 mg MTX 10 mg MTX 4 mg None
7 None None None None None None None None None
8 MTX 12 mg MTX 12 mg MTX 12 mg MTX 12 mg MTX 12 mg None None None None
9 AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg None None None None
10 None None IVCY None None None None None None
11 TAC 3 mg TAC 3 mg TAC 3 mg TAC 3 mg TAC 3 mg None None None None
12 None None None None None None None None None
13 AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg
14 None None None None None None None None None
15 AZ 100 mg AZ 100 mg AZ 100 mg AZ 100 mg AZ 100 mg None None None None
16 None None None None None None None None None
IVCY cyclophosphamide pulse therapy i.v., MTX methotrexate, AZ azathioprine, TAC tacrolimus
MPZ retention rate and safety
The 1-year MPZ retention rate was 100%. Although three patients had an infection, all patients continued MPZ. Adverse events before and after the initiation of MPZ therapy are shown in Table 5. After MPZ therapy initiation, cases 1 and 11 developed bacterial pneumonia that required hospitalization. Sputum culture identified Moraxella catarrhalis in case 1 and Pseudomonas aeruginosa in case 11. In both patients, a drip infusion of antibiotics improved their condition. Case 15 also developed bacterial pneumonia. Because the general and respiratory conditions were favorable, the patient received oral antibiotic therapy at the outpatient clinic and improved. All three patients who had an infection after the initiation of MPZ therapy had the same infection within 1 year before initiation. None of the patients had a new infection after the initiation of therapy. Table 5 Adverse events before and after introduction of MPZ
Case No. Pre-MPZ Post-MPZ
1 Bacterial pneumonia (hospitalization) Bacterial pneumonia (hospitalization)
Bacterial species: Moraxella catarrhalis
2 None None
3 None None
4 Drug-induced liver injury None
5 Sinusitis surgery, bacterial bronchitis None
6 Bacterial bronchitis, infectious otitis media None
7 None None
8 None None
9 None None
10 None None
11 Bacterial pneumonia (hospitalization) Bacterial pneumonia (hospitalization)
Bacterial species: Pseudomonas aeruginosa
12 None None
13 Bacterial pneumonia (hospitalization) None
14 Bacterial bronchitis None
15 Bacterial pneumonia Bacterial pneumonia
16 None None
Discussion
The results of this study demonstrated the effectiveness and safety of MPZ for relapsing or refractory EGPA in a real-world setting by comparing the clinical courses before and after the initiation of MPZ therapy. During the 1-year period before MPZ therapy initiation, BVASs increased as CS doses were tapered, although the effectiveness of immunosuppressants in controlling disease activity was inadequate to allow CS dose reduction. Although many patients used AZ as a concomitant immunosuppressant before MPZ therapy initiation in this study, it has been previously reported that AZ is not useful for maintenance therapy [13]. In this study, BVASs and eosinophil counts significantly decreased 1 month after MPZ therapy initiation. The doses of CS and immunosuppressants were also successfully reduced (Figs. 2a, c, d). MPZ was a useful drug for maintenance therapy that exerted a more consistent effect in controlling disease activity than existing immunosuppressants.
Although the 16 patients included in this study had relatively low eosinophil counts (Table 1), the IL-5 levels before MPZ initiation were significantly higher than those of healthy controls. However, MPZ was effective even in patients whose serum concentration of IL-5 was comparable to that of healthy controls. We believe that these results indicate that MPZ is an effective treatment option in patients with relapsing or refractory EGPA, regardless of IL-5 concentration.
The MPZ retention rate was 100%, and the incidence of infections tended to decrease after MPZ initiation (Table 2). These results confirm the safety of MPZ. In particular, a severe infection that required hospitalization was noted only in two patients with a history of infection, and there was no occurrence of a new serious infection. These results can be considered useful. The reduced incidence of infection might be attributable to the significant reduction in concomitant CS doses and the reduced number of patients using concomitant immunosuppressant after MPZ therapy initiation (Fig. 2d; Tables 3 and 4). The long-term oral administration of CS induces infections and various complications, including osteoporosis, diabetes, hypertension, dyslipidemia, and femoral head necrosis. We did not observe a significant increase in VDI scores nor an increased incidence of complications owing to CS after MPZ therapy initiation. Thus, we demonstrated that MPZ therapy was sufficiently effective in controlling disease activity and prevented adverse events induced by CS and immunosuppressants. In the future, it is important that a long-term investigation is conducted to determine whether long-term MPZ therapy allows the dose reduction or discontinuation of CS without relapse and whether VDI increases.
However, this study has important limitations. For example, this study had limited statistical power owing to the small sample size. Additionally, because the Pre-MPZ group was set as the control group to compare the effects of MPZ therapy with, the control group might be inadequate. Moreover, few countries recommend subcutaneous MPZ injection at a dose of 300 mg for EGPA, such as Japan. A strength of this study is that although there are some case reports of the use of MPZ at a dose of 300 mg [14] and a case series of the use of MPZ at 100 mg for the treatment of comorbid asthma [15], no studies have investigated the safety and effectiveness of MPZ at 300 mg in real-world clinical practice. To the best of our knowledge, this is the first study to demonstrate the safety and effectiveness of MPZ at 300 mg in a real-world setting.
Supplementary Information
Additional file 1: Supplementary Table 1. Clinical manifestations, Japanese Ministry of Health, Labor and Welfare criteria items and classification criteria of the American College of Rheumatology criteria at diagnosis.
Additional file 2: Supplementary Table 2. Baseline characteristic of 16 Patients with Eosinophilic Granulomatosis with Polyangiitis.
Additional file 3: Supplementary Fig. 1. Serum IL-5 concentration of 16 Patients with EGPA before initiating MPZ and health controls (HC group). P values were determined by Mann-Whitney’s U test. p* < 0.01: EGPA group (n = 16) vs. HC (n = 6).
Abbreviations
MPZ Mepolizumab
EGPA Eosinophilic granulomatosis with polyangiitis
CS Corticosteroids
BVAS Birmingham vasculitis activity score
VDI Vasculitis damage index
CY Cyclophosphamide
IVCY Intravenous cyclophosphamide
AZ Azathioprine
MTX Methotrexate
CsA Cyclosporine
TAC Tacrolimus
IVIG Intravenous immunoglobulin
Pre-MPZ 1-Year period before initiating MPZ therapy
Post-MPZ 1-Year period after initiating MPZ
Supplementary information
Supplementary information accompanies this paper at 10.1186/s13075-021-02462-6.
Acknowledgements
The authors thank the study participants, without whom this study would never have been accomplished as well as the investigators for their participation in the study, especially those in Kitakyushu General Hospital, Tobata General Hospital, Saiseikai Shimonoseki General Hospital, Fukuoka Yutaka Central Hospital, Nakama Municipal Hospital, and Steel Memorial Yahata Hospital.
Authors’ contributions
MU contributed to the study design, overall review, writing of the manuscript, and the other authors were involved in the performance of the study and review of the manuscript. YT, MI, KN, SI, and SN participated in the study design and coordination. All authors read and approved the final manuscript.
Funding
No specific funding was received from any bodies in the public, commercial, or not-for-profit sectors to carry out the work described in this article.
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
Ethical approval was obtained from the University of Occupational and Environmental Health Japan Ethics Committee following the Helsinki Declaration. This retrospective study was approved by the institutional review board, and the requirement to obtain informed consent was waived.
Consent for publication
Not applicable.
Competing interests
Y. Tanaka has received speaking fees and/or honoraria from Daiichi-Sankyo, Astellas, Eli Lilly, Chugai, Sanofi, Abbvie, Pfizer, YL Biologics, Bristol-Myers, Glaxo-Smithkline, UCB, Mitsubishi-Tanabe, Novartis, Eisai, Takeda, Janssen, and Asahi-kasei and has received research grants from Mitsubishi-Tanabe, Bristol-Myers, Eisai, Chugai, Takeda, Abbvie, Astellas, Daiichi-Sankyo, Ono, MSD, and Taisho-Toyama.
K. Nakano has received speaking fees from Astellas, UCB, Mitsubishi-Tanabe, and Eisai and has received research grants from Mitsubishi-Tanabe, Eisai, and Eli Lilly.
S. Nakayamada received speaking fees and/or honoraria from Bristol-Myers, Sanofi, Abbvie, Eisai, Eli Lilly, Chugai, Asahi-kasei, and Pfizer (less than $10,000 each) and also research grants from Mitsubishi-Tanabe, Takeda, Novartis, and MSD.
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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33726827 | 20,033,098 | 2021-03-16 |
What was the administration route of drug 'IMMUNE GLOBULIN NOS'? | Effectiveness and safety of mepolizumab in combination with corticosteroids in patients with eosinophilic granulomatosis with polyangiitis.
Mepolizumab (MPZ), an anti-interleukin-5 antibody, is effective for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). However, its effectiveness has not been adequately evaluated in real-world clinical practice. In this study, we assessed the effectiveness and safety of MPZ (300 mg) for relapsing/refractory EGPA resistant to corticosteroids (CS) for 1 year in real-world settings.
We administered MPZ (300 mg) to 16 patients with relapsing/refractory EGPA resistant to CS (Post-MPZ). We also retrospectively collected data from the same patients for the 12 months before the administration of MPZ (Pre-MPZ). The primary endpoint was the 12-month remission rate after MPZ administration and the secondary endpoints were the Birmingham vasculitis activity score (BVAS), vasculitis damage index (VDI), eosinophil counts, changes in concomitant CS doses/concomitant immunosuppressant use, MPZ retention rate, and incidence of adverse events. The clinical course was compared between Pre-MPZ and Post-MPZ.
The 12-month remission rate after the initiation of MPZ was 75%. No change was observed in BVAS, eosinophil count, or concomitant CS dose over time in the Pre-MPZ group, whereas all these parameters were significantly decreased over time in the Post-MPZ group. The number of patients using concomitant immunosuppressant also decreased over time in the Post-MPZ group. VDI did not increase in either group. The MPZ retention rate was 100% and only three patients (18.8%) had infections. Changes in BVAS, eosinophil count, and cumulative concomitant CS dose were significantly lower in the Post-MPZ group than in the Pre-MPZ group. There was no significant difference in the changes in VDI between the groups.
This study demonstrated that MPZ is effective and safe for EGPA. Furthermore, MPZ decreases disease activity, increases remission rate, and has a CS-sparing effect.
Key messages
MPZ is safe for the treatment of EGPA in real-world clinical practice.
Comparing to Pre-MPZ, MPZ possesses the high remission rate and CS sparing effect.
Background
Eosinophilic granulomatosis with polyangiitis (EGPA) is a disease that is preceded by asthma or allergic rhinitis. EGPA causes various symptoms owing to vasculitis, including fever and purpura, and increases peripheral eosinophil counts [1, 2]. Corticosteroids (CS) are used in remission induction therapy and maintenance therapy for EGPA. Patients with severe vasculitis symptoms and those who respond poorly to CS are treated with cyclophosphamide (CY), azathioprine (AZ), methotrexate (MTX), cyclosporine (CsA)/tacrolimus (TAC), or intravenous immunoglobulin (IVIG). However, EGPA often relapses during CS dose reduction; hence, CS dose reduction is often challenging [3–5].
In recent years, mepolizumab (MPZ), an anti-interleukin-5 (IL-5) monoclonal antibody, has been reported to extend the remission period of EGPA and reduce the CS dose required [6]. Although MPZ was listed in the National Health Insurance drug price list for the treatment of EGPA in Japan in 2018, its effectiveness and safety have not been adequately evaluated in real-world clinical practice. Although the dose of MPZ administered in previous studies was 100 mg/month, which is the same dose used for the treatment of bronchial asthma, an MPZ dose of 300 mg is used in some countries, including Japan. Thus, we investigated the effectiveness and safety of MPZ at a dose of 300 mg/month in a real-world setting.
Methods
Patients
In this study, MPZ (300 mg) was administered to 16 patients with relapsing or refractory EGPA who were receiving the standard of care, mainly CS [7, 8]. In Japan, the use of MPZ is allowed when the effect of CS therapy is insufficient. All patients used in this study met this criterion. All patients were diagnosed with EGPA according to the diagnostic criteria for EGPA, as proposed by the Japanese Ministry of Health, Labour and Welfare, and met the classification criteria of the American College of Rheumatology [9] (Table 1, Supplementary Table 1). Patients in remission and those with relapsing or refractory EGPA were defined as follows according to the criteria of the Mepolizumab Treatment in Relapsing or Refractory EGPA trial [6]: patients with remission had a Birmingham vasculitis activity score (BVAS) of 0 and were treated with oral CS at a dose of ≤ 4 mg/day; patients with relapsing EGPA had an increased oral CS dose, started concomitant immunosuppressive therapy, had an increased concomitant immunosuppressant dose, had an increased BVAS [10], or had a history of hospitalization; and patients with refractory EGPA experienced no relapse and achieved no remission within the last 1 year. Table 1 Baseline characteristic of 16 patients with eosinophilic granulomatosis with polyangiitis
Pre-MPZ (n = 16) Post–MPZ (n = 16) P value*
Clinical manifestations at diagnosis, n (%) Asthma 16 (100), general 10 (62.5), cutaneous 8 (50.0), ENT 5 (31.3), chest 8 (50.0), cardiomyopathy 3 (18.8), abdominal 1 (6.3), neuropathy 8 (50.0), ANCA positive status 5 (31.3), biopsy findings 12 (75)
Male/female/age at MPZ introduction 7/9/61.5 [53.3–70.5]
Disease duration (months) at MPZ introduction 54 [22–144]
Treatment history, n (%) CS pulse 2 (12.5), high-dose CS 14 (87.5), low-dose CS 2 (12.5), IVCY 9 (56.3), IVIG 6 (37.5), RTX 1 (6.3), MTX 6 (37.5), AZ 12 (75.0), TAC 1 (6.3)
Relapsing/refractory/remission, n (%) 4 (25.0)/11 (68.7)/1 (6.3) 10 (62.5)/6 (37.5)/0 (0) ND
Concomitant CS dose (PSL mg/day) 8.0 [5.0–11.5] 6.5 [2.6–10.0] 0.2012
Concomitant CS < 4 mg/day (PSL), n (%) 3 (18.8) 5 (31.3) 0.1573
Concomitant immunosuppressant, n (%) AZ 6 (37.5), MTX 5 (31.3), TAC 1 (6.3) AZ 6 (37.5), MTX 4 (25.0), TAC 1 (6.3)
Without immunosuppressant, n (%) 6 (37.5) 7 (43.8) 0.3173
BVAS 0 [0–2.0] 1.0 [0–3.8] 0.1084
BVAS > 0, n (%) 4 (25.0) 8 (50.0) 0.3173
BVAS items Asthma 2 (12.5), sinonasal 2 (12.5), chest 1 (6.3) Asthma 6 (37.5), general 1 (6.3), cutaneous 2 (12.5), sinonasal 2 (12.5), chest 3 (18.8),
VDI 3.5 [3.0–4.8] 4.0 [3.0–5.8] 0.5577
VDI items Chronic bronchial asthma 16 (100), chronic respiratory failure 1 (6.3), abnormal respiratory function 7 (43.8), old myocardial infarction 2 (12.5), cardiomyopathy 2 (12.5), low vision 1 (6.3), chronic sinusitis 6 (37.5), deafness 3 (18.8), peripheral neuropathy 8 (50.0), diabetes 4 (25), hypertension 4 (25), osteoporosis 5 (31.3), other 3 (18.8) Chronic bronchial asthma 16 (100), chronic respiratory failure 1 (6.3), abnormal respiratory function 8 (50.0), old myocardial infarction 2 (12.5), cardiomyopathy 2 (12.5), low vision 1 (6.3), chronic sinusitis 7 (43.8), deafness 3 (18.8), peripheral neuropathy 8 (50.0), diabetes 4 (25), hypertension 4 (25), osteoporosis 5 (31.3), other 5 (31.3)
ANCA-positive status, n (%) 0 (0) 1 (6.3) ND
Absolute eosinophil count (/μL) 178.6 [48.7–370.2] 183 [60.0–2479] 0.1591
CRP (mg/dL) 0.06 [0.03–0.09] 0.09 [0.05–0.24] 0.0593
CS corticosteroid (prednisolone or equivalent), IVCY cyclophosphamide pulse therapy i.v., RTX rituximab, MTX methotrexate, AZ azathioprine, TAC tacrolimus, BVAS Birmingham Vasculitis Activity Score, VDI vasculitis damage index, ND not detected by McNemar test. Data are shown by median [quartile] or n (%). P values were determined by McNemar test or Wilcoxon signed-rank test. *P < 0.05: Pre-MPZ (n = 16) vs. Post-MPZ (n = 16)
The patients were followed up for 12 months after the introduction of MPZ at our hospital and affiliated institutions, during the period between the domestic introduction of MPZ in May 2018 until August 2020 (Post-MPZ). Additionally, we retrospectively collected data from the same patients for the 12 months before the initiation of MPZ therapy (Pre-MPZ). All patients received maintenance therapy according to the standard of care. The standard of care in this study was defined as treatment with CS, intravenous CY, intravenous immunoglobulin, azathioprine, MTX, or CsA/TAC. The Human Ethics Review Committee of our university reviewed and approved this study (No. H27-014). We also complied with the Declaration of Helsinki. All participants provided informed consent prior to inclusion in the study. Details that might disclose the identity of the study subjects were omitted.
Clinical measurement
This study was a multicenter and ambispective cohort study in which MPZ at a dose of 300 mg/month was administered to 16 patients with relapsing or refractory EGPA to investigate the effectiveness and safety of MPZ over 1 year.
The primary endpoint was the remission rate. The secondary endpoints were the BVAS (overall and for each item), vasculitis damage index (VDI) (overall and for each item) [11, 12], eosinophil counts, daily and cumulative concomitant CS doses, presence or absence of changes/addition of immunosuppressant(s), MPZ retention rate, and incidence of adverse events. Additionally, the reduction in BVAS, change in VDI, reduction in peripheral eosinophil counts, and cumulative concomitant CS doses were compared between the 1-year period before the initiation of MPZ therapy (Pre-MPZ; month − 12 to month 0) and 1-year period after the initiation of MPZ (Post-MPZ; month 0 to month 12). To express the results of the two groups synchronously, the original timeframes Pre-MPZ (− 12 (baseline), − 11, − 9, and − 6 months) are represented as 0 (baseline), 1, 3, and 6 months, respectively.
Measurement of serum concentration of IL-5
The serum concentration of IL-5 at the baseline (before MPZ initiation) was measured using the enzyme-linked immunosorbent assay (ELISA) (R&D SYSTEMS Human IL-5 Duo Set ELISA, P249454) and compared with that of six age- and sex-matched healthy controls.
Statistical analysis
Data are expressed as the median (interquartile range). For statistical analysis, data from cases in which MPZ was discontinued or the disease relapsed were complemented using the last observation carried forward method. Differences between groups (Post-MPZ vs. Pre-MPZ) and between data measured at the baseline and each observation point (Post-MPZ: month 0 vs. month 1, 3, 6, 12) were compared using the Wilcoxon signed-rank test or McNemar test. Differences in the serum IL-5 concentration between the patients and healthy controls were compared using the Mann-Whitney U test.
The timeframes of both groups were represented synchronously and compared [− 12 months (baseline) in the Pre-MPZ corresponded to 0 months (baseline) in the Post-MPZ group]. All reported P values are two-sided. Remission was defined as a BVAS score of 0 and CS less than 4 mg/day. All analyses were conducted using JMP version 14.0.0 (SAS Institute Inc.). The post hoc power of this study for the comparison between month 0 and the other observation points in the Post-MPZ group was 0.37 for BVAS, 0.99 for VDI, 0.36 for absolute eosinophil count, and 0.76 for concomitant CS dose (α error, 0.05; 1-β error, post hoc power).
Results
Patient background
The characteristics of the patients are shown in Table 1. The characteristics of each patient at the time of EGPA diagnosis are shown in Supplementary Table 1 and those at the time of MPZ therapy initiation are shown in Supplementary Table 2. At the time of MPZ therapy initiation, the median age [interquartile range] of the 16 patients with EGPA was 61.5 [53.3–70.5] years and the disease duration was 54 [22–144] months. Regarding medical history, all patients were treated with CS. The Pre-MPZ group included four patients with relapsing EGPA, 11 with refractory EGPA, and one in remission, whereas the Post-MPZ group included 10 patients with relapsing EGPA and six with refractory EGPA. No statistically significant differences were observed in the concomitant CS dose or the rate of concomitant immunosuppressant use between the groups. There were also no statistically significant differences in BVAS, VDI, positivity rate for anti-neutrophil cytoplasmic antibody, eosinophil counts, or C-reactive protein level between the groups. The IL-5 concentration before MPZ therapy initiation was 1.88 [0.28–8.95] pg/mL, which was significantly higher than that in the six age- and sex-matched healthy controls (0.027 [0.003–0.55], P = *0.0063 using Mann-Whitney U test; Supplementary Fig. 1).
Effectiveness of MPZ
The remission rates (the primary endpoint) were 6.3% (1/16 patients) at month 1, 12.5% (2/16 patients) at month 3, 6.3% (1/16 patients) at month 6, and 0% at month 12 in the Pre-MPZ group. The corresponding rates in the Post-MPZ group were 12.5% (2/16 patients) at month 1, 31.3% (5/16 patients) at month 3, 50.0% (8/16 patients) at month 6, and 75.0% (12/16 patients) at month 12. In this group, the remission rate increased at month 12 (Fig. 1a). Fig. 1 Comparison of effectiveness between the Pre-MPZ and the Post-MPZ. a Remission rates. b BVAS. c VDI. d Eosinophil counts. e Concomitant CS doses. BVAS, Birmingham vasculitis activity score; CS, corticosteroid; VDI, vasculitis damage index. P values were determined by Wilcoxon signed-rank test. *P < 0.05: baseline (month 0) vs. each observation points (month 0,1, 3, 6, and 12)
In the Pre-MPZ group, the BVASs were 0 [0–2.0] at month 1, 0 [0–2.0] at month 3, 0 [0–2.0] at month 6, and 1.0 [0–3.8] at month 12. In the Post-MPZ group, the BVASs were 0 [0–2.8] at month 1, 0 [0–0] at month 3, 0 [0–0] at month 6, and 0 [0–0] at month 12. The BVASs at month 1 and afterward significantly decreased from the BVAS at month 0 (Fig. 1b). The decrease in BVAS during the 1-year period in the Post-MPZ group was 0.5 [0–3.5], which was significantly higher than that in the Pre-MPZ group (− 1.0 [− 3.0–0]; Fig. 2a). Fig. 2 Comparison of changes of each item between the 12-month period in Pre-MPZ and Post-MPZ. a Changes in BVAS, b increase in VDI, c reduction in peripheral eosinophil counts (/μL), and d accumulated concomitant CS dose (mg/year). BVAS, Birmingham vasculitis activity score; CS, corticosteroid; VDI, vasculitis damage index. P values were determined by Wilcoxon signed-rank test. *P < 0.05: Pre-MPZ vs. Post-MPZ
Based on the changes in BVASs for each item, respiratory symptoms were exacerbated in the Pre-MPZ group but improved immediately after the initiation of MPZ therapy. The number of patients with symptoms decreased from 11/16 to 2/16 after 1 year of treatment. Ear, nose, and throat symptoms also improved, as the number of patients with these symptoms decreased from 6/16 to 3/16 patients, 1 year after the initiation of MPZ therapy. In contrast, neuropathy did not improve in either the Post-MPZ or Pre-MPZ groups. In the Post-MPZ group, no organ dysfunction was exacerbated at month 12 (Table 2). Table 2 Changes in organ damage before and after the introduction of MPZ
Pre-MPZ Post-MPZ
-12 M -11 M -9 M -6 M 0 M 1 M 3 M 6 M 12 M
General symptoms 0 0 1 (6.3%) 1 (6.3%) 1 (6.3%) 1 (6.3%) 0 1 (6.3%) 0
Cutaneous manifestations 1 (6.3%) 1 (6.3%) 1 (6.3%) 1 (6.3%) 2 (12.5%) 2 (12.5%) 0 1 (6.3%) 0
ENT manifestations 6 (37.5%) 6 (37.5%) 6 (37.5%) 6 (37.5%) 6 (37.5%) 6 (37.5%) 6 (37.5%) 4 (25.0%) 3 (18.8%)
Chest manifestations 6 (37.5%) 6 (37.5%) 8 (50.0%) 8 (50.0%) 11 (68.8%) 5 (31.3%) 2 (12.5%) 2 (12.5%) 2 (12.5%)
Nervous system manifestations 7 (45.8%) 7 (45.8%) 7 (45.8%) 8 (50.0%) 8 (50.0%) 8 (50.0%) 7 (43.8%) 7 (43.8%) 7 (43.8%)
ENT ear, nose, throat
In the Pre-MPZ group, the VDI scores were 3.5 [3.0–4.8] at month 1, 4.0 [3.0–5.5] at month 3, 4.0 [3.0–5.5] at month 6, and 4.0 [3.0–5.5] at month 12. In the Post-MPZ group, the VDI scores were 4.0 [3.0–5.5] at month 1, 4.0 [3.0–5.5] at month 3, 4.0 [3.0–5.5] at month 6, and 4.0 [3.0–5.5] at month 12, with no significant changes (Fig. 1c). The increase in the VDI score during the 1-year period was 0 [0–0.8] in the Pre-MPZ and 0 [0–0] in the Post-MPZ groups, with no significant difference between the groups (Fig. 2b).
In the Pre-MPZ group, the eosinophil counts were 280.4 [63.2–426.8]/μL at month 1, 217.8 [93.3–1354.2]/μL at month 3, and 293.9 [39.1–880.7]/μL at month 6. In the Post-MPZ group, the eosinophil counts were 54.8 [10.6–99.8]/μL at month 1, 25.2 [12.8–53.9]/μL at month 3, 29.4 [9.63–42.5]/μL at month 6, and 28.8 [20.5–68.0] at month 12, with a significant reduction from month 1 onwards (Fig. 1d). The reduction in the eosinophil counts during the 1-year period in the Post-MPZ group was 146.2 [9.88–2449.9], which was significantly higher than that in the Pre-MPZ group (− 8.8 [− 2927.4–175.4]; Fig. 2c).
The changes in the concomitant CS dose in each patient are shown in Table 3. In the Pre-MPZ group, the concomitant CS doses were 8.0 [5.0–10.0] mg/day at month 1, 7.0 [3.5–10.0] mg/day at month 3, 6.5 [2.6–10.0] mg/day at month 6, and 6.0 [2.6–10.0] mg/day at month 12. In the Post-MPZ group, the concomitant CS doses were 6.5 [2.6–10.0] mg/day at month 1, 5.0 [2.3–7.4] mg/day at month 3, 4.5 [0.5–5.0] mg/day at month 6, and 2.5 [0.1–3.8] mg/day at month 12, with a significant reduction from month 3 onwards (Fig. 1e). The concomitant CS dose was significantly lower in the Post-MPZ group (1655 [570.0–2190.0] mg/year) than in the Pre-MPZ group (2665 [1473.8–3993.8] mg/year; Fig. 2d). The changes in the use of immunosuppressants are shown in Table 4. The number of patients using concomitant immunosuppressant(s) reduced from 10 to nine patients at 1 year in the Pre-MPZ group and from nine to five patients in the Post-MPZ group. Table 3 Changes in the concomitant corticosteroids use before and after the introduction of MPZ (PSL mg/day)
Case No. Pre-MPZ Post-MPZ
− 12 months − 11 months − 9 months − 6 months 0 months 1 months 3 months 6 months 12 months
1 5 mg 5 mg 30 mg 15 mg 15 mg 15 mg 10 mg 10 mg 5 mg
2 5 mg 5 mg 7.5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg
3 8 mg 8 mg 3.5 mg 2.5 mg 2.5 mg 2.5 mg 2 mg 2 mg 1.5 mg
4 12 mg 12 mg 12 mg 12 mg 12 mg 10 mg 8 mg 9 mg 4 mg
5 8 mg 8 mg 7 mg 7 mg 7 mg 7 mg 5 mg 5 mg 3 mg
6 1 mg 1 mg 1 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg
7 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg
8 10 mg 9 mg 7 mg 6 mg 6 mg 6 mg 5 mg 3 mg 0.5 mg
9 5 mg 5 mg 4 mg 3 mg 3 mg 3 mg 3 mg 0 mg 0 mg
10 15 mg 10 mg 5 mg 35 mg 20 mg 15 mg 7.5 mg 5 mg 3 mg
11 8 mg 8 mg 7 mg 7 mg 7 mg 7 mg 5 mg 5 mg 2 mg
12 20 mg 15 mg 10 mg 10 mg 10 mg 10 mg 7 mg 5 mg 2 mg
13 10 mg 10 mg 10 mg 10 mg 10 mg 10 mg 8 mg 6 mg 5 mg
14 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 3 mg 3 mg
15 20 mg 15 mg 8 mg 7 mg 7 mg 7 mg 5 mg 4 mg 3 mg
16 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg 0 mg
Table 4 Changes in the concomitant immunosuppressants use before and after the introduction of MPZ
Case No. Pre-MPZ Post-MPZ
− 12 months − 11 months − 9 months − 6 months 0 months 1 months 3 months 6 months 12 months
1 MTX 8 mg MTX 8 mg None None None None None None None
2 MTX 8 mg+AZ 125 mg MTX 8 mg+AZ 125 mg MTX 8 mg+AZ 125 mg MTX 8 mg+AZ 125 mg MTX 8 mg+AZ 125 mg AZ125 mg AZ125 mg AZ125 mg AZ100 mg
3 AZ50 mg AZ50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg
4 None None AZ 50 mg None None None None MTX 8 mg MTX 8 mg
5 MTX 6 mg+AZ 50 mg MTX 6 mg+AZ 50 mg MTX 6 mg+AZ 50 mg MTX 6 mg+AZ 50 mg MTX 6 mg+AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg
6 MTX 16 mg MTX 16 mg MTX 16 mg MTX 16 mg MTX 16 mg MTX 16 mg MTX 10 mg MTX 4 mg None
7 None None None None None None None None None
8 MTX 12 mg MTX 12 mg MTX 12 mg MTX 12 mg MTX 12 mg None None None None
9 AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg None None None None
10 None None IVCY None None None None None None
11 TAC 3 mg TAC 3 mg TAC 3 mg TAC 3 mg TAC 3 mg None None None None
12 None None None None None None None None None
13 AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg AZ 50 mg
14 None None None None None None None None None
15 AZ 100 mg AZ 100 mg AZ 100 mg AZ 100 mg AZ 100 mg None None None None
16 None None None None None None None None None
IVCY cyclophosphamide pulse therapy i.v., MTX methotrexate, AZ azathioprine, TAC tacrolimus
MPZ retention rate and safety
The 1-year MPZ retention rate was 100%. Although three patients had an infection, all patients continued MPZ. Adverse events before and after the initiation of MPZ therapy are shown in Table 5. After MPZ therapy initiation, cases 1 and 11 developed bacterial pneumonia that required hospitalization. Sputum culture identified Moraxella catarrhalis in case 1 and Pseudomonas aeruginosa in case 11. In both patients, a drip infusion of antibiotics improved their condition. Case 15 also developed bacterial pneumonia. Because the general and respiratory conditions were favorable, the patient received oral antibiotic therapy at the outpatient clinic and improved. All three patients who had an infection after the initiation of MPZ therapy had the same infection within 1 year before initiation. None of the patients had a new infection after the initiation of therapy. Table 5 Adverse events before and after introduction of MPZ
Case No. Pre-MPZ Post-MPZ
1 Bacterial pneumonia (hospitalization) Bacterial pneumonia (hospitalization)
Bacterial species: Moraxella catarrhalis
2 None None
3 None None
4 Drug-induced liver injury None
5 Sinusitis surgery, bacterial bronchitis None
6 Bacterial bronchitis, infectious otitis media None
7 None None
8 None None
9 None None
10 None None
11 Bacterial pneumonia (hospitalization) Bacterial pneumonia (hospitalization)
Bacterial species: Pseudomonas aeruginosa
12 None None
13 Bacterial pneumonia (hospitalization) None
14 Bacterial bronchitis None
15 Bacterial pneumonia Bacterial pneumonia
16 None None
Discussion
The results of this study demonstrated the effectiveness and safety of MPZ for relapsing or refractory EGPA in a real-world setting by comparing the clinical courses before and after the initiation of MPZ therapy. During the 1-year period before MPZ therapy initiation, BVASs increased as CS doses were tapered, although the effectiveness of immunosuppressants in controlling disease activity was inadequate to allow CS dose reduction. Although many patients used AZ as a concomitant immunosuppressant before MPZ therapy initiation in this study, it has been previously reported that AZ is not useful for maintenance therapy [13]. In this study, BVASs and eosinophil counts significantly decreased 1 month after MPZ therapy initiation. The doses of CS and immunosuppressants were also successfully reduced (Figs. 2a, c, d). MPZ was a useful drug for maintenance therapy that exerted a more consistent effect in controlling disease activity than existing immunosuppressants.
Although the 16 patients included in this study had relatively low eosinophil counts (Table 1), the IL-5 levels before MPZ initiation were significantly higher than those of healthy controls. However, MPZ was effective even in patients whose serum concentration of IL-5 was comparable to that of healthy controls. We believe that these results indicate that MPZ is an effective treatment option in patients with relapsing or refractory EGPA, regardless of IL-5 concentration.
The MPZ retention rate was 100%, and the incidence of infections tended to decrease after MPZ initiation (Table 2). These results confirm the safety of MPZ. In particular, a severe infection that required hospitalization was noted only in two patients with a history of infection, and there was no occurrence of a new serious infection. These results can be considered useful. The reduced incidence of infection might be attributable to the significant reduction in concomitant CS doses and the reduced number of patients using concomitant immunosuppressant after MPZ therapy initiation (Fig. 2d; Tables 3 and 4). The long-term oral administration of CS induces infections and various complications, including osteoporosis, diabetes, hypertension, dyslipidemia, and femoral head necrosis. We did not observe a significant increase in VDI scores nor an increased incidence of complications owing to CS after MPZ therapy initiation. Thus, we demonstrated that MPZ therapy was sufficiently effective in controlling disease activity and prevented adverse events induced by CS and immunosuppressants. In the future, it is important that a long-term investigation is conducted to determine whether long-term MPZ therapy allows the dose reduction or discontinuation of CS without relapse and whether VDI increases.
However, this study has important limitations. For example, this study had limited statistical power owing to the small sample size. Additionally, because the Pre-MPZ group was set as the control group to compare the effects of MPZ therapy with, the control group might be inadequate. Moreover, few countries recommend subcutaneous MPZ injection at a dose of 300 mg for EGPA, such as Japan. A strength of this study is that although there are some case reports of the use of MPZ at a dose of 300 mg [14] and a case series of the use of MPZ at 100 mg for the treatment of comorbid asthma [15], no studies have investigated the safety and effectiveness of MPZ at 300 mg in real-world clinical practice. To the best of our knowledge, this is the first study to demonstrate the safety and effectiveness of MPZ at 300 mg in a real-world setting.
Supplementary Information
Additional file 1: Supplementary Table 1. Clinical manifestations, Japanese Ministry of Health, Labor and Welfare criteria items and classification criteria of the American College of Rheumatology criteria at diagnosis.
Additional file 2: Supplementary Table 2. Baseline characteristic of 16 Patients with Eosinophilic Granulomatosis with Polyangiitis.
Additional file 3: Supplementary Fig. 1. Serum IL-5 concentration of 16 Patients with EGPA before initiating MPZ and health controls (HC group). P values were determined by Mann-Whitney’s U test. p* < 0.01: EGPA group (n = 16) vs. HC (n = 6).
Abbreviations
MPZ Mepolizumab
EGPA Eosinophilic granulomatosis with polyangiitis
CS Corticosteroids
BVAS Birmingham vasculitis activity score
VDI Vasculitis damage index
CY Cyclophosphamide
IVCY Intravenous cyclophosphamide
AZ Azathioprine
MTX Methotrexate
CsA Cyclosporine
TAC Tacrolimus
IVIG Intravenous immunoglobulin
Pre-MPZ 1-Year period before initiating MPZ therapy
Post-MPZ 1-Year period after initiating MPZ
Supplementary information
Supplementary information accompanies this paper at 10.1186/s13075-021-02462-6.
Acknowledgements
The authors thank the study participants, without whom this study would never have been accomplished as well as the investigators for their participation in the study, especially those in Kitakyushu General Hospital, Tobata General Hospital, Saiseikai Shimonoseki General Hospital, Fukuoka Yutaka Central Hospital, Nakama Municipal Hospital, and Steel Memorial Yahata Hospital.
Authors’ contributions
MU contributed to the study design, overall review, writing of the manuscript, and the other authors were involved in the performance of the study and review of the manuscript. YT, MI, KN, SI, and SN participated in the study design and coordination. All authors read and approved the final manuscript.
Funding
No specific funding was received from any bodies in the public, commercial, or not-for-profit sectors to carry out the work described in this article.
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
Ethical approval was obtained from the University of Occupational and Environmental Health Japan Ethics Committee following the Helsinki Declaration. This retrospective study was approved by the institutional review board, and the requirement to obtain informed consent was waived.
Consent for publication
Not applicable.
Competing interests
Y. Tanaka has received speaking fees and/or honoraria from Daiichi-Sankyo, Astellas, Eli Lilly, Chugai, Sanofi, Abbvie, Pfizer, YL Biologics, Bristol-Myers, Glaxo-Smithkline, UCB, Mitsubishi-Tanabe, Novartis, Eisai, Takeda, Janssen, and Asahi-kasei and has received research grants from Mitsubishi-Tanabe, Bristol-Myers, Eisai, Chugai, Takeda, Abbvie, Astellas, Daiichi-Sankyo, Ono, MSD, and Taisho-Toyama.
K. Nakano has received speaking fees from Astellas, UCB, Mitsubishi-Tanabe, and Eisai and has received research grants from Mitsubishi-Tanabe, Eisai, and Eli Lilly.
S. Nakayamada received speaking fees and/or honoraria from Bristol-Myers, Sanofi, Abbvie, Eisai, Eli Lilly, Chugai, Asahi-kasei, and Pfizer (less than $10,000 each) and also research grants from Mitsubishi-Tanabe, Takeda, Novartis, and MSD.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33726827 | 20,035,498 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adverse event'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaemia'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Back pain'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Constipation'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cough'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dyspnoea'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Febrile neutropenia'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Headache'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatotoxicity'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nasal congestion'. | Safety of switching between rituximab biosimilars in onco-hematology.
Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
Introduction
Biosimilars are approved on the basis of a comprehensive comparability exercise aimed at establishing the similarity to the reference medicinal products in terms of quality, biological activity, safety and efficacy1.
The first biosimilars introduced in Europe in 2006, were biosimilar somatropins2. Until recently, only biosimilars of these lower molecular-weight biologics were available. This changed in September 2013 when the European Medicines Agency (EMA) recommended the granting of marketing authorization for the first time for two biosimilar versions of the monoclonal antibody (mAb) infliximab3.
As of 1st January 2021, there are 58 authorized products in the EU and 29 in the USA4. Existing data on switching for selected biosimilars have been generated from several studies5–7. In more than 10 years of clinical experience, no substantial clinical and safety differences have been detected8. However, especially for newly marketed biosimilars, concerns are raised with respect to the practice of switching in patients already treated with a specific biologic product (either reference or biosimilar)9.
Differently for the FDA, the EMA does not make a distinction between biosimilars and interchangeable products and advice to prescribers fall under the responsibility of member states10.
In Europe, biosimilars have become a reality, with some biosimilars achieving market share of > 90%, while in the USA, the uptake of biosimilars has been modest thus far11.
The first biosimilar rituximab was approved in 20179. The equivalence between reference rituximab (MABTHERA) and its biosimilars—in terms of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity—has been demonstrated in randomized, double-blind, controlled trials12–15.
After a careful review of the scientific evidence on rituximab, hematologists and pharmacists working at Trento General Hospital agreed that reference and biosimilar products could be used interchangeably in all patients, both naïve and experienced ones. Consequently, in 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital: TRUXIMA (Mundipharma) in the first year and RIXATHON (Sandoz) in the second one. It was also agreed to conduct a prospective observational study specifically focusing on safety to build patient and physician confidence.
The aim of the study was to document any adverse event (AE) reported in association with the use of biosimilar rituximab and with the practice of switching between different products in patients with Non Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL).
Methods
The study was conducted in accordance with ethical principles derived from guidelines that included the Declaration of Helsinki16, as well as following all relevant local requirements. The Ethics Committee of the Health Trust of the Autonomous Province of Trento approved the study protocol (2018/n.4586). Informed consent was secured from all subjects in this study. Patients were treated according to the usual practice and no additional procedure was carried out. Each patient was informed about the objectives of the study and provided written informed consent to collect and analyze data for research purposes.
The study population consisted of adult patients with NHL and CLL, consecutively admitted into the Hematology Unit of the Trento General Hospital from March 10th 2018 to March 10th 2019, whose therapy included rituximab administration. Patients were followed up until the first of the following dates: last follow up visit, death, end of study (30 September 2019).
Baseline characteristics were ascertained at the time of the first infusion of rituximab (dosed at 375 mg/m2 as part of standard treatment), during the study period. Data were collected on patient characteristics (i.e., diagnosis, age, body surface area, performance status), previous treatment and concomitant medications, premedications, rituximab indications, dosage and administration.
During the study period, patients may have received: (a) either a biosimilar or the reference product (no-switch group); (b) two biosimilar products (switch during the study period); (c) a rituximab formulation (reference or biosimilar) that was different from the one received before the study period (anamnestic switch).
Adverse events (AEs) of interest consisted of Infusion Related Reactions (IRR) (i.e., type of reaction, treatment of reaction, duration of interruption of infusion) and other adverse events occurring between different infusions, regardless of their severity (grade 1–4). Safety follow-up took place at every administration of rituximab; information on adverse events occurring at home was obtained at every clinical access (at least once per month). The causality assessment for all drug–event couples was made by the attending physicians using the Naranjo algorithm17.
NHL and CLL disease activity was assessed according to the local clinical practice routine, after the third cycle (week 9) and at the end-of-treatment visit, and was grouped as overall response rate, complete response, partial response, stable disease, progressive disease18,19.
Performance status was assessed by clinicians using the Eastern Cooperative Oncologic Group Scale (ECOG) scale20.
We described the characteristics of patients included in the study using counts with percentages and median with interquartile range (IQR) for categorical and continuous variables, respectively. The incidence of AEs among patients with “no-switch”, “switch during the study period” and “anamnestic switch” was analysed through a Chi-square test for categorical variables. Both the number of patients and the number of infusions were used as denominator of the events of interest. The study population represented the experience of a single hospital and no formal sample size calculation was carried out.
Results and discussion
Eighty-three patients (37 women and 46 men) affected by NHL (n = 72) and CLL (n = 11) were included in the study (Table 1). Patients had a median age of 71 years (interquartile range-IQR 63–79 years) and more than 20% had a performance status ≥ 3. The median follow-up of the patients was 10.5 months (IQR 7–14 months).Table 1 Characteristics of patients.
N. of patients 83
Female [n (%)] 37 (44.0%)
BSA (m2) [median (IQR)] 1.8 (1.7–1.9)
Age at diagnosis (years) [median (IQR)] 68 (62–78)
Age at baseline (years) [median (IQR)] 71 (63–79)
Diagnosis [n (%)]
NHL 72 (86.9%)
Indolent NHL
Follicular lymphoma 19 (23.8%)
Extranodal marginal zone (MALT) 1 (1.2%)
Aggressive NHL
Diffuse large B-cell CD20 positive 51 (60.7%)
Mantle cell lymphoma 1 (1.2%)
CLL 11 (13.1%)
Performance status [n (%)]
0 4 (4.8%)
1 27 (32.1%)
2 33 (39.9%)
≥ 3 17 (20.2%)
NA 2 (3.6%)
Cycles of rituximab, total cycles n. 465 [n (%)]
Biosimilar-TRUXIMA 163 (34.9%)
Biosimilar-RIXATHON 302 (63.6%)
Switch, total patients n. 83 [n (%)]
No switch 33 (40.5%)
Switch during the study period 26 (31.9%)
Anamnestic switch 24 (28.6%)
Response, NHL [n (%)]
Complete response 60 (83.6%)
Partial response 7 (9.6%)
Progressive disease 3 (4.1%)
Not evaluated (ongoing treatment) 2 (2.7%)
Response, CLL [n (%)]
Complete response 2 (18.2%)
Partial response 2 (18.2%)
Progressive disease 2 (18.2%)
Stable disease 2 (18.2%)
Not evaluated (ongoing treatment) 3 (27.2%)
n number, BSA body surface area, IQR inter quartile range, NHL Non Hodgkin’s Lymphoma, CLL chronic lymphocytic leukemia, NA not available.
During the study period the patient population received 465 infusions of intravenous rituximab (163 TRUXIMA, and 302 RIXATHON). The median dosage received was 652 mg (range 500–900 mg). The median number of infusions per patient was 5.6 (range 1–8 infusions). All patients (n = 83) received biosimilars. Among non-switchers, 33 patients (40%) received a biosimilar formulation. At least one switch was experienced by the remaining 50 patients (60%): 26 (31%) during the study period and 24 (29%) before the study period (anamnestic switch).
Adverse events (n = 146) were reported in 71 patients (85.5%). Fifty-five (66.3%) and 10 (12.0%) patients had respectively neutropenia or anemia of grade 1–2. Treatment-related grade 3–4 AEs were reported in five patients (6.0%): neutropenia in two patients, and febrile neutropenia, thrombocytopenia, liver toxicity, in one patient each. Six patients experienced rituximab related adverse events of grade 1, which is consistent with the scientific literature (Table 2)21.Table 2 Hematologic and non-hematologic adverse events registered during the study perioda (March 2018- March 2019).
Adverse events Any grade Grade 3–4 Rituximab related AEb
Grade 1–2
n (%) n (%) n (%)
Hematologic
Neutropenia 57 (68.7) 2 (2.4) –
Anemia 10 (12.0) – –
Febrile Neutropenia 2 (2.4) 1 (1.2) –
Thrombocytopenia 2 (2.4) 1 (1.2) –
Non hematologic
Fever 13 (15.7) – 2 (2.4)
Tingling of the hands or feet 7 (8.4) – –
Rash 6 (7.2) – –
Urinary tract infection 5 (6.0) – –
Nause 4 (4.8) – –
Constipation 4 (4.8) – –
Cough 2 (2.4) – –
Stuffy nose 2 (2.4) – 2 (2.4)
Liver toxicity 1 (1.2) 1 (1.2) –
Throat itching 1 (1.2) – 1 (1.2)
Back pain 1 (1.2) – 1 (1.2)
Dyspnea 1 (1.2) – 1 (1.2)
Tremors 1 (1.2) – 1 (1.2)
Headache 1 (1.2) – 1 (1.2)
Other 26 (31.3) – –
N number.
aEvents experienced by at least two patients, or grade 3–4, or causally related to rituximab, are reported in the table.
bThe events were assessed as causally related to rituximab by the attending clinicians.
The incidence of AEs was similar in patients who received one or two biosimilar formulations, both for any events (32/33 patients in the no switch group vs 25/26 patients with a switch during the study period, p = 0.86) and for events of grade 3–4 (2/33 vs 1/26; p = 0.70).
The proportion of AEs was lower in patients who were receiving a rituximab formulation (one biosimilar or the other) that was different from the one before the study period (14 out of 24 patients, 58%; 2 events of grade 3–4) (data not shown).
After a median follow-up of 10 months, adverse events reported were similar in terms of seriousness and frequency, regardless of rituximab formulation and switching. The incidence of events was lower only in the group of prevalent patients who had been already treated in the past with a different rituximab formulation (anamnestic switching).
To our knowledge, this is the first real‐life cohort study assessing the safety of switching between different rituximab formulations (biosimilars and originator) in NHL and CLL patients.
Although some open-label studies have shown an increased number of withdrawals or AEs following a switch, these outcomes were less frequently observed in randomized studies9,21 suggesting the potential occurrence of a “nocebo” effect resulting from negative expectations toward the biosimilar22.
The results of this study support the position that switching between biosimilars, or from reference rituximab to its biosimilars, as part of routine clinical practice in NHL and CLL patients, has the same safety profile expected in patients continuously treated with reference rituximab. Data from post-marketing studies and real-world experience are needed to provide additional information to supplement the strong evidence already obtained on biosimilars from RCTs.
The increasing availability of biosimilars has led to significant healthcare savings and provided greater patient access to high cost therapeutics23. However, the cost-saving potential depends on various factors, such as the price of the reference product and the competition market24.
A cost-analysis study conducted in Europe, predicted that switching to a rituximab biosimilar would save €56.82 million over a year25.
In the setting of our hematology unit of a general hospital, this shared approach has increased clinicians and patients confidence in biosimilars with respect to safety, generating at the same time a 45% reduction in the price of rituximab (around 400,000 euros savings in one year).
Acknowledgements
The authors would like to thank the patients participating in this study.
Author contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S.A., G.T. and S.A.M.U. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Data availability
The data that support the findings of this study are available on request from the corresponding author [S.U.]. The data are not publicly available because they contain information that could compromise research participant privacy/consent.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | RITUXIMAB-ABBS | DrugsGivenReaction | CC BY | 33727667 | 19,187,223 | 2021-03-16 |
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