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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Steatohepatitis'. | Fatal acute-on-chronic liver failure in amiodarone-related steatohepatitis: a case report.
BACKGROUND
Amiodarone is an antiarrhythmic drug that has been recognized to induce hepatotoxicity. We report a case of acute-on-chronic liver failure (ACLF) in a patient who was receiving amiodarone for more than 2 years. The patient developed cirrhosis and suppurative microabscesses of the liver and died of progressive liver failure.
METHODS
A 69-year-old woman with risk factors for nonalcoholic fatty liver disease (NAFLD) was treated with oral amiodarone at a daily dose of 400 mg for more than 2 years, until she developed epigastralgia and vomiting. Initial laboratory findings included leukocytosis and elevated liver enzymes. Images of abdominal computed tomography scan revealed diffusely increased hepatic attenuation density (in contrast to decreased density in NAFLD), hepatomegaly, periportal edema, and ascites. Liver biopsy targeting the hotspot identified through positron emission tomography confirmed the diagnosis of amiodarone-associated chronic steatohepatitis and superimposed microabscesses. The patient died of progressive ACLF despite intensive supportive care.
CONCLUSIONS
Accumulation of amiodarone can result in chronic liver disease and pose an additional risk of ACLF following infection.
Background
Acute-on-chronic liver failure (ACLF) is a process of rapid deterioration in liver function occurring against a background of chronic liver disease characterized by multisystem organ failure, systemic inflammation, and high short-term mortality. Chronic liver disease is infrequently caused by potential hepatotoxic agents, such as amiodarone [1]. We report a rare case of ACLF caused by acute suppurative microabscesses superimposed on chronic drug-induced liver injury (DILI) associated with amiodarone.
Case presentation
A 69-year-old woman was admitted to our hospital for postprandial epigastralgia and vomiting for 2 weeks. She had a history of diabetes mellitus and hyperlipidemia, and she had undergone bypass surgery for coronary arterial disease 2.5 years previously. She had no alcohol consumption. Initial evaluation revealed distended abdomen, epigastric tenderness, neutrophilic leukocytosis (17.3 k/μL), elevated C-reactive protein, pyuria, liver panel abnormalities (i.e., hepatitis and conjugated hyperbilirubinemia), and coagulopathy. At presentation, the serum levels of aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, direct bilirubin, albumin, and international normalized ratio of prothrombin time were 226 U/L, 108 U/L, 11.72 mg/dL, 6.97 mg/dL, 2.1 g/dL, and 1.44, respectively. Two months before this admission, the serum levels of AST, ALT, total bilirubin, and direct bilirubin were 144 U/L, 131U/L, 0.64 mg/dL, and 0.21 mg/dL, respectively. The AST to platelet ratio index (APRI) score was 2.04, an increase from 1.23 in 2 years. A hepatopathy screening including viral hepatitis (hepatitis B, C, D, and E), auto-immune and hereditary liver disease was negative, except a document of remote hepatitis A infection. Computed tomography (CT) scanning disclosed hepatomegaly, periportal edema, and ascites (Fig. 1a, b). Notably, a diffuse increase in hepatic attenuation density, a hallmark of iron or amiodarone deposition, was observed. Amiodarone had been prescribed at a daily dose of 400 mg (estimated total cumulative dose exposure of 360 g) since the bypass surgery for tachyarrhythmia. Liver attenuation was approximately 50 Hounsfield units (HU) before exposure to amiodarone (Fig. 1c) and had increased one-fold by the following year. Amiodarone was discontinued upon admission. Broad-spectrum antibiotics were used to treat a documented vancomycin-resistant enterococcal urinary tract infection and other potential occult infections without significant clinical improvement. Leukocytosis persisted and a fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan 3 weeks after admission revealed multiple areas of active inflammation within the liver (Fig. 1d). The pathological findings of a targeted biopsy of the largest hot spot (Fig. 1d, arrow) in the FDG-PET scan revealed multifocal necrotizing suppurative microabscesses accompanied by aggregates of granulation tissue and histiocytes (Fig. 1e). No pathogen was observed on acid-fast, periodic-acid-Schiff, and Grocott's methenamine silver staining. Moreover, the liver parenchyma demonstrated cirrhosis and regenerative nodules associated with prominent periseptal ballooned hepatocytes containing numerous Mallory-Denk bodies (Fig. 1f). The changes of selective liver panels since the initial presentation were illustrated in Fig. 2. A rare presentation of ACLF was confirmed based on the findings of amiodarone-associated chronic steatohepatitis and superimposed microabscesses. The patient’s Chronic Liver Failure Consortium (CLIF-C) ACLF score was calculated to be 69.4, and the model for the end-stage liver disease (MELD) score was high (> 30), indicating an unfavorable outcome [2] (Fig. 3). The patient’s clinical condition deteriorated, and she died of progressive liver and renal failure.Fig. 1 Development and diagnosis of ACLF. a–c Serial changes in hepatic signal intensity on CT imaging. High attenuation (90–100 HU) following (a) the use of amiodarone and (b) periportal edema in ACLF. c Low attenuation (50 HU) of liver parenchyma 2 years prior to exposure to amiodarone. d FDG-PET scanning demonstrated focal hypermetabolic hepatic lesions in both lobes, with a maximum standardized uptake value of 8.8 (arrow). e, f Histopathological examination showed (e) suppurative microabscesses (dotted frame) and (f) numerous Mallory-Denk bodies in the periseptal hepatocytes
Fig. 2 Trends of liver function tests since the initial presentation. AST, aspartate transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase; T-Bil, total bilirubin; D-Bil, direct bilirubin
Fig. 3 Trend of severity scores since the initial presentation. ACLF, acute-on-chronic liver failure; AD, acute decompensation; CLIF-C, Chronic Liver Failure Consortium; MELD, Model for End-stage Liver Disease
Discussion and conclusions
Amiodarone accounts for 1–3% of all DILIs, most commonly exhibiting a hepatocellular injury pattern, particularly in patients with older age, lower body surface area, and dyslipidemia [3]. Elevation of liver enzymes following high-dose intravenous infusion can occur and is mediated through direct hepatotoxicity, which is usually transient and self-reversible; by contrast, liver cirrhosis due to chronic use of low-dose amiodarone is caused by nonallergic idiosyncratic reactions of accumulation-related injury [4]. Amiodarone could induce lysosomal phospholipidosis, resulting in formation of Mallory-Denk bodies in the liver and inhibiting phagocytosis, the latter of which might impair macrophage function and contribute to ACLF progression as observed in the present case [5]. Steatohepatitis associated with amiodarone, through inhibition of the β-oxidation of free fatty acid in the mitochondria [4], exhibits high HU values, in contrast to hypointensity (low HU values) of the liver in nonalcoholic steatohepatitis associated with metabolic syndrome. However, additional hepatotoxicity by amiodarone on top of steatohepatitis related to her metabolic syndrome/insulin resistance is the most likely scenario of her chronic liver disease based on the above negative hepatopathy panel [6].
With the development of toxicity, no definite treatment exists for amiodarone-induced liver injury apart from drug discontinuation, and the mortality rate is as high as 60% at 5 months. The cumulative dose in our patient was 360 g over 2.5 years, close to the reported dose deemed sufficient to induce liver cirrhosis [7]. Together with acute inflammation and possibly macrophage dysfunction, we propose that amiodarone serves as a crucial contributor to the development of ACLF.
In conclusion, accumulation of amiodarone can result in chronic liver disease and pose an additional risk of developing ACLF following infections.
Abbreviations
ACLFacute-on-chronic liver failure
ALTalanine transaminase;
ASTaspartate transaminase
CLIF-Cchronic liver failure consortium
CTcomputed tomography
DILIdrug-induced liver injury
FDGfluorodeoxyglucose
HUhounsfield unit
MELDmodel for end-stage liver disease
PETposition emission tomography
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
None.
Authors’ contributions
WIJ analyzed and interpreted the patient data regarding the liver disease and the infection. TJH performed the histological examination of the liver. WIJ and HCM were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
Nil.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Waived.
Consent for publication
Written consent for publication from the next of kin was obtained.
Competing interests
Nothing to report. | AMIODARONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33530924 | 18,942,904 | 2021-02-02 |
What was the dosage of drug 'AMIODARONE HYDROCHLORIDE'? | Fatal acute-on-chronic liver failure in amiodarone-related steatohepatitis: a case report.
BACKGROUND
Amiodarone is an antiarrhythmic drug that has been recognized to induce hepatotoxicity. We report a case of acute-on-chronic liver failure (ACLF) in a patient who was receiving amiodarone for more than 2 years. The patient developed cirrhosis and suppurative microabscesses of the liver and died of progressive liver failure.
METHODS
A 69-year-old woman with risk factors for nonalcoholic fatty liver disease (NAFLD) was treated with oral amiodarone at a daily dose of 400 mg for more than 2 years, until she developed epigastralgia and vomiting. Initial laboratory findings included leukocytosis and elevated liver enzymes. Images of abdominal computed tomography scan revealed diffusely increased hepatic attenuation density (in contrast to decreased density in NAFLD), hepatomegaly, periportal edema, and ascites. Liver biopsy targeting the hotspot identified through positron emission tomography confirmed the diagnosis of amiodarone-associated chronic steatohepatitis and superimposed microabscesses. The patient died of progressive ACLF despite intensive supportive care.
CONCLUSIONS
Accumulation of amiodarone can result in chronic liver disease and pose an additional risk of ACLF following infection.
Background
Acute-on-chronic liver failure (ACLF) is a process of rapid deterioration in liver function occurring against a background of chronic liver disease characterized by multisystem organ failure, systemic inflammation, and high short-term mortality. Chronic liver disease is infrequently caused by potential hepatotoxic agents, such as amiodarone [1]. We report a rare case of ACLF caused by acute suppurative microabscesses superimposed on chronic drug-induced liver injury (DILI) associated with amiodarone.
Case presentation
A 69-year-old woman was admitted to our hospital for postprandial epigastralgia and vomiting for 2 weeks. She had a history of diabetes mellitus and hyperlipidemia, and she had undergone bypass surgery for coronary arterial disease 2.5 years previously. She had no alcohol consumption. Initial evaluation revealed distended abdomen, epigastric tenderness, neutrophilic leukocytosis (17.3 k/μL), elevated C-reactive protein, pyuria, liver panel abnormalities (i.e., hepatitis and conjugated hyperbilirubinemia), and coagulopathy. At presentation, the serum levels of aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, direct bilirubin, albumin, and international normalized ratio of prothrombin time were 226 U/L, 108 U/L, 11.72 mg/dL, 6.97 mg/dL, 2.1 g/dL, and 1.44, respectively. Two months before this admission, the serum levels of AST, ALT, total bilirubin, and direct bilirubin were 144 U/L, 131U/L, 0.64 mg/dL, and 0.21 mg/dL, respectively. The AST to platelet ratio index (APRI) score was 2.04, an increase from 1.23 in 2 years. A hepatopathy screening including viral hepatitis (hepatitis B, C, D, and E), auto-immune and hereditary liver disease was negative, except a document of remote hepatitis A infection. Computed tomography (CT) scanning disclosed hepatomegaly, periportal edema, and ascites (Fig. 1a, b). Notably, a diffuse increase in hepatic attenuation density, a hallmark of iron or amiodarone deposition, was observed. Amiodarone had been prescribed at a daily dose of 400 mg (estimated total cumulative dose exposure of 360 g) since the bypass surgery for tachyarrhythmia. Liver attenuation was approximately 50 Hounsfield units (HU) before exposure to amiodarone (Fig. 1c) and had increased one-fold by the following year. Amiodarone was discontinued upon admission. Broad-spectrum antibiotics were used to treat a documented vancomycin-resistant enterococcal urinary tract infection and other potential occult infections without significant clinical improvement. Leukocytosis persisted and a fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan 3 weeks after admission revealed multiple areas of active inflammation within the liver (Fig. 1d). The pathological findings of a targeted biopsy of the largest hot spot (Fig. 1d, arrow) in the FDG-PET scan revealed multifocal necrotizing suppurative microabscesses accompanied by aggregates of granulation tissue and histiocytes (Fig. 1e). No pathogen was observed on acid-fast, periodic-acid-Schiff, and Grocott's methenamine silver staining. Moreover, the liver parenchyma demonstrated cirrhosis and regenerative nodules associated with prominent periseptal ballooned hepatocytes containing numerous Mallory-Denk bodies (Fig. 1f). The changes of selective liver panels since the initial presentation were illustrated in Fig. 2. A rare presentation of ACLF was confirmed based on the findings of amiodarone-associated chronic steatohepatitis and superimposed microabscesses. The patient’s Chronic Liver Failure Consortium (CLIF-C) ACLF score was calculated to be 69.4, and the model for the end-stage liver disease (MELD) score was high (> 30), indicating an unfavorable outcome [2] (Fig. 3). The patient’s clinical condition deteriorated, and she died of progressive liver and renal failure.Fig. 1 Development and diagnosis of ACLF. a–c Serial changes in hepatic signal intensity on CT imaging. High attenuation (90–100 HU) following (a) the use of amiodarone and (b) periportal edema in ACLF. c Low attenuation (50 HU) of liver parenchyma 2 years prior to exposure to amiodarone. d FDG-PET scanning demonstrated focal hypermetabolic hepatic lesions in both lobes, with a maximum standardized uptake value of 8.8 (arrow). e, f Histopathological examination showed (e) suppurative microabscesses (dotted frame) and (f) numerous Mallory-Denk bodies in the periseptal hepatocytes
Fig. 2 Trends of liver function tests since the initial presentation. AST, aspartate transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase; T-Bil, total bilirubin; D-Bil, direct bilirubin
Fig. 3 Trend of severity scores since the initial presentation. ACLF, acute-on-chronic liver failure; AD, acute decompensation; CLIF-C, Chronic Liver Failure Consortium; MELD, Model for End-stage Liver Disease
Discussion and conclusions
Amiodarone accounts for 1–3% of all DILIs, most commonly exhibiting a hepatocellular injury pattern, particularly in patients with older age, lower body surface area, and dyslipidemia [3]. Elevation of liver enzymes following high-dose intravenous infusion can occur and is mediated through direct hepatotoxicity, which is usually transient and self-reversible; by contrast, liver cirrhosis due to chronic use of low-dose amiodarone is caused by nonallergic idiosyncratic reactions of accumulation-related injury [4]. Amiodarone could induce lysosomal phospholipidosis, resulting in formation of Mallory-Denk bodies in the liver and inhibiting phagocytosis, the latter of which might impair macrophage function and contribute to ACLF progression as observed in the present case [5]. Steatohepatitis associated with amiodarone, through inhibition of the β-oxidation of free fatty acid in the mitochondria [4], exhibits high HU values, in contrast to hypointensity (low HU values) of the liver in nonalcoholic steatohepatitis associated with metabolic syndrome. However, additional hepatotoxicity by amiodarone on top of steatohepatitis related to her metabolic syndrome/insulin resistance is the most likely scenario of her chronic liver disease based on the above negative hepatopathy panel [6].
With the development of toxicity, no definite treatment exists for amiodarone-induced liver injury apart from drug discontinuation, and the mortality rate is as high as 60% at 5 months. The cumulative dose in our patient was 360 g over 2.5 years, close to the reported dose deemed sufficient to induce liver cirrhosis [7]. Together with acute inflammation and possibly macrophage dysfunction, we propose that amiodarone serves as a crucial contributor to the development of ACLF.
In conclusion, accumulation of amiodarone can result in chronic liver disease and pose an additional risk of developing ACLF following infections.
Abbreviations
ACLFacute-on-chronic liver failure
ALTalanine transaminase;
ASTaspartate transaminase
CLIF-Cchronic liver failure consortium
CTcomputed tomography
DILIdrug-induced liver injury
FDGfluorodeoxyglucose
HUhounsfield unit
MELDmodel for end-stage liver disease
PETposition emission tomography
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
None.
Authors’ contributions
WIJ analyzed and interpreted the patient data regarding the liver disease and the infection. TJH performed the histological examination of the liver. WIJ and HCM were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
Nil.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Waived.
Consent for publication
Written consent for publication from the next of kin was obtained.
Competing interests
Nothing to report. | ESTIMATED TOTAL CUMULATIVE DOSE EXPOSURE OF 360 G | DrugDosageText | CC BY | 33530924 | 18,942,904 | 2021-02-02 |
What was the outcome of reaction 'Abscess'? | Fatal acute-on-chronic liver failure in amiodarone-related steatohepatitis: a case report.
BACKGROUND
Amiodarone is an antiarrhythmic drug that has been recognized to induce hepatotoxicity. We report a case of acute-on-chronic liver failure (ACLF) in a patient who was receiving amiodarone for more than 2 years. The patient developed cirrhosis and suppurative microabscesses of the liver and died of progressive liver failure.
METHODS
A 69-year-old woman with risk factors for nonalcoholic fatty liver disease (NAFLD) was treated with oral amiodarone at a daily dose of 400 mg for more than 2 years, until she developed epigastralgia and vomiting. Initial laboratory findings included leukocytosis and elevated liver enzymes. Images of abdominal computed tomography scan revealed diffusely increased hepatic attenuation density (in contrast to decreased density in NAFLD), hepatomegaly, periportal edema, and ascites. Liver biopsy targeting the hotspot identified through positron emission tomography confirmed the diagnosis of amiodarone-associated chronic steatohepatitis and superimposed microabscesses. The patient died of progressive ACLF despite intensive supportive care.
CONCLUSIONS
Accumulation of amiodarone can result in chronic liver disease and pose an additional risk of ACLF following infection.
Background
Acute-on-chronic liver failure (ACLF) is a process of rapid deterioration in liver function occurring against a background of chronic liver disease characterized by multisystem organ failure, systemic inflammation, and high short-term mortality. Chronic liver disease is infrequently caused by potential hepatotoxic agents, such as amiodarone [1]. We report a rare case of ACLF caused by acute suppurative microabscesses superimposed on chronic drug-induced liver injury (DILI) associated with amiodarone.
Case presentation
A 69-year-old woman was admitted to our hospital for postprandial epigastralgia and vomiting for 2 weeks. She had a history of diabetes mellitus and hyperlipidemia, and she had undergone bypass surgery for coronary arterial disease 2.5 years previously. She had no alcohol consumption. Initial evaluation revealed distended abdomen, epigastric tenderness, neutrophilic leukocytosis (17.3 k/μL), elevated C-reactive protein, pyuria, liver panel abnormalities (i.e., hepatitis and conjugated hyperbilirubinemia), and coagulopathy. At presentation, the serum levels of aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, direct bilirubin, albumin, and international normalized ratio of prothrombin time were 226 U/L, 108 U/L, 11.72 mg/dL, 6.97 mg/dL, 2.1 g/dL, and 1.44, respectively. Two months before this admission, the serum levels of AST, ALT, total bilirubin, and direct bilirubin were 144 U/L, 131U/L, 0.64 mg/dL, and 0.21 mg/dL, respectively. The AST to platelet ratio index (APRI) score was 2.04, an increase from 1.23 in 2 years. A hepatopathy screening including viral hepatitis (hepatitis B, C, D, and E), auto-immune and hereditary liver disease was negative, except a document of remote hepatitis A infection. Computed tomography (CT) scanning disclosed hepatomegaly, periportal edema, and ascites (Fig. 1a, b). Notably, a diffuse increase in hepatic attenuation density, a hallmark of iron or amiodarone deposition, was observed. Amiodarone had been prescribed at a daily dose of 400 mg (estimated total cumulative dose exposure of 360 g) since the bypass surgery for tachyarrhythmia. Liver attenuation was approximately 50 Hounsfield units (HU) before exposure to amiodarone (Fig. 1c) and had increased one-fold by the following year. Amiodarone was discontinued upon admission. Broad-spectrum antibiotics were used to treat a documented vancomycin-resistant enterococcal urinary tract infection and other potential occult infections without significant clinical improvement. Leukocytosis persisted and a fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan 3 weeks after admission revealed multiple areas of active inflammation within the liver (Fig. 1d). The pathological findings of a targeted biopsy of the largest hot spot (Fig. 1d, arrow) in the FDG-PET scan revealed multifocal necrotizing suppurative microabscesses accompanied by aggregates of granulation tissue and histiocytes (Fig. 1e). No pathogen was observed on acid-fast, periodic-acid-Schiff, and Grocott's methenamine silver staining. Moreover, the liver parenchyma demonstrated cirrhosis and regenerative nodules associated with prominent periseptal ballooned hepatocytes containing numerous Mallory-Denk bodies (Fig. 1f). The changes of selective liver panels since the initial presentation were illustrated in Fig. 2. A rare presentation of ACLF was confirmed based on the findings of amiodarone-associated chronic steatohepatitis and superimposed microabscesses. The patient’s Chronic Liver Failure Consortium (CLIF-C) ACLF score was calculated to be 69.4, and the model for the end-stage liver disease (MELD) score was high (> 30), indicating an unfavorable outcome [2] (Fig. 3). The patient’s clinical condition deteriorated, and she died of progressive liver and renal failure.Fig. 1 Development and diagnosis of ACLF. a–c Serial changes in hepatic signal intensity on CT imaging. High attenuation (90–100 HU) following (a) the use of amiodarone and (b) periportal edema in ACLF. c Low attenuation (50 HU) of liver parenchyma 2 years prior to exposure to amiodarone. d FDG-PET scanning demonstrated focal hypermetabolic hepatic lesions in both lobes, with a maximum standardized uptake value of 8.8 (arrow). e, f Histopathological examination showed (e) suppurative microabscesses (dotted frame) and (f) numerous Mallory-Denk bodies in the periseptal hepatocytes
Fig. 2 Trends of liver function tests since the initial presentation. AST, aspartate transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase; T-Bil, total bilirubin; D-Bil, direct bilirubin
Fig. 3 Trend of severity scores since the initial presentation. ACLF, acute-on-chronic liver failure; AD, acute decompensation; CLIF-C, Chronic Liver Failure Consortium; MELD, Model for End-stage Liver Disease
Discussion and conclusions
Amiodarone accounts for 1–3% of all DILIs, most commonly exhibiting a hepatocellular injury pattern, particularly in patients with older age, lower body surface area, and dyslipidemia [3]. Elevation of liver enzymes following high-dose intravenous infusion can occur and is mediated through direct hepatotoxicity, which is usually transient and self-reversible; by contrast, liver cirrhosis due to chronic use of low-dose amiodarone is caused by nonallergic idiosyncratic reactions of accumulation-related injury [4]. Amiodarone could induce lysosomal phospholipidosis, resulting in formation of Mallory-Denk bodies in the liver and inhibiting phagocytosis, the latter of which might impair macrophage function and contribute to ACLF progression as observed in the present case [5]. Steatohepatitis associated with amiodarone, through inhibition of the β-oxidation of free fatty acid in the mitochondria [4], exhibits high HU values, in contrast to hypointensity (low HU values) of the liver in nonalcoholic steatohepatitis associated with metabolic syndrome. However, additional hepatotoxicity by amiodarone on top of steatohepatitis related to her metabolic syndrome/insulin resistance is the most likely scenario of her chronic liver disease based on the above negative hepatopathy panel [6].
With the development of toxicity, no definite treatment exists for amiodarone-induced liver injury apart from drug discontinuation, and the mortality rate is as high as 60% at 5 months. The cumulative dose in our patient was 360 g over 2.5 years, close to the reported dose deemed sufficient to induce liver cirrhosis [7]. Together with acute inflammation and possibly macrophage dysfunction, we propose that amiodarone serves as a crucial contributor to the development of ACLF.
In conclusion, accumulation of amiodarone can result in chronic liver disease and pose an additional risk of developing ACLF following infections.
Abbreviations
ACLFacute-on-chronic liver failure
ALTalanine transaminase;
ASTaspartate transaminase
CLIF-Cchronic liver failure consortium
CTcomputed tomography
DILIdrug-induced liver injury
FDGfluorodeoxyglucose
HUhounsfield unit
MELDmodel for end-stage liver disease
PETposition emission tomography
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
None.
Authors’ contributions
WIJ analyzed and interpreted the patient data regarding the liver disease and the infection. TJH performed the histological examination of the liver. WIJ and HCM were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
Nil.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Waived.
Consent for publication
Written consent for publication from the next of kin was obtained.
Competing interests
Nothing to report. | Fatal | ReactionOutcome | CC BY | 33530924 | 18,942,904 | 2021-02-02 |
What was the outcome of reaction 'Acute on chronic liver failure'? | Fatal acute-on-chronic liver failure in amiodarone-related steatohepatitis: a case report.
BACKGROUND
Amiodarone is an antiarrhythmic drug that has been recognized to induce hepatotoxicity. We report a case of acute-on-chronic liver failure (ACLF) in a patient who was receiving amiodarone for more than 2 years. The patient developed cirrhosis and suppurative microabscesses of the liver and died of progressive liver failure.
METHODS
A 69-year-old woman with risk factors for nonalcoholic fatty liver disease (NAFLD) was treated with oral amiodarone at a daily dose of 400 mg for more than 2 years, until she developed epigastralgia and vomiting. Initial laboratory findings included leukocytosis and elevated liver enzymes. Images of abdominal computed tomography scan revealed diffusely increased hepatic attenuation density (in contrast to decreased density in NAFLD), hepatomegaly, periportal edema, and ascites. Liver biopsy targeting the hotspot identified through positron emission tomography confirmed the diagnosis of amiodarone-associated chronic steatohepatitis and superimposed microabscesses. The patient died of progressive ACLF despite intensive supportive care.
CONCLUSIONS
Accumulation of amiodarone can result in chronic liver disease and pose an additional risk of ACLF following infection.
Background
Acute-on-chronic liver failure (ACLF) is a process of rapid deterioration in liver function occurring against a background of chronic liver disease characterized by multisystem organ failure, systemic inflammation, and high short-term mortality. Chronic liver disease is infrequently caused by potential hepatotoxic agents, such as amiodarone [1]. We report a rare case of ACLF caused by acute suppurative microabscesses superimposed on chronic drug-induced liver injury (DILI) associated with amiodarone.
Case presentation
A 69-year-old woman was admitted to our hospital for postprandial epigastralgia and vomiting for 2 weeks. She had a history of diabetes mellitus and hyperlipidemia, and she had undergone bypass surgery for coronary arterial disease 2.5 years previously. She had no alcohol consumption. Initial evaluation revealed distended abdomen, epigastric tenderness, neutrophilic leukocytosis (17.3 k/μL), elevated C-reactive protein, pyuria, liver panel abnormalities (i.e., hepatitis and conjugated hyperbilirubinemia), and coagulopathy. At presentation, the serum levels of aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, direct bilirubin, albumin, and international normalized ratio of prothrombin time were 226 U/L, 108 U/L, 11.72 mg/dL, 6.97 mg/dL, 2.1 g/dL, and 1.44, respectively. Two months before this admission, the serum levels of AST, ALT, total bilirubin, and direct bilirubin were 144 U/L, 131U/L, 0.64 mg/dL, and 0.21 mg/dL, respectively. The AST to platelet ratio index (APRI) score was 2.04, an increase from 1.23 in 2 years. A hepatopathy screening including viral hepatitis (hepatitis B, C, D, and E), auto-immune and hereditary liver disease was negative, except a document of remote hepatitis A infection. Computed tomography (CT) scanning disclosed hepatomegaly, periportal edema, and ascites (Fig. 1a, b). Notably, a diffuse increase in hepatic attenuation density, a hallmark of iron or amiodarone deposition, was observed. Amiodarone had been prescribed at a daily dose of 400 mg (estimated total cumulative dose exposure of 360 g) since the bypass surgery for tachyarrhythmia. Liver attenuation was approximately 50 Hounsfield units (HU) before exposure to amiodarone (Fig. 1c) and had increased one-fold by the following year. Amiodarone was discontinued upon admission. Broad-spectrum antibiotics were used to treat a documented vancomycin-resistant enterococcal urinary tract infection and other potential occult infections without significant clinical improvement. Leukocytosis persisted and a fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan 3 weeks after admission revealed multiple areas of active inflammation within the liver (Fig. 1d). The pathological findings of a targeted biopsy of the largest hot spot (Fig. 1d, arrow) in the FDG-PET scan revealed multifocal necrotizing suppurative microabscesses accompanied by aggregates of granulation tissue and histiocytes (Fig. 1e). No pathogen was observed on acid-fast, periodic-acid-Schiff, and Grocott's methenamine silver staining. Moreover, the liver parenchyma demonstrated cirrhosis and regenerative nodules associated with prominent periseptal ballooned hepatocytes containing numerous Mallory-Denk bodies (Fig. 1f). The changes of selective liver panels since the initial presentation were illustrated in Fig. 2. A rare presentation of ACLF was confirmed based on the findings of amiodarone-associated chronic steatohepatitis and superimposed microabscesses. The patient’s Chronic Liver Failure Consortium (CLIF-C) ACLF score was calculated to be 69.4, and the model for the end-stage liver disease (MELD) score was high (> 30), indicating an unfavorable outcome [2] (Fig. 3). The patient’s clinical condition deteriorated, and she died of progressive liver and renal failure.Fig. 1 Development and diagnosis of ACLF. a–c Serial changes in hepatic signal intensity on CT imaging. High attenuation (90–100 HU) following (a) the use of amiodarone and (b) periportal edema in ACLF. c Low attenuation (50 HU) of liver parenchyma 2 years prior to exposure to amiodarone. d FDG-PET scanning demonstrated focal hypermetabolic hepatic lesions in both lobes, with a maximum standardized uptake value of 8.8 (arrow). e, f Histopathological examination showed (e) suppurative microabscesses (dotted frame) and (f) numerous Mallory-Denk bodies in the periseptal hepatocytes
Fig. 2 Trends of liver function tests since the initial presentation. AST, aspartate transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase; T-Bil, total bilirubin; D-Bil, direct bilirubin
Fig. 3 Trend of severity scores since the initial presentation. ACLF, acute-on-chronic liver failure; AD, acute decompensation; CLIF-C, Chronic Liver Failure Consortium; MELD, Model for End-stage Liver Disease
Discussion and conclusions
Amiodarone accounts for 1–3% of all DILIs, most commonly exhibiting a hepatocellular injury pattern, particularly in patients with older age, lower body surface area, and dyslipidemia [3]. Elevation of liver enzymes following high-dose intravenous infusion can occur and is mediated through direct hepatotoxicity, which is usually transient and self-reversible; by contrast, liver cirrhosis due to chronic use of low-dose amiodarone is caused by nonallergic idiosyncratic reactions of accumulation-related injury [4]. Amiodarone could induce lysosomal phospholipidosis, resulting in formation of Mallory-Denk bodies in the liver and inhibiting phagocytosis, the latter of which might impair macrophage function and contribute to ACLF progression as observed in the present case [5]. Steatohepatitis associated with amiodarone, through inhibition of the β-oxidation of free fatty acid in the mitochondria [4], exhibits high HU values, in contrast to hypointensity (low HU values) of the liver in nonalcoholic steatohepatitis associated with metabolic syndrome. However, additional hepatotoxicity by amiodarone on top of steatohepatitis related to her metabolic syndrome/insulin resistance is the most likely scenario of her chronic liver disease based on the above negative hepatopathy panel [6].
With the development of toxicity, no definite treatment exists for amiodarone-induced liver injury apart from drug discontinuation, and the mortality rate is as high as 60% at 5 months. The cumulative dose in our patient was 360 g over 2.5 years, close to the reported dose deemed sufficient to induce liver cirrhosis [7]. Together with acute inflammation and possibly macrophage dysfunction, we propose that amiodarone serves as a crucial contributor to the development of ACLF.
In conclusion, accumulation of amiodarone can result in chronic liver disease and pose an additional risk of developing ACLF following infections.
Abbreviations
ACLFacute-on-chronic liver failure
ALTalanine transaminase;
ASTaspartate transaminase
CLIF-Cchronic liver failure consortium
CTcomputed tomography
DILIdrug-induced liver injury
FDGfluorodeoxyglucose
HUhounsfield unit
MELDmodel for end-stage liver disease
PETposition emission tomography
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
None.
Authors’ contributions
WIJ analyzed and interpreted the patient data regarding the liver disease and the infection. TJH performed the histological examination of the liver. WIJ and HCM were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
Nil.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Waived.
Consent for publication
Written consent for publication from the next of kin was obtained.
Competing interests
Nothing to report. | Fatal | ReactionOutcome | CC BY | 33530924 | 18,942,904 | 2021-02-02 |
What was the outcome of reaction 'Steatohepatitis'? | Fatal acute-on-chronic liver failure in amiodarone-related steatohepatitis: a case report.
BACKGROUND
Amiodarone is an antiarrhythmic drug that has been recognized to induce hepatotoxicity. We report a case of acute-on-chronic liver failure (ACLF) in a patient who was receiving amiodarone for more than 2 years. The patient developed cirrhosis and suppurative microabscesses of the liver and died of progressive liver failure.
METHODS
A 69-year-old woman with risk factors for nonalcoholic fatty liver disease (NAFLD) was treated with oral amiodarone at a daily dose of 400 mg for more than 2 years, until she developed epigastralgia and vomiting. Initial laboratory findings included leukocytosis and elevated liver enzymes. Images of abdominal computed tomography scan revealed diffusely increased hepatic attenuation density (in contrast to decreased density in NAFLD), hepatomegaly, periportal edema, and ascites. Liver biopsy targeting the hotspot identified through positron emission tomography confirmed the diagnosis of amiodarone-associated chronic steatohepatitis and superimposed microabscesses. The patient died of progressive ACLF despite intensive supportive care.
CONCLUSIONS
Accumulation of amiodarone can result in chronic liver disease and pose an additional risk of ACLF following infection.
Background
Acute-on-chronic liver failure (ACLF) is a process of rapid deterioration in liver function occurring against a background of chronic liver disease characterized by multisystem organ failure, systemic inflammation, and high short-term mortality. Chronic liver disease is infrequently caused by potential hepatotoxic agents, such as amiodarone [1]. We report a rare case of ACLF caused by acute suppurative microabscesses superimposed on chronic drug-induced liver injury (DILI) associated with amiodarone.
Case presentation
A 69-year-old woman was admitted to our hospital for postprandial epigastralgia and vomiting for 2 weeks. She had a history of diabetes mellitus and hyperlipidemia, and she had undergone bypass surgery for coronary arterial disease 2.5 years previously. She had no alcohol consumption. Initial evaluation revealed distended abdomen, epigastric tenderness, neutrophilic leukocytosis (17.3 k/μL), elevated C-reactive protein, pyuria, liver panel abnormalities (i.e., hepatitis and conjugated hyperbilirubinemia), and coagulopathy. At presentation, the serum levels of aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, direct bilirubin, albumin, and international normalized ratio of prothrombin time were 226 U/L, 108 U/L, 11.72 mg/dL, 6.97 mg/dL, 2.1 g/dL, and 1.44, respectively. Two months before this admission, the serum levels of AST, ALT, total bilirubin, and direct bilirubin were 144 U/L, 131U/L, 0.64 mg/dL, and 0.21 mg/dL, respectively. The AST to platelet ratio index (APRI) score was 2.04, an increase from 1.23 in 2 years. A hepatopathy screening including viral hepatitis (hepatitis B, C, D, and E), auto-immune and hereditary liver disease was negative, except a document of remote hepatitis A infection. Computed tomography (CT) scanning disclosed hepatomegaly, periportal edema, and ascites (Fig. 1a, b). Notably, a diffuse increase in hepatic attenuation density, a hallmark of iron or amiodarone deposition, was observed. Amiodarone had been prescribed at a daily dose of 400 mg (estimated total cumulative dose exposure of 360 g) since the bypass surgery for tachyarrhythmia. Liver attenuation was approximately 50 Hounsfield units (HU) before exposure to amiodarone (Fig. 1c) and had increased one-fold by the following year. Amiodarone was discontinued upon admission. Broad-spectrum antibiotics were used to treat a documented vancomycin-resistant enterococcal urinary tract infection and other potential occult infections without significant clinical improvement. Leukocytosis persisted and a fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan 3 weeks after admission revealed multiple areas of active inflammation within the liver (Fig. 1d). The pathological findings of a targeted biopsy of the largest hot spot (Fig. 1d, arrow) in the FDG-PET scan revealed multifocal necrotizing suppurative microabscesses accompanied by aggregates of granulation tissue and histiocytes (Fig. 1e). No pathogen was observed on acid-fast, periodic-acid-Schiff, and Grocott's methenamine silver staining. Moreover, the liver parenchyma demonstrated cirrhosis and regenerative nodules associated with prominent periseptal ballooned hepatocytes containing numerous Mallory-Denk bodies (Fig. 1f). The changes of selective liver panels since the initial presentation were illustrated in Fig. 2. A rare presentation of ACLF was confirmed based on the findings of amiodarone-associated chronic steatohepatitis and superimposed microabscesses. The patient’s Chronic Liver Failure Consortium (CLIF-C) ACLF score was calculated to be 69.4, and the model for the end-stage liver disease (MELD) score was high (> 30), indicating an unfavorable outcome [2] (Fig. 3). The patient’s clinical condition deteriorated, and she died of progressive liver and renal failure.Fig. 1 Development and diagnosis of ACLF. a–c Serial changes in hepatic signal intensity on CT imaging. High attenuation (90–100 HU) following (a) the use of amiodarone and (b) periportal edema in ACLF. c Low attenuation (50 HU) of liver parenchyma 2 years prior to exposure to amiodarone. d FDG-PET scanning demonstrated focal hypermetabolic hepatic lesions in both lobes, with a maximum standardized uptake value of 8.8 (arrow). e, f Histopathological examination showed (e) suppurative microabscesses (dotted frame) and (f) numerous Mallory-Denk bodies in the periseptal hepatocytes
Fig. 2 Trends of liver function tests since the initial presentation. AST, aspartate transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase; T-Bil, total bilirubin; D-Bil, direct bilirubin
Fig. 3 Trend of severity scores since the initial presentation. ACLF, acute-on-chronic liver failure; AD, acute decompensation; CLIF-C, Chronic Liver Failure Consortium; MELD, Model for End-stage Liver Disease
Discussion and conclusions
Amiodarone accounts for 1–3% of all DILIs, most commonly exhibiting a hepatocellular injury pattern, particularly in patients with older age, lower body surface area, and dyslipidemia [3]. Elevation of liver enzymes following high-dose intravenous infusion can occur and is mediated through direct hepatotoxicity, which is usually transient and self-reversible; by contrast, liver cirrhosis due to chronic use of low-dose amiodarone is caused by nonallergic idiosyncratic reactions of accumulation-related injury [4]. Amiodarone could induce lysosomal phospholipidosis, resulting in formation of Mallory-Denk bodies in the liver and inhibiting phagocytosis, the latter of which might impair macrophage function and contribute to ACLF progression as observed in the present case [5]. Steatohepatitis associated with amiodarone, through inhibition of the β-oxidation of free fatty acid in the mitochondria [4], exhibits high HU values, in contrast to hypointensity (low HU values) of the liver in nonalcoholic steatohepatitis associated with metabolic syndrome. However, additional hepatotoxicity by amiodarone on top of steatohepatitis related to her metabolic syndrome/insulin resistance is the most likely scenario of her chronic liver disease based on the above negative hepatopathy panel [6].
With the development of toxicity, no definite treatment exists for amiodarone-induced liver injury apart from drug discontinuation, and the mortality rate is as high as 60% at 5 months. The cumulative dose in our patient was 360 g over 2.5 years, close to the reported dose deemed sufficient to induce liver cirrhosis [7]. Together with acute inflammation and possibly macrophage dysfunction, we propose that amiodarone serves as a crucial contributor to the development of ACLF.
In conclusion, accumulation of amiodarone can result in chronic liver disease and pose an additional risk of developing ACLF following infections.
Abbreviations
ACLFacute-on-chronic liver failure
ALTalanine transaminase;
ASTaspartate transaminase
CLIF-Cchronic liver failure consortium
CTcomputed tomography
DILIdrug-induced liver injury
FDGfluorodeoxyglucose
HUhounsfield unit
MELDmodel for end-stage liver disease
PETposition emission tomography
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
None.
Authors’ contributions
WIJ analyzed and interpreted the patient data regarding the liver disease and the infection. TJH performed the histological examination of the liver. WIJ and HCM were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
Nil.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Waived.
Consent for publication
Written consent for publication from the next of kin was obtained.
Competing interests
Nothing to report. | Fatal | ReactionOutcome | CC BY | 33530924 | 18,942,904 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Herpes simplex'. | Herpes simplex virus type 1 related acute retinal necrosis following an encephalitis illness: a case report.
BACKGROUND
Virus encephalitis is found to be a risk factor for acute retinal necrosis (ARN).
METHODS
We herein presented a case of a 20-year-old teenage boy who suffered from encephalitis of unknown etiology with early negative pathologic results, and was primarily treated with systemic administration of high-dose steroids without antiviral therapy. He later had sudden vision loss in his right eye. Intravitreal and intravenous antiviral treatments were immediately started due to suspected ARN. Herpes simplex virus (HSV)-1 was identified later in the vitreous humor of the patient. After the surgery of retinal detachment (RD), obvious improvements in vision were observed. However, the patient had recurrent RD and vision declination 5 weeks later.
CONCLUSIONS
The case with suspected viral encephalitis should be treated with antiviral therapy regardless of early virologic results in order to avoid complications of a missed viral encephalitis diagnosis, especially if systemic steroid treatment is being considered.
Background
Acute retinal necrosis (ARN) is a serious and potential blinding viral ocular infection, and it rapidly develops and progresses in immunocompetent people, causing uveitis with necrotizing retinitis [1]. Varicella-zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2 are the most common causative viruses of ARN [1]. It is assumed that reactivation amid immune dysfunction of the virus leads to ARN, along with central nervous system infection [2]. The association between viral encephalitis and ARN has been reported in one per 1.6–2.0 million people [3]. Therefore, additional attention with regard to ocular clinical manifestations is specially needed in patients with encephalitis after systemic treatment with steroids, as they could affect the body immunity and cause reactivation of the virus. Viral encephalitis should be aware of as it is a risk factor of ARN, and so antiviral treatment is recommended for suspected viral encephalitis.
Case presentation
A 20-year-old teenage boy with abrupt fever, confusion, and epileptic seizures was referred to the Department of Neurology of the Guangzhou General Military Hospital. The patient was otherwise a healthy boy until he had an unusual health status prior to 5 days. Cerebral spinal fluid (CSF) analysis was performed on admission, and the result showed negative Pandy test with a predominance of lymphocytes. Besides, CSF test for Mycobacterium tuberculosis, herpes simplex virus (HSV), cytomegalovirus (CMV), and rubella virus revealed negative results. Two days later, antibody analysis of autoimmune encephalitis was also shown to be normal. Brain magnetic resonance imaging (MRI) showed hypersignal intensity in bilateral frontal as well as temporal lobe.
Next, the patient was diagnosed with encephalitis due to unidentified etiology, and then systemic administration of steroids was given without antiviral treatment. He was prescribed with intravenous methylprednisolone, 1 g/d for 3 consecutive days, followed by 0.5 g/d for 3 days, and then was maintained on 80 mg/d for 2 weeks. Two weeks after admission, the boy showed no sign of improvement. A second brain MRI showed much worsened manifestation of hypersignal in both bilateral frontal and temporal lobe, and a second CSF analysis showed negative results of the pathogen as shown in the first CSF analysis. He was therefore presumed to have “autoimmune encephalitis” by primary neurologists and was prescribed with gamma globulin 25 g/d for 5 days. Later, he had less fever and seizures, and improvements were observed in his oral expression. So, intravenous methylprednisolone administration was gradually reduced and replaced it by oral prednisone of 60 mg/d and then was discharged. One day after being discharged, he had sudden vision loss in his right eye, and then the boy was urgently referred to our hospital.
Investigations
After admitting in our hospital, the patient’s physical and neurological exams were found to be unremarkable. His best corrected visual acuity (BCVA) showed light perception with correct light location in the temporal region of the right eye (OD), and 20/20 with that of the left eye (OS). Ophthalmological examination of his right eye revealed positive Tyndall (+) and cell (++) in the anterior chamber, with obvious opacity (+++) in the vitreous chamber. The fundus of his right eye showed yellow-white lesions, with narrowing retinal vessels and white-sheath and peripheral hemorrhage. Also several tiny retinal holes that lead to retinal detachment (RD) were observed in the peripheral retina (Fig. 1a). No remarkable changes were observed in his left eye.
Fig. 1 Fundus photographs of the right eye. a On admission. The blue arrows represent severe occlusive vasculitis, with macula involved in the peripheral retina, and white arrow represents several tiny holes on superior-nasal degeneration area. b On discharge day. Retinal detachment was repaired with retinal vasculitis and edema showed great improvement
New brain MRI performed in our hospital suggested multiple abnormal signals in the brain parenchyma, which were in accordance with the manifestations of viral encephalitis (Fig. 2). So, viral-related retinal disorders were highly suspected in our case. Vitreous humor was obtained through vitreous chamber tapping to perform polymerase chain reaction (PCR) analysis. DNA of HSV-1 virus (9.0 × 106/ml) was identified 5 days after intravitreal antiviral treatment, and the positive results of IgG and IgM antibodies in the blood serology also supported HSV-1 infection, thus confirming the diagnosis of ARN by HSV-1.
Fig. 2 Hypersignal intensity of left temporal lobe in MRI with T2 flair
Treatment
Intravitreal administration of ganciclovir (0.4 mg/ 0.1 ml) was immediately performed following vitreous chamber tapping at the time of admission to our hospital. Two days later, the boy was relieved from vitreous opacities (+). Antiviral treatment was therefore considered to be effective, and broad-spectrum antiviral medicine (ganciclovir 250 mg every 12-h) was started intravenously, and then replaced with intravenous acyclovir (500 mg every 8-h) after confirmation of HSV pathogen. As the patient also suffered from RD, his right eye was treated by pars plana vitrectomy (PPV), endolaser and silicone oil tamponade 3 days after admission. During the surgery, a second time intravitreal ganciclovir (0.4 mg/0.1 mg) was given.
Outcomes and follow-up
The patient received intravenous antiviral treatment for 2 weeks and was discharged with oral antiviral medicine (famciclovir 375 mg twice a day) as planned for 3 to 4 months. On the day of discharge, BCVA was 20/80 OD and retinal edema in his right eye has been greatly relieved (Fig. 1b). At 5 weeks of follow-up, recurrent vision declination occurred with 20/500 OD due to recurrent RD (Fig. 3). Therefore, silicon oil displacement and endolaser were performed to repair the retina, as well as intravitreal ganciclovir (0.4 mg/0.1 mg) was given for third time. The BCVA of his right eye was increased to 20/80 within 3 days after the surgery. Six months later, after removing the silicone oil, the BCVA was shown to be 20/200 OD with complicated cataract.
Fig. 3 OCT images of the right eye. a On discharge day and b at 5 weeks after discharge
Discussion and conclusion
Our patient due to encephalitis suffered from HSV related ARN after systemic administration of steroids. HSV-infected ARN could be a serious threat that leads to vision loss. Therefore, early awareness and timely antiviral treatment of suspected viral encephalitis are critical in such patients.
The possible reason for the cause of ARN in this patient might be due to viral encephalitis. HSV-1 virus encephalitis is usually characterized by altered mental health status, seizures, somnolence, increased cellularity with predominant lymphocytes in CSF, as well as hypersignal intensity in the MRI of temporal lobes [4], and all these clinical manifestations were observed in our patient. In our case, encephalitis was highly suspected to be caused by viral infection. However, lack of direct evidence of the virus in CSF impeded antiviral treatment. The patient later suffered from ARN due to HSV, suggesting that the virus might come from the brain. Due to the negative evidence in CSF, it could result in low positive predictive value [5] or procedural-related problems. To repeat CSF analysis is important in suspected viral encephalitis. ARN has been reported in cases with prior [6], simultaneous [7], or post [8] presence of herpetic simplex encephalitis or meningitis, and the interval between ARN and meningitis/encephalitis varied from 2 to 5 weeks [9]. A possible underlying mechanism has demonstrated bidirectional fast-axonal transport in neurons [10], and the viral genes play a critical role for antegrade and retrograde axonal transportation.
Immunocompromise after systemic administration of high-dose steroids could be another possible reason for the triggering of ARN in the current case. There are several possible explanations for steroids contributing to the occurrence of ARN. Firstly, high-dose steroids might affect body immunity, promote viral replication, and worsen necrotizing retinopathy [11]. The virus might reach the eye from the brain by a trans-axonal route. Secondly, the triggering event of systemic administration of high-dose steroids could reactivate HSV infection [12], and the latent HSV in several sites is connected to the eye, finally resulting in herpetic ocular disease that involves the cornea, iris, or even the retina [13]. When treating patients with encephalitis, for whom systemic administration of steroids is an inevitable regimen, neurologists should be aware that it might lead to immunocompromise, posing a serious threat in triggering ARN. In addition, according to prior studies on treatment of HSV1-encephalitis by combining with acyclovir, a study showed that treatment without corticosteroid was associated with poorer outcomes [14], while another study found no positive effects by adding dexamethasone to acyclovir [15]. Therefore, the use of corticosteroid therapy for viral encephalitis depends on the discretion of clinicians. As patients with encephalitis always present with confusion, which prevents them from timely and precise expression of their ocular discomforts, and so attention should be paid with regard to ocular clinical manifestations.
Intravitreal and intravenous antiviral treatment was then immediately started in this patient, and this is because of high suspicion of ARN according to ocular manifestations. So, diagnostic testing of vitreous humor before antiviral treatment has been done, and later corresponding adjustments were made. Topical and systemic antiviral treatment is an urgent need, as it is beneficial for the visual acuity and thus could decrease the risk of infection to the other eye [16]. As documented previously, there were up to 70% of untreated patients with bilateral ARN [17]. In our case, ARN was presented in a single eye, but it is assumed that the contralateral eye might also be affected if timely and precise antiviral treatment is not given. With a better understanding of antiviral treatment, the rate of bilateralization according to the recently reported studies on ARN has been found to be significantly decreased into 10–20% [18].
The challenges concerning diagnosis as well as prognosis were posed in this case. The CSF initially revealed negative results for viral encephalitis, and the diagnosis of ARN was later confirmed by PCR analysis with HSV-1 in the vitreous humor, and this is widely available to clinicians with good sensitivity and specificity [19]. According to a recent study, the correlation of quantitative DNA PCR and clinical prognosis in ARN has revealed that a number of copies superior to 5.0 × 106/ml showed association with a higher probability of RD [20]. In our case, the quantitative DNA of HSV-1 was 9.0 × 106/ml, suggesting a poor prognosis of vision in accordance with recurrent RD and vision declination during the follow-up period.
In the suspected case of viral encephalitis, antiviral therapy should be performed regardless of early PCR results to avoid complications of missed viral encephalitis, especially if systemic glucocorticoid therapy is being considered. Besides, special awareness and careful evaluation on neuro-ophthalmological assessment should be paid in any patients with a central nervous system disease. The clinical decision-making should be tailored to suit patients with ARN related to encephalitis, considering the extent and severity of the diseases and symptoms, as well as disease progression. Furthermore, consultation with a multidisciplinary team related to ophthalmology is highly recommended.
Abbreviations
ARNAcute retinal necrosis
HSVHerpes simplex virus
BCVABest corrected visual acuity
CSFCerebral spinal fluid
RDRetinal detachment
PCRPolymerase chain reaction
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Pingting Zhong and Siwen Zang contributed equally to this work.
We gratefully thank the patient and his parents for their kind participation in the study.
Authors’ contributions
Z. PT and Z. SW wrote the manuscript, analyzed the data, and reviewed the literature. Y. HH performed the surgery. Z. PT and Z. SW collected ophthalmologic data and assisted in drafting the manuscript. Y. HH and Y. XH revised the manuscript and discussions. All authors read and approved the final manuscript.
Funding
This work was supported by Science and Technology Program of Guangzhou, China (202002020049) (Y. XH); Project of Investigation on Health Status of Employees in Financial Industry in Guangzhou (Z012014075) (Y. XH).
Availability of data and materials
All data generated or analyzed during this study are included in this article and are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
This study is a case report, the study design was approved by the ethics review board of the Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences. Written informed consent was obtained from the participant.
Consent for publication
Written informed consent was obtained from the patient for publication of this case and any accompanying images. This report does not contain any personal information that could lead to the identification of the patient.
Competing interests
The authors declare that they have no competing interests. | HUMAN IMMUNOGLOBULIN G, METHYLPREDNISOLONE, PREDNISONE | DrugsGivenReaction | CC BY | 33530932 | 18,947,754 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Herpes virus infection'. | Herpes simplex virus type 1 related acute retinal necrosis following an encephalitis illness: a case report.
BACKGROUND
Virus encephalitis is found to be a risk factor for acute retinal necrosis (ARN).
METHODS
We herein presented a case of a 20-year-old teenage boy who suffered from encephalitis of unknown etiology with early negative pathologic results, and was primarily treated with systemic administration of high-dose steroids without antiviral therapy. He later had sudden vision loss in his right eye. Intravitreal and intravenous antiviral treatments were immediately started due to suspected ARN. Herpes simplex virus (HSV)-1 was identified later in the vitreous humor of the patient. After the surgery of retinal detachment (RD), obvious improvements in vision were observed. However, the patient had recurrent RD and vision declination 5 weeks later.
CONCLUSIONS
The case with suspected viral encephalitis should be treated with antiviral therapy regardless of early virologic results in order to avoid complications of a missed viral encephalitis diagnosis, especially if systemic steroid treatment is being considered.
Background
Acute retinal necrosis (ARN) is a serious and potential blinding viral ocular infection, and it rapidly develops and progresses in immunocompetent people, causing uveitis with necrotizing retinitis [1]. Varicella-zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2 are the most common causative viruses of ARN [1]. It is assumed that reactivation amid immune dysfunction of the virus leads to ARN, along with central nervous system infection [2]. The association between viral encephalitis and ARN has been reported in one per 1.6–2.0 million people [3]. Therefore, additional attention with regard to ocular clinical manifestations is specially needed in patients with encephalitis after systemic treatment with steroids, as they could affect the body immunity and cause reactivation of the virus. Viral encephalitis should be aware of as it is a risk factor of ARN, and so antiviral treatment is recommended for suspected viral encephalitis.
Case presentation
A 20-year-old teenage boy with abrupt fever, confusion, and epileptic seizures was referred to the Department of Neurology of the Guangzhou General Military Hospital. The patient was otherwise a healthy boy until he had an unusual health status prior to 5 days. Cerebral spinal fluid (CSF) analysis was performed on admission, and the result showed negative Pandy test with a predominance of lymphocytes. Besides, CSF test for Mycobacterium tuberculosis, herpes simplex virus (HSV), cytomegalovirus (CMV), and rubella virus revealed negative results. Two days later, antibody analysis of autoimmune encephalitis was also shown to be normal. Brain magnetic resonance imaging (MRI) showed hypersignal intensity in bilateral frontal as well as temporal lobe.
Next, the patient was diagnosed with encephalitis due to unidentified etiology, and then systemic administration of steroids was given without antiviral treatment. He was prescribed with intravenous methylprednisolone, 1 g/d for 3 consecutive days, followed by 0.5 g/d for 3 days, and then was maintained on 80 mg/d for 2 weeks. Two weeks after admission, the boy showed no sign of improvement. A second brain MRI showed much worsened manifestation of hypersignal in both bilateral frontal and temporal lobe, and a second CSF analysis showed negative results of the pathogen as shown in the first CSF analysis. He was therefore presumed to have “autoimmune encephalitis” by primary neurologists and was prescribed with gamma globulin 25 g/d for 5 days. Later, he had less fever and seizures, and improvements were observed in his oral expression. So, intravenous methylprednisolone administration was gradually reduced and replaced it by oral prednisone of 60 mg/d and then was discharged. One day after being discharged, he had sudden vision loss in his right eye, and then the boy was urgently referred to our hospital.
Investigations
After admitting in our hospital, the patient’s physical and neurological exams were found to be unremarkable. His best corrected visual acuity (BCVA) showed light perception with correct light location in the temporal region of the right eye (OD), and 20/20 with that of the left eye (OS). Ophthalmological examination of his right eye revealed positive Tyndall (+) and cell (++) in the anterior chamber, with obvious opacity (+++) in the vitreous chamber. The fundus of his right eye showed yellow-white lesions, with narrowing retinal vessels and white-sheath and peripheral hemorrhage. Also several tiny retinal holes that lead to retinal detachment (RD) were observed in the peripheral retina (Fig. 1a). No remarkable changes were observed in his left eye.
Fig. 1 Fundus photographs of the right eye. a On admission. The blue arrows represent severe occlusive vasculitis, with macula involved in the peripheral retina, and white arrow represents several tiny holes on superior-nasal degeneration area. b On discharge day. Retinal detachment was repaired with retinal vasculitis and edema showed great improvement
New brain MRI performed in our hospital suggested multiple abnormal signals in the brain parenchyma, which were in accordance with the manifestations of viral encephalitis (Fig. 2). So, viral-related retinal disorders were highly suspected in our case. Vitreous humor was obtained through vitreous chamber tapping to perform polymerase chain reaction (PCR) analysis. DNA of HSV-1 virus (9.0 × 106/ml) was identified 5 days after intravitreal antiviral treatment, and the positive results of IgG and IgM antibodies in the blood serology also supported HSV-1 infection, thus confirming the diagnosis of ARN by HSV-1.
Fig. 2 Hypersignal intensity of left temporal lobe in MRI with T2 flair
Treatment
Intravitreal administration of ganciclovir (0.4 mg/ 0.1 ml) was immediately performed following vitreous chamber tapping at the time of admission to our hospital. Two days later, the boy was relieved from vitreous opacities (+). Antiviral treatment was therefore considered to be effective, and broad-spectrum antiviral medicine (ganciclovir 250 mg every 12-h) was started intravenously, and then replaced with intravenous acyclovir (500 mg every 8-h) after confirmation of HSV pathogen. As the patient also suffered from RD, his right eye was treated by pars plana vitrectomy (PPV), endolaser and silicone oil tamponade 3 days after admission. During the surgery, a second time intravitreal ganciclovir (0.4 mg/0.1 mg) was given.
Outcomes and follow-up
The patient received intravenous antiviral treatment for 2 weeks and was discharged with oral antiviral medicine (famciclovir 375 mg twice a day) as planned for 3 to 4 months. On the day of discharge, BCVA was 20/80 OD and retinal edema in his right eye has been greatly relieved (Fig. 1b). At 5 weeks of follow-up, recurrent vision declination occurred with 20/500 OD due to recurrent RD (Fig. 3). Therefore, silicon oil displacement and endolaser were performed to repair the retina, as well as intravitreal ganciclovir (0.4 mg/0.1 mg) was given for third time. The BCVA of his right eye was increased to 20/80 within 3 days after the surgery. Six months later, after removing the silicone oil, the BCVA was shown to be 20/200 OD with complicated cataract.
Fig. 3 OCT images of the right eye. a On discharge day and b at 5 weeks after discharge
Discussion and conclusion
Our patient due to encephalitis suffered from HSV related ARN after systemic administration of steroids. HSV-infected ARN could be a serious threat that leads to vision loss. Therefore, early awareness and timely antiviral treatment of suspected viral encephalitis are critical in such patients.
The possible reason for the cause of ARN in this patient might be due to viral encephalitis. HSV-1 virus encephalitis is usually characterized by altered mental health status, seizures, somnolence, increased cellularity with predominant lymphocytes in CSF, as well as hypersignal intensity in the MRI of temporal lobes [4], and all these clinical manifestations were observed in our patient. In our case, encephalitis was highly suspected to be caused by viral infection. However, lack of direct evidence of the virus in CSF impeded antiviral treatment. The patient later suffered from ARN due to HSV, suggesting that the virus might come from the brain. Due to the negative evidence in CSF, it could result in low positive predictive value [5] or procedural-related problems. To repeat CSF analysis is important in suspected viral encephalitis. ARN has been reported in cases with prior [6], simultaneous [7], or post [8] presence of herpetic simplex encephalitis or meningitis, and the interval between ARN and meningitis/encephalitis varied from 2 to 5 weeks [9]. A possible underlying mechanism has demonstrated bidirectional fast-axonal transport in neurons [10], and the viral genes play a critical role for antegrade and retrograde axonal transportation.
Immunocompromise after systemic administration of high-dose steroids could be another possible reason for the triggering of ARN in the current case. There are several possible explanations for steroids contributing to the occurrence of ARN. Firstly, high-dose steroids might affect body immunity, promote viral replication, and worsen necrotizing retinopathy [11]. The virus might reach the eye from the brain by a trans-axonal route. Secondly, the triggering event of systemic administration of high-dose steroids could reactivate HSV infection [12], and the latent HSV in several sites is connected to the eye, finally resulting in herpetic ocular disease that involves the cornea, iris, or even the retina [13]. When treating patients with encephalitis, for whom systemic administration of steroids is an inevitable regimen, neurologists should be aware that it might lead to immunocompromise, posing a serious threat in triggering ARN. In addition, according to prior studies on treatment of HSV1-encephalitis by combining with acyclovir, a study showed that treatment without corticosteroid was associated with poorer outcomes [14], while another study found no positive effects by adding dexamethasone to acyclovir [15]. Therefore, the use of corticosteroid therapy for viral encephalitis depends on the discretion of clinicians. As patients with encephalitis always present with confusion, which prevents them from timely and precise expression of their ocular discomforts, and so attention should be paid with regard to ocular clinical manifestations.
Intravitreal and intravenous antiviral treatment was then immediately started in this patient, and this is because of high suspicion of ARN according to ocular manifestations. So, diagnostic testing of vitreous humor before antiviral treatment has been done, and later corresponding adjustments were made. Topical and systemic antiviral treatment is an urgent need, as it is beneficial for the visual acuity and thus could decrease the risk of infection to the other eye [16]. As documented previously, there were up to 70% of untreated patients with bilateral ARN [17]. In our case, ARN was presented in a single eye, but it is assumed that the contralateral eye might also be affected if timely and precise antiviral treatment is not given. With a better understanding of antiviral treatment, the rate of bilateralization according to the recently reported studies on ARN has been found to be significantly decreased into 10–20% [18].
The challenges concerning diagnosis as well as prognosis were posed in this case. The CSF initially revealed negative results for viral encephalitis, and the diagnosis of ARN was later confirmed by PCR analysis with HSV-1 in the vitreous humor, and this is widely available to clinicians with good sensitivity and specificity [19]. According to a recent study, the correlation of quantitative DNA PCR and clinical prognosis in ARN has revealed that a number of copies superior to 5.0 × 106/ml showed association with a higher probability of RD [20]. In our case, the quantitative DNA of HSV-1 was 9.0 × 106/ml, suggesting a poor prognosis of vision in accordance with recurrent RD and vision declination during the follow-up period.
In the suspected case of viral encephalitis, antiviral therapy should be performed regardless of early PCR results to avoid complications of missed viral encephalitis, especially if systemic glucocorticoid therapy is being considered. Besides, special awareness and careful evaluation on neuro-ophthalmological assessment should be paid in any patients with a central nervous system disease. The clinical decision-making should be tailored to suit patients with ARN related to encephalitis, considering the extent and severity of the diseases and symptoms, as well as disease progression. Furthermore, consultation with a multidisciplinary team related to ophthalmology is highly recommended.
Abbreviations
ARNAcute retinal necrosis
HSVHerpes simplex virus
BCVABest corrected visual acuity
CSFCerebral spinal fluid
RDRetinal detachment
PCRPolymerase chain reaction
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Pingting Zhong and Siwen Zang contributed equally to this work.
We gratefully thank the patient and his parents for their kind participation in the study.
Authors’ contributions
Z. PT and Z. SW wrote the manuscript, analyzed the data, and reviewed the literature. Y. HH performed the surgery. Z. PT and Z. SW collected ophthalmologic data and assisted in drafting the manuscript. Y. HH and Y. XH revised the manuscript and discussions. All authors read and approved the final manuscript.
Funding
This work was supported by Science and Technology Program of Guangzhou, China (202002020049) (Y. XH); Project of Investigation on Health Status of Employees in Financial Industry in Guangzhou (Z012014075) (Y. XH).
Availability of data and materials
All data generated or analyzed during this study are included in this article and are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
This study is a case report, the study design was approved by the ethics review board of the Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences. Written informed consent was obtained from the participant.
Consent for publication
Written informed consent was obtained from the patient for publication of this case and any accompanying images. This report does not contain any personal information that could lead to the identification of the patient.
Competing interests
The authors declare that they have no competing interests. | IMMUNE GLOBULIN NOS, METHYLPREDNISOLONE, PREDNISONE | DrugsGivenReaction | CC BY | 33530932 | 19,013,150 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Herpes simplex virus type 1 related acute retinal necrosis following an encephalitis illness: a case report.
BACKGROUND
Virus encephalitis is found to be a risk factor for acute retinal necrosis (ARN).
METHODS
We herein presented a case of a 20-year-old teenage boy who suffered from encephalitis of unknown etiology with early negative pathologic results, and was primarily treated with systemic administration of high-dose steroids without antiviral therapy. He later had sudden vision loss in his right eye. Intravitreal and intravenous antiviral treatments were immediately started due to suspected ARN. Herpes simplex virus (HSV)-1 was identified later in the vitreous humor of the patient. After the surgery of retinal detachment (RD), obvious improvements in vision were observed. However, the patient had recurrent RD and vision declination 5 weeks later.
CONCLUSIONS
The case with suspected viral encephalitis should be treated with antiviral therapy regardless of early virologic results in order to avoid complications of a missed viral encephalitis diagnosis, especially if systemic steroid treatment is being considered.
Background
Acute retinal necrosis (ARN) is a serious and potential blinding viral ocular infection, and it rapidly develops and progresses in immunocompetent people, causing uveitis with necrotizing retinitis [1]. Varicella-zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2 are the most common causative viruses of ARN [1]. It is assumed that reactivation amid immune dysfunction of the virus leads to ARN, along with central nervous system infection [2]. The association between viral encephalitis and ARN has been reported in one per 1.6–2.0 million people [3]. Therefore, additional attention with regard to ocular clinical manifestations is specially needed in patients with encephalitis after systemic treatment with steroids, as they could affect the body immunity and cause reactivation of the virus. Viral encephalitis should be aware of as it is a risk factor of ARN, and so antiviral treatment is recommended for suspected viral encephalitis.
Case presentation
A 20-year-old teenage boy with abrupt fever, confusion, and epileptic seizures was referred to the Department of Neurology of the Guangzhou General Military Hospital. The patient was otherwise a healthy boy until he had an unusual health status prior to 5 days. Cerebral spinal fluid (CSF) analysis was performed on admission, and the result showed negative Pandy test with a predominance of lymphocytes. Besides, CSF test for Mycobacterium tuberculosis, herpes simplex virus (HSV), cytomegalovirus (CMV), and rubella virus revealed negative results. Two days later, antibody analysis of autoimmune encephalitis was also shown to be normal. Brain magnetic resonance imaging (MRI) showed hypersignal intensity in bilateral frontal as well as temporal lobe.
Next, the patient was diagnosed with encephalitis due to unidentified etiology, and then systemic administration of steroids was given without antiviral treatment. He was prescribed with intravenous methylprednisolone, 1 g/d for 3 consecutive days, followed by 0.5 g/d for 3 days, and then was maintained on 80 mg/d for 2 weeks. Two weeks after admission, the boy showed no sign of improvement. A second brain MRI showed much worsened manifestation of hypersignal in both bilateral frontal and temporal lobe, and a second CSF analysis showed negative results of the pathogen as shown in the first CSF analysis. He was therefore presumed to have “autoimmune encephalitis” by primary neurologists and was prescribed with gamma globulin 25 g/d for 5 days. Later, he had less fever and seizures, and improvements were observed in his oral expression. So, intravenous methylprednisolone administration was gradually reduced and replaced it by oral prednisone of 60 mg/d and then was discharged. One day after being discharged, he had sudden vision loss in his right eye, and then the boy was urgently referred to our hospital.
Investigations
After admitting in our hospital, the patient’s physical and neurological exams were found to be unremarkable. His best corrected visual acuity (BCVA) showed light perception with correct light location in the temporal region of the right eye (OD), and 20/20 with that of the left eye (OS). Ophthalmological examination of his right eye revealed positive Tyndall (+) and cell (++) in the anterior chamber, with obvious opacity (+++) in the vitreous chamber. The fundus of his right eye showed yellow-white lesions, with narrowing retinal vessels and white-sheath and peripheral hemorrhage. Also several tiny retinal holes that lead to retinal detachment (RD) were observed in the peripheral retina (Fig. 1a). No remarkable changes were observed in his left eye.
Fig. 1 Fundus photographs of the right eye. a On admission. The blue arrows represent severe occlusive vasculitis, with macula involved in the peripheral retina, and white arrow represents several tiny holes on superior-nasal degeneration area. b On discharge day. Retinal detachment was repaired with retinal vasculitis and edema showed great improvement
New brain MRI performed in our hospital suggested multiple abnormal signals in the brain parenchyma, which were in accordance with the manifestations of viral encephalitis (Fig. 2). So, viral-related retinal disorders were highly suspected in our case. Vitreous humor was obtained through vitreous chamber tapping to perform polymerase chain reaction (PCR) analysis. DNA of HSV-1 virus (9.0 × 106/ml) was identified 5 days after intravitreal antiviral treatment, and the positive results of IgG and IgM antibodies in the blood serology also supported HSV-1 infection, thus confirming the diagnosis of ARN by HSV-1.
Fig. 2 Hypersignal intensity of left temporal lobe in MRI with T2 flair
Treatment
Intravitreal administration of ganciclovir (0.4 mg/ 0.1 ml) was immediately performed following vitreous chamber tapping at the time of admission to our hospital. Two days later, the boy was relieved from vitreous opacities (+). Antiviral treatment was therefore considered to be effective, and broad-spectrum antiviral medicine (ganciclovir 250 mg every 12-h) was started intravenously, and then replaced with intravenous acyclovir (500 mg every 8-h) after confirmation of HSV pathogen. As the patient also suffered from RD, his right eye was treated by pars plana vitrectomy (PPV), endolaser and silicone oil tamponade 3 days after admission. During the surgery, a second time intravitreal ganciclovir (0.4 mg/0.1 mg) was given.
Outcomes and follow-up
The patient received intravenous antiviral treatment for 2 weeks and was discharged with oral antiviral medicine (famciclovir 375 mg twice a day) as planned for 3 to 4 months. On the day of discharge, BCVA was 20/80 OD and retinal edema in his right eye has been greatly relieved (Fig. 1b). At 5 weeks of follow-up, recurrent vision declination occurred with 20/500 OD due to recurrent RD (Fig. 3). Therefore, silicon oil displacement and endolaser were performed to repair the retina, as well as intravitreal ganciclovir (0.4 mg/0.1 mg) was given for third time. The BCVA of his right eye was increased to 20/80 within 3 days after the surgery. Six months later, after removing the silicone oil, the BCVA was shown to be 20/200 OD with complicated cataract.
Fig. 3 OCT images of the right eye. a On discharge day and b at 5 weeks after discharge
Discussion and conclusion
Our patient due to encephalitis suffered from HSV related ARN after systemic administration of steroids. HSV-infected ARN could be a serious threat that leads to vision loss. Therefore, early awareness and timely antiviral treatment of suspected viral encephalitis are critical in such patients.
The possible reason for the cause of ARN in this patient might be due to viral encephalitis. HSV-1 virus encephalitis is usually characterized by altered mental health status, seizures, somnolence, increased cellularity with predominant lymphocytes in CSF, as well as hypersignal intensity in the MRI of temporal lobes [4], and all these clinical manifestations were observed in our patient. In our case, encephalitis was highly suspected to be caused by viral infection. However, lack of direct evidence of the virus in CSF impeded antiviral treatment. The patient later suffered from ARN due to HSV, suggesting that the virus might come from the brain. Due to the negative evidence in CSF, it could result in low positive predictive value [5] or procedural-related problems. To repeat CSF analysis is important in suspected viral encephalitis. ARN has been reported in cases with prior [6], simultaneous [7], or post [8] presence of herpetic simplex encephalitis or meningitis, and the interval between ARN and meningitis/encephalitis varied from 2 to 5 weeks [9]. A possible underlying mechanism has demonstrated bidirectional fast-axonal transport in neurons [10], and the viral genes play a critical role for antegrade and retrograde axonal transportation.
Immunocompromise after systemic administration of high-dose steroids could be another possible reason for the triggering of ARN in the current case. There are several possible explanations for steroids contributing to the occurrence of ARN. Firstly, high-dose steroids might affect body immunity, promote viral replication, and worsen necrotizing retinopathy [11]. The virus might reach the eye from the brain by a trans-axonal route. Secondly, the triggering event of systemic administration of high-dose steroids could reactivate HSV infection [12], and the latent HSV in several sites is connected to the eye, finally resulting in herpetic ocular disease that involves the cornea, iris, or even the retina [13]. When treating patients with encephalitis, for whom systemic administration of steroids is an inevitable regimen, neurologists should be aware that it might lead to immunocompromise, posing a serious threat in triggering ARN. In addition, according to prior studies on treatment of HSV1-encephalitis by combining with acyclovir, a study showed that treatment without corticosteroid was associated with poorer outcomes [14], while another study found no positive effects by adding dexamethasone to acyclovir [15]. Therefore, the use of corticosteroid therapy for viral encephalitis depends on the discretion of clinicians. As patients with encephalitis always present with confusion, which prevents them from timely and precise expression of their ocular discomforts, and so attention should be paid with regard to ocular clinical manifestations.
Intravitreal and intravenous antiviral treatment was then immediately started in this patient, and this is because of high suspicion of ARN according to ocular manifestations. So, diagnostic testing of vitreous humor before antiviral treatment has been done, and later corresponding adjustments were made. Topical and systemic antiviral treatment is an urgent need, as it is beneficial for the visual acuity and thus could decrease the risk of infection to the other eye [16]. As documented previously, there were up to 70% of untreated patients with bilateral ARN [17]. In our case, ARN was presented in a single eye, but it is assumed that the contralateral eye might also be affected if timely and precise antiviral treatment is not given. With a better understanding of antiviral treatment, the rate of bilateralization according to the recently reported studies on ARN has been found to be significantly decreased into 10–20% [18].
The challenges concerning diagnosis as well as prognosis were posed in this case. The CSF initially revealed negative results for viral encephalitis, and the diagnosis of ARN was later confirmed by PCR analysis with HSV-1 in the vitreous humor, and this is widely available to clinicians with good sensitivity and specificity [19]. According to a recent study, the correlation of quantitative DNA PCR and clinical prognosis in ARN has revealed that a number of copies superior to 5.0 × 106/ml showed association with a higher probability of RD [20]. In our case, the quantitative DNA of HSV-1 was 9.0 × 106/ml, suggesting a poor prognosis of vision in accordance with recurrent RD and vision declination during the follow-up period.
In the suspected case of viral encephalitis, antiviral therapy should be performed regardless of early PCR results to avoid complications of missed viral encephalitis, especially if systemic glucocorticoid therapy is being considered. Besides, special awareness and careful evaluation on neuro-ophthalmological assessment should be paid in any patients with a central nervous system disease. The clinical decision-making should be tailored to suit patients with ARN related to encephalitis, considering the extent and severity of the diseases and symptoms, as well as disease progression. Furthermore, consultation with a multidisciplinary team related to ophthalmology is highly recommended.
Abbreviations
ARNAcute retinal necrosis
HSVHerpes simplex virus
BCVABest corrected visual acuity
CSFCerebral spinal fluid
RDRetinal detachment
PCRPolymerase chain reaction
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Pingting Zhong and Siwen Zang contributed equally to this work.
We gratefully thank the patient and his parents for their kind participation in the study.
Authors’ contributions
Z. PT and Z. SW wrote the manuscript, analyzed the data, and reviewed the literature. Y. HH performed the surgery. Z. PT and Z. SW collected ophthalmologic data and assisted in drafting the manuscript. Y. HH and Y. XH revised the manuscript and discussions. All authors read and approved the final manuscript.
Funding
This work was supported by Science and Technology Program of Guangzhou, China (202002020049) (Y. XH); Project of Investigation on Health Status of Employees in Financial Industry in Guangzhou (Z012014075) (Y. XH).
Availability of data and materials
All data generated or analyzed during this study are included in this article and are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
This study is a case report, the study design was approved by the ethics review board of the Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences. Written informed consent was obtained from the participant.
Consent for publication
Written informed consent was obtained from the patient for publication of this case and any accompanying images. This report does not contain any personal information that could lead to the identification of the patient.
Competing interests
The authors declare that they have no competing interests. | IMMUNE GLOBULIN NOS, METHYLPREDNISOLONE, PREDNISONE | DrugsGivenReaction | CC BY | 33530932 | 19,013,150 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Retinal detachment'. | Herpes simplex virus type 1 related acute retinal necrosis following an encephalitis illness: a case report.
BACKGROUND
Virus encephalitis is found to be a risk factor for acute retinal necrosis (ARN).
METHODS
We herein presented a case of a 20-year-old teenage boy who suffered from encephalitis of unknown etiology with early negative pathologic results, and was primarily treated with systemic administration of high-dose steroids without antiviral therapy. He later had sudden vision loss in his right eye. Intravitreal and intravenous antiviral treatments were immediately started due to suspected ARN. Herpes simplex virus (HSV)-1 was identified later in the vitreous humor of the patient. After the surgery of retinal detachment (RD), obvious improvements in vision were observed. However, the patient had recurrent RD and vision declination 5 weeks later.
CONCLUSIONS
The case with suspected viral encephalitis should be treated with antiviral therapy regardless of early virologic results in order to avoid complications of a missed viral encephalitis diagnosis, especially if systemic steroid treatment is being considered.
Background
Acute retinal necrosis (ARN) is a serious and potential blinding viral ocular infection, and it rapidly develops and progresses in immunocompetent people, causing uveitis with necrotizing retinitis [1]. Varicella-zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2 are the most common causative viruses of ARN [1]. It is assumed that reactivation amid immune dysfunction of the virus leads to ARN, along with central nervous system infection [2]. The association between viral encephalitis and ARN has been reported in one per 1.6–2.0 million people [3]. Therefore, additional attention with regard to ocular clinical manifestations is specially needed in patients with encephalitis after systemic treatment with steroids, as they could affect the body immunity and cause reactivation of the virus. Viral encephalitis should be aware of as it is a risk factor of ARN, and so antiviral treatment is recommended for suspected viral encephalitis.
Case presentation
A 20-year-old teenage boy with abrupt fever, confusion, and epileptic seizures was referred to the Department of Neurology of the Guangzhou General Military Hospital. The patient was otherwise a healthy boy until he had an unusual health status prior to 5 days. Cerebral spinal fluid (CSF) analysis was performed on admission, and the result showed negative Pandy test with a predominance of lymphocytes. Besides, CSF test for Mycobacterium tuberculosis, herpes simplex virus (HSV), cytomegalovirus (CMV), and rubella virus revealed negative results. Two days later, antibody analysis of autoimmune encephalitis was also shown to be normal. Brain magnetic resonance imaging (MRI) showed hypersignal intensity in bilateral frontal as well as temporal lobe.
Next, the patient was diagnosed with encephalitis due to unidentified etiology, and then systemic administration of steroids was given without antiviral treatment. He was prescribed with intravenous methylprednisolone, 1 g/d for 3 consecutive days, followed by 0.5 g/d for 3 days, and then was maintained on 80 mg/d for 2 weeks. Two weeks after admission, the boy showed no sign of improvement. A second brain MRI showed much worsened manifestation of hypersignal in both bilateral frontal and temporal lobe, and a second CSF analysis showed negative results of the pathogen as shown in the first CSF analysis. He was therefore presumed to have “autoimmune encephalitis” by primary neurologists and was prescribed with gamma globulin 25 g/d for 5 days. Later, he had less fever and seizures, and improvements were observed in his oral expression. So, intravenous methylprednisolone administration was gradually reduced and replaced it by oral prednisone of 60 mg/d and then was discharged. One day after being discharged, he had sudden vision loss in his right eye, and then the boy was urgently referred to our hospital.
Investigations
After admitting in our hospital, the patient’s physical and neurological exams were found to be unremarkable. His best corrected visual acuity (BCVA) showed light perception with correct light location in the temporal region of the right eye (OD), and 20/20 with that of the left eye (OS). Ophthalmological examination of his right eye revealed positive Tyndall (+) and cell (++) in the anterior chamber, with obvious opacity (+++) in the vitreous chamber. The fundus of his right eye showed yellow-white lesions, with narrowing retinal vessels and white-sheath and peripheral hemorrhage. Also several tiny retinal holes that lead to retinal detachment (RD) were observed in the peripheral retina (Fig. 1a). No remarkable changes were observed in his left eye.
Fig. 1 Fundus photographs of the right eye. a On admission. The blue arrows represent severe occlusive vasculitis, with macula involved in the peripheral retina, and white arrow represents several tiny holes on superior-nasal degeneration area. b On discharge day. Retinal detachment was repaired with retinal vasculitis and edema showed great improvement
New brain MRI performed in our hospital suggested multiple abnormal signals in the brain parenchyma, which were in accordance with the manifestations of viral encephalitis (Fig. 2). So, viral-related retinal disorders were highly suspected in our case. Vitreous humor was obtained through vitreous chamber tapping to perform polymerase chain reaction (PCR) analysis. DNA of HSV-1 virus (9.0 × 106/ml) was identified 5 days after intravitreal antiviral treatment, and the positive results of IgG and IgM antibodies in the blood serology also supported HSV-1 infection, thus confirming the diagnosis of ARN by HSV-1.
Fig. 2 Hypersignal intensity of left temporal lobe in MRI with T2 flair
Treatment
Intravitreal administration of ganciclovir (0.4 mg/ 0.1 ml) was immediately performed following vitreous chamber tapping at the time of admission to our hospital. Two days later, the boy was relieved from vitreous opacities (+). Antiviral treatment was therefore considered to be effective, and broad-spectrum antiviral medicine (ganciclovir 250 mg every 12-h) was started intravenously, and then replaced with intravenous acyclovir (500 mg every 8-h) after confirmation of HSV pathogen. As the patient also suffered from RD, his right eye was treated by pars plana vitrectomy (PPV), endolaser and silicone oil tamponade 3 days after admission. During the surgery, a second time intravitreal ganciclovir (0.4 mg/0.1 mg) was given.
Outcomes and follow-up
The patient received intravenous antiviral treatment for 2 weeks and was discharged with oral antiviral medicine (famciclovir 375 mg twice a day) as planned for 3 to 4 months. On the day of discharge, BCVA was 20/80 OD and retinal edema in his right eye has been greatly relieved (Fig. 1b). At 5 weeks of follow-up, recurrent vision declination occurred with 20/500 OD due to recurrent RD (Fig. 3). Therefore, silicon oil displacement and endolaser were performed to repair the retina, as well as intravitreal ganciclovir (0.4 mg/0.1 mg) was given for third time. The BCVA of his right eye was increased to 20/80 within 3 days after the surgery. Six months later, after removing the silicone oil, the BCVA was shown to be 20/200 OD with complicated cataract.
Fig. 3 OCT images of the right eye. a On discharge day and b at 5 weeks after discharge
Discussion and conclusion
Our patient due to encephalitis suffered from HSV related ARN after systemic administration of steroids. HSV-infected ARN could be a serious threat that leads to vision loss. Therefore, early awareness and timely antiviral treatment of suspected viral encephalitis are critical in such patients.
The possible reason for the cause of ARN in this patient might be due to viral encephalitis. HSV-1 virus encephalitis is usually characterized by altered mental health status, seizures, somnolence, increased cellularity with predominant lymphocytes in CSF, as well as hypersignal intensity in the MRI of temporal lobes [4], and all these clinical manifestations were observed in our patient. In our case, encephalitis was highly suspected to be caused by viral infection. However, lack of direct evidence of the virus in CSF impeded antiviral treatment. The patient later suffered from ARN due to HSV, suggesting that the virus might come from the brain. Due to the negative evidence in CSF, it could result in low positive predictive value [5] or procedural-related problems. To repeat CSF analysis is important in suspected viral encephalitis. ARN has been reported in cases with prior [6], simultaneous [7], or post [8] presence of herpetic simplex encephalitis or meningitis, and the interval between ARN and meningitis/encephalitis varied from 2 to 5 weeks [9]. A possible underlying mechanism has demonstrated bidirectional fast-axonal transport in neurons [10], and the viral genes play a critical role for antegrade and retrograde axonal transportation.
Immunocompromise after systemic administration of high-dose steroids could be another possible reason for the triggering of ARN in the current case. There are several possible explanations for steroids contributing to the occurrence of ARN. Firstly, high-dose steroids might affect body immunity, promote viral replication, and worsen necrotizing retinopathy [11]. The virus might reach the eye from the brain by a trans-axonal route. Secondly, the triggering event of systemic administration of high-dose steroids could reactivate HSV infection [12], and the latent HSV in several sites is connected to the eye, finally resulting in herpetic ocular disease that involves the cornea, iris, or even the retina [13]. When treating patients with encephalitis, for whom systemic administration of steroids is an inevitable regimen, neurologists should be aware that it might lead to immunocompromise, posing a serious threat in triggering ARN. In addition, according to prior studies on treatment of HSV1-encephalitis by combining with acyclovir, a study showed that treatment without corticosteroid was associated with poorer outcomes [14], while another study found no positive effects by adding dexamethasone to acyclovir [15]. Therefore, the use of corticosteroid therapy for viral encephalitis depends on the discretion of clinicians. As patients with encephalitis always present with confusion, which prevents them from timely and precise expression of their ocular discomforts, and so attention should be paid with regard to ocular clinical manifestations.
Intravitreal and intravenous antiviral treatment was then immediately started in this patient, and this is because of high suspicion of ARN according to ocular manifestations. So, diagnostic testing of vitreous humor before antiviral treatment has been done, and later corresponding adjustments were made. Topical and systemic antiviral treatment is an urgent need, as it is beneficial for the visual acuity and thus could decrease the risk of infection to the other eye [16]. As documented previously, there were up to 70% of untreated patients with bilateral ARN [17]. In our case, ARN was presented in a single eye, but it is assumed that the contralateral eye might also be affected if timely and precise antiviral treatment is not given. With a better understanding of antiviral treatment, the rate of bilateralization according to the recently reported studies on ARN has been found to be significantly decreased into 10–20% [18].
The challenges concerning diagnosis as well as prognosis were posed in this case. The CSF initially revealed negative results for viral encephalitis, and the diagnosis of ARN was later confirmed by PCR analysis with HSV-1 in the vitreous humor, and this is widely available to clinicians with good sensitivity and specificity [19]. According to a recent study, the correlation of quantitative DNA PCR and clinical prognosis in ARN has revealed that a number of copies superior to 5.0 × 106/ml showed association with a higher probability of RD [20]. In our case, the quantitative DNA of HSV-1 was 9.0 × 106/ml, suggesting a poor prognosis of vision in accordance with recurrent RD and vision declination during the follow-up period.
In the suspected case of viral encephalitis, antiviral therapy should be performed regardless of early PCR results to avoid complications of missed viral encephalitis, especially if systemic glucocorticoid therapy is being considered. Besides, special awareness and careful evaluation on neuro-ophthalmological assessment should be paid in any patients with a central nervous system disease. The clinical decision-making should be tailored to suit patients with ARN related to encephalitis, considering the extent and severity of the diseases and symptoms, as well as disease progression. Furthermore, consultation with a multidisciplinary team related to ophthalmology is highly recommended.
Abbreviations
ARNAcute retinal necrosis
HSVHerpes simplex virus
BCVABest corrected visual acuity
CSFCerebral spinal fluid
RDRetinal detachment
PCRPolymerase chain reaction
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Pingting Zhong and Siwen Zang contributed equally to this work.
We gratefully thank the patient and his parents for their kind participation in the study.
Authors’ contributions
Z. PT and Z. SW wrote the manuscript, analyzed the data, and reviewed the literature. Y. HH performed the surgery. Z. PT and Z. SW collected ophthalmologic data and assisted in drafting the manuscript. Y. HH and Y. XH revised the manuscript and discussions. All authors read and approved the final manuscript.
Funding
This work was supported by Science and Technology Program of Guangzhou, China (202002020049) (Y. XH); Project of Investigation on Health Status of Employees in Financial Industry in Guangzhou (Z012014075) (Y. XH).
Availability of data and materials
All data generated or analyzed during this study are included in this article and are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
This study is a case report, the study design was approved by the ethics review board of the Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences. Written informed consent was obtained from the participant.
Consent for publication
Written informed consent was obtained from the patient for publication of this case and any accompanying images. This report does not contain any personal information that could lead to the identification of the patient.
Competing interests
The authors declare that they have no competing interests. | IMMUNE GLOBULIN NOS, METHYLPREDNISOLONE, PREDNISONE | DrugsGivenReaction | CC BY | 33530932 | 19,013,150 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sudden visual loss'. | Herpes simplex virus type 1 related acute retinal necrosis following an encephalitis illness: a case report.
BACKGROUND
Virus encephalitis is found to be a risk factor for acute retinal necrosis (ARN).
METHODS
We herein presented a case of a 20-year-old teenage boy who suffered from encephalitis of unknown etiology with early negative pathologic results, and was primarily treated with systemic administration of high-dose steroids without antiviral therapy. He later had sudden vision loss in his right eye. Intravitreal and intravenous antiviral treatments were immediately started due to suspected ARN. Herpes simplex virus (HSV)-1 was identified later in the vitreous humor of the patient. After the surgery of retinal detachment (RD), obvious improvements in vision were observed. However, the patient had recurrent RD and vision declination 5 weeks later.
CONCLUSIONS
The case with suspected viral encephalitis should be treated with antiviral therapy regardless of early virologic results in order to avoid complications of a missed viral encephalitis diagnosis, especially if systemic steroid treatment is being considered.
Background
Acute retinal necrosis (ARN) is a serious and potential blinding viral ocular infection, and it rapidly develops and progresses in immunocompetent people, causing uveitis with necrotizing retinitis [1]. Varicella-zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2 are the most common causative viruses of ARN [1]. It is assumed that reactivation amid immune dysfunction of the virus leads to ARN, along with central nervous system infection [2]. The association between viral encephalitis and ARN has been reported in one per 1.6–2.0 million people [3]. Therefore, additional attention with regard to ocular clinical manifestations is specially needed in patients with encephalitis after systemic treatment with steroids, as they could affect the body immunity and cause reactivation of the virus. Viral encephalitis should be aware of as it is a risk factor of ARN, and so antiviral treatment is recommended for suspected viral encephalitis.
Case presentation
A 20-year-old teenage boy with abrupt fever, confusion, and epileptic seizures was referred to the Department of Neurology of the Guangzhou General Military Hospital. The patient was otherwise a healthy boy until he had an unusual health status prior to 5 days. Cerebral spinal fluid (CSF) analysis was performed on admission, and the result showed negative Pandy test with a predominance of lymphocytes. Besides, CSF test for Mycobacterium tuberculosis, herpes simplex virus (HSV), cytomegalovirus (CMV), and rubella virus revealed negative results. Two days later, antibody analysis of autoimmune encephalitis was also shown to be normal. Brain magnetic resonance imaging (MRI) showed hypersignal intensity in bilateral frontal as well as temporal lobe.
Next, the patient was diagnosed with encephalitis due to unidentified etiology, and then systemic administration of steroids was given without antiviral treatment. He was prescribed with intravenous methylprednisolone, 1 g/d for 3 consecutive days, followed by 0.5 g/d for 3 days, and then was maintained on 80 mg/d for 2 weeks. Two weeks after admission, the boy showed no sign of improvement. A second brain MRI showed much worsened manifestation of hypersignal in both bilateral frontal and temporal lobe, and a second CSF analysis showed negative results of the pathogen as shown in the first CSF analysis. He was therefore presumed to have “autoimmune encephalitis” by primary neurologists and was prescribed with gamma globulin 25 g/d for 5 days. Later, he had less fever and seizures, and improvements were observed in his oral expression. So, intravenous methylprednisolone administration was gradually reduced and replaced it by oral prednisone of 60 mg/d and then was discharged. One day after being discharged, he had sudden vision loss in his right eye, and then the boy was urgently referred to our hospital.
Investigations
After admitting in our hospital, the patient’s physical and neurological exams were found to be unremarkable. His best corrected visual acuity (BCVA) showed light perception with correct light location in the temporal region of the right eye (OD), and 20/20 with that of the left eye (OS). Ophthalmological examination of his right eye revealed positive Tyndall (+) and cell (++) in the anterior chamber, with obvious opacity (+++) in the vitreous chamber. The fundus of his right eye showed yellow-white lesions, with narrowing retinal vessels and white-sheath and peripheral hemorrhage. Also several tiny retinal holes that lead to retinal detachment (RD) were observed in the peripheral retina (Fig. 1a). No remarkable changes were observed in his left eye.
Fig. 1 Fundus photographs of the right eye. a On admission. The blue arrows represent severe occlusive vasculitis, with macula involved in the peripheral retina, and white arrow represents several tiny holes on superior-nasal degeneration area. b On discharge day. Retinal detachment was repaired with retinal vasculitis and edema showed great improvement
New brain MRI performed in our hospital suggested multiple abnormal signals in the brain parenchyma, which were in accordance with the manifestations of viral encephalitis (Fig. 2). So, viral-related retinal disorders were highly suspected in our case. Vitreous humor was obtained through vitreous chamber tapping to perform polymerase chain reaction (PCR) analysis. DNA of HSV-1 virus (9.0 × 106/ml) was identified 5 days after intravitreal antiviral treatment, and the positive results of IgG and IgM antibodies in the blood serology also supported HSV-1 infection, thus confirming the diagnosis of ARN by HSV-1.
Fig. 2 Hypersignal intensity of left temporal lobe in MRI with T2 flair
Treatment
Intravitreal administration of ganciclovir (0.4 mg/ 0.1 ml) was immediately performed following vitreous chamber tapping at the time of admission to our hospital. Two days later, the boy was relieved from vitreous opacities (+). Antiviral treatment was therefore considered to be effective, and broad-spectrum antiviral medicine (ganciclovir 250 mg every 12-h) was started intravenously, and then replaced with intravenous acyclovir (500 mg every 8-h) after confirmation of HSV pathogen. As the patient also suffered from RD, his right eye was treated by pars plana vitrectomy (PPV), endolaser and silicone oil tamponade 3 days after admission. During the surgery, a second time intravitreal ganciclovir (0.4 mg/0.1 mg) was given.
Outcomes and follow-up
The patient received intravenous antiviral treatment for 2 weeks and was discharged with oral antiviral medicine (famciclovir 375 mg twice a day) as planned for 3 to 4 months. On the day of discharge, BCVA was 20/80 OD and retinal edema in his right eye has been greatly relieved (Fig. 1b). At 5 weeks of follow-up, recurrent vision declination occurred with 20/500 OD due to recurrent RD (Fig. 3). Therefore, silicon oil displacement and endolaser were performed to repair the retina, as well as intravitreal ganciclovir (0.4 mg/0.1 mg) was given for third time. The BCVA of his right eye was increased to 20/80 within 3 days after the surgery. Six months later, after removing the silicone oil, the BCVA was shown to be 20/200 OD with complicated cataract.
Fig. 3 OCT images of the right eye. a On discharge day and b at 5 weeks after discharge
Discussion and conclusion
Our patient due to encephalitis suffered from HSV related ARN after systemic administration of steroids. HSV-infected ARN could be a serious threat that leads to vision loss. Therefore, early awareness and timely antiviral treatment of suspected viral encephalitis are critical in such patients.
The possible reason for the cause of ARN in this patient might be due to viral encephalitis. HSV-1 virus encephalitis is usually characterized by altered mental health status, seizures, somnolence, increased cellularity with predominant lymphocytes in CSF, as well as hypersignal intensity in the MRI of temporal lobes [4], and all these clinical manifestations were observed in our patient. In our case, encephalitis was highly suspected to be caused by viral infection. However, lack of direct evidence of the virus in CSF impeded antiviral treatment. The patient later suffered from ARN due to HSV, suggesting that the virus might come from the brain. Due to the negative evidence in CSF, it could result in low positive predictive value [5] or procedural-related problems. To repeat CSF analysis is important in suspected viral encephalitis. ARN has been reported in cases with prior [6], simultaneous [7], or post [8] presence of herpetic simplex encephalitis or meningitis, and the interval between ARN and meningitis/encephalitis varied from 2 to 5 weeks [9]. A possible underlying mechanism has demonstrated bidirectional fast-axonal transport in neurons [10], and the viral genes play a critical role for antegrade and retrograde axonal transportation.
Immunocompromise after systemic administration of high-dose steroids could be another possible reason for the triggering of ARN in the current case. There are several possible explanations for steroids contributing to the occurrence of ARN. Firstly, high-dose steroids might affect body immunity, promote viral replication, and worsen necrotizing retinopathy [11]. The virus might reach the eye from the brain by a trans-axonal route. Secondly, the triggering event of systemic administration of high-dose steroids could reactivate HSV infection [12], and the latent HSV in several sites is connected to the eye, finally resulting in herpetic ocular disease that involves the cornea, iris, or even the retina [13]. When treating patients with encephalitis, for whom systemic administration of steroids is an inevitable regimen, neurologists should be aware that it might lead to immunocompromise, posing a serious threat in triggering ARN. In addition, according to prior studies on treatment of HSV1-encephalitis by combining with acyclovir, a study showed that treatment without corticosteroid was associated with poorer outcomes [14], while another study found no positive effects by adding dexamethasone to acyclovir [15]. Therefore, the use of corticosteroid therapy for viral encephalitis depends on the discretion of clinicians. As patients with encephalitis always present with confusion, which prevents them from timely and precise expression of their ocular discomforts, and so attention should be paid with regard to ocular clinical manifestations.
Intravitreal and intravenous antiviral treatment was then immediately started in this patient, and this is because of high suspicion of ARN according to ocular manifestations. So, diagnostic testing of vitreous humor before antiviral treatment has been done, and later corresponding adjustments were made. Topical and systemic antiviral treatment is an urgent need, as it is beneficial for the visual acuity and thus could decrease the risk of infection to the other eye [16]. As documented previously, there were up to 70% of untreated patients with bilateral ARN [17]. In our case, ARN was presented in a single eye, but it is assumed that the contralateral eye might also be affected if timely and precise antiviral treatment is not given. With a better understanding of antiviral treatment, the rate of bilateralization according to the recently reported studies on ARN has been found to be significantly decreased into 10–20% [18].
The challenges concerning diagnosis as well as prognosis were posed in this case. The CSF initially revealed negative results for viral encephalitis, and the diagnosis of ARN was later confirmed by PCR analysis with HSV-1 in the vitreous humor, and this is widely available to clinicians with good sensitivity and specificity [19]. According to a recent study, the correlation of quantitative DNA PCR and clinical prognosis in ARN has revealed that a number of copies superior to 5.0 × 106/ml showed association with a higher probability of RD [20]. In our case, the quantitative DNA of HSV-1 was 9.0 × 106/ml, suggesting a poor prognosis of vision in accordance with recurrent RD and vision declination during the follow-up period.
In the suspected case of viral encephalitis, antiviral therapy should be performed regardless of early PCR results to avoid complications of missed viral encephalitis, especially if systemic glucocorticoid therapy is being considered. Besides, special awareness and careful evaluation on neuro-ophthalmological assessment should be paid in any patients with a central nervous system disease. The clinical decision-making should be tailored to suit patients with ARN related to encephalitis, considering the extent and severity of the diseases and symptoms, as well as disease progression. Furthermore, consultation with a multidisciplinary team related to ophthalmology is highly recommended.
Abbreviations
ARNAcute retinal necrosis
HSVHerpes simplex virus
BCVABest corrected visual acuity
CSFCerebral spinal fluid
RDRetinal detachment
PCRPolymerase chain reaction
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Pingting Zhong and Siwen Zang contributed equally to this work.
We gratefully thank the patient and his parents for their kind participation in the study.
Authors’ contributions
Z. PT and Z. SW wrote the manuscript, analyzed the data, and reviewed the literature. Y. HH performed the surgery. Z. PT and Z. SW collected ophthalmologic data and assisted in drafting the manuscript. Y. HH and Y. XH revised the manuscript and discussions. All authors read and approved the final manuscript.
Funding
This work was supported by Science and Technology Program of Guangzhou, China (202002020049) (Y. XH); Project of Investigation on Health Status of Employees in Financial Industry in Guangzhou (Z012014075) (Y. XH).
Availability of data and materials
All data generated or analyzed during this study are included in this article and are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
This study is a case report, the study design was approved by the ethics review board of the Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences. Written informed consent was obtained from the participant.
Consent for publication
Written informed consent was obtained from the patient for publication of this case and any accompanying images. This report does not contain any personal information that could lead to the identification of the patient.
Competing interests
The authors declare that they have no competing interests. | IMMUNE GLOBULIN NOS, METHYLPREDNISOLONE, PREDNISONE | DrugsGivenReaction | CC BY | 33530932 | 19,013,150 | 2021-02-02 |
What was the administration route of drug 'METHYLPREDNISOLONE'? | Herpes simplex virus type 1 related acute retinal necrosis following an encephalitis illness: a case report.
BACKGROUND
Virus encephalitis is found to be a risk factor for acute retinal necrosis (ARN).
METHODS
We herein presented a case of a 20-year-old teenage boy who suffered from encephalitis of unknown etiology with early negative pathologic results, and was primarily treated with systemic administration of high-dose steroids without antiviral therapy. He later had sudden vision loss in his right eye. Intravitreal and intravenous antiviral treatments were immediately started due to suspected ARN. Herpes simplex virus (HSV)-1 was identified later in the vitreous humor of the patient. After the surgery of retinal detachment (RD), obvious improvements in vision were observed. However, the patient had recurrent RD and vision declination 5 weeks later.
CONCLUSIONS
The case with suspected viral encephalitis should be treated with antiviral therapy regardless of early virologic results in order to avoid complications of a missed viral encephalitis diagnosis, especially if systemic steroid treatment is being considered.
Background
Acute retinal necrosis (ARN) is a serious and potential blinding viral ocular infection, and it rapidly develops and progresses in immunocompetent people, causing uveitis with necrotizing retinitis [1]. Varicella-zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2 are the most common causative viruses of ARN [1]. It is assumed that reactivation amid immune dysfunction of the virus leads to ARN, along with central nervous system infection [2]. The association between viral encephalitis and ARN has been reported in one per 1.6–2.0 million people [3]. Therefore, additional attention with regard to ocular clinical manifestations is specially needed in patients with encephalitis after systemic treatment with steroids, as they could affect the body immunity and cause reactivation of the virus. Viral encephalitis should be aware of as it is a risk factor of ARN, and so antiviral treatment is recommended for suspected viral encephalitis.
Case presentation
A 20-year-old teenage boy with abrupt fever, confusion, and epileptic seizures was referred to the Department of Neurology of the Guangzhou General Military Hospital. The patient was otherwise a healthy boy until he had an unusual health status prior to 5 days. Cerebral spinal fluid (CSF) analysis was performed on admission, and the result showed negative Pandy test with a predominance of lymphocytes. Besides, CSF test for Mycobacterium tuberculosis, herpes simplex virus (HSV), cytomegalovirus (CMV), and rubella virus revealed negative results. Two days later, antibody analysis of autoimmune encephalitis was also shown to be normal. Brain magnetic resonance imaging (MRI) showed hypersignal intensity in bilateral frontal as well as temporal lobe.
Next, the patient was diagnosed with encephalitis due to unidentified etiology, and then systemic administration of steroids was given without antiviral treatment. He was prescribed with intravenous methylprednisolone, 1 g/d for 3 consecutive days, followed by 0.5 g/d for 3 days, and then was maintained on 80 mg/d for 2 weeks. Two weeks after admission, the boy showed no sign of improvement. A second brain MRI showed much worsened manifestation of hypersignal in both bilateral frontal and temporal lobe, and a second CSF analysis showed negative results of the pathogen as shown in the first CSF analysis. He was therefore presumed to have “autoimmune encephalitis” by primary neurologists and was prescribed with gamma globulin 25 g/d for 5 days. Later, he had less fever and seizures, and improvements were observed in his oral expression. So, intravenous methylprednisolone administration was gradually reduced and replaced it by oral prednisone of 60 mg/d and then was discharged. One day after being discharged, he had sudden vision loss in his right eye, and then the boy was urgently referred to our hospital.
Investigations
After admitting in our hospital, the patient’s physical and neurological exams were found to be unremarkable. His best corrected visual acuity (BCVA) showed light perception with correct light location in the temporal region of the right eye (OD), and 20/20 with that of the left eye (OS). Ophthalmological examination of his right eye revealed positive Tyndall (+) and cell (++) in the anterior chamber, with obvious opacity (+++) in the vitreous chamber. The fundus of his right eye showed yellow-white lesions, with narrowing retinal vessels and white-sheath and peripheral hemorrhage. Also several tiny retinal holes that lead to retinal detachment (RD) were observed in the peripheral retina (Fig. 1a). No remarkable changes were observed in his left eye.
Fig. 1 Fundus photographs of the right eye. a On admission. The blue arrows represent severe occlusive vasculitis, with macula involved in the peripheral retina, and white arrow represents several tiny holes on superior-nasal degeneration area. b On discharge day. Retinal detachment was repaired with retinal vasculitis and edema showed great improvement
New brain MRI performed in our hospital suggested multiple abnormal signals in the brain parenchyma, which were in accordance with the manifestations of viral encephalitis (Fig. 2). So, viral-related retinal disorders were highly suspected in our case. Vitreous humor was obtained through vitreous chamber tapping to perform polymerase chain reaction (PCR) analysis. DNA of HSV-1 virus (9.0 × 106/ml) was identified 5 days after intravitreal antiviral treatment, and the positive results of IgG and IgM antibodies in the blood serology also supported HSV-1 infection, thus confirming the diagnosis of ARN by HSV-1.
Fig. 2 Hypersignal intensity of left temporal lobe in MRI with T2 flair
Treatment
Intravitreal administration of ganciclovir (0.4 mg/ 0.1 ml) was immediately performed following vitreous chamber tapping at the time of admission to our hospital. Two days later, the boy was relieved from vitreous opacities (+). Antiviral treatment was therefore considered to be effective, and broad-spectrum antiviral medicine (ganciclovir 250 mg every 12-h) was started intravenously, and then replaced with intravenous acyclovir (500 mg every 8-h) after confirmation of HSV pathogen. As the patient also suffered from RD, his right eye was treated by pars plana vitrectomy (PPV), endolaser and silicone oil tamponade 3 days after admission. During the surgery, a second time intravitreal ganciclovir (0.4 mg/0.1 mg) was given.
Outcomes and follow-up
The patient received intravenous antiviral treatment for 2 weeks and was discharged with oral antiviral medicine (famciclovir 375 mg twice a day) as planned for 3 to 4 months. On the day of discharge, BCVA was 20/80 OD and retinal edema in his right eye has been greatly relieved (Fig. 1b). At 5 weeks of follow-up, recurrent vision declination occurred with 20/500 OD due to recurrent RD (Fig. 3). Therefore, silicon oil displacement and endolaser were performed to repair the retina, as well as intravitreal ganciclovir (0.4 mg/0.1 mg) was given for third time. The BCVA of his right eye was increased to 20/80 within 3 days after the surgery. Six months later, after removing the silicone oil, the BCVA was shown to be 20/200 OD with complicated cataract.
Fig. 3 OCT images of the right eye. a On discharge day and b at 5 weeks after discharge
Discussion and conclusion
Our patient due to encephalitis suffered from HSV related ARN after systemic administration of steroids. HSV-infected ARN could be a serious threat that leads to vision loss. Therefore, early awareness and timely antiviral treatment of suspected viral encephalitis are critical in such patients.
The possible reason for the cause of ARN in this patient might be due to viral encephalitis. HSV-1 virus encephalitis is usually characterized by altered mental health status, seizures, somnolence, increased cellularity with predominant lymphocytes in CSF, as well as hypersignal intensity in the MRI of temporal lobes [4], and all these clinical manifestations were observed in our patient. In our case, encephalitis was highly suspected to be caused by viral infection. However, lack of direct evidence of the virus in CSF impeded antiviral treatment. The patient later suffered from ARN due to HSV, suggesting that the virus might come from the brain. Due to the negative evidence in CSF, it could result in low positive predictive value [5] or procedural-related problems. To repeat CSF analysis is important in suspected viral encephalitis. ARN has been reported in cases with prior [6], simultaneous [7], or post [8] presence of herpetic simplex encephalitis or meningitis, and the interval between ARN and meningitis/encephalitis varied from 2 to 5 weeks [9]. A possible underlying mechanism has demonstrated bidirectional fast-axonal transport in neurons [10], and the viral genes play a critical role for antegrade and retrograde axonal transportation.
Immunocompromise after systemic administration of high-dose steroids could be another possible reason for the triggering of ARN in the current case. There are several possible explanations for steroids contributing to the occurrence of ARN. Firstly, high-dose steroids might affect body immunity, promote viral replication, and worsen necrotizing retinopathy [11]. The virus might reach the eye from the brain by a trans-axonal route. Secondly, the triggering event of systemic administration of high-dose steroids could reactivate HSV infection [12], and the latent HSV in several sites is connected to the eye, finally resulting in herpetic ocular disease that involves the cornea, iris, or even the retina [13]. When treating patients with encephalitis, for whom systemic administration of steroids is an inevitable regimen, neurologists should be aware that it might lead to immunocompromise, posing a serious threat in triggering ARN. In addition, according to prior studies on treatment of HSV1-encephalitis by combining with acyclovir, a study showed that treatment without corticosteroid was associated with poorer outcomes [14], while another study found no positive effects by adding dexamethasone to acyclovir [15]. Therefore, the use of corticosteroid therapy for viral encephalitis depends on the discretion of clinicians. As patients with encephalitis always present with confusion, which prevents them from timely and precise expression of their ocular discomforts, and so attention should be paid with regard to ocular clinical manifestations.
Intravitreal and intravenous antiviral treatment was then immediately started in this patient, and this is because of high suspicion of ARN according to ocular manifestations. So, diagnostic testing of vitreous humor before antiviral treatment has been done, and later corresponding adjustments were made. Topical and systemic antiviral treatment is an urgent need, as it is beneficial for the visual acuity and thus could decrease the risk of infection to the other eye [16]. As documented previously, there were up to 70% of untreated patients with bilateral ARN [17]. In our case, ARN was presented in a single eye, but it is assumed that the contralateral eye might also be affected if timely and precise antiviral treatment is not given. With a better understanding of antiviral treatment, the rate of bilateralization according to the recently reported studies on ARN has been found to be significantly decreased into 10–20% [18].
The challenges concerning diagnosis as well as prognosis were posed in this case. The CSF initially revealed negative results for viral encephalitis, and the diagnosis of ARN was later confirmed by PCR analysis with HSV-1 in the vitreous humor, and this is widely available to clinicians with good sensitivity and specificity [19]. According to a recent study, the correlation of quantitative DNA PCR and clinical prognosis in ARN has revealed that a number of copies superior to 5.0 × 106/ml showed association with a higher probability of RD [20]. In our case, the quantitative DNA of HSV-1 was 9.0 × 106/ml, suggesting a poor prognosis of vision in accordance with recurrent RD and vision declination during the follow-up period.
In the suspected case of viral encephalitis, antiviral therapy should be performed regardless of early PCR results to avoid complications of missed viral encephalitis, especially if systemic glucocorticoid therapy is being considered. Besides, special awareness and careful evaluation on neuro-ophthalmological assessment should be paid in any patients with a central nervous system disease. The clinical decision-making should be tailored to suit patients with ARN related to encephalitis, considering the extent and severity of the diseases and symptoms, as well as disease progression. Furthermore, consultation with a multidisciplinary team related to ophthalmology is highly recommended.
Abbreviations
ARNAcute retinal necrosis
HSVHerpes simplex virus
BCVABest corrected visual acuity
CSFCerebral spinal fluid
RDRetinal detachment
PCRPolymerase chain reaction
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Pingting Zhong and Siwen Zang contributed equally to this work.
We gratefully thank the patient and his parents for their kind participation in the study.
Authors’ contributions
Z. PT and Z. SW wrote the manuscript, analyzed the data, and reviewed the literature. Y. HH performed the surgery. Z. PT and Z. SW collected ophthalmologic data and assisted in drafting the manuscript. Y. HH and Y. XH revised the manuscript and discussions. All authors read and approved the final manuscript.
Funding
This work was supported by Science and Technology Program of Guangzhou, China (202002020049) (Y. XH); Project of Investigation on Health Status of Employees in Financial Industry in Guangzhou (Z012014075) (Y. XH).
Availability of data and materials
All data generated or analyzed during this study are included in this article and are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
This study is a case report, the study design was approved by the ethics review board of the Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences. Written informed consent was obtained from the participant.
Consent for publication
Written informed consent was obtained from the patient for publication of this case and any accompanying images. This report does not contain any personal information that could lead to the identification of the patient.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33530932 | 18,947,754 | 2021-02-02 |
What was the administration route of drug 'PREDNISONE'? | Herpes simplex virus type 1 related acute retinal necrosis following an encephalitis illness: a case report.
BACKGROUND
Virus encephalitis is found to be a risk factor for acute retinal necrosis (ARN).
METHODS
We herein presented a case of a 20-year-old teenage boy who suffered from encephalitis of unknown etiology with early negative pathologic results, and was primarily treated with systemic administration of high-dose steroids without antiviral therapy. He later had sudden vision loss in his right eye. Intravitreal and intravenous antiviral treatments were immediately started due to suspected ARN. Herpes simplex virus (HSV)-1 was identified later in the vitreous humor of the patient. After the surgery of retinal detachment (RD), obvious improvements in vision were observed. However, the patient had recurrent RD and vision declination 5 weeks later.
CONCLUSIONS
The case with suspected viral encephalitis should be treated with antiviral therapy regardless of early virologic results in order to avoid complications of a missed viral encephalitis diagnosis, especially if systemic steroid treatment is being considered.
Background
Acute retinal necrosis (ARN) is a serious and potential blinding viral ocular infection, and it rapidly develops and progresses in immunocompetent people, causing uveitis with necrotizing retinitis [1]. Varicella-zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2 are the most common causative viruses of ARN [1]. It is assumed that reactivation amid immune dysfunction of the virus leads to ARN, along with central nervous system infection [2]. The association between viral encephalitis and ARN has been reported in one per 1.6–2.0 million people [3]. Therefore, additional attention with regard to ocular clinical manifestations is specially needed in patients with encephalitis after systemic treatment with steroids, as they could affect the body immunity and cause reactivation of the virus. Viral encephalitis should be aware of as it is a risk factor of ARN, and so antiviral treatment is recommended for suspected viral encephalitis.
Case presentation
A 20-year-old teenage boy with abrupt fever, confusion, and epileptic seizures was referred to the Department of Neurology of the Guangzhou General Military Hospital. The patient was otherwise a healthy boy until he had an unusual health status prior to 5 days. Cerebral spinal fluid (CSF) analysis was performed on admission, and the result showed negative Pandy test with a predominance of lymphocytes. Besides, CSF test for Mycobacterium tuberculosis, herpes simplex virus (HSV), cytomegalovirus (CMV), and rubella virus revealed negative results. Two days later, antibody analysis of autoimmune encephalitis was also shown to be normal. Brain magnetic resonance imaging (MRI) showed hypersignal intensity in bilateral frontal as well as temporal lobe.
Next, the patient was diagnosed with encephalitis due to unidentified etiology, and then systemic administration of steroids was given without antiviral treatment. He was prescribed with intravenous methylprednisolone, 1 g/d for 3 consecutive days, followed by 0.5 g/d for 3 days, and then was maintained on 80 mg/d for 2 weeks. Two weeks after admission, the boy showed no sign of improvement. A second brain MRI showed much worsened manifestation of hypersignal in both bilateral frontal and temporal lobe, and a second CSF analysis showed negative results of the pathogen as shown in the first CSF analysis. He was therefore presumed to have “autoimmune encephalitis” by primary neurologists and was prescribed with gamma globulin 25 g/d for 5 days. Later, he had less fever and seizures, and improvements were observed in his oral expression. So, intravenous methylprednisolone administration was gradually reduced and replaced it by oral prednisone of 60 mg/d and then was discharged. One day after being discharged, he had sudden vision loss in his right eye, and then the boy was urgently referred to our hospital.
Investigations
After admitting in our hospital, the patient’s physical and neurological exams were found to be unremarkable. His best corrected visual acuity (BCVA) showed light perception with correct light location in the temporal region of the right eye (OD), and 20/20 with that of the left eye (OS). Ophthalmological examination of his right eye revealed positive Tyndall (+) and cell (++) in the anterior chamber, with obvious opacity (+++) in the vitreous chamber. The fundus of his right eye showed yellow-white lesions, with narrowing retinal vessels and white-sheath and peripheral hemorrhage. Also several tiny retinal holes that lead to retinal detachment (RD) were observed in the peripheral retina (Fig. 1a). No remarkable changes were observed in his left eye.
Fig. 1 Fundus photographs of the right eye. a On admission. The blue arrows represent severe occlusive vasculitis, with macula involved in the peripheral retina, and white arrow represents several tiny holes on superior-nasal degeneration area. b On discharge day. Retinal detachment was repaired with retinal vasculitis and edema showed great improvement
New brain MRI performed in our hospital suggested multiple abnormal signals in the brain parenchyma, which were in accordance with the manifestations of viral encephalitis (Fig. 2). So, viral-related retinal disorders were highly suspected in our case. Vitreous humor was obtained through vitreous chamber tapping to perform polymerase chain reaction (PCR) analysis. DNA of HSV-1 virus (9.0 × 106/ml) was identified 5 days after intravitreal antiviral treatment, and the positive results of IgG and IgM antibodies in the blood serology also supported HSV-1 infection, thus confirming the diagnosis of ARN by HSV-1.
Fig. 2 Hypersignal intensity of left temporal lobe in MRI with T2 flair
Treatment
Intravitreal administration of ganciclovir (0.4 mg/ 0.1 ml) was immediately performed following vitreous chamber tapping at the time of admission to our hospital. Two days later, the boy was relieved from vitreous opacities (+). Antiviral treatment was therefore considered to be effective, and broad-spectrum antiviral medicine (ganciclovir 250 mg every 12-h) was started intravenously, and then replaced with intravenous acyclovir (500 mg every 8-h) after confirmation of HSV pathogen. As the patient also suffered from RD, his right eye was treated by pars plana vitrectomy (PPV), endolaser and silicone oil tamponade 3 days after admission. During the surgery, a second time intravitreal ganciclovir (0.4 mg/0.1 mg) was given.
Outcomes and follow-up
The patient received intravenous antiviral treatment for 2 weeks and was discharged with oral antiviral medicine (famciclovir 375 mg twice a day) as planned for 3 to 4 months. On the day of discharge, BCVA was 20/80 OD and retinal edema in his right eye has been greatly relieved (Fig. 1b). At 5 weeks of follow-up, recurrent vision declination occurred with 20/500 OD due to recurrent RD (Fig. 3). Therefore, silicon oil displacement and endolaser were performed to repair the retina, as well as intravitreal ganciclovir (0.4 mg/0.1 mg) was given for third time. The BCVA of his right eye was increased to 20/80 within 3 days after the surgery. Six months later, after removing the silicone oil, the BCVA was shown to be 20/200 OD with complicated cataract.
Fig. 3 OCT images of the right eye. a On discharge day and b at 5 weeks after discharge
Discussion and conclusion
Our patient due to encephalitis suffered from HSV related ARN after systemic administration of steroids. HSV-infected ARN could be a serious threat that leads to vision loss. Therefore, early awareness and timely antiviral treatment of suspected viral encephalitis are critical in such patients.
The possible reason for the cause of ARN in this patient might be due to viral encephalitis. HSV-1 virus encephalitis is usually characterized by altered mental health status, seizures, somnolence, increased cellularity with predominant lymphocytes in CSF, as well as hypersignal intensity in the MRI of temporal lobes [4], and all these clinical manifestations were observed in our patient. In our case, encephalitis was highly suspected to be caused by viral infection. However, lack of direct evidence of the virus in CSF impeded antiviral treatment. The patient later suffered from ARN due to HSV, suggesting that the virus might come from the brain. Due to the negative evidence in CSF, it could result in low positive predictive value [5] or procedural-related problems. To repeat CSF analysis is important in suspected viral encephalitis. ARN has been reported in cases with prior [6], simultaneous [7], or post [8] presence of herpetic simplex encephalitis or meningitis, and the interval between ARN and meningitis/encephalitis varied from 2 to 5 weeks [9]. A possible underlying mechanism has demonstrated bidirectional fast-axonal transport in neurons [10], and the viral genes play a critical role for antegrade and retrograde axonal transportation.
Immunocompromise after systemic administration of high-dose steroids could be another possible reason for the triggering of ARN in the current case. There are several possible explanations for steroids contributing to the occurrence of ARN. Firstly, high-dose steroids might affect body immunity, promote viral replication, and worsen necrotizing retinopathy [11]. The virus might reach the eye from the brain by a trans-axonal route. Secondly, the triggering event of systemic administration of high-dose steroids could reactivate HSV infection [12], and the latent HSV in several sites is connected to the eye, finally resulting in herpetic ocular disease that involves the cornea, iris, or even the retina [13]. When treating patients with encephalitis, for whom systemic administration of steroids is an inevitable regimen, neurologists should be aware that it might lead to immunocompromise, posing a serious threat in triggering ARN. In addition, according to prior studies on treatment of HSV1-encephalitis by combining with acyclovir, a study showed that treatment without corticosteroid was associated with poorer outcomes [14], while another study found no positive effects by adding dexamethasone to acyclovir [15]. Therefore, the use of corticosteroid therapy for viral encephalitis depends on the discretion of clinicians. As patients with encephalitis always present with confusion, which prevents them from timely and precise expression of their ocular discomforts, and so attention should be paid with regard to ocular clinical manifestations.
Intravitreal and intravenous antiviral treatment was then immediately started in this patient, and this is because of high suspicion of ARN according to ocular manifestations. So, diagnostic testing of vitreous humor before antiviral treatment has been done, and later corresponding adjustments were made. Topical and systemic antiviral treatment is an urgent need, as it is beneficial for the visual acuity and thus could decrease the risk of infection to the other eye [16]. As documented previously, there were up to 70% of untreated patients with bilateral ARN [17]. In our case, ARN was presented in a single eye, but it is assumed that the contralateral eye might also be affected if timely and precise antiviral treatment is not given. With a better understanding of antiviral treatment, the rate of bilateralization according to the recently reported studies on ARN has been found to be significantly decreased into 10–20% [18].
The challenges concerning diagnosis as well as prognosis were posed in this case. The CSF initially revealed negative results for viral encephalitis, and the diagnosis of ARN was later confirmed by PCR analysis with HSV-1 in the vitreous humor, and this is widely available to clinicians with good sensitivity and specificity [19]. According to a recent study, the correlation of quantitative DNA PCR and clinical prognosis in ARN has revealed that a number of copies superior to 5.0 × 106/ml showed association with a higher probability of RD [20]. In our case, the quantitative DNA of HSV-1 was 9.0 × 106/ml, suggesting a poor prognosis of vision in accordance with recurrent RD and vision declination during the follow-up period.
In the suspected case of viral encephalitis, antiviral therapy should be performed regardless of early PCR results to avoid complications of missed viral encephalitis, especially if systemic glucocorticoid therapy is being considered. Besides, special awareness and careful evaluation on neuro-ophthalmological assessment should be paid in any patients with a central nervous system disease. The clinical decision-making should be tailored to suit patients with ARN related to encephalitis, considering the extent and severity of the diseases and symptoms, as well as disease progression. Furthermore, consultation with a multidisciplinary team related to ophthalmology is highly recommended.
Abbreviations
ARNAcute retinal necrosis
HSVHerpes simplex virus
BCVABest corrected visual acuity
CSFCerebral spinal fluid
RDRetinal detachment
PCRPolymerase chain reaction
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Pingting Zhong and Siwen Zang contributed equally to this work.
We gratefully thank the patient and his parents for their kind participation in the study.
Authors’ contributions
Z. PT and Z. SW wrote the manuscript, analyzed the data, and reviewed the literature. Y. HH performed the surgery. Z. PT and Z. SW collected ophthalmologic data and assisted in drafting the manuscript. Y. HH and Y. XH revised the manuscript and discussions. All authors read and approved the final manuscript.
Funding
This work was supported by Science and Technology Program of Guangzhou, China (202002020049) (Y. XH); Project of Investigation on Health Status of Employees in Financial Industry in Guangzhou (Z012014075) (Y. XH).
Availability of data and materials
All data generated or analyzed during this study are included in this article and are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
This study is a case report, the study design was approved by the ethics review board of the Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences. Written informed consent was obtained from the participant.
Consent for publication
Written informed consent was obtained from the patient for publication of this case and any accompanying images. This report does not contain any personal information that could lead to the identification of the patient.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33530932 | 18,947,754 | 2021-02-02 |
What was the outcome of reaction 'Herpes simplex'? | Herpes simplex virus type 1 related acute retinal necrosis following an encephalitis illness: a case report.
BACKGROUND
Virus encephalitis is found to be a risk factor for acute retinal necrosis (ARN).
METHODS
We herein presented a case of a 20-year-old teenage boy who suffered from encephalitis of unknown etiology with early negative pathologic results, and was primarily treated with systemic administration of high-dose steroids without antiviral therapy. He later had sudden vision loss in his right eye. Intravitreal and intravenous antiviral treatments were immediately started due to suspected ARN. Herpes simplex virus (HSV)-1 was identified later in the vitreous humor of the patient. After the surgery of retinal detachment (RD), obvious improvements in vision were observed. However, the patient had recurrent RD and vision declination 5 weeks later.
CONCLUSIONS
The case with suspected viral encephalitis should be treated with antiviral therapy regardless of early virologic results in order to avoid complications of a missed viral encephalitis diagnosis, especially if systemic steroid treatment is being considered.
Background
Acute retinal necrosis (ARN) is a serious and potential blinding viral ocular infection, and it rapidly develops and progresses in immunocompetent people, causing uveitis with necrotizing retinitis [1]. Varicella-zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2 are the most common causative viruses of ARN [1]. It is assumed that reactivation amid immune dysfunction of the virus leads to ARN, along with central nervous system infection [2]. The association between viral encephalitis and ARN has been reported in one per 1.6–2.0 million people [3]. Therefore, additional attention with regard to ocular clinical manifestations is specially needed in patients with encephalitis after systemic treatment with steroids, as they could affect the body immunity and cause reactivation of the virus. Viral encephalitis should be aware of as it is a risk factor of ARN, and so antiviral treatment is recommended for suspected viral encephalitis.
Case presentation
A 20-year-old teenage boy with abrupt fever, confusion, and epileptic seizures was referred to the Department of Neurology of the Guangzhou General Military Hospital. The patient was otherwise a healthy boy until he had an unusual health status prior to 5 days. Cerebral spinal fluid (CSF) analysis was performed on admission, and the result showed negative Pandy test with a predominance of lymphocytes. Besides, CSF test for Mycobacterium tuberculosis, herpes simplex virus (HSV), cytomegalovirus (CMV), and rubella virus revealed negative results. Two days later, antibody analysis of autoimmune encephalitis was also shown to be normal. Brain magnetic resonance imaging (MRI) showed hypersignal intensity in bilateral frontal as well as temporal lobe.
Next, the patient was diagnosed with encephalitis due to unidentified etiology, and then systemic administration of steroids was given without antiviral treatment. He was prescribed with intravenous methylprednisolone, 1 g/d for 3 consecutive days, followed by 0.5 g/d for 3 days, and then was maintained on 80 mg/d for 2 weeks. Two weeks after admission, the boy showed no sign of improvement. A second brain MRI showed much worsened manifestation of hypersignal in both bilateral frontal and temporal lobe, and a second CSF analysis showed negative results of the pathogen as shown in the first CSF analysis. He was therefore presumed to have “autoimmune encephalitis” by primary neurologists and was prescribed with gamma globulin 25 g/d for 5 days. Later, he had less fever and seizures, and improvements were observed in his oral expression. So, intravenous methylprednisolone administration was gradually reduced and replaced it by oral prednisone of 60 mg/d and then was discharged. One day after being discharged, he had sudden vision loss in his right eye, and then the boy was urgently referred to our hospital.
Investigations
After admitting in our hospital, the patient’s physical and neurological exams were found to be unremarkable. His best corrected visual acuity (BCVA) showed light perception with correct light location in the temporal region of the right eye (OD), and 20/20 with that of the left eye (OS). Ophthalmological examination of his right eye revealed positive Tyndall (+) and cell (++) in the anterior chamber, with obvious opacity (+++) in the vitreous chamber. The fundus of his right eye showed yellow-white lesions, with narrowing retinal vessels and white-sheath and peripheral hemorrhage. Also several tiny retinal holes that lead to retinal detachment (RD) were observed in the peripheral retina (Fig. 1a). No remarkable changes were observed in his left eye.
Fig. 1 Fundus photographs of the right eye. a On admission. The blue arrows represent severe occlusive vasculitis, with macula involved in the peripheral retina, and white arrow represents several tiny holes on superior-nasal degeneration area. b On discharge day. Retinal detachment was repaired with retinal vasculitis and edema showed great improvement
New brain MRI performed in our hospital suggested multiple abnormal signals in the brain parenchyma, which were in accordance with the manifestations of viral encephalitis (Fig. 2). So, viral-related retinal disorders were highly suspected in our case. Vitreous humor was obtained through vitreous chamber tapping to perform polymerase chain reaction (PCR) analysis. DNA of HSV-1 virus (9.0 × 106/ml) was identified 5 days after intravitreal antiviral treatment, and the positive results of IgG and IgM antibodies in the blood serology also supported HSV-1 infection, thus confirming the diagnosis of ARN by HSV-1.
Fig. 2 Hypersignal intensity of left temporal lobe in MRI with T2 flair
Treatment
Intravitreal administration of ganciclovir (0.4 mg/ 0.1 ml) was immediately performed following vitreous chamber tapping at the time of admission to our hospital. Two days later, the boy was relieved from vitreous opacities (+). Antiviral treatment was therefore considered to be effective, and broad-spectrum antiviral medicine (ganciclovir 250 mg every 12-h) was started intravenously, and then replaced with intravenous acyclovir (500 mg every 8-h) after confirmation of HSV pathogen. As the patient also suffered from RD, his right eye was treated by pars plana vitrectomy (PPV), endolaser and silicone oil tamponade 3 days after admission. During the surgery, a second time intravitreal ganciclovir (0.4 mg/0.1 mg) was given.
Outcomes and follow-up
The patient received intravenous antiviral treatment for 2 weeks and was discharged with oral antiviral medicine (famciclovir 375 mg twice a day) as planned for 3 to 4 months. On the day of discharge, BCVA was 20/80 OD and retinal edema in his right eye has been greatly relieved (Fig. 1b). At 5 weeks of follow-up, recurrent vision declination occurred with 20/500 OD due to recurrent RD (Fig. 3). Therefore, silicon oil displacement and endolaser were performed to repair the retina, as well as intravitreal ganciclovir (0.4 mg/0.1 mg) was given for third time. The BCVA of his right eye was increased to 20/80 within 3 days after the surgery. Six months later, after removing the silicone oil, the BCVA was shown to be 20/200 OD with complicated cataract.
Fig. 3 OCT images of the right eye. a On discharge day and b at 5 weeks after discharge
Discussion and conclusion
Our patient due to encephalitis suffered from HSV related ARN after systemic administration of steroids. HSV-infected ARN could be a serious threat that leads to vision loss. Therefore, early awareness and timely antiviral treatment of suspected viral encephalitis are critical in such patients.
The possible reason for the cause of ARN in this patient might be due to viral encephalitis. HSV-1 virus encephalitis is usually characterized by altered mental health status, seizures, somnolence, increased cellularity with predominant lymphocytes in CSF, as well as hypersignal intensity in the MRI of temporal lobes [4], and all these clinical manifestations were observed in our patient. In our case, encephalitis was highly suspected to be caused by viral infection. However, lack of direct evidence of the virus in CSF impeded antiviral treatment. The patient later suffered from ARN due to HSV, suggesting that the virus might come from the brain. Due to the negative evidence in CSF, it could result in low positive predictive value [5] or procedural-related problems. To repeat CSF analysis is important in suspected viral encephalitis. ARN has been reported in cases with prior [6], simultaneous [7], or post [8] presence of herpetic simplex encephalitis or meningitis, and the interval between ARN and meningitis/encephalitis varied from 2 to 5 weeks [9]. A possible underlying mechanism has demonstrated bidirectional fast-axonal transport in neurons [10], and the viral genes play a critical role for antegrade and retrograde axonal transportation.
Immunocompromise after systemic administration of high-dose steroids could be another possible reason for the triggering of ARN in the current case. There are several possible explanations for steroids contributing to the occurrence of ARN. Firstly, high-dose steroids might affect body immunity, promote viral replication, and worsen necrotizing retinopathy [11]. The virus might reach the eye from the brain by a trans-axonal route. Secondly, the triggering event of systemic administration of high-dose steroids could reactivate HSV infection [12], and the latent HSV in several sites is connected to the eye, finally resulting in herpetic ocular disease that involves the cornea, iris, or even the retina [13]. When treating patients with encephalitis, for whom systemic administration of steroids is an inevitable regimen, neurologists should be aware that it might lead to immunocompromise, posing a serious threat in triggering ARN. In addition, according to prior studies on treatment of HSV1-encephalitis by combining with acyclovir, a study showed that treatment without corticosteroid was associated with poorer outcomes [14], while another study found no positive effects by adding dexamethasone to acyclovir [15]. Therefore, the use of corticosteroid therapy for viral encephalitis depends on the discretion of clinicians. As patients with encephalitis always present with confusion, which prevents them from timely and precise expression of their ocular discomforts, and so attention should be paid with regard to ocular clinical manifestations.
Intravitreal and intravenous antiviral treatment was then immediately started in this patient, and this is because of high suspicion of ARN according to ocular manifestations. So, diagnostic testing of vitreous humor before antiviral treatment has been done, and later corresponding adjustments were made. Topical and systemic antiviral treatment is an urgent need, as it is beneficial for the visual acuity and thus could decrease the risk of infection to the other eye [16]. As documented previously, there were up to 70% of untreated patients with bilateral ARN [17]. In our case, ARN was presented in a single eye, but it is assumed that the contralateral eye might also be affected if timely and precise antiviral treatment is not given. With a better understanding of antiviral treatment, the rate of bilateralization according to the recently reported studies on ARN has been found to be significantly decreased into 10–20% [18].
The challenges concerning diagnosis as well as prognosis were posed in this case. The CSF initially revealed negative results for viral encephalitis, and the diagnosis of ARN was later confirmed by PCR analysis with HSV-1 in the vitreous humor, and this is widely available to clinicians with good sensitivity and specificity [19]. According to a recent study, the correlation of quantitative DNA PCR and clinical prognosis in ARN has revealed that a number of copies superior to 5.0 × 106/ml showed association with a higher probability of RD [20]. In our case, the quantitative DNA of HSV-1 was 9.0 × 106/ml, suggesting a poor prognosis of vision in accordance with recurrent RD and vision declination during the follow-up period.
In the suspected case of viral encephalitis, antiviral therapy should be performed regardless of early PCR results to avoid complications of missed viral encephalitis, especially if systemic glucocorticoid therapy is being considered. Besides, special awareness and careful evaluation on neuro-ophthalmological assessment should be paid in any patients with a central nervous system disease. The clinical decision-making should be tailored to suit patients with ARN related to encephalitis, considering the extent and severity of the diseases and symptoms, as well as disease progression. Furthermore, consultation with a multidisciplinary team related to ophthalmology is highly recommended.
Abbreviations
ARNAcute retinal necrosis
HSVHerpes simplex virus
BCVABest corrected visual acuity
CSFCerebral spinal fluid
RDRetinal detachment
PCRPolymerase chain reaction
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Pingting Zhong and Siwen Zang contributed equally to this work.
We gratefully thank the patient and his parents for their kind participation in the study.
Authors’ contributions
Z. PT and Z. SW wrote the manuscript, analyzed the data, and reviewed the literature. Y. HH performed the surgery. Z. PT and Z. SW collected ophthalmologic data and assisted in drafting the manuscript. Y. HH and Y. XH revised the manuscript and discussions. All authors read and approved the final manuscript.
Funding
This work was supported by Science and Technology Program of Guangzhou, China (202002020049) (Y. XH); Project of Investigation on Health Status of Employees in Financial Industry in Guangzhou (Z012014075) (Y. XH).
Availability of data and materials
All data generated or analyzed during this study are included in this article and are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
This study is a case report, the study design was approved by the ethics review board of the Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences. Written informed consent was obtained from the participant.
Consent for publication
Written informed consent was obtained from the patient for publication of this case and any accompanying images. This report does not contain any personal information that could lead to the identification of the patient.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33530932 | 18,947,754 | 2021-02-02 |
What was the outcome of reaction 'Herpes virus infection'? | Herpes simplex virus type 1 related acute retinal necrosis following an encephalitis illness: a case report.
BACKGROUND
Virus encephalitis is found to be a risk factor for acute retinal necrosis (ARN).
METHODS
We herein presented a case of a 20-year-old teenage boy who suffered from encephalitis of unknown etiology with early negative pathologic results, and was primarily treated with systemic administration of high-dose steroids without antiviral therapy. He later had sudden vision loss in his right eye. Intravitreal and intravenous antiviral treatments were immediately started due to suspected ARN. Herpes simplex virus (HSV)-1 was identified later in the vitreous humor of the patient. After the surgery of retinal detachment (RD), obvious improvements in vision were observed. However, the patient had recurrent RD and vision declination 5 weeks later.
CONCLUSIONS
The case with suspected viral encephalitis should be treated with antiviral therapy regardless of early virologic results in order to avoid complications of a missed viral encephalitis diagnosis, especially if systemic steroid treatment is being considered.
Background
Acute retinal necrosis (ARN) is a serious and potential blinding viral ocular infection, and it rapidly develops and progresses in immunocompetent people, causing uveitis with necrotizing retinitis [1]. Varicella-zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2 are the most common causative viruses of ARN [1]. It is assumed that reactivation amid immune dysfunction of the virus leads to ARN, along with central nervous system infection [2]. The association between viral encephalitis and ARN has been reported in one per 1.6–2.0 million people [3]. Therefore, additional attention with regard to ocular clinical manifestations is specially needed in patients with encephalitis after systemic treatment with steroids, as they could affect the body immunity and cause reactivation of the virus. Viral encephalitis should be aware of as it is a risk factor of ARN, and so antiviral treatment is recommended for suspected viral encephalitis.
Case presentation
A 20-year-old teenage boy with abrupt fever, confusion, and epileptic seizures was referred to the Department of Neurology of the Guangzhou General Military Hospital. The patient was otherwise a healthy boy until he had an unusual health status prior to 5 days. Cerebral spinal fluid (CSF) analysis was performed on admission, and the result showed negative Pandy test with a predominance of lymphocytes. Besides, CSF test for Mycobacterium tuberculosis, herpes simplex virus (HSV), cytomegalovirus (CMV), and rubella virus revealed negative results. Two days later, antibody analysis of autoimmune encephalitis was also shown to be normal. Brain magnetic resonance imaging (MRI) showed hypersignal intensity in bilateral frontal as well as temporal lobe.
Next, the patient was diagnosed with encephalitis due to unidentified etiology, and then systemic administration of steroids was given without antiviral treatment. He was prescribed with intravenous methylprednisolone, 1 g/d for 3 consecutive days, followed by 0.5 g/d for 3 days, and then was maintained on 80 mg/d for 2 weeks. Two weeks after admission, the boy showed no sign of improvement. A second brain MRI showed much worsened manifestation of hypersignal in both bilateral frontal and temporal lobe, and a second CSF analysis showed negative results of the pathogen as shown in the first CSF analysis. He was therefore presumed to have “autoimmune encephalitis” by primary neurologists and was prescribed with gamma globulin 25 g/d for 5 days. Later, he had less fever and seizures, and improvements were observed in his oral expression. So, intravenous methylprednisolone administration was gradually reduced and replaced it by oral prednisone of 60 mg/d and then was discharged. One day after being discharged, he had sudden vision loss in his right eye, and then the boy was urgently referred to our hospital.
Investigations
After admitting in our hospital, the patient’s physical and neurological exams were found to be unremarkable. His best corrected visual acuity (BCVA) showed light perception with correct light location in the temporal region of the right eye (OD), and 20/20 with that of the left eye (OS). Ophthalmological examination of his right eye revealed positive Tyndall (+) and cell (++) in the anterior chamber, with obvious opacity (+++) in the vitreous chamber. The fundus of his right eye showed yellow-white lesions, with narrowing retinal vessels and white-sheath and peripheral hemorrhage. Also several tiny retinal holes that lead to retinal detachment (RD) were observed in the peripheral retina (Fig. 1a). No remarkable changes were observed in his left eye.
Fig. 1 Fundus photographs of the right eye. a On admission. The blue arrows represent severe occlusive vasculitis, with macula involved in the peripheral retina, and white arrow represents several tiny holes on superior-nasal degeneration area. b On discharge day. Retinal detachment was repaired with retinal vasculitis and edema showed great improvement
New brain MRI performed in our hospital suggested multiple abnormal signals in the brain parenchyma, which were in accordance with the manifestations of viral encephalitis (Fig. 2). So, viral-related retinal disorders were highly suspected in our case. Vitreous humor was obtained through vitreous chamber tapping to perform polymerase chain reaction (PCR) analysis. DNA of HSV-1 virus (9.0 × 106/ml) was identified 5 days after intravitreal antiviral treatment, and the positive results of IgG and IgM antibodies in the blood serology also supported HSV-1 infection, thus confirming the diagnosis of ARN by HSV-1.
Fig. 2 Hypersignal intensity of left temporal lobe in MRI with T2 flair
Treatment
Intravitreal administration of ganciclovir (0.4 mg/ 0.1 ml) was immediately performed following vitreous chamber tapping at the time of admission to our hospital. Two days later, the boy was relieved from vitreous opacities (+). Antiviral treatment was therefore considered to be effective, and broad-spectrum antiviral medicine (ganciclovir 250 mg every 12-h) was started intravenously, and then replaced with intravenous acyclovir (500 mg every 8-h) after confirmation of HSV pathogen. As the patient also suffered from RD, his right eye was treated by pars plana vitrectomy (PPV), endolaser and silicone oil tamponade 3 days after admission. During the surgery, a second time intravitreal ganciclovir (0.4 mg/0.1 mg) was given.
Outcomes and follow-up
The patient received intravenous antiviral treatment for 2 weeks and was discharged with oral antiviral medicine (famciclovir 375 mg twice a day) as planned for 3 to 4 months. On the day of discharge, BCVA was 20/80 OD and retinal edema in his right eye has been greatly relieved (Fig. 1b). At 5 weeks of follow-up, recurrent vision declination occurred with 20/500 OD due to recurrent RD (Fig. 3). Therefore, silicon oil displacement and endolaser were performed to repair the retina, as well as intravitreal ganciclovir (0.4 mg/0.1 mg) was given for third time. The BCVA of his right eye was increased to 20/80 within 3 days after the surgery. Six months later, after removing the silicone oil, the BCVA was shown to be 20/200 OD with complicated cataract.
Fig. 3 OCT images of the right eye. a On discharge day and b at 5 weeks after discharge
Discussion and conclusion
Our patient due to encephalitis suffered from HSV related ARN after systemic administration of steroids. HSV-infected ARN could be a serious threat that leads to vision loss. Therefore, early awareness and timely antiviral treatment of suspected viral encephalitis are critical in such patients.
The possible reason for the cause of ARN in this patient might be due to viral encephalitis. HSV-1 virus encephalitis is usually characterized by altered mental health status, seizures, somnolence, increased cellularity with predominant lymphocytes in CSF, as well as hypersignal intensity in the MRI of temporal lobes [4], and all these clinical manifestations were observed in our patient. In our case, encephalitis was highly suspected to be caused by viral infection. However, lack of direct evidence of the virus in CSF impeded antiviral treatment. The patient later suffered from ARN due to HSV, suggesting that the virus might come from the brain. Due to the negative evidence in CSF, it could result in low positive predictive value [5] or procedural-related problems. To repeat CSF analysis is important in suspected viral encephalitis. ARN has been reported in cases with prior [6], simultaneous [7], or post [8] presence of herpetic simplex encephalitis or meningitis, and the interval between ARN and meningitis/encephalitis varied from 2 to 5 weeks [9]. A possible underlying mechanism has demonstrated bidirectional fast-axonal transport in neurons [10], and the viral genes play a critical role for antegrade and retrograde axonal transportation.
Immunocompromise after systemic administration of high-dose steroids could be another possible reason for the triggering of ARN in the current case. There are several possible explanations for steroids contributing to the occurrence of ARN. Firstly, high-dose steroids might affect body immunity, promote viral replication, and worsen necrotizing retinopathy [11]. The virus might reach the eye from the brain by a trans-axonal route. Secondly, the triggering event of systemic administration of high-dose steroids could reactivate HSV infection [12], and the latent HSV in several sites is connected to the eye, finally resulting in herpetic ocular disease that involves the cornea, iris, or even the retina [13]. When treating patients with encephalitis, for whom systemic administration of steroids is an inevitable regimen, neurologists should be aware that it might lead to immunocompromise, posing a serious threat in triggering ARN. In addition, according to prior studies on treatment of HSV1-encephalitis by combining with acyclovir, a study showed that treatment without corticosteroid was associated with poorer outcomes [14], while another study found no positive effects by adding dexamethasone to acyclovir [15]. Therefore, the use of corticosteroid therapy for viral encephalitis depends on the discretion of clinicians. As patients with encephalitis always present with confusion, which prevents them from timely and precise expression of their ocular discomforts, and so attention should be paid with regard to ocular clinical manifestations.
Intravitreal and intravenous antiviral treatment was then immediately started in this patient, and this is because of high suspicion of ARN according to ocular manifestations. So, diagnostic testing of vitreous humor before antiviral treatment has been done, and later corresponding adjustments were made. Topical and systemic antiviral treatment is an urgent need, as it is beneficial for the visual acuity and thus could decrease the risk of infection to the other eye [16]. As documented previously, there were up to 70% of untreated patients with bilateral ARN [17]. In our case, ARN was presented in a single eye, but it is assumed that the contralateral eye might also be affected if timely and precise antiviral treatment is not given. With a better understanding of antiviral treatment, the rate of bilateralization according to the recently reported studies on ARN has been found to be significantly decreased into 10–20% [18].
The challenges concerning diagnosis as well as prognosis were posed in this case. The CSF initially revealed negative results for viral encephalitis, and the diagnosis of ARN was later confirmed by PCR analysis with HSV-1 in the vitreous humor, and this is widely available to clinicians with good sensitivity and specificity [19]. According to a recent study, the correlation of quantitative DNA PCR and clinical prognosis in ARN has revealed that a number of copies superior to 5.0 × 106/ml showed association with a higher probability of RD [20]. In our case, the quantitative DNA of HSV-1 was 9.0 × 106/ml, suggesting a poor prognosis of vision in accordance with recurrent RD and vision declination during the follow-up period.
In the suspected case of viral encephalitis, antiviral therapy should be performed regardless of early PCR results to avoid complications of missed viral encephalitis, especially if systemic glucocorticoid therapy is being considered. Besides, special awareness and careful evaluation on neuro-ophthalmological assessment should be paid in any patients with a central nervous system disease. The clinical decision-making should be tailored to suit patients with ARN related to encephalitis, considering the extent and severity of the diseases and symptoms, as well as disease progression. Furthermore, consultation with a multidisciplinary team related to ophthalmology is highly recommended.
Abbreviations
ARNAcute retinal necrosis
HSVHerpes simplex virus
BCVABest corrected visual acuity
CSFCerebral spinal fluid
RDRetinal detachment
PCRPolymerase chain reaction
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Pingting Zhong and Siwen Zang contributed equally to this work.
We gratefully thank the patient and his parents for their kind participation in the study.
Authors’ contributions
Z. PT and Z. SW wrote the manuscript, analyzed the data, and reviewed the literature. Y. HH performed the surgery. Z. PT and Z. SW collected ophthalmologic data and assisted in drafting the manuscript. Y. HH and Y. XH revised the manuscript and discussions. All authors read and approved the final manuscript.
Funding
This work was supported by Science and Technology Program of Guangzhou, China (202002020049) (Y. XH); Project of Investigation on Health Status of Employees in Financial Industry in Guangzhou (Z012014075) (Y. XH).
Availability of data and materials
All data generated or analyzed during this study are included in this article and are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
This study is a case report, the study design was approved by the ethics review board of the Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences. Written informed consent was obtained from the participant.
Consent for publication
Written informed consent was obtained from the patient for publication of this case and any accompanying images. This report does not contain any personal information that could lead to the identification of the patient.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33530932 | 19,013,150 | 2021-02-02 |
What was the outcome of reaction 'Retinal detachment'? | Herpes simplex virus type 1 related acute retinal necrosis following an encephalitis illness: a case report.
BACKGROUND
Virus encephalitis is found to be a risk factor for acute retinal necrosis (ARN).
METHODS
We herein presented a case of a 20-year-old teenage boy who suffered from encephalitis of unknown etiology with early negative pathologic results, and was primarily treated with systemic administration of high-dose steroids without antiviral therapy. He later had sudden vision loss in his right eye. Intravitreal and intravenous antiviral treatments were immediately started due to suspected ARN. Herpes simplex virus (HSV)-1 was identified later in the vitreous humor of the patient. After the surgery of retinal detachment (RD), obvious improvements in vision were observed. However, the patient had recurrent RD and vision declination 5 weeks later.
CONCLUSIONS
The case with suspected viral encephalitis should be treated with antiviral therapy regardless of early virologic results in order to avoid complications of a missed viral encephalitis diagnosis, especially if systemic steroid treatment is being considered.
Background
Acute retinal necrosis (ARN) is a serious and potential blinding viral ocular infection, and it rapidly develops and progresses in immunocompetent people, causing uveitis with necrotizing retinitis [1]. Varicella-zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2 are the most common causative viruses of ARN [1]. It is assumed that reactivation amid immune dysfunction of the virus leads to ARN, along with central nervous system infection [2]. The association between viral encephalitis and ARN has been reported in one per 1.6–2.0 million people [3]. Therefore, additional attention with regard to ocular clinical manifestations is specially needed in patients with encephalitis after systemic treatment with steroids, as they could affect the body immunity and cause reactivation of the virus. Viral encephalitis should be aware of as it is a risk factor of ARN, and so antiviral treatment is recommended for suspected viral encephalitis.
Case presentation
A 20-year-old teenage boy with abrupt fever, confusion, and epileptic seizures was referred to the Department of Neurology of the Guangzhou General Military Hospital. The patient was otherwise a healthy boy until he had an unusual health status prior to 5 days. Cerebral spinal fluid (CSF) analysis was performed on admission, and the result showed negative Pandy test with a predominance of lymphocytes. Besides, CSF test for Mycobacterium tuberculosis, herpes simplex virus (HSV), cytomegalovirus (CMV), and rubella virus revealed negative results. Two days later, antibody analysis of autoimmune encephalitis was also shown to be normal. Brain magnetic resonance imaging (MRI) showed hypersignal intensity in bilateral frontal as well as temporal lobe.
Next, the patient was diagnosed with encephalitis due to unidentified etiology, and then systemic administration of steroids was given without antiviral treatment. He was prescribed with intravenous methylprednisolone, 1 g/d for 3 consecutive days, followed by 0.5 g/d for 3 days, and then was maintained on 80 mg/d for 2 weeks. Two weeks after admission, the boy showed no sign of improvement. A second brain MRI showed much worsened manifestation of hypersignal in both bilateral frontal and temporal lobe, and a second CSF analysis showed negative results of the pathogen as shown in the first CSF analysis. He was therefore presumed to have “autoimmune encephalitis” by primary neurologists and was prescribed with gamma globulin 25 g/d for 5 days. Later, he had less fever and seizures, and improvements were observed in his oral expression. So, intravenous methylprednisolone administration was gradually reduced and replaced it by oral prednisone of 60 mg/d and then was discharged. One day after being discharged, he had sudden vision loss in his right eye, and then the boy was urgently referred to our hospital.
Investigations
After admitting in our hospital, the patient’s physical and neurological exams were found to be unremarkable. His best corrected visual acuity (BCVA) showed light perception with correct light location in the temporal region of the right eye (OD), and 20/20 with that of the left eye (OS). Ophthalmological examination of his right eye revealed positive Tyndall (+) and cell (++) in the anterior chamber, with obvious opacity (+++) in the vitreous chamber. The fundus of his right eye showed yellow-white lesions, with narrowing retinal vessels and white-sheath and peripheral hemorrhage. Also several tiny retinal holes that lead to retinal detachment (RD) were observed in the peripheral retina (Fig. 1a). No remarkable changes were observed in his left eye.
Fig. 1 Fundus photographs of the right eye. a On admission. The blue arrows represent severe occlusive vasculitis, with macula involved in the peripheral retina, and white arrow represents several tiny holes on superior-nasal degeneration area. b On discharge day. Retinal detachment was repaired with retinal vasculitis and edema showed great improvement
New brain MRI performed in our hospital suggested multiple abnormal signals in the brain parenchyma, which were in accordance with the manifestations of viral encephalitis (Fig. 2). So, viral-related retinal disorders were highly suspected in our case. Vitreous humor was obtained through vitreous chamber tapping to perform polymerase chain reaction (PCR) analysis. DNA of HSV-1 virus (9.0 × 106/ml) was identified 5 days after intravitreal antiviral treatment, and the positive results of IgG and IgM antibodies in the blood serology also supported HSV-1 infection, thus confirming the diagnosis of ARN by HSV-1.
Fig. 2 Hypersignal intensity of left temporal lobe in MRI with T2 flair
Treatment
Intravitreal administration of ganciclovir (0.4 mg/ 0.1 ml) was immediately performed following vitreous chamber tapping at the time of admission to our hospital. Two days later, the boy was relieved from vitreous opacities (+). Antiviral treatment was therefore considered to be effective, and broad-spectrum antiviral medicine (ganciclovir 250 mg every 12-h) was started intravenously, and then replaced with intravenous acyclovir (500 mg every 8-h) after confirmation of HSV pathogen. As the patient also suffered from RD, his right eye was treated by pars plana vitrectomy (PPV), endolaser and silicone oil tamponade 3 days after admission. During the surgery, a second time intravitreal ganciclovir (0.4 mg/0.1 mg) was given.
Outcomes and follow-up
The patient received intravenous antiviral treatment for 2 weeks and was discharged with oral antiviral medicine (famciclovir 375 mg twice a day) as planned for 3 to 4 months. On the day of discharge, BCVA was 20/80 OD and retinal edema in his right eye has been greatly relieved (Fig. 1b). At 5 weeks of follow-up, recurrent vision declination occurred with 20/500 OD due to recurrent RD (Fig. 3). Therefore, silicon oil displacement and endolaser were performed to repair the retina, as well as intravitreal ganciclovir (0.4 mg/0.1 mg) was given for third time. The BCVA of his right eye was increased to 20/80 within 3 days after the surgery. Six months later, after removing the silicone oil, the BCVA was shown to be 20/200 OD with complicated cataract.
Fig. 3 OCT images of the right eye. a On discharge day and b at 5 weeks after discharge
Discussion and conclusion
Our patient due to encephalitis suffered from HSV related ARN after systemic administration of steroids. HSV-infected ARN could be a serious threat that leads to vision loss. Therefore, early awareness and timely antiviral treatment of suspected viral encephalitis are critical in such patients.
The possible reason for the cause of ARN in this patient might be due to viral encephalitis. HSV-1 virus encephalitis is usually characterized by altered mental health status, seizures, somnolence, increased cellularity with predominant lymphocytes in CSF, as well as hypersignal intensity in the MRI of temporal lobes [4], and all these clinical manifestations were observed in our patient. In our case, encephalitis was highly suspected to be caused by viral infection. However, lack of direct evidence of the virus in CSF impeded antiviral treatment. The patient later suffered from ARN due to HSV, suggesting that the virus might come from the brain. Due to the negative evidence in CSF, it could result in low positive predictive value [5] or procedural-related problems. To repeat CSF analysis is important in suspected viral encephalitis. ARN has been reported in cases with prior [6], simultaneous [7], or post [8] presence of herpetic simplex encephalitis or meningitis, and the interval between ARN and meningitis/encephalitis varied from 2 to 5 weeks [9]. A possible underlying mechanism has demonstrated bidirectional fast-axonal transport in neurons [10], and the viral genes play a critical role for antegrade and retrograde axonal transportation.
Immunocompromise after systemic administration of high-dose steroids could be another possible reason for the triggering of ARN in the current case. There are several possible explanations for steroids contributing to the occurrence of ARN. Firstly, high-dose steroids might affect body immunity, promote viral replication, and worsen necrotizing retinopathy [11]. The virus might reach the eye from the brain by a trans-axonal route. Secondly, the triggering event of systemic administration of high-dose steroids could reactivate HSV infection [12], and the latent HSV in several sites is connected to the eye, finally resulting in herpetic ocular disease that involves the cornea, iris, or even the retina [13]. When treating patients with encephalitis, for whom systemic administration of steroids is an inevitable regimen, neurologists should be aware that it might lead to immunocompromise, posing a serious threat in triggering ARN. In addition, according to prior studies on treatment of HSV1-encephalitis by combining with acyclovir, a study showed that treatment without corticosteroid was associated with poorer outcomes [14], while another study found no positive effects by adding dexamethasone to acyclovir [15]. Therefore, the use of corticosteroid therapy for viral encephalitis depends on the discretion of clinicians. As patients with encephalitis always present with confusion, which prevents them from timely and precise expression of their ocular discomforts, and so attention should be paid with regard to ocular clinical manifestations.
Intravitreal and intravenous antiviral treatment was then immediately started in this patient, and this is because of high suspicion of ARN according to ocular manifestations. So, diagnostic testing of vitreous humor before antiviral treatment has been done, and later corresponding adjustments were made. Topical and systemic antiviral treatment is an urgent need, as it is beneficial for the visual acuity and thus could decrease the risk of infection to the other eye [16]. As documented previously, there were up to 70% of untreated patients with bilateral ARN [17]. In our case, ARN was presented in a single eye, but it is assumed that the contralateral eye might also be affected if timely and precise antiviral treatment is not given. With a better understanding of antiviral treatment, the rate of bilateralization according to the recently reported studies on ARN has been found to be significantly decreased into 10–20% [18].
The challenges concerning diagnosis as well as prognosis were posed in this case. The CSF initially revealed negative results for viral encephalitis, and the diagnosis of ARN was later confirmed by PCR analysis with HSV-1 in the vitreous humor, and this is widely available to clinicians with good sensitivity and specificity [19]. According to a recent study, the correlation of quantitative DNA PCR and clinical prognosis in ARN has revealed that a number of copies superior to 5.0 × 106/ml showed association with a higher probability of RD [20]. In our case, the quantitative DNA of HSV-1 was 9.0 × 106/ml, suggesting a poor prognosis of vision in accordance with recurrent RD and vision declination during the follow-up period.
In the suspected case of viral encephalitis, antiviral therapy should be performed regardless of early PCR results to avoid complications of missed viral encephalitis, especially if systemic glucocorticoid therapy is being considered. Besides, special awareness and careful evaluation on neuro-ophthalmological assessment should be paid in any patients with a central nervous system disease. The clinical decision-making should be tailored to suit patients with ARN related to encephalitis, considering the extent and severity of the diseases and symptoms, as well as disease progression. Furthermore, consultation with a multidisciplinary team related to ophthalmology is highly recommended.
Abbreviations
ARNAcute retinal necrosis
HSVHerpes simplex virus
BCVABest corrected visual acuity
CSFCerebral spinal fluid
RDRetinal detachment
PCRPolymerase chain reaction
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Pingting Zhong and Siwen Zang contributed equally to this work.
We gratefully thank the patient and his parents for their kind participation in the study.
Authors’ contributions
Z. PT and Z. SW wrote the manuscript, analyzed the data, and reviewed the literature. Y. HH performed the surgery. Z. PT and Z. SW collected ophthalmologic data and assisted in drafting the manuscript. Y. HH and Y. XH revised the manuscript and discussions. All authors read and approved the final manuscript.
Funding
This work was supported by Science and Technology Program of Guangzhou, China (202002020049) (Y. XH); Project of Investigation on Health Status of Employees in Financial Industry in Guangzhou (Z012014075) (Y. XH).
Availability of data and materials
All data generated or analyzed during this study are included in this article and are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
This study is a case report, the study design was approved by the ethics review board of the Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences. Written informed consent was obtained from the participant.
Consent for publication
Written informed consent was obtained from the patient for publication of this case and any accompanying images. This report does not contain any personal information that could lead to the identification of the patient.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33530932 | 19,013,150 | 2021-02-02 |
What was the outcome of reaction 'Sudden visual loss'? | Herpes simplex virus type 1 related acute retinal necrosis following an encephalitis illness: a case report.
BACKGROUND
Virus encephalitis is found to be a risk factor for acute retinal necrosis (ARN).
METHODS
We herein presented a case of a 20-year-old teenage boy who suffered from encephalitis of unknown etiology with early negative pathologic results, and was primarily treated with systemic administration of high-dose steroids without antiviral therapy. He later had sudden vision loss in his right eye. Intravitreal and intravenous antiviral treatments were immediately started due to suspected ARN. Herpes simplex virus (HSV)-1 was identified later in the vitreous humor of the patient. After the surgery of retinal detachment (RD), obvious improvements in vision were observed. However, the patient had recurrent RD and vision declination 5 weeks later.
CONCLUSIONS
The case with suspected viral encephalitis should be treated with antiviral therapy regardless of early virologic results in order to avoid complications of a missed viral encephalitis diagnosis, especially if systemic steroid treatment is being considered.
Background
Acute retinal necrosis (ARN) is a serious and potential blinding viral ocular infection, and it rapidly develops and progresses in immunocompetent people, causing uveitis with necrotizing retinitis [1]. Varicella-zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2 are the most common causative viruses of ARN [1]. It is assumed that reactivation amid immune dysfunction of the virus leads to ARN, along with central nervous system infection [2]. The association between viral encephalitis and ARN has been reported in one per 1.6–2.0 million people [3]. Therefore, additional attention with regard to ocular clinical manifestations is specially needed in patients with encephalitis after systemic treatment with steroids, as they could affect the body immunity and cause reactivation of the virus. Viral encephalitis should be aware of as it is a risk factor of ARN, and so antiviral treatment is recommended for suspected viral encephalitis.
Case presentation
A 20-year-old teenage boy with abrupt fever, confusion, and epileptic seizures was referred to the Department of Neurology of the Guangzhou General Military Hospital. The patient was otherwise a healthy boy until he had an unusual health status prior to 5 days. Cerebral spinal fluid (CSF) analysis was performed on admission, and the result showed negative Pandy test with a predominance of lymphocytes. Besides, CSF test for Mycobacterium tuberculosis, herpes simplex virus (HSV), cytomegalovirus (CMV), and rubella virus revealed negative results. Two days later, antibody analysis of autoimmune encephalitis was also shown to be normal. Brain magnetic resonance imaging (MRI) showed hypersignal intensity in bilateral frontal as well as temporal lobe.
Next, the patient was diagnosed with encephalitis due to unidentified etiology, and then systemic administration of steroids was given without antiviral treatment. He was prescribed with intravenous methylprednisolone, 1 g/d for 3 consecutive days, followed by 0.5 g/d for 3 days, and then was maintained on 80 mg/d for 2 weeks. Two weeks after admission, the boy showed no sign of improvement. A second brain MRI showed much worsened manifestation of hypersignal in both bilateral frontal and temporal lobe, and a second CSF analysis showed negative results of the pathogen as shown in the first CSF analysis. He was therefore presumed to have “autoimmune encephalitis” by primary neurologists and was prescribed with gamma globulin 25 g/d for 5 days. Later, he had less fever and seizures, and improvements were observed in his oral expression. So, intravenous methylprednisolone administration was gradually reduced and replaced it by oral prednisone of 60 mg/d and then was discharged. One day after being discharged, he had sudden vision loss in his right eye, and then the boy was urgently referred to our hospital.
Investigations
After admitting in our hospital, the patient’s physical and neurological exams were found to be unremarkable. His best corrected visual acuity (BCVA) showed light perception with correct light location in the temporal region of the right eye (OD), and 20/20 with that of the left eye (OS). Ophthalmological examination of his right eye revealed positive Tyndall (+) and cell (++) in the anterior chamber, with obvious opacity (+++) in the vitreous chamber. The fundus of his right eye showed yellow-white lesions, with narrowing retinal vessels and white-sheath and peripheral hemorrhage. Also several tiny retinal holes that lead to retinal detachment (RD) were observed in the peripheral retina (Fig. 1a). No remarkable changes were observed in his left eye.
Fig. 1 Fundus photographs of the right eye. a On admission. The blue arrows represent severe occlusive vasculitis, with macula involved in the peripheral retina, and white arrow represents several tiny holes on superior-nasal degeneration area. b On discharge day. Retinal detachment was repaired with retinal vasculitis and edema showed great improvement
New brain MRI performed in our hospital suggested multiple abnormal signals in the brain parenchyma, which were in accordance with the manifestations of viral encephalitis (Fig. 2). So, viral-related retinal disorders were highly suspected in our case. Vitreous humor was obtained through vitreous chamber tapping to perform polymerase chain reaction (PCR) analysis. DNA of HSV-1 virus (9.0 × 106/ml) was identified 5 days after intravitreal antiviral treatment, and the positive results of IgG and IgM antibodies in the blood serology also supported HSV-1 infection, thus confirming the diagnosis of ARN by HSV-1.
Fig. 2 Hypersignal intensity of left temporal lobe in MRI with T2 flair
Treatment
Intravitreal administration of ganciclovir (0.4 mg/ 0.1 ml) was immediately performed following vitreous chamber tapping at the time of admission to our hospital. Two days later, the boy was relieved from vitreous opacities (+). Antiviral treatment was therefore considered to be effective, and broad-spectrum antiviral medicine (ganciclovir 250 mg every 12-h) was started intravenously, and then replaced with intravenous acyclovir (500 mg every 8-h) after confirmation of HSV pathogen. As the patient also suffered from RD, his right eye was treated by pars plana vitrectomy (PPV), endolaser and silicone oil tamponade 3 days after admission. During the surgery, a second time intravitreal ganciclovir (0.4 mg/0.1 mg) was given.
Outcomes and follow-up
The patient received intravenous antiviral treatment for 2 weeks and was discharged with oral antiviral medicine (famciclovir 375 mg twice a day) as planned for 3 to 4 months. On the day of discharge, BCVA was 20/80 OD and retinal edema in his right eye has been greatly relieved (Fig. 1b). At 5 weeks of follow-up, recurrent vision declination occurred with 20/500 OD due to recurrent RD (Fig. 3). Therefore, silicon oil displacement and endolaser were performed to repair the retina, as well as intravitreal ganciclovir (0.4 mg/0.1 mg) was given for third time. The BCVA of his right eye was increased to 20/80 within 3 days after the surgery. Six months later, after removing the silicone oil, the BCVA was shown to be 20/200 OD with complicated cataract.
Fig. 3 OCT images of the right eye. a On discharge day and b at 5 weeks after discharge
Discussion and conclusion
Our patient due to encephalitis suffered from HSV related ARN after systemic administration of steroids. HSV-infected ARN could be a serious threat that leads to vision loss. Therefore, early awareness and timely antiviral treatment of suspected viral encephalitis are critical in such patients.
The possible reason for the cause of ARN in this patient might be due to viral encephalitis. HSV-1 virus encephalitis is usually characterized by altered mental health status, seizures, somnolence, increased cellularity with predominant lymphocytes in CSF, as well as hypersignal intensity in the MRI of temporal lobes [4], and all these clinical manifestations were observed in our patient. In our case, encephalitis was highly suspected to be caused by viral infection. However, lack of direct evidence of the virus in CSF impeded antiviral treatment. The patient later suffered from ARN due to HSV, suggesting that the virus might come from the brain. Due to the negative evidence in CSF, it could result in low positive predictive value [5] or procedural-related problems. To repeat CSF analysis is important in suspected viral encephalitis. ARN has been reported in cases with prior [6], simultaneous [7], or post [8] presence of herpetic simplex encephalitis or meningitis, and the interval between ARN and meningitis/encephalitis varied from 2 to 5 weeks [9]. A possible underlying mechanism has demonstrated bidirectional fast-axonal transport in neurons [10], and the viral genes play a critical role for antegrade and retrograde axonal transportation.
Immunocompromise after systemic administration of high-dose steroids could be another possible reason for the triggering of ARN in the current case. There are several possible explanations for steroids contributing to the occurrence of ARN. Firstly, high-dose steroids might affect body immunity, promote viral replication, and worsen necrotizing retinopathy [11]. The virus might reach the eye from the brain by a trans-axonal route. Secondly, the triggering event of systemic administration of high-dose steroids could reactivate HSV infection [12], and the latent HSV in several sites is connected to the eye, finally resulting in herpetic ocular disease that involves the cornea, iris, or even the retina [13]. When treating patients with encephalitis, for whom systemic administration of steroids is an inevitable regimen, neurologists should be aware that it might lead to immunocompromise, posing a serious threat in triggering ARN. In addition, according to prior studies on treatment of HSV1-encephalitis by combining with acyclovir, a study showed that treatment without corticosteroid was associated with poorer outcomes [14], while another study found no positive effects by adding dexamethasone to acyclovir [15]. Therefore, the use of corticosteroid therapy for viral encephalitis depends on the discretion of clinicians. As patients with encephalitis always present with confusion, which prevents them from timely and precise expression of their ocular discomforts, and so attention should be paid with regard to ocular clinical manifestations.
Intravitreal and intravenous antiviral treatment was then immediately started in this patient, and this is because of high suspicion of ARN according to ocular manifestations. So, diagnostic testing of vitreous humor before antiviral treatment has been done, and later corresponding adjustments were made. Topical and systemic antiviral treatment is an urgent need, as it is beneficial for the visual acuity and thus could decrease the risk of infection to the other eye [16]. As documented previously, there were up to 70% of untreated patients with bilateral ARN [17]. In our case, ARN was presented in a single eye, but it is assumed that the contralateral eye might also be affected if timely and precise antiviral treatment is not given. With a better understanding of antiviral treatment, the rate of bilateralization according to the recently reported studies on ARN has been found to be significantly decreased into 10–20% [18].
The challenges concerning diagnosis as well as prognosis were posed in this case. The CSF initially revealed negative results for viral encephalitis, and the diagnosis of ARN was later confirmed by PCR analysis with HSV-1 in the vitreous humor, and this is widely available to clinicians with good sensitivity and specificity [19]. According to a recent study, the correlation of quantitative DNA PCR and clinical prognosis in ARN has revealed that a number of copies superior to 5.0 × 106/ml showed association with a higher probability of RD [20]. In our case, the quantitative DNA of HSV-1 was 9.0 × 106/ml, suggesting a poor prognosis of vision in accordance with recurrent RD and vision declination during the follow-up period.
In the suspected case of viral encephalitis, antiviral therapy should be performed regardless of early PCR results to avoid complications of missed viral encephalitis, especially if systemic glucocorticoid therapy is being considered. Besides, special awareness and careful evaluation on neuro-ophthalmological assessment should be paid in any patients with a central nervous system disease. The clinical decision-making should be tailored to suit patients with ARN related to encephalitis, considering the extent and severity of the diseases and symptoms, as well as disease progression. Furthermore, consultation with a multidisciplinary team related to ophthalmology is highly recommended.
Abbreviations
ARNAcute retinal necrosis
HSVHerpes simplex virus
BCVABest corrected visual acuity
CSFCerebral spinal fluid
RDRetinal detachment
PCRPolymerase chain reaction
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Pingting Zhong and Siwen Zang contributed equally to this work.
We gratefully thank the patient and his parents for their kind participation in the study.
Authors’ contributions
Z. PT and Z. SW wrote the manuscript, analyzed the data, and reviewed the literature. Y. HH performed the surgery. Z. PT and Z. SW collected ophthalmologic data and assisted in drafting the manuscript. Y. HH and Y. XH revised the manuscript and discussions. All authors read and approved the final manuscript.
Funding
This work was supported by Science and Technology Program of Guangzhou, China (202002020049) (Y. XH); Project of Investigation on Health Status of Employees in Financial Industry in Guangzhou (Z012014075) (Y. XH).
Availability of data and materials
All data generated or analyzed during this study are included in this article and are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
This study is a case report, the study design was approved by the ethics review board of the Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences. Written informed consent was obtained from the participant.
Consent for publication
Written informed consent was obtained from the patient for publication of this case and any accompanying images. This report does not contain any personal information that could lead to the identification of the patient.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33530932 | 19,013,150 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'CD4 lymphocytes decreased'. | Increased multiple sclerosis disease activity in patients transitioned from fingolimod to dimethyl fumarate: a case series.
BACKGROUND
Fingolimod is a S1P1 receptor modulator that prevents activated lymphocyte egress from lymphoid tissues causing lymphopenia, mainly affecting CD4+ T lymphocytes. Withdrawal from fingolimod can be followed by severe disease reactivation, and this coincides with return of autoreactive lymphocytes into circulation. The CD8+ T cytotoxic population returns prior to the regulatory CD4+ T lymphocytes leading to a state of dysregulation, which may contribute to the rebound and severity of clinical relapses. On the other hand, dimethyl fumarate (DMF) preferentially reduces CD8+ T lymphocytes, has the same efficacy as fingolimod, and therefore, was expected to be a suitable oral alternative to reduce the rebound associated with fingolimod withdrawal.
METHODS
We present six patients with relapsing-remitting MS who developed an unexpected increase in disease activity after transitioning from fingolimod to DMF. All patients were clinically and radiologically stable on fingolimod for at least 1 year. The switch in therapy was due to significantly low CD4+ T lymphocyte count ≤65 cells/ul (normal range 490-1740 cells/ul), after discussing the results with the patients and the potential risk for opportunistic infections including cryptococcal infections. DMF was introduced following a washout period of 5 to 11 weeks to allow reconstitution of the immune system and for the absolute lymphocyte count to reach ≥500 cells/ul. Every patient who experienced a relapse had several enhancing lesions in the brain and/or spinal cord between 12 to 23 weeks after cessation of fingolimod and 1 to 18 weeks after starting DMF. All relapses were treated with intravenous methylprednisolone with good clinical responses.
CONCLUSIONS
The anticipated beneficial response of DMF treatment to mitigate rebound after fingolimod therapy cessation was not observed. Our patients experienced rebound disease despite being on treatment with DMF. Additional studies are necessary to understand which treatments are most effective to transition to after discontinuing fingolimod.
Background
Fingolimod is an oral immunomodulatory agent approved to treat relapsing MS. It modulates S1P1 receptors blocking the egress of activated lymphocytes from lymph nodes with resultant lymphopenia, predominantly affecting CD4+ T cells [1, 2]. There are no specific guidelines for the monitoring of lymphocyte subsets of MS patients on fingolimod. However, several cases of cryptococcal infections have been reported in MS patients treated with fingolimod and low CD4+ T cell count [3–5]. Disease rebound within 6 months after fingolimod withdrawal has been documented [6–8], including several MS patients who were switched from fingolimod to dimethyl fumarate (DMF) [9]. The mechanism of rebound after fingolimod cessation is not well understood. Therefore, selection of a disease modifying therapy to prevent disease reactivation after fingolimod discontinuation remains a challenge in clinical practice.
Case presentation
Case 1
A 37-year-old woman diagnosed with MS in 2008 and treated with interferon-beta was transitioned to fingolimod in 2012 due to sub-optimal response. She remained clinically stable. In November 2017, she had sustained lymphopenia for 1 year with an absolute CD4+ T cell count of 33 cell/ul (normal range 490–1740 cells/ul). Fingolimod was discontinued in December 2017, and she started DMF in February 2018. Five weeks later, she developed weakness of both legs. MRIs brain and cervical spine showed several new enhancing lesions in the brain and one cervical at C2 level. She experienced another episode of walking difficulties and paresthesia in her legs in May 2018. MRI of brain showed 6 new enhancing lesions. Both episodes were treated with intravenous methylprednisolone with complete recovery.
Case 2
A 34-year-old woman diagnosed with MS in 2005 and treated with glatiramer acetate (GA) since 2010 was transitioned to fingolimod in 2013 due to sub-optimal response. Fingolimod was discontinued in December 2017 due to low CD4+ T cell count (< 20 cells/ul). Four days after starting DMF in mid-February 2018, she developed slurred speech, dizziness, paraparesis and ataxia. MRI studies showed several brain and cervical enhancing lesions at C2 and C4–5 levels. (Fig. 1) She was treated with intravenous methylprednisolone with good clinical response.
Fig. 1 MRI of brain: a. Axial FLAIR b. Axial Post-Gadolinium. Patient had a severe MS relapse after fingolimod discontinuation for 12 weeks and on treatment with DMF for 4 days. MRI of brain showed multiple enhancing lesions with a nodular and ring enhancement pattern in the brainstem, posterior fossa, and cerebral hemispheres bilaterally (Case 2)
Case 3
A 33-year-old man diagnosed with MS was started on fingolimod in 2014. He remained clinically stable. Fingolimod was stopped in December 2017 due to sustained low CD4+ T cell count (≤61 cells/ul), and DMF was started in February 2018. In mid-April 2018, he experienced tingling, first in the left hand followed by bilateral hands and feet, tightness in the abdomen above the waist bilaterally and perianal numbness. MRI of brain and cervical spine showed new enhancing lesions in the brain and within the cord at C4–5 level. Recovery was complete after treatment with intravenous methylprednisolone.
Case 4
A 50-year-old woman diagnosed with MS in 2014 and treated with interferon-beta was switched to fingolimod in 2016 due to poor tolerability. Fingolimod was discontinued in November 2017 due to low CD4+ T cell count (< 20 cells/ul), and she was transitioned to DMF in January 2018. In mid-April 2018, she experienced right foot cramping, numbness/pain from her right breast down to her right foot for 2–3 weeks, with weakness of right leg, and walking difficulties. MRI of cervical and thoracic spine showed enhancing cord lesions at C4 and C7-T1 levels, within the right cerebellum, and at T9, T10, and T11 levels. She recovered well after intravenous methylprednisolone treatment. MRI of brain done after IV steroids showed three new non-enhancing lesions.
Case 5
A 42-year-old woman diagnosed with MS in 2007 started treatment with fingolimod in 2012. In November 2017, fingolimod was discontinued due to sustained lymphopenia and low CD4+ T cell count (≤20 cells/ul). She was transitioned to DMF in January 2018. She complained of headache for 2 weeks and weakness of her legs in May 2018. Brain MRI showed four new lesions, three were enhancing. Treatment with intravenous methylprednisolone resulted in complete recovery.
Case 6
A 33-year-old woman diagnosed with MS in 2010 treated with GA and then peg-interferon beta-1a, was switched to fingolimod in 2017 due to sub-optimal response. Fingolimod was discontinued in February 2018 due to lymphopenia and low CD4+ T cell count (< 20 cells/uL). She was transitioned to DMF in March 2018. In mid-July 2018, she experienced bilateral ascending numbness of the legs up to her hips over 2 days. MRIs demonstrated a new brain enhancing lesion and two new lesions in the thoracic cord, one of which was enhancing. She had a complete recovery after treatment with intravenous methylprednisolone.
Results
Six relapsing-remitting MS patients (five women and one man), with a mean age of 38 years (range 33–50 years) at the time of fingolimod discontinuation, experienced increased disease activity with several enhancing lesions in the brain and/or spinal cord after being transitioned to DMF.
All the patients were treated with fingolimod for at least 1 year (range 1 to 5.5 years), and were clinically and radiologically stable prior to the transition in therapy. After a discussion with patients, a decision was made to switch treatments due to concerns for the risk of opportunistic infections including cryptococcal infections given the significantly low CD4+ T lymphocyte count [7, 8]. A wash out period (5 to 11 weeks) was done to allow the reconstitution of the immune system and for the absolute lymphocyte count (ALC) to return to ≥500 cells/ul prior to starting DMF. MS relapses were observed 12 to 23 weeks after fingolimod cessation and between 1 to 18 weeks after starting DMF. All relapses were successfully treated with intravenous methylprednisolone (Table 1).
Table 1 Case Summary
Case # Age at fingolimod cessation (Y) Sex Disease Duration (Y) Prior DMTs Treatment duration on fingolimod (Y) ALC/CD4 at the time of stopping fingolimod (cells/uL) Wash out period (W) ALC/CD4 baseline to start DMF (cells/uL) Treatment duration at time of relapse (W) ALC/CD4 at the time of relapse (cells/uL) New/Gd+ lesions at the time of relapse Response to IV steroid treatment (Yes/No)
1 37 F 10 INF-β (Rebif) 5 300/33 8 1400/ND 5 1700/615 Brain & Cervical spine Yes
2 34 F 13 GA (Copaxone) 4 282/<20 11 644/ND <1 (4 days) 626/252 Brain & Cervical spine Yes
3 33 M 3 None 3 567/61 7 1006/389 10 950/ND Brain & Cervical spine Yes
4 50 F 4 INF-β (Rebif & Plegridy) 1 270/<20 8 1000/551 14 - Brain, Cervical & Thoracic spine Yes
5 42 F 11 None 5.5 467/20 9 1036/295 13 1241/ND Brain Yes
6 33 F 8 GA (Copaxone) & INF-β (Plegridy) 1 509/<20 5 912/ND 18 1600/ND Brain & Thoracic spine Yes
Absolute lymphocyte count (ALC): Normal reference range 850-3900 cells/ul (Quest Diagnostics)
Absolute CD4+ lymphocyte count: Normal reference range 490-1740 cells/ul (Quest Diagnostics)
ND Not done, Y Year, W Week, Gd + Lesions Gadolinium enhancing lesions
Discussion and conclusions
CD4+ and CD8+ T lymphocytes play important roles in MS immunopathogenesis [10–13]. Expansion of T cell clones in active demyelinating MS brain lesions, showed a predominance of CD8+ T cells in all studied lesions, suggesting that these lymphocytes may be involved in auto-immune responses and cause tissue damage by cytotoxicity or cytokine release [11]. MS lesions may also contain regulatory CD4+ and CD8+ T cells that could halt the pathogenic processes, suggesting a dual and protective role of these cells [11, 13]. The balance between the immunomodulatory effects of these T cell subpopulations may be essential for disease remission.
The mechanism of rebound following discontinuation of fingolimod is unclear. It is postulated that the rebound may be mediated by the fast reappearance of previously entrapped autoreactive lymphocytes into the CNS [14]. Severe rebound after fingolimod discontinuation in mice with relapsing-remitting EAE was preceded by upregulation of S1P1 receptors in entrapped lymphocytes in lymph nodes followed by their egress into the circulation and subsequent CNS infiltration [15]. Mice that have a selective knockout of S1P1 receptors in their astrocytes developed attenuated EAE [16]. Astrocytic S1P1 overexpression after fingolimod cessation resulting in the release of inflammatory cytokines and nitric oxide may also contribute to MS rebound [17].
Another plausible hypothesis is that there is differential susceptibility of lymphocyte subsets to entrapment into secondary lymphoid organs, and an equally differential susceptibility for their return to circulation after withdrawal from fingolimod therapy. It is known that CD4+ T cells are most susceptible to entrapment, followed by CD8+ T cells [1, 2]. CD4+ T lymphocytes are the last to recover after withdrawal from fingolimod [18]. During this period of sequential return of lymphocytes, a dysregulated state may occur when autoreactive cytotoxic CD8+ T cells return earlier than the regulatory CD4+ T cells. The injury to the CNS may be mediated by the cytotoxic CD8+ T cells that remain unregulated. The injury may result in large tumefactive lesions in the brain, quite similar to the large lesions of acute disseminated encephalomyelitis (ADEM)-like event described in pediatric MS reported to be mediated by cytotoxic CD8+ T cells [19]. If the mechanism of CNS injury with the characteristic tumefactive lesions is primarily mediated by CD8+ T cells, DMF which is known to preferentially deplete the CD8+ T cell population [20] could be helpful in mitigating the fingolimod rebound phenomenon.
In our case series, the six patients experienced increased MS disease activity after transitioning from fingolimod to DMF, despite being on treatment, and one patient (Case 1) had a second relapse 3 months after starting DMF. This was an unexpected experience as DMF is an oral drug with an equivalent efficacy to fingolimod [21, 22]. Other authors have reported a similar experience with this transition strategy [9, 23]. It is likely that several immunopathogenic mechanisms are involved in MS disease reactivation after fingolimod cessation.
Limitations of this report include that it is a retrospective chart review, and the sample size is small and therefore, conclusions regarding treatment selection after fingolimod discontinuation cannot be drawn. This case series may help bring awareness to other providers who care for patients with MS of similar clinical scenarios. Further research is needed to determine the most effective treatment options after discontinuing fingolimod.
Abbreviations
MSMultiple sclerosis
DMFDimethyl fumarate
PMLProgressive multifocal leukoencephalopathy
S1P1Sphingosine-1-phosphate receptor 1
MRIMagnetic resonance imaging
GAGlatiramer acetate
ALCAbsolute lymphocyte count
CNSCentral nervous system
EAEExperimental autoimmune encephalomyelitis
ADEMAcute disseminated encephalomyelitis
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors made substantial contributions to this manuscript. SD conceived of the present case series. SD and JH identified the patients, obtained all pertinent patient information, and reviewed the literature. SD wrote the first draft which was then critically revised and edited by KR, LT, and JH. SD and JH finalized the manuscript. All authors have read and approved the final manuscript.
Funding
The author(s) did not receive financial support for the authorship and/or publication of this article.
Availability of data and materials
All data related to this case report are contained within the manuscript. The first author can provide the original data if needed.
Ethics approval and consent to participate
Ethics approval not applicable. All patients provided informed consent prior to submission.
Consent for publication
Written informed consent was obtained from each patient to be included this case series and all the cases and images were provided in a de-identified manner. A copy of the written consent is available for review by the editor of this journal.
Competing interests
S.D. received honoraria for consulting services from Novartis. J.H. and L.T. received honoraria for consulting services from Biogen. K.R. received honoraria for consulting services from Novartis, Biogen, EMD Serono, Genzyme, TG Therapeutics. | FINGOLIMOD | DrugsGivenReaction | CC BY | 33530945 | 19,013,510 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lymphopenia'. | Increased multiple sclerosis disease activity in patients transitioned from fingolimod to dimethyl fumarate: a case series.
BACKGROUND
Fingolimod is a S1P1 receptor modulator that prevents activated lymphocyte egress from lymphoid tissues causing lymphopenia, mainly affecting CD4+ T lymphocytes. Withdrawal from fingolimod can be followed by severe disease reactivation, and this coincides with return of autoreactive lymphocytes into circulation. The CD8+ T cytotoxic population returns prior to the regulatory CD4+ T lymphocytes leading to a state of dysregulation, which may contribute to the rebound and severity of clinical relapses. On the other hand, dimethyl fumarate (DMF) preferentially reduces CD8+ T lymphocytes, has the same efficacy as fingolimod, and therefore, was expected to be a suitable oral alternative to reduce the rebound associated with fingolimod withdrawal.
METHODS
We present six patients with relapsing-remitting MS who developed an unexpected increase in disease activity after transitioning from fingolimod to DMF. All patients were clinically and radiologically stable on fingolimod for at least 1 year. The switch in therapy was due to significantly low CD4+ T lymphocyte count ≤65 cells/ul (normal range 490-1740 cells/ul), after discussing the results with the patients and the potential risk for opportunistic infections including cryptococcal infections. DMF was introduced following a washout period of 5 to 11 weeks to allow reconstitution of the immune system and for the absolute lymphocyte count to reach ≥500 cells/ul. Every patient who experienced a relapse had several enhancing lesions in the brain and/or spinal cord between 12 to 23 weeks after cessation of fingolimod and 1 to 18 weeks after starting DMF. All relapses were treated with intravenous methylprednisolone with good clinical responses.
CONCLUSIONS
The anticipated beneficial response of DMF treatment to mitigate rebound after fingolimod therapy cessation was not observed. Our patients experienced rebound disease despite being on treatment with DMF. Additional studies are necessary to understand which treatments are most effective to transition to after discontinuing fingolimod.
Background
Fingolimod is an oral immunomodulatory agent approved to treat relapsing MS. It modulates S1P1 receptors blocking the egress of activated lymphocytes from lymph nodes with resultant lymphopenia, predominantly affecting CD4+ T cells [1, 2]. There are no specific guidelines for the monitoring of lymphocyte subsets of MS patients on fingolimod. However, several cases of cryptococcal infections have been reported in MS patients treated with fingolimod and low CD4+ T cell count [3–5]. Disease rebound within 6 months after fingolimod withdrawal has been documented [6–8], including several MS patients who were switched from fingolimod to dimethyl fumarate (DMF) [9]. The mechanism of rebound after fingolimod cessation is not well understood. Therefore, selection of a disease modifying therapy to prevent disease reactivation after fingolimod discontinuation remains a challenge in clinical practice.
Case presentation
Case 1
A 37-year-old woman diagnosed with MS in 2008 and treated with interferon-beta was transitioned to fingolimod in 2012 due to sub-optimal response. She remained clinically stable. In November 2017, she had sustained lymphopenia for 1 year with an absolute CD4+ T cell count of 33 cell/ul (normal range 490–1740 cells/ul). Fingolimod was discontinued in December 2017, and she started DMF in February 2018. Five weeks later, she developed weakness of both legs. MRIs brain and cervical spine showed several new enhancing lesions in the brain and one cervical at C2 level. She experienced another episode of walking difficulties and paresthesia in her legs in May 2018. MRI of brain showed 6 new enhancing lesions. Both episodes were treated with intravenous methylprednisolone with complete recovery.
Case 2
A 34-year-old woman diagnosed with MS in 2005 and treated with glatiramer acetate (GA) since 2010 was transitioned to fingolimod in 2013 due to sub-optimal response. Fingolimod was discontinued in December 2017 due to low CD4+ T cell count (< 20 cells/ul). Four days after starting DMF in mid-February 2018, she developed slurred speech, dizziness, paraparesis and ataxia. MRI studies showed several brain and cervical enhancing lesions at C2 and C4–5 levels. (Fig. 1) She was treated with intravenous methylprednisolone with good clinical response.
Fig. 1 MRI of brain: a. Axial FLAIR b. Axial Post-Gadolinium. Patient had a severe MS relapse after fingolimod discontinuation for 12 weeks and on treatment with DMF for 4 days. MRI of brain showed multiple enhancing lesions with a nodular and ring enhancement pattern in the brainstem, posterior fossa, and cerebral hemispheres bilaterally (Case 2)
Case 3
A 33-year-old man diagnosed with MS was started on fingolimod in 2014. He remained clinically stable. Fingolimod was stopped in December 2017 due to sustained low CD4+ T cell count (≤61 cells/ul), and DMF was started in February 2018. In mid-April 2018, he experienced tingling, first in the left hand followed by bilateral hands and feet, tightness in the abdomen above the waist bilaterally and perianal numbness. MRI of brain and cervical spine showed new enhancing lesions in the brain and within the cord at C4–5 level. Recovery was complete after treatment with intravenous methylprednisolone.
Case 4
A 50-year-old woman diagnosed with MS in 2014 and treated with interferon-beta was switched to fingolimod in 2016 due to poor tolerability. Fingolimod was discontinued in November 2017 due to low CD4+ T cell count (< 20 cells/ul), and she was transitioned to DMF in January 2018. In mid-April 2018, she experienced right foot cramping, numbness/pain from her right breast down to her right foot for 2–3 weeks, with weakness of right leg, and walking difficulties. MRI of cervical and thoracic spine showed enhancing cord lesions at C4 and C7-T1 levels, within the right cerebellum, and at T9, T10, and T11 levels. She recovered well after intravenous methylprednisolone treatment. MRI of brain done after IV steroids showed three new non-enhancing lesions.
Case 5
A 42-year-old woman diagnosed with MS in 2007 started treatment with fingolimod in 2012. In November 2017, fingolimod was discontinued due to sustained lymphopenia and low CD4+ T cell count (≤20 cells/ul). She was transitioned to DMF in January 2018. She complained of headache for 2 weeks and weakness of her legs in May 2018. Brain MRI showed four new lesions, three were enhancing. Treatment with intravenous methylprednisolone resulted in complete recovery.
Case 6
A 33-year-old woman diagnosed with MS in 2010 treated with GA and then peg-interferon beta-1a, was switched to fingolimod in 2017 due to sub-optimal response. Fingolimod was discontinued in February 2018 due to lymphopenia and low CD4+ T cell count (< 20 cells/uL). She was transitioned to DMF in March 2018. In mid-July 2018, she experienced bilateral ascending numbness of the legs up to her hips over 2 days. MRIs demonstrated a new brain enhancing lesion and two new lesions in the thoracic cord, one of which was enhancing. She had a complete recovery after treatment with intravenous methylprednisolone.
Results
Six relapsing-remitting MS patients (five women and one man), with a mean age of 38 years (range 33–50 years) at the time of fingolimod discontinuation, experienced increased disease activity with several enhancing lesions in the brain and/or spinal cord after being transitioned to DMF.
All the patients were treated with fingolimod for at least 1 year (range 1 to 5.5 years), and were clinically and radiologically stable prior to the transition in therapy. After a discussion with patients, a decision was made to switch treatments due to concerns for the risk of opportunistic infections including cryptococcal infections given the significantly low CD4+ T lymphocyte count [7, 8]. A wash out period (5 to 11 weeks) was done to allow the reconstitution of the immune system and for the absolute lymphocyte count (ALC) to return to ≥500 cells/ul prior to starting DMF. MS relapses were observed 12 to 23 weeks after fingolimod cessation and between 1 to 18 weeks after starting DMF. All relapses were successfully treated with intravenous methylprednisolone (Table 1).
Table 1 Case Summary
Case # Age at fingolimod cessation (Y) Sex Disease Duration (Y) Prior DMTs Treatment duration on fingolimod (Y) ALC/CD4 at the time of stopping fingolimod (cells/uL) Wash out period (W) ALC/CD4 baseline to start DMF (cells/uL) Treatment duration at time of relapse (W) ALC/CD4 at the time of relapse (cells/uL) New/Gd+ lesions at the time of relapse Response to IV steroid treatment (Yes/No)
1 37 F 10 INF-β (Rebif) 5 300/33 8 1400/ND 5 1700/615 Brain & Cervical spine Yes
2 34 F 13 GA (Copaxone) 4 282/<20 11 644/ND <1 (4 days) 626/252 Brain & Cervical spine Yes
3 33 M 3 None 3 567/61 7 1006/389 10 950/ND Brain & Cervical spine Yes
4 50 F 4 INF-β (Rebif & Plegridy) 1 270/<20 8 1000/551 14 - Brain, Cervical & Thoracic spine Yes
5 42 F 11 None 5.5 467/20 9 1036/295 13 1241/ND Brain Yes
6 33 F 8 GA (Copaxone) & INF-β (Plegridy) 1 509/<20 5 912/ND 18 1600/ND Brain & Thoracic spine Yes
Absolute lymphocyte count (ALC): Normal reference range 850-3900 cells/ul (Quest Diagnostics)
Absolute CD4+ lymphocyte count: Normal reference range 490-1740 cells/ul (Quest Diagnostics)
ND Not done, Y Year, W Week, Gd + Lesions Gadolinium enhancing lesions
Discussion and conclusions
CD4+ and CD8+ T lymphocytes play important roles in MS immunopathogenesis [10–13]. Expansion of T cell clones in active demyelinating MS brain lesions, showed a predominance of CD8+ T cells in all studied lesions, suggesting that these lymphocytes may be involved in auto-immune responses and cause tissue damage by cytotoxicity or cytokine release [11]. MS lesions may also contain regulatory CD4+ and CD8+ T cells that could halt the pathogenic processes, suggesting a dual and protective role of these cells [11, 13]. The balance between the immunomodulatory effects of these T cell subpopulations may be essential for disease remission.
The mechanism of rebound following discontinuation of fingolimod is unclear. It is postulated that the rebound may be mediated by the fast reappearance of previously entrapped autoreactive lymphocytes into the CNS [14]. Severe rebound after fingolimod discontinuation in mice with relapsing-remitting EAE was preceded by upregulation of S1P1 receptors in entrapped lymphocytes in lymph nodes followed by their egress into the circulation and subsequent CNS infiltration [15]. Mice that have a selective knockout of S1P1 receptors in their astrocytes developed attenuated EAE [16]. Astrocytic S1P1 overexpression after fingolimod cessation resulting in the release of inflammatory cytokines and nitric oxide may also contribute to MS rebound [17].
Another plausible hypothesis is that there is differential susceptibility of lymphocyte subsets to entrapment into secondary lymphoid organs, and an equally differential susceptibility for their return to circulation after withdrawal from fingolimod therapy. It is known that CD4+ T cells are most susceptible to entrapment, followed by CD8+ T cells [1, 2]. CD4+ T lymphocytes are the last to recover after withdrawal from fingolimod [18]. During this period of sequential return of lymphocytes, a dysregulated state may occur when autoreactive cytotoxic CD8+ T cells return earlier than the regulatory CD4+ T cells. The injury to the CNS may be mediated by the cytotoxic CD8+ T cells that remain unregulated. The injury may result in large tumefactive lesions in the brain, quite similar to the large lesions of acute disseminated encephalomyelitis (ADEM)-like event described in pediatric MS reported to be mediated by cytotoxic CD8+ T cells [19]. If the mechanism of CNS injury with the characteristic tumefactive lesions is primarily mediated by CD8+ T cells, DMF which is known to preferentially deplete the CD8+ T cell population [20] could be helpful in mitigating the fingolimod rebound phenomenon.
In our case series, the six patients experienced increased MS disease activity after transitioning from fingolimod to DMF, despite being on treatment, and one patient (Case 1) had a second relapse 3 months after starting DMF. This was an unexpected experience as DMF is an oral drug with an equivalent efficacy to fingolimod [21, 22]. Other authors have reported a similar experience with this transition strategy [9, 23]. It is likely that several immunopathogenic mechanisms are involved in MS disease reactivation after fingolimod cessation.
Limitations of this report include that it is a retrospective chart review, and the sample size is small and therefore, conclusions regarding treatment selection after fingolimod discontinuation cannot be drawn. This case series may help bring awareness to other providers who care for patients with MS of similar clinical scenarios. Further research is needed to determine the most effective treatment options after discontinuing fingolimod.
Abbreviations
MSMultiple sclerosis
DMFDimethyl fumarate
PMLProgressive multifocal leukoencephalopathy
S1P1Sphingosine-1-phosphate receptor 1
MRIMagnetic resonance imaging
GAGlatiramer acetate
ALCAbsolute lymphocyte count
CNSCentral nervous system
EAEExperimental autoimmune encephalomyelitis
ADEMAcute disseminated encephalomyelitis
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors made substantial contributions to this manuscript. SD conceived of the present case series. SD and JH identified the patients, obtained all pertinent patient information, and reviewed the literature. SD wrote the first draft which was then critically revised and edited by KR, LT, and JH. SD and JH finalized the manuscript. All authors have read and approved the final manuscript.
Funding
The author(s) did not receive financial support for the authorship and/or publication of this article.
Availability of data and materials
All data related to this case report are contained within the manuscript. The first author can provide the original data if needed.
Ethics approval and consent to participate
Ethics approval not applicable. All patients provided informed consent prior to submission.
Consent for publication
Written informed consent was obtained from each patient to be included this case series and all the cases and images were provided in a de-identified manner. A copy of the written consent is available for review by the editor of this journal.
Competing interests
S.D. received honoraria for consulting services from Novartis. J.H. and L.T. received honoraria for consulting services from Biogen. K.R. received honoraria for consulting services from Novartis, Biogen, EMD Serono, Genzyme, TG Therapeutics. | FINGOLIMOD | DrugsGivenReaction | CC BY | 33530945 | 19,014,081 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Multiple sclerosis relapse'. | Increased multiple sclerosis disease activity in patients transitioned from fingolimod to dimethyl fumarate: a case series.
BACKGROUND
Fingolimod is a S1P1 receptor modulator that prevents activated lymphocyte egress from lymphoid tissues causing lymphopenia, mainly affecting CD4+ T lymphocytes. Withdrawal from fingolimod can be followed by severe disease reactivation, and this coincides with return of autoreactive lymphocytes into circulation. The CD8+ T cytotoxic population returns prior to the regulatory CD4+ T lymphocytes leading to a state of dysregulation, which may contribute to the rebound and severity of clinical relapses. On the other hand, dimethyl fumarate (DMF) preferentially reduces CD8+ T lymphocytes, has the same efficacy as fingolimod, and therefore, was expected to be a suitable oral alternative to reduce the rebound associated with fingolimod withdrawal.
METHODS
We present six patients with relapsing-remitting MS who developed an unexpected increase in disease activity after transitioning from fingolimod to DMF. All patients were clinically and radiologically stable on fingolimod for at least 1 year. The switch in therapy was due to significantly low CD4+ T lymphocyte count ≤65 cells/ul (normal range 490-1740 cells/ul), after discussing the results with the patients and the potential risk for opportunistic infections including cryptococcal infections. DMF was introduced following a washout period of 5 to 11 weeks to allow reconstitution of the immune system and for the absolute lymphocyte count to reach ≥500 cells/ul. Every patient who experienced a relapse had several enhancing lesions in the brain and/or spinal cord between 12 to 23 weeks after cessation of fingolimod and 1 to 18 weeks after starting DMF. All relapses were treated with intravenous methylprednisolone with good clinical responses.
CONCLUSIONS
The anticipated beneficial response of DMF treatment to mitigate rebound after fingolimod therapy cessation was not observed. Our patients experienced rebound disease despite being on treatment with DMF. Additional studies are necessary to understand which treatments are most effective to transition to after discontinuing fingolimod.
Background
Fingolimod is an oral immunomodulatory agent approved to treat relapsing MS. It modulates S1P1 receptors blocking the egress of activated lymphocytes from lymph nodes with resultant lymphopenia, predominantly affecting CD4+ T cells [1, 2]. There are no specific guidelines for the monitoring of lymphocyte subsets of MS patients on fingolimod. However, several cases of cryptococcal infections have been reported in MS patients treated with fingolimod and low CD4+ T cell count [3–5]. Disease rebound within 6 months after fingolimod withdrawal has been documented [6–8], including several MS patients who were switched from fingolimod to dimethyl fumarate (DMF) [9]. The mechanism of rebound after fingolimod cessation is not well understood. Therefore, selection of a disease modifying therapy to prevent disease reactivation after fingolimod discontinuation remains a challenge in clinical practice.
Case presentation
Case 1
A 37-year-old woman diagnosed with MS in 2008 and treated with interferon-beta was transitioned to fingolimod in 2012 due to sub-optimal response. She remained clinically stable. In November 2017, she had sustained lymphopenia for 1 year with an absolute CD4+ T cell count of 33 cell/ul (normal range 490–1740 cells/ul). Fingolimod was discontinued in December 2017, and she started DMF in February 2018. Five weeks later, she developed weakness of both legs. MRIs brain and cervical spine showed several new enhancing lesions in the brain and one cervical at C2 level. She experienced another episode of walking difficulties and paresthesia in her legs in May 2018. MRI of brain showed 6 new enhancing lesions. Both episodes were treated with intravenous methylprednisolone with complete recovery.
Case 2
A 34-year-old woman diagnosed with MS in 2005 and treated with glatiramer acetate (GA) since 2010 was transitioned to fingolimod in 2013 due to sub-optimal response. Fingolimod was discontinued in December 2017 due to low CD4+ T cell count (< 20 cells/ul). Four days after starting DMF in mid-February 2018, she developed slurred speech, dizziness, paraparesis and ataxia. MRI studies showed several brain and cervical enhancing lesions at C2 and C4–5 levels. (Fig. 1) She was treated with intravenous methylprednisolone with good clinical response.
Fig. 1 MRI of brain: a. Axial FLAIR b. Axial Post-Gadolinium. Patient had a severe MS relapse after fingolimod discontinuation for 12 weeks and on treatment with DMF for 4 days. MRI of brain showed multiple enhancing lesions with a nodular and ring enhancement pattern in the brainstem, posterior fossa, and cerebral hemispheres bilaterally (Case 2)
Case 3
A 33-year-old man diagnosed with MS was started on fingolimod in 2014. He remained clinically stable. Fingolimod was stopped in December 2017 due to sustained low CD4+ T cell count (≤61 cells/ul), and DMF was started in February 2018. In mid-April 2018, he experienced tingling, first in the left hand followed by bilateral hands and feet, tightness in the abdomen above the waist bilaterally and perianal numbness. MRI of brain and cervical spine showed new enhancing lesions in the brain and within the cord at C4–5 level. Recovery was complete after treatment with intravenous methylprednisolone.
Case 4
A 50-year-old woman diagnosed with MS in 2014 and treated with interferon-beta was switched to fingolimod in 2016 due to poor tolerability. Fingolimod was discontinued in November 2017 due to low CD4+ T cell count (< 20 cells/ul), and she was transitioned to DMF in January 2018. In mid-April 2018, she experienced right foot cramping, numbness/pain from her right breast down to her right foot for 2–3 weeks, with weakness of right leg, and walking difficulties. MRI of cervical and thoracic spine showed enhancing cord lesions at C4 and C7-T1 levels, within the right cerebellum, and at T9, T10, and T11 levels. She recovered well after intravenous methylprednisolone treatment. MRI of brain done after IV steroids showed three new non-enhancing lesions.
Case 5
A 42-year-old woman diagnosed with MS in 2007 started treatment with fingolimod in 2012. In November 2017, fingolimod was discontinued due to sustained lymphopenia and low CD4+ T cell count (≤20 cells/ul). She was transitioned to DMF in January 2018. She complained of headache for 2 weeks and weakness of her legs in May 2018. Brain MRI showed four new lesions, three were enhancing. Treatment with intravenous methylprednisolone resulted in complete recovery.
Case 6
A 33-year-old woman diagnosed with MS in 2010 treated with GA and then peg-interferon beta-1a, was switched to fingolimod in 2017 due to sub-optimal response. Fingolimod was discontinued in February 2018 due to lymphopenia and low CD4+ T cell count (< 20 cells/uL). She was transitioned to DMF in March 2018. In mid-July 2018, she experienced bilateral ascending numbness of the legs up to her hips over 2 days. MRIs demonstrated a new brain enhancing lesion and two new lesions in the thoracic cord, one of which was enhancing. She had a complete recovery after treatment with intravenous methylprednisolone.
Results
Six relapsing-remitting MS patients (five women and one man), with a mean age of 38 years (range 33–50 years) at the time of fingolimod discontinuation, experienced increased disease activity with several enhancing lesions in the brain and/or spinal cord after being transitioned to DMF.
All the patients were treated with fingolimod for at least 1 year (range 1 to 5.5 years), and were clinically and radiologically stable prior to the transition in therapy. After a discussion with patients, a decision was made to switch treatments due to concerns for the risk of opportunistic infections including cryptococcal infections given the significantly low CD4+ T lymphocyte count [7, 8]. A wash out period (5 to 11 weeks) was done to allow the reconstitution of the immune system and for the absolute lymphocyte count (ALC) to return to ≥500 cells/ul prior to starting DMF. MS relapses were observed 12 to 23 weeks after fingolimod cessation and between 1 to 18 weeks after starting DMF. All relapses were successfully treated with intravenous methylprednisolone (Table 1).
Table 1 Case Summary
Case # Age at fingolimod cessation (Y) Sex Disease Duration (Y) Prior DMTs Treatment duration on fingolimod (Y) ALC/CD4 at the time of stopping fingolimod (cells/uL) Wash out period (W) ALC/CD4 baseline to start DMF (cells/uL) Treatment duration at time of relapse (W) ALC/CD4 at the time of relapse (cells/uL) New/Gd+ lesions at the time of relapse Response to IV steroid treatment (Yes/No)
1 37 F 10 INF-β (Rebif) 5 300/33 8 1400/ND 5 1700/615 Brain & Cervical spine Yes
2 34 F 13 GA (Copaxone) 4 282/<20 11 644/ND <1 (4 days) 626/252 Brain & Cervical spine Yes
3 33 M 3 None 3 567/61 7 1006/389 10 950/ND Brain & Cervical spine Yes
4 50 F 4 INF-β (Rebif & Plegridy) 1 270/<20 8 1000/551 14 - Brain, Cervical & Thoracic spine Yes
5 42 F 11 None 5.5 467/20 9 1036/295 13 1241/ND Brain Yes
6 33 F 8 GA (Copaxone) & INF-β (Plegridy) 1 509/<20 5 912/ND 18 1600/ND Brain & Thoracic spine Yes
Absolute lymphocyte count (ALC): Normal reference range 850-3900 cells/ul (Quest Diagnostics)
Absolute CD4+ lymphocyte count: Normal reference range 490-1740 cells/ul (Quest Diagnostics)
ND Not done, Y Year, W Week, Gd + Lesions Gadolinium enhancing lesions
Discussion and conclusions
CD4+ and CD8+ T lymphocytes play important roles in MS immunopathogenesis [10–13]. Expansion of T cell clones in active demyelinating MS brain lesions, showed a predominance of CD8+ T cells in all studied lesions, suggesting that these lymphocytes may be involved in auto-immune responses and cause tissue damage by cytotoxicity or cytokine release [11]. MS lesions may also contain regulatory CD4+ and CD8+ T cells that could halt the pathogenic processes, suggesting a dual and protective role of these cells [11, 13]. The balance between the immunomodulatory effects of these T cell subpopulations may be essential for disease remission.
The mechanism of rebound following discontinuation of fingolimod is unclear. It is postulated that the rebound may be mediated by the fast reappearance of previously entrapped autoreactive lymphocytes into the CNS [14]. Severe rebound after fingolimod discontinuation in mice with relapsing-remitting EAE was preceded by upregulation of S1P1 receptors in entrapped lymphocytes in lymph nodes followed by their egress into the circulation and subsequent CNS infiltration [15]. Mice that have a selective knockout of S1P1 receptors in their astrocytes developed attenuated EAE [16]. Astrocytic S1P1 overexpression after fingolimod cessation resulting in the release of inflammatory cytokines and nitric oxide may also contribute to MS rebound [17].
Another plausible hypothesis is that there is differential susceptibility of lymphocyte subsets to entrapment into secondary lymphoid organs, and an equally differential susceptibility for their return to circulation after withdrawal from fingolimod therapy. It is known that CD4+ T cells are most susceptible to entrapment, followed by CD8+ T cells [1, 2]. CD4+ T lymphocytes are the last to recover after withdrawal from fingolimod [18]. During this period of sequential return of lymphocytes, a dysregulated state may occur when autoreactive cytotoxic CD8+ T cells return earlier than the regulatory CD4+ T cells. The injury to the CNS may be mediated by the cytotoxic CD8+ T cells that remain unregulated. The injury may result in large tumefactive lesions in the brain, quite similar to the large lesions of acute disseminated encephalomyelitis (ADEM)-like event described in pediatric MS reported to be mediated by cytotoxic CD8+ T cells [19]. If the mechanism of CNS injury with the characteristic tumefactive lesions is primarily mediated by CD8+ T cells, DMF which is known to preferentially deplete the CD8+ T cell population [20] could be helpful in mitigating the fingolimod rebound phenomenon.
In our case series, the six patients experienced increased MS disease activity after transitioning from fingolimod to DMF, despite being on treatment, and one patient (Case 1) had a second relapse 3 months after starting DMF. This was an unexpected experience as DMF is an oral drug with an equivalent efficacy to fingolimod [21, 22]. Other authors have reported a similar experience with this transition strategy [9, 23]. It is likely that several immunopathogenic mechanisms are involved in MS disease reactivation after fingolimod cessation.
Limitations of this report include that it is a retrospective chart review, and the sample size is small and therefore, conclusions regarding treatment selection after fingolimod discontinuation cannot be drawn. This case series may help bring awareness to other providers who care for patients with MS of similar clinical scenarios. Further research is needed to determine the most effective treatment options after discontinuing fingolimod.
Abbreviations
MSMultiple sclerosis
DMFDimethyl fumarate
PMLProgressive multifocal leukoencephalopathy
S1P1Sphingosine-1-phosphate receptor 1
MRIMagnetic resonance imaging
GAGlatiramer acetate
ALCAbsolute lymphocyte count
CNSCentral nervous system
EAEExperimental autoimmune encephalomyelitis
ADEMAcute disseminated encephalomyelitis
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors made substantial contributions to this manuscript. SD conceived of the present case series. SD and JH identified the patients, obtained all pertinent patient information, and reviewed the literature. SD wrote the first draft which was then critically revised and edited by KR, LT, and JH. SD and JH finalized the manuscript. All authors have read and approved the final manuscript.
Funding
The author(s) did not receive financial support for the authorship and/or publication of this article.
Availability of data and materials
All data related to this case report are contained within the manuscript. The first author can provide the original data if needed.
Ethics approval and consent to participate
Ethics approval not applicable. All patients provided informed consent prior to submission.
Consent for publication
Written informed consent was obtained from each patient to be included this case series and all the cases and images were provided in a de-identified manner. A copy of the written consent is available for review by the editor of this journal.
Competing interests
S.D. received honoraria for consulting services from Novartis. J.H. and L.T. received honoraria for consulting services from Biogen. K.R. received honoraria for consulting services from Novartis, Biogen, EMD Serono, Genzyme, TG Therapeutics. | FINGOLIMOD | DrugsGivenReaction | CC BY | 33530945 | 19,013,510 | 2021-02-02 |
What was the outcome of reaction 'Multiple sclerosis relapse'? | Increased multiple sclerosis disease activity in patients transitioned from fingolimod to dimethyl fumarate: a case series.
BACKGROUND
Fingolimod is a S1P1 receptor modulator that prevents activated lymphocyte egress from lymphoid tissues causing lymphopenia, mainly affecting CD4+ T lymphocytes. Withdrawal from fingolimod can be followed by severe disease reactivation, and this coincides with return of autoreactive lymphocytes into circulation. The CD8+ T cytotoxic population returns prior to the regulatory CD4+ T lymphocytes leading to a state of dysregulation, which may contribute to the rebound and severity of clinical relapses. On the other hand, dimethyl fumarate (DMF) preferentially reduces CD8+ T lymphocytes, has the same efficacy as fingolimod, and therefore, was expected to be a suitable oral alternative to reduce the rebound associated with fingolimod withdrawal.
METHODS
We present six patients with relapsing-remitting MS who developed an unexpected increase in disease activity after transitioning from fingolimod to DMF. All patients were clinically and radiologically stable on fingolimod for at least 1 year. The switch in therapy was due to significantly low CD4+ T lymphocyte count ≤65 cells/ul (normal range 490-1740 cells/ul), after discussing the results with the patients and the potential risk for opportunistic infections including cryptococcal infections. DMF was introduced following a washout period of 5 to 11 weeks to allow reconstitution of the immune system and for the absolute lymphocyte count to reach ≥500 cells/ul. Every patient who experienced a relapse had several enhancing lesions in the brain and/or spinal cord between 12 to 23 weeks after cessation of fingolimod and 1 to 18 weeks after starting DMF. All relapses were treated with intravenous methylprednisolone with good clinical responses.
CONCLUSIONS
The anticipated beneficial response of DMF treatment to mitigate rebound after fingolimod therapy cessation was not observed. Our patients experienced rebound disease despite being on treatment with DMF. Additional studies are necessary to understand which treatments are most effective to transition to after discontinuing fingolimod.
Background
Fingolimod is an oral immunomodulatory agent approved to treat relapsing MS. It modulates S1P1 receptors blocking the egress of activated lymphocytes from lymph nodes with resultant lymphopenia, predominantly affecting CD4+ T cells [1, 2]. There are no specific guidelines for the monitoring of lymphocyte subsets of MS patients on fingolimod. However, several cases of cryptococcal infections have been reported in MS patients treated with fingolimod and low CD4+ T cell count [3–5]. Disease rebound within 6 months after fingolimod withdrawal has been documented [6–8], including several MS patients who were switched from fingolimod to dimethyl fumarate (DMF) [9]. The mechanism of rebound after fingolimod cessation is not well understood. Therefore, selection of a disease modifying therapy to prevent disease reactivation after fingolimod discontinuation remains a challenge in clinical practice.
Case presentation
Case 1
A 37-year-old woman diagnosed with MS in 2008 and treated with interferon-beta was transitioned to fingolimod in 2012 due to sub-optimal response. She remained clinically stable. In November 2017, she had sustained lymphopenia for 1 year with an absolute CD4+ T cell count of 33 cell/ul (normal range 490–1740 cells/ul). Fingolimod was discontinued in December 2017, and she started DMF in February 2018. Five weeks later, she developed weakness of both legs. MRIs brain and cervical spine showed several new enhancing lesions in the brain and one cervical at C2 level. She experienced another episode of walking difficulties and paresthesia in her legs in May 2018. MRI of brain showed 6 new enhancing lesions. Both episodes were treated with intravenous methylprednisolone with complete recovery.
Case 2
A 34-year-old woman diagnosed with MS in 2005 and treated with glatiramer acetate (GA) since 2010 was transitioned to fingolimod in 2013 due to sub-optimal response. Fingolimod was discontinued in December 2017 due to low CD4+ T cell count (< 20 cells/ul). Four days after starting DMF in mid-February 2018, she developed slurred speech, dizziness, paraparesis and ataxia. MRI studies showed several brain and cervical enhancing lesions at C2 and C4–5 levels. (Fig. 1) She was treated with intravenous methylprednisolone with good clinical response.
Fig. 1 MRI of brain: a. Axial FLAIR b. Axial Post-Gadolinium. Patient had a severe MS relapse after fingolimod discontinuation for 12 weeks and on treatment with DMF for 4 days. MRI of brain showed multiple enhancing lesions with a nodular and ring enhancement pattern in the brainstem, posterior fossa, and cerebral hemispheres bilaterally (Case 2)
Case 3
A 33-year-old man diagnosed with MS was started on fingolimod in 2014. He remained clinically stable. Fingolimod was stopped in December 2017 due to sustained low CD4+ T cell count (≤61 cells/ul), and DMF was started in February 2018. In mid-April 2018, he experienced tingling, first in the left hand followed by bilateral hands and feet, tightness in the abdomen above the waist bilaterally and perianal numbness. MRI of brain and cervical spine showed new enhancing lesions in the brain and within the cord at C4–5 level. Recovery was complete after treatment with intravenous methylprednisolone.
Case 4
A 50-year-old woman diagnosed with MS in 2014 and treated with interferon-beta was switched to fingolimod in 2016 due to poor tolerability. Fingolimod was discontinued in November 2017 due to low CD4+ T cell count (< 20 cells/ul), and she was transitioned to DMF in January 2018. In mid-April 2018, she experienced right foot cramping, numbness/pain from her right breast down to her right foot for 2–3 weeks, with weakness of right leg, and walking difficulties. MRI of cervical and thoracic spine showed enhancing cord lesions at C4 and C7-T1 levels, within the right cerebellum, and at T9, T10, and T11 levels. She recovered well after intravenous methylprednisolone treatment. MRI of brain done after IV steroids showed three new non-enhancing lesions.
Case 5
A 42-year-old woman diagnosed with MS in 2007 started treatment with fingolimod in 2012. In November 2017, fingolimod was discontinued due to sustained lymphopenia and low CD4+ T cell count (≤20 cells/ul). She was transitioned to DMF in January 2018. She complained of headache for 2 weeks and weakness of her legs in May 2018. Brain MRI showed four new lesions, three were enhancing. Treatment with intravenous methylprednisolone resulted in complete recovery.
Case 6
A 33-year-old woman diagnosed with MS in 2010 treated with GA and then peg-interferon beta-1a, was switched to fingolimod in 2017 due to sub-optimal response. Fingolimod was discontinued in February 2018 due to lymphopenia and low CD4+ T cell count (< 20 cells/uL). She was transitioned to DMF in March 2018. In mid-July 2018, she experienced bilateral ascending numbness of the legs up to her hips over 2 days. MRIs demonstrated a new brain enhancing lesion and two new lesions in the thoracic cord, one of which was enhancing. She had a complete recovery after treatment with intravenous methylprednisolone.
Results
Six relapsing-remitting MS patients (five women and one man), with a mean age of 38 years (range 33–50 years) at the time of fingolimod discontinuation, experienced increased disease activity with several enhancing lesions in the brain and/or spinal cord after being transitioned to DMF.
All the patients were treated with fingolimod for at least 1 year (range 1 to 5.5 years), and were clinically and radiologically stable prior to the transition in therapy. After a discussion with patients, a decision was made to switch treatments due to concerns for the risk of opportunistic infections including cryptococcal infections given the significantly low CD4+ T lymphocyte count [7, 8]. A wash out period (5 to 11 weeks) was done to allow the reconstitution of the immune system and for the absolute lymphocyte count (ALC) to return to ≥500 cells/ul prior to starting DMF. MS relapses were observed 12 to 23 weeks after fingolimod cessation and between 1 to 18 weeks after starting DMF. All relapses were successfully treated with intravenous methylprednisolone (Table 1).
Table 1 Case Summary
Case # Age at fingolimod cessation (Y) Sex Disease Duration (Y) Prior DMTs Treatment duration on fingolimod (Y) ALC/CD4 at the time of stopping fingolimod (cells/uL) Wash out period (W) ALC/CD4 baseline to start DMF (cells/uL) Treatment duration at time of relapse (W) ALC/CD4 at the time of relapse (cells/uL) New/Gd+ lesions at the time of relapse Response to IV steroid treatment (Yes/No)
1 37 F 10 INF-β (Rebif) 5 300/33 8 1400/ND 5 1700/615 Brain & Cervical spine Yes
2 34 F 13 GA (Copaxone) 4 282/<20 11 644/ND <1 (4 days) 626/252 Brain & Cervical spine Yes
3 33 M 3 None 3 567/61 7 1006/389 10 950/ND Brain & Cervical spine Yes
4 50 F 4 INF-β (Rebif & Plegridy) 1 270/<20 8 1000/551 14 - Brain, Cervical & Thoracic spine Yes
5 42 F 11 None 5.5 467/20 9 1036/295 13 1241/ND Brain Yes
6 33 F 8 GA (Copaxone) & INF-β (Plegridy) 1 509/<20 5 912/ND 18 1600/ND Brain & Thoracic spine Yes
Absolute lymphocyte count (ALC): Normal reference range 850-3900 cells/ul (Quest Diagnostics)
Absolute CD4+ lymphocyte count: Normal reference range 490-1740 cells/ul (Quest Diagnostics)
ND Not done, Y Year, W Week, Gd + Lesions Gadolinium enhancing lesions
Discussion and conclusions
CD4+ and CD8+ T lymphocytes play important roles in MS immunopathogenesis [10–13]. Expansion of T cell clones in active demyelinating MS brain lesions, showed a predominance of CD8+ T cells in all studied lesions, suggesting that these lymphocytes may be involved in auto-immune responses and cause tissue damage by cytotoxicity or cytokine release [11]. MS lesions may also contain regulatory CD4+ and CD8+ T cells that could halt the pathogenic processes, suggesting a dual and protective role of these cells [11, 13]. The balance between the immunomodulatory effects of these T cell subpopulations may be essential for disease remission.
The mechanism of rebound following discontinuation of fingolimod is unclear. It is postulated that the rebound may be mediated by the fast reappearance of previously entrapped autoreactive lymphocytes into the CNS [14]. Severe rebound after fingolimod discontinuation in mice with relapsing-remitting EAE was preceded by upregulation of S1P1 receptors in entrapped lymphocytes in lymph nodes followed by their egress into the circulation and subsequent CNS infiltration [15]. Mice that have a selective knockout of S1P1 receptors in their astrocytes developed attenuated EAE [16]. Astrocytic S1P1 overexpression after fingolimod cessation resulting in the release of inflammatory cytokines and nitric oxide may also contribute to MS rebound [17].
Another plausible hypothesis is that there is differential susceptibility of lymphocyte subsets to entrapment into secondary lymphoid organs, and an equally differential susceptibility for their return to circulation after withdrawal from fingolimod therapy. It is known that CD4+ T cells are most susceptible to entrapment, followed by CD8+ T cells [1, 2]. CD4+ T lymphocytes are the last to recover after withdrawal from fingolimod [18]. During this period of sequential return of lymphocytes, a dysregulated state may occur when autoreactive cytotoxic CD8+ T cells return earlier than the regulatory CD4+ T cells. The injury to the CNS may be mediated by the cytotoxic CD8+ T cells that remain unregulated. The injury may result in large tumefactive lesions in the brain, quite similar to the large lesions of acute disseminated encephalomyelitis (ADEM)-like event described in pediatric MS reported to be mediated by cytotoxic CD8+ T cells [19]. If the mechanism of CNS injury with the characteristic tumefactive lesions is primarily mediated by CD8+ T cells, DMF which is known to preferentially deplete the CD8+ T cell population [20] could be helpful in mitigating the fingolimod rebound phenomenon.
In our case series, the six patients experienced increased MS disease activity after transitioning from fingolimod to DMF, despite being on treatment, and one patient (Case 1) had a second relapse 3 months after starting DMF. This was an unexpected experience as DMF is an oral drug with an equivalent efficacy to fingolimod [21, 22]. Other authors have reported a similar experience with this transition strategy [9, 23]. It is likely that several immunopathogenic mechanisms are involved in MS disease reactivation after fingolimod cessation.
Limitations of this report include that it is a retrospective chart review, and the sample size is small and therefore, conclusions regarding treatment selection after fingolimod discontinuation cannot be drawn. This case series may help bring awareness to other providers who care for patients with MS of similar clinical scenarios. Further research is needed to determine the most effective treatment options after discontinuing fingolimod.
Abbreviations
MSMultiple sclerosis
DMFDimethyl fumarate
PMLProgressive multifocal leukoencephalopathy
S1P1Sphingosine-1-phosphate receptor 1
MRIMagnetic resonance imaging
GAGlatiramer acetate
ALCAbsolute lymphocyte count
CNSCentral nervous system
EAEExperimental autoimmune encephalomyelitis
ADEMAcute disseminated encephalomyelitis
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Acknowledgements
Not applicable.
Authors’ contributions
All authors made substantial contributions to this manuscript. SD conceived of the present case series. SD and JH identified the patients, obtained all pertinent patient information, and reviewed the literature. SD wrote the first draft which was then critically revised and edited by KR, LT, and JH. SD and JH finalized the manuscript. All authors have read and approved the final manuscript.
Funding
The author(s) did not receive financial support for the authorship and/or publication of this article.
Availability of data and materials
All data related to this case report are contained within the manuscript. The first author can provide the original data if needed.
Ethics approval and consent to participate
Ethics approval not applicable. All patients provided informed consent prior to submission.
Consent for publication
Written informed consent was obtained from each patient to be included this case series and all the cases and images were provided in a de-identified manner. A copy of the written consent is available for review by the editor of this journal.
Competing interests
S.D. received honoraria for consulting services from Novartis. J.H. and L.T. received honoraria for consulting services from Biogen. K.R. received honoraria for consulting services from Novartis, Biogen, EMD Serono, Genzyme, TG Therapeutics. | Recovered | ReactionOutcome | CC BY | 33530945 | 19,014,081 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Coma scale abnormal'. | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | DULOXETINE, FLUNITRAZEPAM, QUETIAPINE, TRAZODONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrocardiogram QT prolonged'. | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | DULOXETINE, FLUNITRAZEPAM, QUETIAPINE, TRAZODONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intentional overdose'. | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | DULOXETINE, FLUNITRAZEPAM, QUETIAPINE, TRAZODONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Suicide attempt'. | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | DULOXETINE, FLUNITRAZEPAM, QUETIAPINE, TRAZODONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
What is the weight of the patient? | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | 64 kg. | Weight | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
What was the administration route of drug 'DULOXETINE'? | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
What was the administration route of drug 'FLUNITRAZEPAM'? | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
What was the administration route of drug 'QUETIAPINE'? | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
What was the administration route of drug 'TRAZODONE HYDROCHLORIDE'? | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
What was the dosage of drug 'DULOXETINE'? | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | 780 mg (milligrams). | DrugDosage | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
What was the dosage of drug 'FLUNITRAZEPAM'? | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | 18 mg (milligrams). | DrugDosage | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
What was the dosage of drug 'QUETIAPINE'? | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | 850 mg (milligrams). | DrugDosage | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
What was the dosage of drug 'TRAZODONE HYDROCHLORIDE'? | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | 1100 mg (milligrams). | DrugDosage | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
What was the outcome of reaction 'Coma scale abnormal'? | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
What was the outcome of reaction 'Electrocardiogram QT prolonged'? | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
What was the outcome of reaction 'Intentional overdose'? | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
What was the outcome of reaction 'Suicide attempt'? | Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.
BACKGROUND
Combinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.
METHODS
The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.
CONCLUSIONS
Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.
Background
Therapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.
In general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].
Case presentation
Here we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).
Table 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone
Time after administration (h) of oral dose
1 32 56
Aspartate aminotransferase (U/L) 15 138 122
Alanine aminotransferase (U/L) 18 27 34
Serum creatinine (mg/dL) 0.66 0.71 0.64
Creatinine clearance (mL/min) 139 129 143
Frozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.
The patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.
Fig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2
Based on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:
dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.
Fig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])
Table 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study
Parameter Abbreviation (unit) Duloxetine Flunitrazepam Quetiapine Trazodone
Model input parameters
Molecular weight MW 297 313 384 372
Octanol–water partition coefficient logP 4.26 1.78 2.99 3.85
Plasma unbound fraction fu,p 0.114 0.324 0.125 0.0732
Blood–plasma concentration ratio Rb 0.843 0.921 0.852 0.805
Liver–plasma concentration ratio Kp,h 3.18 1.17 2.69 3.01
Fraction absorbed × intestinal availability Fa·Fg 1 1 1 1
Absorption rate constant ka (1/h) 0.372 ± 0.007a 2.48 ± 0.05 2.86 ± 0.05 1.12 ± 0.26
Transfer rate constant k12 (1/h) – 0.28 ± 0.02 – –
Transfer rate constant k21 (1/h) – 0.04 ± 0.01 – –
Volume of systemic circulation V1 (L) 755 ± 1a 80.7 ± 0.1 206 ± 1 66.2 ± 9.5
Hepatic intrinsic clearance CLh,int (L/h) 385 ± 1a 15.8 ± 0.1 954 ± 1 173 ± 16
Hepatic clearance CLh (L/h) 30.2 4.84 53.4 11.2
Renal clearance CLr (L/h) 3.0 0.48 5.3 1.1
Estimated values
Cmax in plasma ng/mL 44.9 (0.93)b 9.12 (1.08) 44.2 (0.98) 491 (0.72)
AUC in plasma ng·h/mL 1210 (1.19) 52.1 (1.02) 172 (0.95) 3610 (0.77)
Reported levels
Cmax in plasma ng/mL 48.5 ± 8.3c 8.47d 45.0e 681 ± 128f
AUC in plasma ng·h/mL 1020 ± 220 51.2 181 4670 ± 790
aData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]
The measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.
Discussion and conclusions
Although the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.
Relatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.
Simplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.
Abbreviations
CIsConfidence intervals
PBPKPhysiologically based pharmacokinetic
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.
Authors’ contributions
KA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Kyoto Medical Center.
Consent for publication
Informed consent was obtained from the patient.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33531089 | 19,095,550 | 2021-02-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Burning sensation'. | Vulvar Cancer with Cutaneous and Breast Metastases.
Vulvar cancer accounts for about 5% of cancer of female genitalia. It may initially present as benign symptoms resulting in potential delay in diagnosis. Few cases of distant metastases to skin or breast have been reported. We present the case of a 76-year-old female with possible delay in diagnosis of her squamous cell carcinoma of vulva. After 4 months of the diagnosis, she presented with concurrent cutaneous and breast metastases.
1. Introduction
There were estimated 6120 new cases of vulvar cancer in the US in the year 2020, accounting for about 5% of cancer of female genitalia and 0.6% of all cancers in women [1]. The median age at diagnosis of vulvar cancer is 68 years [2]. Vulvar cancer may initially present with nonspecific symptoms like pruritus, pain, burning sensation, bleeding, and lumps. This may be diagnosed as inflammation of Bartholin's gland or inflammation, atrophy, or hypertrophy of vulva which may delay the diagnosis of vulvar cancer. Vulvar cancer may also arise from preexisting, known disease, like lichen sclerosus, and identifying their evolution towards tumor may be difficult, especially in early stages. Squamous cell carcinoma (SCC) accounts for about 90% of vulvar carcinoma. SCC usually presents as localized disease (59%); however, 30% presents with spread to the regional lymph node, 6% with distant metastases, and 5% unstaged [2]. Our PubMed-based search revealed that only 3 cases of vulvar carcinoma metastasis to breast and 16 cases of metastases to skin have been documented prior to our case report. Here, we present a case of squamous cell carcinoma of vulva with potential delay in diagnosis, which after 4 months of diagnosis presented with concurrent metastases to breast and skin.
2. Case Description
A 76-year-old female with a past medical history of coronary artery disease status postcoronary artery bypass graft, hypertension, and aortic stenosis status postmetallic aortic valve replacement presented to the emergency department, with intense vaginal pain and bleeding for three weeks. She had history of 30 pack-years smoking in the past. She had presented to gynaecology clinic about 9 months back with mild vaginal itching and spotting. She was initially given clotrimazole/betamethasone cream which she did not tolerate because of burning sensation and then was given topical oestrogen ointment with partial resolution of her symptoms. A transvaginal ultrasound showed an endometrial strip of 5 mm, but no mass was visualized. She was planned for hysteroscopy and dilatation and curettage if symptoms persist; however, there was no follow-up with the gynaecology clinic for 7 months prior to this emergency department visit. Currently, her pelvic examination revealed midline clitoral mass with erythematous foul-smelling discharge; however, examination was limited due to severe tenderness. Rest of the physical examination was unremarkable. Examination under anaesthesia showed 4.5 cm clitoral mass encompassing right and left labia minora, which was indurated and erythematous. Biopsy of the mass was compatible with invasive squamous cell carcinoma (Figure 1). The neoplastic cells were positive for CK5/6, p63, AE1/AE3, cam5.2, CK7, and CK34betaE12 while negative for p16, CK20, PR, GCDFP15, HMB-45, Mart 1, PASD, and mucicarmine. CEA-P and S100 showed focal staining. PET CT revealed a focus of increased radiotracer uptake within the region of vaginal orifice and no other focal area of intake. Based on these findings, diagnosis of invasive squamous cell carcinoma was made. Given the comorbidities and extent of disease, she was treated with primary radiotherapy to vulva and pelvis which was completed over next 3 months.
During her regular follow-up 4 months after the diagnosis, she reported improvement of vaginal pain but was found to have a rapidly growing 7 × 5 cm mass palpable in the left upper back. The skin overlying the mass was normal and intact. PET CT showed near complete resolution of uptake in the region of vulva, focal uptake in the region of left inguinal lymph node, right breast, and in the soft tissue lesion of left upper back. Core biopsy of the left upper back lesion was done (Figure 2), and the immunostaining profile was similar to prior vulvar mass biopsy specimen suggesting metastasis from vulva. Ultrasound-guided core needle biopsy of right breast mass (Figure 3) demonstrated invasive squamous cell carcinoma with focal necrosis. The immunophenotype was consistent with metastasis from vulvar primary and back mass metastasis.
She was started on carboplatin and paclitaxel chemotherapy. She received the first cycle of chemotherapy. Her second cycle of chemotherapy was delayed because she was admitted to hospital for pneumonia. After discharge from hospital, she opted for hospice and succumbed to her illness in 9 months from the initial diagnosis of vulvar cancer.
3. Discussion
The most common symptom of vulvar cancer is prolonged history of pruritus, followed by vulvar bleeding, dysuria, discharge, and vaginal pain [3]. Clinicians should opt for vulvar skin biopsy when there are persistent symptoms as valvular itching or there is valvular lesion of uncertain significance. A retrospective study done in 1652 women from 218 gynaecological practice in Germany showed a potential mean delay of diagnosis of 186–328 days [4]. In our case, there was a lag period of around 7 months, when she was last seen in outpatient clinic to her hospitalization when eventually the diagnosis was made. This could have resulted in potential delay in the diagnosis.
Metastasis of vulvar cancer occurs via local spread, lymphatic system, and haematogenous pathway. Lymphatics from vulva mainly drain into the superficial inguinal nodes and then into the deep inguinal lymph nodes and follows the iliac vasculature to the external iliac nodes and ultimately the para-aortic nodes. Lymphatics from clitoris can sometimes proceed directly to the deep inguinal lymph nodes or less commonly to the external iliac nodes [5].
In a retrospective study done in a gynaecological centre in Germany, between 1996 and 2013, 391 patients with primary squamous cell carcinoma were treated, out of which 20 patients (5.1%) had distant metastases, and reported sites were lung, liver, bone, skin, and lymph nodes [6]. Our PubMed-based search revealed only 3 cases of breast metastases reported, out of which 2 were unilateral and 1 was bilateral [7–9]. There were 16 cutaneous metastases reported in thigh, abdomen, left lower back, forearm, buttock, and groin [10]. Our patient presented with concurrent breast and cutaneous metastases 4 months after the diagnosis of vulvar carcinoma. The 5-year relative survival rate for localized vulvar cancer (without spread to lymph node or nearby tissues) is 86%, regional disease (spread to nearby lymph nodes or tissue but not to distant organs) is 53%, and distant spread (spread to lungs, liver, bone, and breast) is 19% [11]. Distant metastases have a very poor prognosis, and treatment is mainly palliative which may include chemotherapy, radiation, or surgery for comfort.
4. Conclusion
Vulvar cancer may initially present as benign appearing symptoms and clinicians dealing with this especially in elderly should monitor closely for an early diagnosis. Vulvar cancer patients during their follow-up should be carefully assessed for distant metastases.
Disclosure
The abstract of this case report was submitted to Northwell Health, the Zucker School of Medicine Academic Day and Research Symposium 2020.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Vulvar mass showing invasive squamous cell carcinoma (H and E, ×100).
Figure 2 Left upper back mass—metastatic squamous cell carcinoma (H and E, ×100).
Figure 3 Right breast mass—metastatic squamous cell carcinoma (H and E, ×100). | BETAMETHASONE DIPROPIONATE\CLOTRIMAZOLE | DrugsGivenReaction | CC BY | 33531907 | 19,129,563 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia'. | Vulvar Cancer with Cutaneous and Breast Metastases.
Vulvar cancer accounts for about 5% of cancer of female genitalia. It may initially present as benign symptoms resulting in potential delay in diagnosis. Few cases of distant metastases to skin or breast have been reported. We present the case of a 76-year-old female with possible delay in diagnosis of her squamous cell carcinoma of vulva. After 4 months of the diagnosis, she presented with concurrent cutaneous and breast metastases.
1. Introduction
There were estimated 6120 new cases of vulvar cancer in the US in the year 2020, accounting for about 5% of cancer of female genitalia and 0.6% of all cancers in women [1]. The median age at diagnosis of vulvar cancer is 68 years [2]. Vulvar cancer may initially present with nonspecific symptoms like pruritus, pain, burning sensation, bleeding, and lumps. This may be diagnosed as inflammation of Bartholin's gland or inflammation, atrophy, or hypertrophy of vulva which may delay the diagnosis of vulvar cancer. Vulvar cancer may also arise from preexisting, known disease, like lichen sclerosus, and identifying their evolution towards tumor may be difficult, especially in early stages. Squamous cell carcinoma (SCC) accounts for about 90% of vulvar carcinoma. SCC usually presents as localized disease (59%); however, 30% presents with spread to the regional lymph node, 6% with distant metastases, and 5% unstaged [2]. Our PubMed-based search revealed that only 3 cases of vulvar carcinoma metastasis to breast and 16 cases of metastases to skin have been documented prior to our case report. Here, we present a case of squamous cell carcinoma of vulva with potential delay in diagnosis, which after 4 months of diagnosis presented with concurrent metastases to breast and skin.
2. Case Description
A 76-year-old female with a past medical history of coronary artery disease status postcoronary artery bypass graft, hypertension, and aortic stenosis status postmetallic aortic valve replacement presented to the emergency department, with intense vaginal pain and bleeding for three weeks. She had history of 30 pack-years smoking in the past. She had presented to gynaecology clinic about 9 months back with mild vaginal itching and spotting. She was initially given clotrimazole/betamethasone cream which she did not tolerate because of burning sensation and then was given topical oestrogen ointment with partial resolution of her symptoms. A transvaginal ultrasound showed an endometrial strip of 5 mm, but no mass was visualized. She was planned for hysteroscopy and dilatation and curettage if symptoms persist; however, there was no follow-up with the gynaecology clinic for 7 months prior to this emergency department visit. Currently, her pelvic examination revealed midline clitoral mass with erythematous foul-smelling discharge; however, examination was limited due to severe tenderness. Rest of the physical examination was unremarkable. Examination under anaesthesia showed 4.5 cm clitoral mass encompassing right and left labia minora, which was indurated and erythematous. Biopsy of the mass was compatible with invasive squamous cell carcinoma (Figure 1). The neoplastic cells were positive for CK5/6, p63, AE1/AE3, cam5.2, CK7, and CK34betaE12 while negative for p16, CK20, PR, GCDFP15, HMB-45, Mart 1, PASD, and mucicarmine. CEA-P and S100 showed focal staining. PET CT revealed a focus of increased radiotracer uptake within the region of vaginal orifice and no other focal area of intake. Based on these findings, diagnosis of invasive squamous cell carcinoma was made. Given the comorbidities and extent of disease, she was treated with primary radiotherapy to vulva and pelvis which was completed over next 3 months.
During her regular follow-up 4 months after the diagnosis, she reported improvement of vaginal pain but was found to have a rapidly growing 7 × 5 cm mass palpable in the left upper back. The skin overlying the mass was normal and intact. PET CT showed near complete resolution of uptake in the region of vulva, focal uptake in the region of left inguinal lymph node, right breast, and in the soft tissue lesion of left upper back. Core biopsy of the left upper back lesion was done (Figure 2), and the immunostaining profile was similar to prior vulvar mass biopsy specimen suggesting metastasis from vulva. Ultrasound-guided core needle biopsy of right breast mass (Figure 3) demonstrated invasive squamous cell carcinoma with focal necrosis. The immunophenotype was consistent with metastasis from vulvar primary and back mass metastasis.
She was started on carboplatin and paclitaxel chemotherapy. She received the first cycle of chemotherapy. Her second cycle of chemotherapy was delayed because she was admitted to hospital for pneumonia. After discharge from hospital, she opted for hospice and succumbed to her illness in 9 months from the initial diagnosis of vulvar cancer.
3. Discussion
The most common symptom of vulvar cancer is prolonged history of pruritus, followed by vulvar bleeding, dysuria, discharge, and vaginal pain [3]. Clinicians should opt for vulvar skin biopsy when there are persistent symptoms as valvular itching or there is valvular lesion of uncertain significance. A retrospective study done in 1652 women from 218 gynaecological practice in Germany showed a potential mean delay of diagnosis of 186–328 days [4]. In our case, there was a lag period of around 7 months, when she was last seen in outpatient clinic to her hospitalization when eventually the diagnosis was made. This could have resulted in potential delay in the diagnosis.
Metastasis of vulvar cancer occurs via local spread, lymphatic system, and haematogenous pathway. Lymphatics from vulva mainly drain into the superficial inguinal nodes and then into the deep inguinal lymph nodes and follows the iliac vasculature to the external iliac nodes and ultimately the para-aortic nodes. Lymphatics from clitoris can sometimes proceed directly to the deep inguinal lymph nodes or less commonly to the external iliac nodes [5].
In a retrospective study done in a gynaecological centre in Germany, between 1996 and 2013, 391 patients with primary squamous cell carcinoma were treated, out of which 20 patients (5.1%) had distant metastases, and reported sites were lung, liver, bone, skin, and lymph nodes [6]. Our PubMed-based search revealed only 3 cases of breast metastases reported, out of which 2 were unilateral and 1 was bilateral [7–9]. There were 16 cutaneous metastases reported in thigh, abdomen, left lower back, forearm, buttock, and groin [10]. Our patient presented with concurrent breast and cutaneous metastases 4 months after the diagnosis of vulvar carcinoma. The 5-year relative survival rate for localized vulvar cancer (without spread to lymph node or nearby tissues) is 86%, regional disease (spread to nearby lymph nodes or tissue but not to distant organs) is 53%, and distant spread (spread to lungs, liver, bone, and breast) is 19% [11]. Distant metastases have a very poor prognosis, and treatment is mainly palliative which may include chemotherapy, radiation, or surgery for comfort.
4. Conclusion
Vulvar cancer may initially present as benign appearing symptoms and clinicians dealing with this especially in elderly should monitor closely for an early diagnosis. Vulvar cancer patients during their follow-up should be carefully assessed for distant metastases.
Disclosure
The abstract of this case report was submitted to Northwell Health, the Zucker School of Medicine Academic Day and Research Symposium 2020.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Vulvar mass showing invasive squamous cell carcinoma (H and E, ×100).
Figure 2 Left upper back mass—metastatic squamous cell carcinoma (H and E, ×100).
Figure 3 Right breast mass—metastatic squamous cell carcinoma (H and E, ×100). | CARBOPLATIN, PACLITAXEL | DrugsGivenReaction | CC BY | 33531907 | 19,188,910 | 2021 |
What was the dosage of drug 'CARBOPLATIN'? | Vulvar Cancer with Cutaneous and Breast Metastases.
Vulvar cancer accounts for about 5% of cancer of female genitalia. It may initially present as benign symptoms resulting in potential delay in diagnosis. Few cases of distant metastases to skin or breast have been reported. We present the case of a 76-year-old female with possible delay in diagnosis of her squamous cell carcinoma of vulva. After 4 months of the diagnosis, she presented with concurrent cutaneous and breast metastases.
1. Introduction
There were estimated 6120 new cases of vulvar cancer in the US in the year 2020, accounting for about 5% of cancer of female genitalia and 0.6% of all cancers in women [1]. The median age at diagnosis of vulvar cancer is 68 years [2]. Vulvar cancer may initially present with nonspecific symptoms like pruritus, pain, burning sensation, bleeding, and lumps. This may be diagnosed as inflammation of Bartholin's gland or inflammation, atrophy, or hypertrophy of vulva which may delay the diagnosis of vulvar cancer. Vulvar cancer may also arise from preexisting, known disease, like lichen sclerosus, and identifying their evolution towards tumor may be difficult, especially in early stages. Squamous cell carcinoma (SCC) accounts for about 90% of vulvar carcinoma. SCC usually presents as localized disease (59%); however, 30% presents with spread to the regional lymph node, 6% with distant metastases, and 5% unstaged [2]. Our PubMed-based search revealed that only 3 cases of vulvar carcinoma metastasis to breast and 16 cases of metastases to skin have been documented prior to our case report. Here, we present a case of squamous cell carcinoma of vulva with potential delay in diagnosis, which after 4 months of diagnosis presented with concurrent metastases to breast and skin.
2. Case Description
A 76-year-old female with a past medical history of coronary artery disease status postcoronary artery bypass graft, hypertension, and aortic stenosis status postmetallic aortic valve replacement presented to the emergency department, with intense vaginal pain and bleeding for three weeks. She had history of 30 pack-years smoking in the past. She had presented to gynaecology clinic about 9 months back with mild vaginal itching and spotting. She was initially given clotrimazole/betamethasone cream which she did not tolerate because of burning sensation and then was given topical oestrogen ointment with partial resolution of her symptoms. A transvaginal ultrasound showed an endometrial strip of 5 mm, but no mass was visualized. She was planned for hysteroscopy and dilatation and curettage if symptoms persist; however, there was no follow-up with the gynaecology clinic for 7 months prior to this emergency department visit. Currently, her pelvic examination revealed midline clitoral mass with erythematous foul-smelling discharge; however, examination was limited due to severe tenderness. Rest of the physical examination was unremarkable. Examination under anaesthesia showed 4.5 cm clitoral mass encompassing right and left labia minora, which was indurated and erythematous. Biopsy of the mass was compatible with invasive squamous cell carcinoma (Figure 1). The neoplastic cells were positive for CK5/6, p63, AE1/AE3, cam5.2, CK7, and CK34betaE12 while negative for p16, CK20, PR, GCDFP15, HMB-45, Mart 1, PASD, and mucicarmine. CEA-P and S100 showed focal staining. PET CT revealed a focus of increased radiotracer uptake within the region of vaginal orifice and no other focal area of intake. Based on these findings, diagnosis of invasive squamous cell carcinoma was made. Given the comorbidities and extent of disease, she was treated with primary radiotherapy to vulva and pelvis which was completed over next 3 months.
During her regular follow-up 4 months after the diagnosis, she reported improvement of vaginal pain but was found to have a rapidly growing 7 × 5 cm mass palpable in the left upper back. The skin overlying the mass was normal and intact. PET CT showed near complete resolution of uptake in the region of vulva, focal uptake in the region of left inguinal lymph node, right breast, and in the soft tissue lesion of left upper back. Core biopsy of the left upper back lesion was done (Figure 2), and the immunostaining profile was similar to prior vulvar mass biopsy specimen suggesting metastasis from vulva. Ultrasound-guided core needle biopsy of right breast mass (Figure 3) demonstrated invasive squamous cell carcinoma with focal necrosis. The immunophenotype was consistent with metastasis from vulvar primary and back mass metastasis.
She was started on carboplatin and paclitaxel chemotherapy. She received the first cycle of chemotherapy. Her second cycle of chemotherapy was delayed because she was admitted to hospital for pneumonia. After discharge from hospital, she opted for hospice and succumbed to her illness in 9 months from the initial diagnosis of vulvar cancer.
3. Discussion
The most common symptom of vulvar cancer is prolonged history of pruritus, followed by vulvar bleeding, dysuria, discharge, and vaginal pain [3]. Clinicians should opt for vulvar skin biopsy when there are persistent symptoms as valvular itching or there is valvular lesion of uncertain significance. A retrospective study done in 1652 women from 218 gynaecological practice in Germany showed a potential mean delay of diagnosis of 186–328 days [4]. In our case, there was a lag period of around 7 months, when she was last seen in outpatient clinic to her hospitalization when eventually the diagnosis was made. This could have resulted in potential delay in the diagnosis.
Metastasis of vulvar cancer occurs via local spread, lymphatic system, and haematogenous pathway. Lymphatics from vulva mainly drain into the superficial inguinal nodes and then into the deep inguinal lymph nodes and follows the iliac vasculature to the external iliac nodes and ultimately the para-aortic nodes. Lymphatics from clitoris can sometimes proceed directly to the deep inguinal lymph nodes or less commonly to the external iliac nodes [5].
In a retrospective study done in a gynaecological centre in Germany, between 1996 and 2013, 391 patients with primary squamous cell carcinoma were treated, out of which 20 patients (5.1%) had distant metastases, and reported sites were lung, liver, bone, skin, and lymph nodes [6]. Our PubMed-based search revealed only 3 cases of breast metastases reported, out of which 2 were unilateral and 1 was bilateral [7–9]. There were 16 cutaneous metastases reported in thigh, abdomen, left lower back, forearm, buttock, and groin [10]. Our patient presented with concurrent breast and cutaneous metastases 4 months after the diagnosis of vulvar carcinoma. The 5-year relative survival rate for localized vulvar cancer (without spread to lymph node or nearby tissues) is 86%, regional disease (spread to nearby lymph nodes or tissue but not to distant organs) is 53%, and distant spread (spread to lungs, liver, bone, and breast) is 19% [11]. Distant metastases have a very poor prognosis, and treatment is mainly palliative which may include chemotherapy, radiation, or surgery for comfort.
4. Conclusion
Vulvar cancer may initially present as benign appearing symptoms and clinicians dealing with this especially in elderly should monitor closely for an early diagnosis. Vulvar cancer patients during their follow-up should be carefully assessed for distant metastases.
Disclosure
The abstract of this case report was submitted to Northwell Health, the Zucker School of Medicine Academic Day and Research Symposium 2020.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Vulvar mass showing invasive squamous cell carcinoma (H and E, ×100).
Figure 2 Left upper back mass—metastatic squamous cell carcinoma (H and E, ×100).
Figure 3 Right breast mass—metastatic squamous cell carcinoma (H and E, ×100). | 1ST CYCLE | DrugDosageText | CC BY | 33531907 | 19,188,910 | 2021 |
What was the dosage of drug 'PACLITAXEL'? | Vulvar Cancer with Cutaneous and Breast Metastases.
Vulvar cancer accounts for about 5% of cancer of female genitalia. It may initially present as benign symptoms resulting in potential delay in diagnosis. Few cases of distant metastases to skin or breast have been reported. We present the case of a 76-year-old female with possible delay in diagnosis of her squamous cell carcinoma of vulva. After 4 months of the diagnosis, she presented with concurrent cutaneous and breast metastases.
1. Introduction
There were estimated 6120 new cases of vulvar cancer in the US in the year 2020, accounting for about 5% of cancer of female genitalia and 0.6% of all cancers in women [1]. The median age at diagnosis of vulvar cancer is 68 years [2]. Vulvar cancer may initially present with nonspecific symptoms like pruritus, pain, burning sensation, bleeding, and lumps. This may be diagnosed as inflammation of Bartholin's gland or inflammation, atrophy, or hypertrophy of vulva which may delay the diagnosis of vulvar cancer. Vulvar cancer may also arise from preexisting, known disease, like lichen sclerosus, and identifying their evolution towards tumor may be difficult, especially in early stages. Squamous cell carcinoma (SCC) accounts for about 90% of vulvar carcinoma. SCC usually presents as localized disease (59%); however, 30% presents with spread to the regional lymph node, 6% with distant metastases, and 5% unstaged [2]. Our PubMed-based search revealed that only 3 cases of vulvar carcinoma metastasis to breast and 16 cases of metastases to skin have been documented prior to our case report. Here, we present a case of squamous cell carcinoma of vulva with potential delay in diagnosis, which after 4 months of diagnosis presented with concurrent metastases to breast and skin.
2. Case Description
A 76-year-old female with a past medical history of coronary artery disease status postcoronary artery bypass graft, hypertension, and aortic stenosis status postmetallic aortic valve replacement presented to the emergency department, with intense vaginal pain and bleeding for three weeks. She had history of 30 pack-years smoking in the past. She had presented to gynaecology clinic about 9 months back with mild vaginal itching and spotting. She was initially given clotrimazole/betamethasone cream which she did not tolerate because of burning sensation and then was given topical oestrogen ointment with partial resolution of her symptoms. A transvaginal ultrasound showed an endometrial strip of 5 mm, but no mass was visualized. She was planned for hysteroscopy and dilatation and curettage if symptoms persist; however, there was no follow-up with the gynaecology clinic for 7 months prior to this emergency department visit. Currently, her pelvic examination revealed midline clitoral mass with erythematous foul-smelling discharge; however, examination was limited due to severe tenderness. Rest of the physical examination was unremarkable. Examination under anaesthesia showed 4.5 cm clitoral mass encompassing right and left labia minora, which was indurated and erythematous. Biopsy of the mass was compatible with invasive squamous cell carcinoma (Figure 1). The neoplastic cells were positive for CK5/6, p63, AE1/AE3, cam5.2, CK7, and CK34betaE12 while negative for p16, CK20, PR, GCDFP15, HMB-45, Mart 1, PASD, and mucicarmine. CEA-P and S100 showed focal staining. PET CT revealed a focus of increased radiotracer uptake within the region of vaginal orifice and no other focal area of intake. Based on these findings, diagnosis of invasive squamous cell carcinoma was made. Given the comorbidities and extent of disease, she was treated with primary radiotherapy to vulva and pelvis which was completed over next 3 months.
During her regular follow-up 4 months after the diagnosis, she reported improvement of vaginal pain but was found to have a rapidly growing 7 × 5 cm mass palpable in the left upper back. The skin overlying the mass was normal and intact. PET CT showed near complete resolution of uptake in the region of vulva, focal uptake in the region of left inguinal lymph node, right breast, and in the soft tissue lesion of left upper back. Core biopsy of the left upper back lesion was done (Figure 2), and the immunostaining profile was similar to prior vulvar mass biopsy specimen suggesting metastasis from vulva. Ultrasound-guided core needle biopsy of right breast mass (Figure 3) demonstrated invasive squamous cell carcinoma with focal necrosis. The immunophenotype was consistent with metastasis from vulvar primary and back mass metastasis.
She was started on carboplatin and paclitaxel chemotherapy. She received the first cycle of chemotherapy. Her second cycle of chemotherapy was delayed because she was admitted to hospital for pneumonia. After discharge from hospital, she opted for hospice and succumbed to her illness in 9 months from the initial diagnosis of vulvar cancer.
3. Discussion
The most common symptom of vulvar cancer is prolonged history of pruritus, followed by vulvar bleeding, dysuria, discharge, and vaginal pain [3]. Clinicians should opt for vulvar skin biopsy when there are persistent symptoms as valvular itching or there is valvular lesion of uncertain significance. A retrospective study done in 1652 women from 218 gynaecological practice in Germany showed a potential mean delay of diagnosis of 186–328 days [4]. In our case, there was a lag period of around 7 months, when she was last seen in outpatient clinic to her hospitalization when eventually the diagnosis was made. This could have resulted in potential delay in the diagnosis.
Metastasis of vulvar cancer occurs via local spread, lymphatic system, and haematogenous pathway. Lymphatics from vulva mainly drain into the superficial inguinal nodes and then into the deep inguinal lymph nodes and follows the iliac vasculature to the external iliac nodes and ultimately the para-aortic nodes. Lymphatics from clitoris can sometimes proceed directly to the deep inguinal lymph nodes or less commonly to the external iliac nodes [5].
In a retrospective study done in a gynaecological centre in Germany, between 1996 and 2013, 391 patients with primary squamous cell carcinoma were treated, out of which 20 patients (5.1%) had distant metastases, and reported sites were lung, liver, bone, skin, and lymph nodes [6]. Our PubMed-based search revealed only 3 cases of breast metastases reported, out of which 2 were unilateral and 1 was bilateral [7–9]. There were 16 cutaneous metastases reported in thigh, abdomen, left lower back, forearm, buttock, and groin [10]. Our patient presented with concurrent breast and cutaneous metastases 4 months after the diagnosis of vulvar carcinoma. The 5-year relative survival rate for localized vulvar cancer (without spread to lymph node or nearby tissues) is 86%, regional disease (spread to nearby lymph nodes or tissue but not to distant organs) is 53%, and distant spread (spread to lungs, liver, bone, and breast) is 19% [11]. Distant metastases have a very poor prognosis, and treatment is mainly palliative which may include chemotherapy, radiation, or surgery for comfort.
4. Conclusion
Vulvar cancer may initially present as benign appearing symptoms and clinicians dealing with this especially in elderly should monitor closely for an early diagnosis. Vulvar cancer patients during their follow-up should be carefully assessed for distant metastases.
Disclosure
The abstract of this case report was submitted to Northwell Health, the Zucker School of Medicine Academic Day and Research Symposium 2020.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Vulvar mass showing invasive squamous cell carcinoma (H and E, ×100).
Figure 2 Left upper back mass—metastatic squamous cell carcinoma (H and E, ×100).
Figure 3 Right breast mass—metastatic squamous cell carcinoma (H and E, ×100). | 1ST CYCLE | DrugDosageText | CC BY | 33531907 | 19,188,910 | 2021 |
What was the outcome of reaction 'Burning sensation'? | Vulvar Cancer with Cutaneous and Breast Metastases.
Vulvar cancer accounts for about 5% of cancer of female genitalia. It may initially present as benign symptoms resulting in potential delay in diagnosis. Few cases of distant metastases to skin or breast have been reported. We present the case of a 76-year-old female with possible delay in diagnosis of her squamous cell carcinoma of vulva. After 4 months of the diagnosis, she presented with concurrent cutaneous and breast metastases.
1. Introduction
There were estimated 6120 new cases of vulvar cancer in the US in the year 2020, accounting for about 5% of cancer of female genitalia and 0.6% of all cancers in women [1]. The median age at diagnosis of vulvar cancer is 68 years [2]. Vulvar cancer may initially present with nonspecific symptoms like pruritus, pain, burning sensation, bleeding, and lumps. This may be diagnosed as inflammation of Bartholin's gland or inflammation, atrophy, or hypertrophy of vulva which may delay the diagnosis of vulvar cancer. Vulvar cancer may also arise from preexisting, known disease, like lichen sclerosus, and identifying their evolution towards tumor may be difficult, especially in early stages. Squamous cell carcinoma (SCC) accounts for about 90% of vulvar carcinoma. SCC usually presents as localized disease (59%); however, 30% presents with spread to the regional lymph node, 6% with distant metastases, and 5% unstaged [2]. Our PubMed-based search revealed that only 3 cases of vulvar carcinoma metastasis to breast and 16 cases of metastases to skin have been documented prior to our case report. Here, we present a case of squamous cell carcinoma of vulva with potential delay in diagnosis, which after 4 months of diagnosis presented with concurrent metastases to breast and skin.
2. Case Description
A 76-year-old female with a past medical history of coronary artery disease status postcoronary artery bypass graft, hypertension, and aortic stenosis status postmetallic aortic valve replacement presented to the emergency department, with intense vaginal pain and bleeding for three weeks. She had history of 30 pack-years smoking in the past. She had presented to gynaecology clinic about 9 months back with mild vaginal itching and spotting. She was initially given clotrimazole/betamethasone cream which she did not tolerate because of burning sensation and then was given topical oestrogen ointment with partial resolution of her symptoms. A transvaginal ultrasound showed an endometrial strip of 5 mm, but no mass was visualized. She was planned for hysteroscopy and dilatation and curettage if symptoms persist; however, there was no follow-up with the gynaecology clinic for 7 months prior to this emergency department visit. Currently, her pelvic examination revealed midline clitoral mass with erythematous foul-smelling discharge; however, examination was limited due to severe tenderness. Rest of the physical examination was unremarkable. Examination under anaesthesia showed 4.5 cm clitoral mass encompassing right and left labia minora, which was indurated and erythematous. Biopsy of the mass was compatible with invasive squamous cell carcinoma (Figure 1). The neoplastic cells were positive for CK5/6, p63, AE1/AE3, cam5.2, CK7, and CK34betaE12 while negative for p16, CK20, PR, GCDFP15, HMB-45, Mart 1, PASD, and mucicarmine. CEA-P and S100 showed focal staining. PET CT revealed a focus of increased radiotracer uptake within the region of vaginal orifice and no other focal area of intake. Based on these findings, diagnosis of invasive squamous cell carcinoma was made. Given the comorbidities and extent of disease, she was treated with primary radiotherapy to vulva and pelvis which was completed over next 3 months.
During her regular follow-up 4 months after the diagnosis, she reported improvement of vaginal pain but was found to have a rapidly growing 7 × 5 cm mass palpable in the left upper back. The skin overlying the mass was normal and intact. PET CT showed near complete resolution of uptake in the region of vulva, focal uptake in the region of left inguinal lymph node, right breast, and in the soft tissue lesion of left upper back. Core biopsy of the left upper back lesion was done (Figure 2), and the immunostaining profile was similar to prior vulvar mass biopsy specimen suggesting metastasis from vulva. Ultrasound-guided core needle biopsy of right breast mass (Figure 3) demonstrated invasive squamous cell carcinoma with focal necrosis. The immunophenotype was consistent with metastasis from vulvar primary and back mass metastasis.
She was started on carboplatin and paclitaxel chemotherapy. She received the first cycle of chemotherapy. Her second cycle of chemotherapy was delayed because she was admitted to hospital for pneumonia. After discharge from hospital, she opted for hospice and succumbed to her illness in 9 months from the initial diagnosis of vulvar cancer.
3. Discussion
The most common symptom of vulvar cancer is prolonged history of pruritus, followed by vulvar bleeding, dysuria, discharge, and vaginal pain [3]. Clinicians should opt for vulvar skin biopsy when there are persistent symptoms as valvular itching or there is valvular lesion of uncertain significance. A retrospective study done in 1652 women from 218 gynaecological practice in Germany showed a potential mean delay of diagnosis of 186–328 days [4]. In our case, there was a lag period of around 7 months, when she was last seen in outpatient clinic to her hospitalization when eventually the diagnosis was made. This could have resulted in potential delay in the diagnosis.
Metastasis of vulvar cancer occurs via local spread, lymphatic system, and haematogenous pathway. Lymphatics from vulva mainly drain into the superficial inguinal nodes and then into the deep inguinal lymph nodes and follows the iliac vasculature to the external iliac nodes and ultimately the para-aortic nodes. Lymphatics from clitoris can sometimes proceed directly to the deep inguinal lymph nodes or less commonly to the external iliac nodes [5].
In a retrospective study done in a gynaecological centre in Germany, between 1996 and 2013, 391 patients with primary squamous cell carcinoma were treated, out of which 20 patients (5.1%) had distant metastases, and reported sites were lung, liver, bone, skin, and lymph nodes [6]. Our PubMed-based search revealed only 3 cases of breast metastases reported, out of which 2 were unilateral and 1 was bilateral [7–9]. There were 16 cutaneous metastases reported in thigh, abdomen, left lower back, forearm, buttock, and groin [10]. Our patient presented with concurrent breast and cutaneous metastases 4 months after the diagnosis of vulvar carcinoma. The 5-year relative survival rate for localized vulvar cancer (without spread to lymph node or nearby tissues) is 86%, regional disease (spread to nearby lymph nodes or tissue but not to distant organs) is 53%, and distant spread (spread to lungs, liver, bone, and breast) is 19% [11]. Distant metastases have a very poor prognosis, and treatment is mainly palliative which may include chemotherapy, radiation, or surgery for comfort.
4. Conclusion
Vulvar cancer may initially present as benign appearing symptoms and clinicians dealing with this especially in elderly should monitor closely for an early diagnosis. Vulvar cancer patients during their follow-up should be carefully assessed for distant metastases.
Disclosure
The abstract of this case report was submitted to Northwell Health, the Zucker School of Medicine Academic Day and Research Symposium 2020.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Vulvar mass showing invasive squamous cell carcinoma (H and E, ×100).
Figure 2 Left upper back mass—metastatic squamous cell carcinoma (H and E, ×100).
Figure 3 Right breast mass—metastatic squamous cell carcinoma (H and E, ×100). | Recovering | ReactionOutcome | CC BY | 33531907 | 19,129,563 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | The six million dollar man.
In this case report, relapse of urticaria after a switch from oma- to mepolizumab successfully led to combination of biologics https://bit.ly/2GykNtI.
To the Editor:
We report here the observation of a 60-year-old male jeweller who was suffering from severe asthma. Asthma onset was reported by age 30. The patient also reported comorbid severe chronic rhinosinusitis with nasal polyposis since adolescence. Aspirin and nonsteroidal anti-inflammatory drug intolerance was considered to worsen the patient's asthma symptoms, since he had experienced one episode of emergency room attendance shortly after aspirin ingestion. Episodes of generalised chronic urticaria led to genuine anaphylactic reactions that were treated with epinephrine twice in the past, but fortunately without the need for orotracheal intubation. No trigger for these episodes could be identified despite appropriate provocation tests.
Recombinant anti-immunoglobulin E antibody (omalizumab) was initiated in 2006 and continued until 2015 because the patient's asthma was uncontrolled despite being managed according to Global Initiative for Asthma (GINA) guidelines: he presented with at least five exacerbations the year before receiving high doses of systemic corticosteroids, and he was eligible for the drug as he had known perennial sensitisations (house dust mite, cypress pollens, etc.) and an elevated serum total IgE level (739 kU·L−1). Oral corticosteroid (OCS) maintenance was established at 20 mg·day−1.
During the first years of treatment with omalizumab the number of exacerbations was reduced and the control of asthma was improved.
Progressive tapering of a maintenance dose of OCS could be achieved down to 10 mg·day−1, but complete weaning was unsuccessful due to asthma relapse.
After the good initial response to omalizumab, exacerbation outbreak and deterioration in the control of the asthma forced us to consider alternative therapies (figure 1). The eosinophil blood count at that time was 1640 per mm3, without grounds for a diagnosis of either ANCA-associated vasculitis or bronchopulmonary aspergillosis based on dedicated examinations including a chest computed tomography scan and autoimmunity assessment. The inhaled treatment observance was good and included maintenance and reliever therapy with a fixed combination of inhaled corticosteroids (ICS) (1500 μg beclometasone dipropionate equivalent) – long-acting β agonist (LABA) and a long-acting muscarinic antagonist (LAMA). Forced expiratory volume in 1 s (FEV1) was 67% of predicted value (June 2015).
FIGURE 1 At a glance: clinical and therapeutic vignette.
The patient was given the opportunity to benefit from more immunotherapy in a clinical trial with anti-IL5R monoclonal antibody (i.e. the ZONDA trial at that time), which suggested the suspension of omalizumab then a washout time of at least 4 months.
At 2 months and also 3 months after omalizumab withdrawal, the patient presented at the emergency department with anaphylactic shock that required use of parenteral steroids at 2 mg·kg−1 for 3 consecutive days. No convincing triggering factor could be identified. On the other hand, the patient's asthma remained relatively unaffected by the withdrawal of omalizumab in terms of control of symptoms, exacerbation rates and lung function.
Considering the risk to vital functions related to these anaphylactic shocks, we introduced another biological, an anti-IL-5 monoclonal antibody (mepolizumab) as part of the registered temporary authorisation utilisation before ZONDA inclusion criteria could be completed, in December 2015. After five injections of this monoclonal antibody, and the daily dose of OCS progressively tapered as the level of asthma control was continuously improving (of note, FEV1 was then at 73% of predicted value), he continued to suffer from episodes of giant urticaria despite a regularly observed treatment with fexofenadine hydrochloride with another emergency admission for angioedema requiring a novel burst of OCS.
After a multidisciplinary concertation meeting, we decided to introduce omalizumab as a concomitant biological treatment at a dose regimen of 300 mg every 4 weeks as indicated for chronic idiopathic urticaria because of the absence of anaphylactic shock during previous treatment with omalizumab.
Since that time, he has received a monthly injection of both mepolizumab and omalizumab on the same day in different shoulders.
Nowadays, this patient is totally weaned from oral glucocorticoids, with controlled asthma and stable lung function with FEV1 at 2.71 L (86% of predicted value) for a forced vital capacity of 4.11 L (103% of predicted value). He no longer complains of skin itching or other anaphylactic manifestations. He has not been hospitalised or admitted to an emergency department. He no longer uses his reliever therapy, has stopped his LAMA therapy and has reduced his daily dose of ICS to 1000 µg·day−1. He has had only one mild exacerbation (probable viral trigger) during the past 3 years of follow-up, which was treated with OCS for 5 days at 0.5 mg·kg−1. The troublesome symptoms of rhinosinusitis are still present.
The use of monoclonal antibodies in asthma is based on the understanding of T2 pathophysiological mechanisms. Currently, the choice between those directed against IL-5 or IgE is relatively insoluble in patients who are eligible for both, which was and still is the case for this patient [1]. Combining biologicals for treating patients with partially responding severe asthma is an attractive option, but to date it has not been used to its full potential because of concerns related to costs, as indicated by the provocative title of this article. Interestingly, this patient presents a relatively clear-cut symptomatology with no overlapping mechanisms despite being placed under the T2 umbrella; he seems to have IgE-dependent urticaria and anaphylactic manifestations considering the good response to omalizumab, especially since these manifestations relapsed during this drug's withdrawal. On the other hand, he appears to have IL5-driven asthma, as there is a connection between the elevated eosinophilic blood count, cortico-dependency, respiratory symptoms and the rhinosinusitis manifestations, and the beautiful response to mepolizumab.
We acknowledge that these elements are mostly clinical and therefore subject to discussion, in particular in terms of the symptoms’ subjectivity, their relatively low specificity, the very long disease evolution and some reported difficulty in establishing a clear clinical distinction between the two. The risk to vital functions and the unacceptable side-effects of systemic corticosteroids have prompted us to propose this exceptional management, but has raised an issue not tackled until today. This patient's profile therefore is in line with approval of both biologicals, because omalizumab is also approved for use in chronic urticaria when resistant to conventional treatments [2]. In addition, the switch of this dual-therapy to dupilumab, an anti-IL4/IL13 monoclonal antibody, could reasonably be considered as evidence of benefits are clear for both severe asthma and chronic urticaria [3]. The quite high blood eosinophil count recorded before initiating mepolizumab (1640 per mm3) might be the only limit as there are no data in this range, patients with counts higher than 1500 per mm3 having been excluded from the randomised controlled trial [4, 5].
The patient gave oral and written consent for this clinical communication.
Conflict of interest: M. Volpato has nothing to disclose.
Conflict of interest: S. Nowak has nothing to disclose.
Conflict of interest: J.L. Bourrain has nothing to disclose.
Conflict of interest: P. Demoly reports grants from Stallergène Greer, ALK, AstraZeneca, Bausch & Lomb and Thermo Fisher Scientific, and personal fees from Sanofi, outside the submitted work.
Conflict of interest: E. Ahmed has nothing to disclose.
Conflict of interest: A. Bourdin reports grants, personal fees, nonfinancial support and other from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Novartis; personal fees and nonfinancial support from Teva; personal fees, nonfinancial support and other from Regeneron and Chiesi Pharmaceuticals; grants, personal fees, nonfinancial support and other from Actelion; personal fees from Gilead; nonfinancial support and other from Roche; and other from Nuvaira, all outside the submitted work.
Conflict of interest: J. Charriot has nothing to disclose. | FEXOFENADINE HYDROCHLORIDE, MEPOLIZUMAB, OMALIZUMAB | DrugsGivenReaction | CC BY-NC | 33532480 | 19,004,595 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Posterior reversible encephalopathy syndrome'. | Posterior Reversible Encephalopathy Syndrome After Azathioprine Administration in Severe Ulcerative Colitis.
Posterior reversible encephalopathy syndrome is a rare syndrome characterized by brain edema and neurological symptoms, often resulting from several drugs. Treatment is based on discontinuation, and diagnosis is thus essential. Only 13 cases of posterior reversible encephalopathy syndrome have been reported in inflammatory bowel diseases, and we present the first after azathioprine in adults. A 56-year-old patient with active ulcerative colitis was found unconscious 5 days after the institution of azathioprine. Right-sided hemiplegia was found after the patient regained consciousness. Magnetic resonance imaging showed altered signal associated with diffusion restriction in the occipital lobe and cerebral vasogenic edema. Complete regression of neurological signs occurred after azathioprine discontinuation.
INTRODUCTION
Posterior reversible encephalopathy syndrome (PRES) is a rare syndrome, first described by Hinchey et al.1 The clinical and radiologic features are characterized by the following: (i) neurological symptoms, consisting of headache, seizure, altered consciousness, focal neurological deficits, and visual abnormality; (ii) subcortical vasogenic edema in the white matter of the occipital and/or the parietal lobes as shown by magnetic resonance imaging; and (iii) resolution of symptoms and imaging findings in most cases.1 Etiology is poorly understood, possibly resulting from endothelial dysfunction and increased vascular permeability caused by inflammatory cytokines or from acute changes in blood pressure (BP).2 The syndrome often represents the side effect of drugs, in many instances immunomodulators. Treatment is mainly supportive and symptomatic, but control of hypertension is essential, as is elimination of possible factors, drugs included.3 PRES is a rare condition, and inflammatory bowel diseases (IBDs) represent 4.4% of patients in large series from the Mayo Clinic.4 In IBD, PRES has been reported in association with cyclosporin and infliximab, but so far never in the English literature after azathioprine, in adults (Table 1). Only one case was reported by Ogawa in Japanese in a pediatric patient.5
Table 1. Cases of posterior reversible encephalopathy syndrome reported in IBD
Reference Disease Disease classificationa Sex Age Drug
Brandeo et al14 UC — F 28 Adalimumab
Kikuchi et al15 UC E3 F 25 Prednisolone, metronidazole, and blood transfusion
Mishra et al16 CD A1L3B3 F 18 Ustekinumab
Mishra et al16 CD A2L3B3 F 54 Ustekinumab
Chow et al17 CD A2L2B3 F 24 Infliximab
Cherian et al18 CD A2L2B1 F 32 Mesalamine and multiple antibiotics
Gümüs et al19 UC — M 14 Granulocyte colony stimulating factor for neutropenia
Haddock et al20 CD A1L2B1 F 8 Infliximab
Zamvar et al21 CD A1L2B2 M 14 Infliximab
Zamvar et al22 UC — F 15 Infliximab
Drummond et al23 CD — F 33 Infliximab
Sood et al24 UC — F 44 Cyclosporine
Ogawa et al5 UC — F 15 Azathioprine
Fugate et al4 3CD; 2UC — — — Undefined
CD, Crohn's disease; IBD, inflammatory bowel diseases; UC, ulcerative colitis.
a Disease characteristics and extent of lesions according to Montreal classification.25
CASE REPORT
A 56-year-old man from Albania presented with worsening of abdominal symptoms, consisting of bloody diarrhea (6–8 daily bowel movements and with night awakening) and colicky pain in the lower abdomen improving after defecation. His body temperature was 37.5°C. The physical examination showed mild abdominal tenderness, and bowel sounds were normal. No rebound tenderness was present. BP was within the normal range. The body mass index was 21.7 kg/m2 after a weight loss of about 9 kg in the past month. Left-side moderate ulcerative colitis (UC) had been diagnosed 1 year before after a complete ileocolonoscopy scored with Mayo Endoscopic subscore of 2, and successfully treated with mesalamine and oral steroids. He had experienced no disease relapse and currently was under oral mesalamine (2.4 g/d). The patient's history was negative for other diseases or surgery and was not consuming other drugs.
On admission, the blood tests showed: high C-reactive protein, 83.9 mg/L; low albumin, 24 g/L; hyposideremic anemia (red blood cell 3.47 × 1012/L; hemoglobin 10.6 g/L; mean corpuscular volume 82 fL); and WBC within the normal range. No metabolic, liver, and kidney abnormalities were noted. Bacterial infections and parasitological infestation were excluded. Serology was negative for viruses (Epstein-Barr Virus, Varicella-Zoster Virus, B and C Hepatitis, and human immunodeficiency virus) except previous exposure to Cytomegalovirus. Fecal calprotectin was >5,900 μ/g. Relapsing UC was thus diagnosed. A plain abdominal radiograph did not show colonic or small bowel gas distention. A proctosigmoidoscopy without insufflation was performed for 30 cm to evaluate disease activity, and showed deep ulcerations surrounded by hyperemic and edematous mucosa and pseudopolyps (Mayo Endoscopic subscore 3) (Figure 1). The patient was treated with methylprednisolone 60 mg/d iv, oral mesalamine 3.6 g/d, and enoxaparin 4000 UI/bid for antithrombotic prophylaxis. Improvement of symptoms was observed over 5 days (2–4 bowel movements, reduction of fecal blood, and abdominal pain), as well as reduction of C-reactive protein.
Figure 1. Proctosigmoidoscopy showing mucosal ulcerations surrounded by hyperemic and edematous mucosa.
Because of the non-European Union Citizenship and the lack of health insurance, azathioprine was prescribed, being less expensive than biologics. The starting dose was 100 mg/d, with strict laboratory tests and clinical monitoring. The drug was initially well tolerated, except for mild headache.
Five days after the institution of azathioprine, the patient was found unconscious. When he regained consciousness, right-sided hemiplegia, deviation of the gaze with reagent mydriatic pupils, and normal BP were observed. No sphincteric release occurred. A computed tomography and angiocomputed tomography excluded cerebrovascular abnormalities. Magnetic resonance imaging was thus performed, showing bilateral alteration of the signal associated with diffusion restriction in the occipital lobe (Figure 2). Findings suggested vasogenic/cytotoxic edema of the cerebral white matter, and PRES was diagnosed. An electroencephalography excluded seizure activity. Azathioprine was discontinued, and methylprednisolone maintained at full doses. Slow, complete regression of neurological signs was observed over the following 4 weeks, further supporting the role of the immunosuppressor as the cause.
Figure 2. Magnetic resonance imaging alteration of the signal associated with diffusion restriction in the occipital lobe, suggestive of cerebral edema in (A) fluid-attenuated inversion recovery sequence, (B) after contrast injection, (C) diffusion weighted imaging sequence, (D) apparent diffusion coefficient sequence.
DISCUSSION
PRES is a rare and reversible neurological disorder, usually presenting with headache, seizure, altered consciousness, focal neurological deficits, and visual abnormalities (Table 2). In a minority of severe cases, when stroke or acute brain hemorrhage are present, it is potentially lethal.6
Table 2. Symptoms associated to posterior reversible encephalopathy syndrome
Seizures
Nonconvulsive status epilepticus
Headache
Visual field deficits
Impaired visual acuity
Focal neurological deficits
Peripheral facial paralysis
Altered sensorium
Paraplegia
Cerebellar syndrome
Acute arterial hypertension/blood pressure fluctuations
Nausea
Vomiting
Four patterns of imaging have been reported in PRES—(i) parietal-occipital pattern (22% of cases), (ii) holohemispheric pattern (23%), (iii) superior-frontal pattern (27%), and (iv) mixed expression of the aforementioned patterns (28%).7
The frequent development of lesions in the posterior parieto-occipital lobes is consistent with the sympathetic innervation, less effectively regulating the blood flow in the vertebrobasilar system when compared with the carotids.8 Two etiopathogenetic theories have been proposed.2 The first one involves acute hypertension, leading to a failure in the autoregulatory mechanisms controlling cerebral perfusion and to a disruption in the blood-brain barrier, both causing edema. This hypothesis is supported by the association of PRES with elevated BP but has been questioned because acute increases in BP rarely overcome the autoregulatory limits of the blood-brain barrier.
The second theory suggests that endothelial disfunction and capillary leakage may result from direct toxic effect (cytotoxic, autoimmune, or drug related), triggering fluid extravasation.
Non–drug-related causes include hypertension, (pre-)eclampsia, sepsis, autoimmune disorders, chronic renal failure, blood transfusion, electrolyte imbalance, acute liver failure, and human immunodeficiency virus infection.9 The role of endothelial dysfunction/capillary leakage in the presence of circulating proinflammatory cytokines is likely.2
The same mechanisms have also been advocated when PRES is reported in association with several drugs or sepsis1,10 (Table 3). Differing classes of drugs are supposedly implicated in the genesis of PRES. Indeed, chemotherapy agents (such as 5-fluorouracil and cisplatin), monoclonal antibodies, small molecules, antibiotics (metronidazole), nonsteroidal anti-inflammatory drugs, and immunomodulators (cyclosporin and tacrolimus) are most often involved.9 Treatment is aimed at resolving potential underlying causative factors such as BP control or the use of anticonvulsant agents, when seizures are present. Steroids improve vasogenic edema and help recovery.11 The high-dose steroid therapy used for controlling the UC flare in our patient before the occurrence of PRES may have contributed to complete regression of neurological signs.
Table 3. Medications associated to posterior reversible encephalopathy syndrome
Immunosuppressants (cyclosporin A, interferon α, tacrolimus/FK-506, and methotrexate)
Biologics (anti-TNFα, bevacizumab, and rituximab)
Tyrosine kinase inhibitors (sorafenib, sunitinib, pazopanib, regorafenib, lenvatinib, and cediranib)
Cytostatics (doxorubicin, vincristine, cyclophosphamide, cytarabine, cisplatin, and tiazofurin)
Erythropoietin
Granulocytic stimulating factor
Antibiotics (linezolid)
Antimycotics (amphotericin B)
Antiretrovirals
Sympaticomimetics and abuse drugs (phenylpropanolamine, ephedrine, pseudoephedrine, and cocaine)
Intravenous contrast agents
Hypercalcemia
Clonidine (after withdrawal)
TNF, tumor necrosis factor.
A systematic electronic search of the literature up to January 2020 using Medline, Embase, and the Cochrane Library identified only 3 reports involving azathioprine. One of them was affected by systemic lupus erythematous12 and the second by mixed connective tissue disease.13 The third case, involving a pediatric UC patient, was reported in a Japanese study.5
To our knowledge, only 13 cases of PRES have been reported in IBD patients, and the present is the first reporting azathioprine-induced encephalopathy in adults. The absence of hypertension, the occurrence of symptoms shortly after the institution of azathioprine therapy, and the complete recovery after suspension of the drug strongly support the role of the immunosuppressor.
DISCLOSURES
Author contributions: All authors contributed equally to this manuscript. F. Vernia is the article guarantor.
Financial disclosure: None to report.
Informed consent was obtained for this case report. | AZATHIOPRINE | DrugsGivenReaction | CC BY-NC-ND | 33532511 | 18,928,762 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Posterior Reversible Encephalopathy Syndrome After Azathioprine Administration in Severe Ulcerative Colitis.
Posterior reversible encephalopathy syndrome is a rare syndrome characterized by brain edema and neurological symptoms, often resulting from several drugs. Treatment is based on discontinuation, and diagnosis is thus essential. Only 13 cases of posterior reversible encephalopathy syndrome have been reported in inflammatory bowel diseases, and we present the first after azathioprine in adults. A 56-year-old patient with active ulcerative colitis was found unconscious 5 days after the institution of azathioprine. Right-sided hemiplegia was found after the patient regained consciousness. Magnetic resonance imaging showed altered signal associated with diffusion restriction in the occipital lobe and cerebral vasogenic edema. Complete regression of neurological signs occurred after azathioprine discontinuation.
INTRODUCTION
Posterior reversible encephalopathy syndrome (PRES) is a rare syndrome, first described by Hinchey et al.1 The clinical and radiologic features are characterized by the following: (i) neurological symptoms, consisting of headache, seizure, altered consciousness, focal neurological deficits, and visual abnormality; (ii) subcortical vasogenic edema in the white matter of the occipital and/or the parietal lobes as shown by magnetic resonance imaging; and (iii) resolution of symptoms and imaging findings in most cases.1 Etiology is poorly understood, possibly resulting from endothelial dysfunction and increased vascular permeability caused by inflammatory cytokines or from acute changes in blood pressure (BP).2 The syndrome often represents the side effect of drugs, in many instances immunomodulators. Treatment is mainly supportive and symptomatic, but control of hypertension is essential, as is elimination of possible factors, drugs included.3 PRES is a rare condition, and inflammatory bowel diseases (IBDs) represent 4.4% of patients in large series from the Mayo Clinic.4 In IBD, PRES has been reported in association with cyclosporin and infliximab, but so far never in the English literature after azathioprine, in adults (Table 1). Only one case was reported by Ogawa in Japanese in a pediatric patient.5
Table 1. Cases of posterior reversible encephalopathy syndrome reported in IBD
Reference Disease Disease classificationa Sex Age Drug
Brandeo et al14 UC — F 28 Adalimumab
Kikuchi et al15 UC E3 F 25 Prednisolone, metronidazole, and blood transfusion
Mishra et al16 CD A1L3B3 F 18 Ustekinumab
Mishra et al16 CD A2L3B3 F 54 Ustekinumab
Chow et al17 CD A2L2B3 F 24 Infliximab
Cherian et al18 CD A2L2B1 F 32 Mesalamine and multiple antibiotics
Gümüs et al19 UC — M 14 Granulocyte colony stimulating factor for neutropenia
Haddock et al20 CD A1L2B1 F 8 Infliximab
Zamvar et al21 CD A1L2B2 M 14 Infliximab
Zamvar et al22 UC — F 15 Infliximab
Drummond et al23 CD — F 33 Infliximab
Sood et al24 UC — F 44 Cyclosporine
Ogawa et al5 UC — F 15 Azathioprine
Fugate et al4 3CD; 2UC — — — Undefined
CD, Crohn's disease; IBD, inflammatory bowel diseases; UC, ulcerative colitis.
a Disease characteristics and extent of lesions according to Montreal classification.25
CASE REPORT
A 56-year-old man from Albania presented with worsening of abdominal symptoms, consisting of bloody diarrhea (6–8 daily bowel movements and with night awakening) and colicky pain in the lower abdomen improving after defecation. His body temperature was 37.5°C. The physical examination showed mild abdominal tenderness, and bowel sounds were normal. No rebound tenderness was present. BP was within the normal range. The body mass index was 21.7 kg/m2 after a weight loss of about 9 kg in the past month. Left-side moderate ulcerative colitis (UC) had been diagnosed 1 year before after a complete ileocolonoscopy scored with Mayo Endoscopic subscore of 2, and successfully treated with mesalamine and oral steroids. He had experienced no disease relapse and currently was under oral mesalamine (2.4 g/d). The patient's history was negative for other diseases or surgery and was not consuming other drugs.
On admission, the blood tests showed: high C-reactive protein, 83.9 mg/L; low albumin, 24 g/L; hyposideremic anemia (red blood cell 3.47 × 1012/L; hemoglobin 10.6 g/L; mean corpuscular volume 82 fL); and WBC within the normal range. No metabolic, liver, and kidney abnormalities were noted. Bacterial infections and parasitological infestation were excluded. Serology was negative for viruses (Epstein-Barr Virus, Varicella-Zoster Virus, B and C Hepatitis, and human immunodeficiency virus) except previous exposure to Cytomegalovirus. Fecal calprotectin was >5,900 μ/g. Relapsing UC was thus diagnosed. A plain abdominal radiograph did not show colonic or small bowel gas distention. A proctosigmoidoscopy without insufflation was performed for 30 cm to evaluate disease activity, and showed deep ulcerations surrounded by hyperemic and edematous mucosa and pseudopolyps (Mayo Endoscopic subscore 3) (Figure 1). The patient was treated with methylprednisolone 60 mg/d iv, oral mesalamine 3.6 g/d, and enoxaparin 4000 UI/bid for antithrombotic prophylaxis. Improvement of symptoms was observed over 5 days (2–4 bowel movements, reduction of fecal blood, and abdominal pain), as well as reduction of C-reactive protein.
Figure 1. Proctosigmoidoscopy showing mucosal ulcerations surrounded by hyperemic and edematous mucosa.
Because of the non-European Union Citizenship and the lack of health insurance, azathioprine was prescribed, being less expensive than biologics. The starting dose was 100 mg/d, with strict laboratory tests and clinical monitoring. The drug was initially well tolerated, except for mild headache.
Five days after the institution of azathioprine, the patient was found unconscious. When he regained consciousness, right-sided hemiplegia, deviation of the gaze with reagent mydriatic pupils, and normal BP were observed. No sphincteric release occurred. A computed tomography and angiocomputed tomography excluded cerebrovascular abnormalities. Magnetic resonance imaging was thus performed, showing bilateral alteration of the signal associated with diffusion restriction in the occipital lobe (Figure 2). Findings suggested vasogenic/cytotoxic edema of the cerebral white matter, and PRES was diagnosed. An electroencephalography excluded seizure activity. Azathioprine was discontinued, and methylprednisolone maintained at full doses. Slow, complete regression of neurological signs was observed over the following 4 weeks, further supporting the role of the immunosuppressor as the cause.
Figure 2. Magnetic resonance imaging alteration of the signal associated with diffusion restriction in the occipital lobe, suggestive of cerebral edema in (A) fluid-attenuated inversion recovery sequence, (B) after contrast injection, (C) diffusion weighted imaging sequence, (D) apparent diffusion coefficient sequence.
DISCUSSION
PRES is a rare and reversible neurological disorder, usually presenting with headache, seizure, altered consciousness, focal neurological deficits, and visual abnormalities (Table 2). In a minority of severe cases, when stroke or acute brain hemorrhage are present, it is potentially lethal.6
Table 2. Symptoms associated to posterior reversible encephalopathy syndrome
Seizures
Nonconvulsive status epilepticus
Headache
Visual field deficits
Impaired visual acuity
Focal neurological deficits
Peripheral facial paralysis
Altered sensorium
Paraplegia
Cerebellar syndrome
Acute arterial hypertension/blood pressure fluctuations
Nausea
Vomiting
Four patterns of imaging have been reported in PRES—(i) parietal-occipital pattern (22% of cases), (ii) holohemispheric pattern (23%), (iii) superior-frontal pattern (27%), and (iv) mixed expression of the aforementioned patterns (28%).7
The frequent development of lesions in the posterior parieto-occipital lobes is consistent with the sympathetic innervation, less effectively regulating the blood flow in the vertebrobasilar system when compared with the carotids.8 Two etiopathogenetic theories have been proposed.2 The first one involves acute hypertension, leading to a failure in the autoregulatory mechanisms controlling cerebral perfusion and to a disruption in the blood-brain barrier, both causing edema. This hypothesis is supported by the association of PRES with elevated BP but has been questioned because acute increases in BP rarely overcome the autoregulatory limits of the blood-brain barrier.
The second theory suggests that endothelial disfunction and capillary leakage may result from direct toxic effect (cytotoxic, autoimmune, or drug related), triggering fluid extravasation.
Non–drug-related causes include hypertension, (pre-)eclampsia, sepsis, autoimmune disorders, chronic renal failure, blood transfusion, electrolyte imbalance, acute liver failure, and human immunodeficiency virus infection.9 The role of endothelial dysfunction/capillary leakage in the presence of circulating proinflammatory cytokines is likely.2
The same mechanisms have also been advocated when PRES is reported in association with several drugs or sepsis1,10 (Table 3). Differing classes of drugs are supposedly implicated in the genesis of PRES. Indeed, chemotherapy agents (such as 5-fluorouracil and cisplatin), monoclonal antibodies, small molecules, antibiotics (metronidazole), nonsteroidal anti-inflammatory drugs, and immunomodulators (cyclosporin and tacrolimus) are most often involved.9 Treatment is aimed at resolving potential underlying causative factors such as BP control or the use of anticonvulsant agents, when seizures are present. Steroids improve vasogenic edema and help recovery.11 The high-dose steroid therapy used for controlling the UC flare in our patient before the occurrence of PRES may have contributed to complete regression of neurological signs.
Table 3. Medications associated to posterior reversible encephalopathy syndrome
Immunosuppressants (cyclosporin A, interferon α, tacrolimus/FK-506, and methotrexate)
Biologics (anti-TNFα, bevacizumab, and rituximab)
Tyrosine kinase inhibitors (sorafenib, sunitinib, pazopanib, regorafenib, lenvatinib, and cediranib)
Cytostatics (doxorubicin, vincristine, cyclophosphamide, cytarabine, cisplatin, and tiazofurin)
Erythropoietin
Granulocytic stimulating factor
Antibiotics (linezolid)
Antimycotics (amphotericin B)
Antiretrovirals
Sympaticomimetics and abuse drugs (phenylpropanolamine, ephedrine, pseudoephedrine, and cocaine)
Intravenous contrast agents
Hypercalcemia
Clonidine (after withdrawal)
TNF, tumor necrosis factor.
A systematic electronic search of the literature up to January 2020 using Medline, Embase, and the Cochrane Library identified only 3 reports involving azathioprine. One of them was affected by systemic lupus erythematous12 and the second by mixed connective tissue disease.13 The third case, involving a pediatric UC patient, was reported in a Japanese study.5
To our knowledge, only 13 cases of PRES have been reported in IBD patients, and the present is the first reporting azathioprine-induced encephalopathy in adults. The absence of hypertension, the occurrence of symptoms shortly after the institution of azathioprine therapy, and the complete recovery after suspension of the drug strongly support the role of the immunosuppressor.
DISCLOSURES
Author contributions: All authors contributed equally to this manuscript. F. Vernia is the article guarantor.
Financial disclosure: None to report.
Informed consent was obtained for this case report. | AZATHIOPRINE | DrugsGivenReaction | CC BY-NC-ND | 33532511 | 18,928,762 | 2021-01 |
What was the outcome of reaction 'Posterior reversible encephalopathy syndrome'? | Posterior Reversible Encephalopathy Syndrome After Azathioprine Administration in Severe Ulcerative Colitis.
Posterior reversible encephalopathy syndrome is a rare syndrome characterized by brain edema and neurological symptoms, often resulting from several drugs. Treatment is based on discontinuation, and diagnosis is thus essential. Only 13 cases of posterior reversible encephalopathy syndrome have been reported in inflammatory bowel diseases, and we present the first after azathioprine in adults. A 56-year-old patient with active ulcerative colitis was found unconscious 5 days after the institution of azathioprine. Right-sided hemiplegia was found after the patient regained consciousness. Magnetic resonance imaging showed altered signal associated with diffusion restriction in the occipital lobe and cerebral vasogenic edema. Complete regression of neurological signs occurred after azathioprine discontinuation.
INTRODUCTION
Posterior reversible encephalopathy syndrome (PRES) is a rare syndrome, first described by Hinchey et al.1 The clinical and radiologic features are characterized by the following: (i) neurological symptoms, consisting of headache, seizure, altered consciousness, focal neurological deficits, and visual abnormality; (ii) subcortical vasogenic edema in the white matter of the occipital and/or the parietal lobes as shown by magnetic resonance imaging; and (iii) resolution of symptoms and imaging findings in most cases.1 Etiology is poorly understood, possibly resulting from endothelial dysfunction and increased vascular permeability caused by inflammatory cytokines or from acute changes in blood pressure (BP).2 The syndrome often represents the side effect of drugs, in many instances immunomodulators. Treatment is mainly supportive and symptomatic, but control of hypertension is essential, as is elimination of possible factors, drugs included.3 PRES is a rare condition, and inflammatory bowel diseases (IBDs) represent 4.4% of patients in large series from the Mayo Clinic.4 In IBD, PRES has been reported in association with cyclosporin and infliximab, but so far never in the English literature after azathioprine, in adults (Table 1). Only one case was reported by Ogawa in Japanese in a pediatric patient.5
Table 1. Cases of posterior reversible encephalopathy syndrome reported in IBD
Reference Disease Disease classificationa Sex Age Drug
Brandeo et al14 UC — F 28 Adalimumab
Kikuchi et al15 UC E3 F 25 Prednisolone, metronidazole, and blood transfusion
Mishra et al16 CD A1L3B3 F 18 Ustekinumab
Mishra et al16 CD A2L3B3 F 54 Ustekinumab
Chow et al17 CD A2L2B3 F 24 Infliximab
Cherian et al18 CD A2L2B1 F 32 Mesalamine and multiple antibiotics
Gümüs et al19 UC — M 14 Granulocyte colony stimulating factor for neutropenia
Haddock et al20 CD A1L2B1 F 8 Infliximab
Zamvar et al21 CD A1L2B2 M 14 Infliximab
Zamvar et al22 UC — F 15 Infliximab
Drummond et al23 CD — F 33 Infliximab
Sood et al24 UC — F 44 Cyclosporine
Ogawa et al5 UC — F 15 Azathioprine
Fugate et al4 3CD; 2UC — — — Undefined
CD, Crohn's disease; IBD, inflammatory bowel diseases; UC, ulcerative colitis.
a Disease characteristics and extent of lesions according to Montreal classification.25
CASE REPORT
A 56-year-old man from Albania presented with worsening of abdominal symptoms, consisting of bloody diarrhea (6–8 daily bowel movements and with night awakening) and colicky pain in the lower abdomen improving after defecation. His body temperature was 37.5°C. The physical examination showed mild abdominal tenderness, and bowel sounds were normal. No rebound tenderness was present. BP was within the normal range. The body mass index was 21.7 kg/m2 after a weight loss of about 9 kg in the past month. Left-side moderate ulcerative colitis (UC) had been diagnosed 1 year before after a complete ileocolonoscopy scored with Mayo Endoscopic subscore of 2, and successfully treated with mesalamine and oral steroids. He had experienced no disease relapse and currently was under oral mesalamine (2.4 g/d). The patient's history was negative for other diseases or surgery and was not consuming other drugs.
On admission, the blood tests showed: high C-reactive protein, 83.9 mg/L; low albumin, 24 g/L; hyposideremic anemia (red blood cell 3.47 × 1012/L; hemoglobin 10.6 g/L; mean corpuscular volume 82 fL); and WBC within the normal range. No metabolic, liver, and kidney abnormalities were noted. Bacterial infections and parasitological infestation were excluded. Serology was negative for viruses (Epstein-Barr Virus, Varicella-Zoster Virus, B and C Hepatitis, and human immunodeficiency virus) except previous exposure to Cytomegalovirus. Fecal calprotectin was >5,900 μ/g. Relapsing UC was thus diagnosed. A plain abdominal radiograph did not show colonic or small bowel gas distention. A proctosigmoidoscopy without insufflation was performed for 30 cm to evaluate disease activity, and showed deep ulcerations surrounded by hyperemic and edematous mucosa and pseudopolyps (Mayo Endoscopic subscore 3) (Figure 1). The patient was treated with methylprednisolone 60 mg/d iv, oral mesalamine 3.6 g/d, and enoxaparin 4000 UI/bid for antithrombotic prophylaxis. Improvement of symptoms was observed over 5 days (2–4 bowel movements, reduction of fecal blood, and abdominal pain), as well as reduction of C-reactive protein.
Figure 1. Proctosigmoidoscopy showing mucosal ulcerations surrounded by hyperemic and edematous mucosa.
Because of the non-European Union Citizenship and the lack of health insurance, azathioprine was prescribed, being less expensive than biologics. The starting dose was 100 mg/d, with strict laboratory tests and clinical monitoring. The drug was initially well tolerated, except for mild headache.
Five days after the institution of azathioprine, the patient was found unconscious. When he regained consciousness, right-sided hemiplegia, deviation of the gaze with reagent mydriatic pupils, and normal BP were observed. No sphincteric release occurred. A computed tomography and angiocomputed tomography excluded cerebrovascular abnormalities. Magnetic resonance imaging was thus performed, showing bilateral alteration of the signal associated with diffusion restriction in the occipital lobe (Figure 2). Findings suggested vasogenic/cytotoxic edema of the cerebral white matter, and PRES was diagnosed. An electroencephalography excluded seizure activity. Azathioprine was discontinued, and methylprednisolone maintained at full doses. Slow, complete regression of neurological signs was observed over the following 4 weeks, further supporting the role of the immunosuppressor as the cause.
Figure 2. Magnetic resonance imaging alteration of the signal associated with diffusion restriction in the occipital lobe, suggestive of cerebral edema in (A) fluid-attenuated inversion recovery sequence, (B) after contrast injection, (C) diffusion weighted imaging sequence, (D) apparent diffusion coefficient sequence.
DISCUSSION
PRES is a rare and reversible neurological disorder, usually presenting with headache, seizure, altered consciousness, focal neurological deficits, and visual abnormalities (Table 2). In a minority of severe cases, when stroke or acute brain hemorrhage are present, it is potentially lethal.6
Table 2. Symptoms associated to posterior reversible encephalopathy syndrome
Seizures
Nonconvulsive status epilepticus
Headache
Visual field deficits
Impaired visual acuity
Focal neurological deficits
Peripheral facial paralysis
Altered sensorium
Paraplegia
Cerebellar syndrome
Acute arterial hypertension/blood pressure fluctuations
Nausea
Vomiting
Four patterns of imaging have been reported in PRES—(i) parietal-occipital pattern (22% of cases), (ii) holohemispheric pattern (23%), (iii) superior-frontal pattern (27%), and (iv) mixed expression of the aforementioned patterns (28%).7
The frequent development of lesions in the posterior parieto-occipital lobes is consistent with the sympathetic innervation, less effectively regulating the blood flow in the vertebrobasilar system when compared with the carotids.8 Two etiopathogenetic theories have been proposed.2 The first one involves acute hypertension, leading to a failure in the autoregulatory mechanisms controlling cerebral perfusion and to a disruption in the blood-brain barrier, both causing edema. This hypothesis is supported by the association of PRES with elevated BP but has been questioned because acute increases in BP rarely overcome the autoregulatory limits of the blood-brain barrier.
The second theory suggests that endothelial disfunction and capillary leakage may result from direct toxic effect (cytotoxic, autoimmune, or drug related), triggering fluid extravasation.
Non–drug-related causes include hypertension, (pre-)eclampsia, sepsis, autoimmune disorders, chronic renal failure, blood transfusion, electrolyte imbalance, acute liver failure, and human immunodeficiency virus infection.9 The role of endothelial dysfunction/capillary leakage in the presence of circulating proinflammatory cytokines is likely.2
The same mechanisms have also been advocated when PRES is reported in association with several drugs or sepsis1,10 (Table 3). Differing classes of drugs are supposedly implicated in the genesis of PRES. Indeed, chemotherapy agents (such as 5-fluorouracil and cisplatin), monoclonal antibodies, small molecules, antibiotics (metronidazole), nonsteroidal anti-inflammatory drugs, and immunomodulators (cyclosporin and tacrolimus) are most often involved.9 Treatment is aimed at resolving potential underlying causative factors such as BP control or the use of anticonvulsant agents, when seizures are present. Steroids improve vasogenic edema and help recovery.11 The high-dose steroid therapy used for controlling the UC flare in our patient before the occurrence of PRES may have contributed to complete regression of neurological signs.
Table 3. Medications associated to posterior reversible encephalopathy syndrome
Immunosuppressants (cyclosporin A, interferon α, tacrolimus/FK-506, and methotrexate)
Biologics (anti-TNFα, bevacizumab, and rituximab)
Tyrosine kinase inhibitors (sorafenib, sunitinib, pazopanib, regorafenib, lenvatinib, and cediranib)
Cytostatics (doxorubicin, vincristine, cyclophosphamide, cytarabine, cisplatin, and tiazofurin)
Erythropoietin
Granulocytic stimulating factor
Antibiotics (linezolid)
Antimycotics (amphotericin B)
Antiretrovirals
Sympaticomimetics and abuse drugs (phenylpropanolamine, ephedrine, pseudoephedrine, and cocaine)
Intravenous contrast agents
Hypercalcemia
Clonidine (after withdrawal)
TNF, tumor necrosis factor.
A systematic electronic search of the literature up to January 2020 using Medline, Embase, and the Cochrane Library identified only 3 reports involving azathioprine. One of them was affected by systemic lupus erythematous12 and the second by mixed connective tissue disease.13 The third case, involving a pediatric UC patient, was reported in a Japanese study.5
To our knowledge, only 13 cases of PRES have been reported in IBD patients, and the present is the first reporting azathioprine-induced encephalopathy in adults. The absence of hypertension, the occurrence of symptoms shortly after the institution of azathioprine therapy, and the complete recovery after suspension of the drug strongly support the role of the immunosuppressor.
DISCLOSURES
Author contributions: All authors contributed equally to this manuscript. F. Vernia is the article guarantor.
Financial disclosure: None to report.
Informed consent was obtained for this case report. | Recovered | ReactionOutcome | CC BY-NC-ND | 33532511 | 18,928,762 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Accidental overdose'. | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | HYDROMORPHONE HYDROCHLORIDE, MORPHINE SULFATE | DrugsGivenReaction | CC BY-NC-ND | 33532753 | 18,997,913 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Depression'. | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | HYDROMORPHONE | DrugsGivenReaction | CC BY-NC-ND | 33532753 | 19,101,502 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyporesponsive to stimuli'. | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | HYDROMORPHONE | DrugsGivenReaction | CC BY-NC-ND | 33532753 | 19,101,502 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Medication error'. | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | HYDROMORPHONE | DrugsGivenReaction | CC BY-NC-ND | 33532753 | 19,101,502 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mental status changes'. | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | HYDROMORPHONE HYDROCHLORIDE, MORPHINE SULFATE | DrugsGivenReaction | CC BY-NC-ND | 33532753 | 18,997,913 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | HYDROMORPHONE HYDROCHLORIDE, MORPHINE SULFATE | DrugsGivenReaction | CC BY-NC-ND | 33532753 | 18,997,913 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use issue'. | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | HYDROMORPHONE HYDROCHLORIDE, MORPHINE SULFATE | DrugsGivenReaction | CC BY-NC-ND | 33532753 | 18,997,913 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Somnolence'. | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | HYDROMORPHONE | DrugsGivenReaction | CC BY-NC-ND | 33532753 | 19,101,502 | 2021-02 |
What was the administration route of drug 'HYDROMORPHONE HYDROCHLORIDE'? | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | Intra-articular | DrugAdministrationRoute | CC BY-NC-ND | 33532753 | 19,021,087 | 2021-02 |
What was the administration route of drug 'HYDROMORPHONE'? | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | Intra-articular | DrugAdministrationRoute | CC BY-NC-ND | 33532753 | 19,032,766 | 2021-02 |
What was the administration route of drug 'MORPHINE SULFATE'? | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | Intra-articular | DrugAdministrationRoute | CC BY-NC-ND | 33532753 | 18,997,913 | 2021-02 |
What was the administration route of drug 'MORPHINE'? | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | Intra-articular | DrugAdministrationRoute | CC BY-NC-ND | 33532753 | 19,032,766 | 2021-02 |
What was the outcome of reaction 'Accidental overdose'? | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | Recovered | ReactionOutcome | CC BY-NC-ND | 33532753 | 18,997,913 | 2021-02 |
What was the outcome of reaction 'Depression'? | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | Recovered | ReactionOutcome | CC BY-NC-ND | 33532753 | 19,101,502 | 2021-02 |
What was the outcome of reaction 'Hyporesponsive to stimuli'? | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | Recovered | ReactionOutcome | CC BY-NC-ND | 33532753 | 19,101,502 | 2021-02 |
What was the outcome of reaction 'Incorrect route of product administration'? | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | Recovered | ReactionOutcome | CC BY-NC-ND | 33532753 | 19,032,766 | 2021-02 |
What was the outcome of reaction 'Medication error'? | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | Recovered | ReactionOutcome | CC BY-NC-ND | 33532753 | 19,101,502 | 2021-02 |
What was the outcome of reaction 'Mental status changes'? | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | Recovered | ReactionOutcome | CC BY-NC-ND | 33532753 | 18,997,913 | 2021-02 |
What was the outcome of reaction 'Respiratory depression'? | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | Recovered | ReactionOutcome | CC BY-NC-ND | 33532753 | 19,101,502 | 2021-02 |
What was the outcome of reaction 'Somnolence'? | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | Recovered | ReactionOutcome | CC BY-NC-ND | 33532753 | 19,101,502 | 2021-02 |
What was the outcome of reaction 'Toxicity to various agents'? | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | Recovered | ReactionOutcome | CC BY-NC-ND | 33532753 | 19,021,087 | 2021-02 |
What was the outcome of reaction 'Wrong product administered'? | Unintentional administration of intra-articular hydromorphone.
Opioid overdose is a very common cause of presentation to the emergency department (ED) in the United States every year, with an average of over 200 ED visits per 100,000 people in 2018. This case demonstrates a scenario with which few emergency physicians are familiar: an inadvertent postoperative administration of intra-articular hydromorphone leading to delayed presentation for altered mental status. In this case a patient erroneously received 10 mg intra-articular hydromorphone immediately after right knee hemiarthroplasty. She was difficult to rouse for 6 hours postoperatively and required transport to the hospital via emergency medical services and administration of naloxone intravenously. After admission she was observed and no further doses of naloxone were required, though she did have prolonged somnolence even after naloxone administration. Her respiratory rate and other vitals remained stable for the duration of her hospitalization. She was discharged after observation with no further ill effects.
1 BACKGROUND
There are many strategies for obtaining appropriate postoperative analgesia after complete and partial knee arthroplasty. One strategy that has been described is the postoperative administration of intra‐articular morphine
1
,
2
, typically between 5 and 15 mg and often in conjunction with intra‐articular administration of a local anesthetic. Such an approach has been suggested to increase postoperative mobility.
3
This is typically well tolerated, though data on the total reduction in postoperative oral and parenteral opioid administration following this approach are equivocal.
4
One agreed‐upon feature of intra‐articular morphine is the delayed response, with studies suggesting the peak effect is 2–3 hours after administration with a total duration of local analgesia of 24 hours. Although there is theoretically minimal systemic absorption from this route, some authors have hypothesized that systemic absorption does occur after intra‐articular morphine injection and that intra‐articular glucuronidation of morphine can lead to prolonged elevation of plasma morphine concentrations.
5
,
6
To our knowledge, there have been no reports of hydromorphone administration, intentional or otherwise, via this route in the literature. There has been description of an intra‐articular morphine overdose, however, which presented similarly to the case described here. Such a medication error may lead to prolonged medication effects, including respiratory depression and altered mental status.
2 CASE REPORT
The patient is a 64‐year‐old female presenting from an outpatient surgical center for inability to arouse the patient after right knee hemiarthroplasty. The patient received 4 mg of midazolam and 100 mcg fentanyl in the preoperative period, approximately 1 hour before induction of general anesthesia. The patient was supposed to receive 10 mg intra‐articular morphine at the end of the procedure; however, the patient erroneously received 10 mg intra‐articular hydromorphone, which is 40 morphine equivalents. The patient arrived at the hospital approximately 6 hours after her surgery had concluded. At no point after the procedure did the patient regain consciousness fully; rather, she was kept in the outpatient postoperative unit under observation for 6 hours and then was transported via emergency medical services to the hospital for further evaluation of refractory somnolence. At the time of presentation to the hospital she was minimally responsive to painful stimuli. Vitals on arrival were heart rate: 78, blood pressure: 112/64, respiratory rate: 12, and O2: 97% on 2L nasal cannula. Initial examination revealed a comatose patient with 1 mm pupils bilaterally who would moan to painful stimuli and withdraw all four extremities from painful stimuli. Respiratory rate was normal at 12; however, respirations were subjectively shallow. The patient did not normally require supplemental oxygen, and despite her normal respiratory rate her respirations were shallow enough that she required supplementation via nasal cannula at the time. She responded briskly to 0.4 mg IV naloxone as she regained consciousness and became alert and responsive to verbal stimuli, though she quickly became somnolent again over the course of 60 minutes. Her respiratory rate remained stable, never dropping below 12 and never becoming hypoxic on 2L nasal cannula, so she was admitted to the hospital for observation without further naloxone administration or the initiation of continuous naloxone infusion. She did not require any further naloxone during her hospitalization and returned to her baseline mental status over the course of 8 hours after admission. She was subsequently discharged without further complication.
3 DISCUSSION
Opiate and opioid overdoses are common causes of altered/depressed mental status in patients who present to emergency departments in the United States. This case highlights a typical presentation of opioid intoxication, with depressed mental status, miosis, and depressed respiratory rate but with a unique route of administration. It was unclear at the time of the case and it remains unclear at this time how long an individual should be observed after intra‐articular opioid injection. The benefits of intra‐articular morphine in postoperative patients include delayed onset and prolonged duration of action
7
; it is these features that led the clinicians in this case to pursue admission for observation out of concern for recrudescence of opioid intoxication. Ultimately, this patient did not require further naloxone beyond an initial dose of 0.4 mg IV. Still, given her delayed presentation after 6 hours of observation in the postoperative suite as well as prolonged somnolence, it would be reasonable to conclude that such patients should be admitted for observation. Of note, this patient was placed on a typical cardiac monitor but did not undergo end‐tidal CO2 (ETCO2) monitoring while an inpatient. ETCO2 monitoring is considered more sensitive for the monitoring of respiratory depression than pulse oximetry and would likely be a better monitor of the need for readministration of naloxone because it is a better predictor of alveolar ventilation than pulse oximetry.
8
This case also highlights a perioperative medication error. This is a very common occurrence, with prior observational studies suggesting an incidence of medication error or adverse event in up to 1 in 20 administrations of perioperative medication.
9
It is for this reason that physicians should have heightened awareness of the possibility of oversedation or inappropriate medication administration whenever a patient presents, as this one did, with altered mental status in the postoperative setting. Further, this highlights the need for all physicians to be diligent in working to avoid medication errors by using closed‐loop communication, bar‐code assisted syringe and medication labeling systems, and other risk‐mitigation strategies.
Although prevention of adverse events, such as this unintentional administration of an inappropriate opioid, should be avoided, we recommend further research into the systemic absorption of intra‐articular opiates and opioids in the future to ensure that patients who present in this way receive optimal care and are observed for an appropriate length of time. We also recommend that emergency physicians be aware of the practice of intra‐articular morphine administration to be able to recognize it in any patients presenting to the emergency department for postoperative altered/depressed mental status. | Recovered | ReactionOutcome | CC BY-NC-ND | 33532753 | 19,021,087 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malignant neoplasm progression'. | Long-term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation-positive lung adenocarcinoma.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Uncommon mutations, excluding exon 19 deletions and exon 21 L858R, comprise 7%-23% of EGFR mutation-positive NSCLC. The treatment of uncommon EGFR mutation-positive NSCLCs is controversial. Here, we present the case of an 81-year-old man who was diagnosed with lung adenocarcinoma cStage IVA harboring the uncommon EGFR L861Q mutation. The patient received oral afatinib treatment (40 mg/day). One month after the initiation of afatinib treatment, Common Terminology Criteria for Adverse Events version 4.0 grade 2 stomatitis was observed. It improved upon afatinib withdrawal. After 10 days of withdrawal, afatinib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, the patient continued treatment with afatinib. A partial response to afatinib treatment was maintained for 49 months until primary tumor regrowth. Afatinib treatment was continued after disease progression, but the patient died of bacterial pneumonia 59 months after initiation of afatinib treatment. Several studies have previously reported a large number of compound mutations with uncommon mutations, and that compound mutation-induced cells are most susceptible to afatinib. This suggests the efficacy of afatinib in clinical practice and that afatinib may be safely administered to elderly patients with appropriate dose reductions.
INTRODUCTION
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. 1 , 2 , 3 Common mutations account for the majority of EGFR mutation‐positive NSCLC. However, 7%–23% of EGFR mutation‐positive NSCLC, except for exon 19 deletions and exon 21 L858R, are uncommon mutations. 4 Retrospective studies discovered that uncommon EGFR mutation‐positive NSCLC developed early resistance to first‐generation EGFR‐TKIs. Afatinib, a second‐generation EGFR‐TKI, was found to have a clinical benefit for patients with NSCLC harboring uncommon EGFR mutations. 5 Osimertinib, a third‐generation TKI, was also found to be clinically effective for treating uncommon EGFR mutation‐positive NSCLC. 6 Treatment of uncommon EGFR mutation‐positive NSCLC is controversial. Moreover, the proportion of elderly participants in clinical trials is small, therefore the safety of EGFR‐TKIs, such as afatinib, in these patients remains unclear. 7
Here, we report a case of a long‐term response to afatinib in an elderly patient harboring uncommon EGFR mutation‐positive lung adenocarcinoma.
CASE REPORT
An 81‐year‐old man was referred to our hospital following chest xray which revealed an abnormal shadow, and he was subsequently diagnosed with lung adenocarcinoma cT1bN0M1a (M: PLE) Stage IVA (Figure 1).
FIGURE 1 Chest computed tomography (CT) findings before the start of afatinib treatment. The yellow arrows indicate the tumor adjacent to the cyst (a) and pleural dissemination (b)
Examination of the DNA sequence of the EGFR gene revealed an uncommon EGFR L861Q mutation. The patient received treatment with afatinib administered orally (40 mg/day). One month later, Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 2 stomatitis was observed, which improved with afatinib withdrawal. After 10 days of withdrawal, afatanib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, grade 1 skin toxicity was observed. However, the patient continued treatment with afatinib. A partial response to afatinib treatment was noted for 49 months until the primary tumor recurred (Figure 2). Treatment with afatinib was continued after disease progression, and he died of bacterial pneumonia 59 months after the initiation of afatinib treatment. The patient provided oral informed consent for the publication of this report.
FIGURE 2 The clinical course of chest computed tomography (CT) findings. (a) The tumor shrunk three months after afatinib administration. (b) The antitumor effect of afatinib was maintained in partial response at 18 months and (c) 42 months after the start of afatinib treatment. (d) The tumor was enlarged 49 months after the initiation of afatinib. The yellow arrows indicate the primary tumor
DISCUSSION
The elderly patient in our report, who presented with lung adenocarcinoma with an uncommon EGFR mutation, developed a long‐term response to afatinib with appropriate dose reduction.
An integrated analysis of LUX‐Lung 2, 3, and 6 reported the clinical benefits of afatinib, a second‐generation TKI, for treating EGFR mutation‐positive NSCLC with uncommon mutations. 5 The objective response rate (ORR) was 71.1%, and the median duration of response (mDoR) was 11.1 months among patients with lung adenocarcinoma harboring uncommon EGFR mutations, namely G719X, L861Q, and S761I. 5 The ORR for EGFR mutation‐positive NSCLC with L861Q was 56.3%. Afatinib has previously been associated with an ORR of 59.6% in EGFR mutation‐positive NSCLC with L861Q. 4 It has been reported that 6.8% of patients with major uncommon EGFR mutation‐positive NSCLC responded to afatinib for more than three years. In our case, the patient remained responsive for more than four years. 4 On the other hand, osimertinib has also been reported to have an ORR of 50% and mDoR of 9.8 months for treating EGFR mutation‐positive NSCLC patients with major uncommon EGFR mutations. 6 The frequency and pattern of compound mutations in EGFR mutations including L858R/del19, G719C/S/A, and L861Q mutations have been reported in 15.9%, 93.3%, and 36.4% of all cases, respectively. 8 Upon analyzing the association between EGFR mutation and resistance, there was no difference between afatinib and osimertinib in terms of the susceptibility of uncommon mutation‐induced cells to them. However, compound mutation‐induced cells have been reported to be most susceptible to afatinib. 8 A large number of compound mutations have been observed in uncommon mutations, suggesting the efficacy of afatinib. Cells carrying the EGFR L861Q mutation have been reported to be less sensitive to EGFR‐specific inhibitors, but more sensitive to pan ERBB inhibitors. This suggests that afatinib may be effective in treating NSCLC harboring EGFR L861Q mutations. 9
Since the proportion of elderly participants in clinical trials is small, the safety of the administration of EGFR‐TKIs, including afatinib, in the elderly population remains unclear. In the LUX‐Lung 3 and 6 analysis, the rate at which patients required dose reduction was higher in the afatinib group. However, the trend was similar among younger and elderly patients. 10 Treatment‐related adverse events are often associated with afatinib dose reductions, regardless of age. Low discontinuation rates with appropriate dose reduction protocols, and dose reductions which have reduced the incidence of grade > 3 AEs but have not significantly altered the treatment effect have been previously reported. 11 There have also been reports of clinical trials starting afatinib at low doses in patients harboring common EGFR mutations, which have shown promising clinical efficacy and good tolerability. A phase II study using low starting doses of afatinib reported that 22% of patients aged 75 years or older who started with afatinib at 20 mg/day were able to increase the dose up to 30 mg/day, and 17% were able to increase the dose to 40 mg/day, with the majority at 20 mg/day. 12 Although the number of patients was small, a phase I study investigating the optimal dose of afatinib in elderly patients recommended 30 mg/day, 13 and other phase II studies also showed that afatinib 30 mg/day was effective and feasible in elderly patients. 14 For the elderly, 20–30 mg/day is considered to be an appropriate dose. Although most reports of low‐dose afatinib are for common mutations, there has been a study reporting that low‐dose afatinib can be safely used without reducing its efficacy in elderly patients harboring uncommon mutations. 15 In this case, an appropriate reduction in the dose of afatinib resulted in a long‐term response. This suggests that the response to treatment could be maintained in elderly patients without the need to discontinue treatment due to adverse events.
In conclusion, afatinib is effective in treating NSCLC harboring uncommon EGFR mutations, and may be administered safely to elderly patients with an appropriate dose reduction.
CONFLICT OF INTEREST
All authors declare that they have no conflicts of interest.
ACKNOWLEDGMENTS
We would like to thank Editage (www.editage.com) for English language editing. | AFATINIB | DrugsGivenReaction | CC BY | 33533191 | 18,477,251 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metastases to lymph nodes'. | Long-term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation-positive lung adenocarcinoma.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Uncommon mutations, excluding exon 19 deletions and exon 21 L858R, comprise 7%-23% of EGFR mutation-positive NSCLC. The treatment of uncommon EGFR mutation-positive NSCLCs is controversial. Here, we present the case of an 81-year-old man who was diagnosed with lung adenocarcinoma cStage IVA harboring the uncommon EGFR L861Q mutation. The patient received oral afatinib treatment (40 mg/day). One month after the initiation of afatinib treatment, Common Terminology Criteria for Adverse Events version 4.0 grade 2 stomatitis was observed. It improved upon afatinib withdrawal. After 10 days of withdrawal, afatinib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, the patient continued treatment with afatinib. A partial response to afatinib treatment was maintained for 49 months until primary tumor regrowth. Afatinib treatment was continued after disease progression, but the patient died of bacterial pneumonia 59 months after initiation of afatinib treatment. Several studies have previously reported a large number of compound mutations with uncommon mutations, and that compound mutation-induced cells are most susceptible to afatinib. This suggests the efficacy of afatinib in clinical practice and that afatinib may be safely administered to elderly patients with appropriate dose reductions.
INTRODUCTION
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. 1 , 2 , 3 Common mutations account for the majority of EGFR mutation‐positive NSCLC. However, 7%–23% of EGFR mutation‐positive NSCLC, except for exon 19 deletions and exon 21 L858R, are uncommon mutations. 4 Retrospective studies discovered that uncommon EGFR mutation‐positive NSCLC developed early resistance to first‐generation EGFR‐TKIs. Afatinib, a second‐generation EGFR‐TKI, was found to have a clinical benefit for patients with NSCLC harboring uncommon EGFR mutations. 5 Osimertinib, a third‐generation TKI, was also found to be clinically effective for treating uncommon EGFR mutation‐positive NSCLC. 6 Treatment of uncommon EGFR mutation‐positive NSCLC is controversial. Moreover, the proportion of elderly participants in clinical trials is small, therefore the safety of EGFR‐TKIs, such as afatinib, in these patients remains unclear. 7
Here, we report a case of a long‐term response to afatinib in an elderly patient harboring uncommon EGFR mutation‐positive lung adenocarcinoma.
CASE REPORT
An 81‐year‐old man was referred to our hospital following chest xray which revealed an abnormal shadow, and he was subsequently diagnosed with lung adenocarcinoma cT1bN0M1a (M: PLE) Stage IVA (Figure 1).
FIGURE 1 Chest computed tomography (CT) findings before the start of afatinib treatment. The yellow arrows indicate the tumor adjacent to the cyst (a) and pleural dissemination (b)
Examination of the DNA sequence of the EGFR gene revealed an uncommon EGFR L861Q mutation. The patient received treatment with afatinib administered orally (40 mg/day). One month later, Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 2 stomatitis was observed, which improved with afatinib withdrawal. After 10 days of withdrawal, afatanib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, grade 1 skin toxicity was observed. However, the patient continued treatment with afatinib. A partial response to afatinib treatment was noted for 49 months until the primary tumor recurred (Figure 2). Treatment with afatinib was continued after disease progression, and he died of bacterial pneumonia 59 months after the initiation of afatinib treatment. The patient provided oral informed consent for the publication of this report.
FIGURE 2 The clinical course of chest computed tomography (CT) findings. (a) The tumor shrunk three months after afatinib administration. (b) The antitumor effect of afatinib was maintained in partial response at 18 months and (c) 42 months after the start of afatinib treatment. (d) The tumor was enlarged 49 months after the initiation of afatinib. The yellow arrows indicate the primary tumor
DISCUSSION
The elderly patient in our report, who presented with lung adenocarcinoma with an uncommon EGFR mutation, developed a long‐term response to afatinib with appropriate dose reduction.
An integrated analysis of LUX‐Lung 2, 3, and 6 reported the clinical benefits of afatinib, a second‐generation TKI, for treating EGFR mutation‐positive NSCLC with uncommon mutations. 5 The objective response rate (ORR) was 71.1%, and the median duration of response (mDoR) was 11.1 months among patients with lung adenocarcinoma harboring uncommon EGFR mutations, namely G719X, L861Q, and S761I. 5 The ORR for EGFR mutation‐positive NSCLC with L861Q was 56.3%. Afatinib has previously been associated with an ORR of 59.6% in EGFR mutation‐positive NSCLC with L861Q. 4 It has been reported that 6.8% of patients with major uncommon EGFR mutation‐positive NSCLC responded to afatinib for more than three years. In our case, the patient remained responsive for more than four years. 4 On the other hand, osimertinib has also been reported to have an ORR of 50% and mDoR of 9.8 months for treating EGFR mutation‐positive NSCLC patients with major uncommon EGFR mutations. 6 The frequency and pattern of compound mutations in EGFR mutations including L858R/del19, G719C/S/A, and L861Q mutations have been reported in 15.9%, 93.3%, and 36.4% of all cases, respectively. 8 Upon analyzing the association between EGFR mutation and resistance, there was no difference between afatinib and osimertinib in terms of the susceptibility of uncommon mutation‐induced cells to them. However, compound mutation‐induced cells have been reported to be most susceptible to afatinib. 8 A large number of compound mutations have been observed in uncommon mutations, suggesting the efficacy of afatinib. Cells carrying the EGFR L861Q mutation have been reported to be less sensitive to EGFR‐specific inhibitors, but more sensitive to pan ERBB inhibitors. This suggests that afatinib may be effective in treating NSCLC harboring EGFR L861Q mutations. 9
Since the proportion of elderly participants in clinical trials is small, the safety of the administration of EGFR‐TKIs, including afatinib, in the elderly population remains unclear. In the LUX‐Lung 3 and 6 analysis, the rate at which patients required dose reduction was higher in the afatinib group. However, the trend was similar among younger and elderly patients. 10 Treatment‐related adverse events are often associated with afatinib dose reductions, regardless of age. Low discontinuation rates with appropriate dose reduction protocols, and dose reductions which have reduced the incidence of grade > 3 AEs but have not significantly altered the treatment effect have been previously reported. 11 There have also been reports of clinical trials starting afatinib at low doses in patients harboring common EGFR mutations, which have shown promising clinical efficacy and good tolerability. A phase II study using low starting doses of afatinib reported that 22% of patients aged 75 years or older who started with afatinib at 20 mg/day were able to increase the dose up to 30 mg/day, and 17% were able to increase the dose to 40 mg/day, with the majority at 20 mg/day. 12 Although the number of patients was small, a phase I study investigating the optimal dose of afatinib in elderly patients recommended 30 mg/day, 13 and other phase II studies also showed that afatinib 30 mg/day was effective and feasible in elderly patients. 14 For the elderly, 20–30 mg/day is considered to be an appropriate dose. Although most reports of low‐dose afatinib are for common mutations, there has been a study reporting that low‐dose afatinib can be safely used without reducing its efficacy in elderly patients harboring uncommon mutations. 15 In this case, an appropriate reduction in the dose of afatinib resulted in a long‐term response. This suggests that the response to treatment could be maintained in elderly patients without the need to discontinue treatment due to adverse events.
In conclusion, afatinib is effective in treating NSCLC harboring uncommon EGFR mutations, and may be administered safely to elderly patients with an appropriate dose reduction.
CONFLICT OF INTEREST
All authors declare that they have no conflicts of interest.
ACKNOWLEDGMENTS
We would like to thank Editage (www.editage.com) for English language editing. | AFATINIB | DrugsGivenReaction | CC BY | 33533191 | 18,477,251 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia bacterial'. | Long-term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation-positive lung adenocarcinoma.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Uncommon mutations, excluding exon 19 deletions and exon 21 L858R, comprise 7%-23% of EGFR mutation-positive NSCLC. The treatment of uncommon EGFR mutation-positive NSCLCs is controversial. Here, we present the case of an 81-year-old man who was diagnosed with lung adenocarcinoma cStage IVA harboring the uncommon EGFR L861Q mutation. The patient received oral afatinib treatment (40 mg/day). One month after the initiation of afatinib treatment, Common Terminology Criteria for Adverse Events version 4.0 grade 2 stomatitis was observed. It improved upon afatinib withdrawal. After 10 days of withdrawal, afatinib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, the patient continued treatment with afatinib. A partial response to afatinib treatment was maintained for 49 months until primary tumor regrowth. Afatinib treatment was continued after disease progression, but the patient died of bacterial pneumonia 59 months after initiation of afatinib treatment. Several studies have previously reported a large number of compound mutations with uncommon mutations, and that compound mutation-induced cells are most susceptible to afatinib. This suggests the efficacy of afatinib in clinical practice and that afatinib may be safely administered to elderly patients with appropriate dose reductions.
INTRODUCTION
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. 1 , 2 , 3 Common mutations account for the majority of EGFR mutation‐positive NSCLC. However, 7%–23% of EGFR mutation‐positive NSCLC, except for exon 19 deletions and exon 21 L858R, are uncommon mutations. 4 Retrospective studies discovered that uncommon EGFR mutation‐positive NSCLC developed early resistance to first‐generation EGFR‐TKIs. Afatinib, a second‐generation EGFR‐TKI, was found to have a clinical benefit for patients with NSCLC harboring uncommon EGFR mutations. 5 Osimertinib, a third‐generation TKI, was also found to be clinically effective for treating uncommon EGFR mutation‐positive NSCLC. 6 Treatment of uncommon EGFR mutation‐positive NSCLC is controversial. Moreover, the proportion of elderly participants in clinical trials is small, therefore the safety of EGFR‐TKIs, such as afatinib, in these patients remains unclear. 7
Here, we report a case of a long‐term response to afatinib in an elderly patient harboring uncommon EGFR mutation‐positive lung adenocarcinoma.
CASE REPORT
An 81‐year‐old man was referred to our hospital following chest xray which revealed an abnormal shadow, and he was subsequently diagnosed with lung adenocarcinoma cT1bN0M1a (M: PLE) Stage IVA (Figure 1).
FIGURE 1 Chest computed tomography (CT) findings before the start of afatinib treatment. The yellow arrows indicate the tumor adjacent to the cyst (a) and pleural dissemination (b)
Examination of the DNA sequence of the EGFR gene revealed an uncommon EGFR L861Q mutation. The patient received treatment with afatinib administered orally (40 mg/day). One month later, Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 2 stomatitis was observed, which improved with afatinib withdrawal. After 10 days of withdrawal, afatanib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, grade 1 skin toxicity was observed. However, the patient continued treatment with afatinib. A partial response to afatinib treatment was noted for 49 months until the primary tumor recurred (Figure 2). Treatment with afatinib was continued after disease progression, and he died of bacterial pneumonia 59 months after the initiation of afatinib treatment. The patient provided oral informed consent for the publication of this report.
FIGURE 2 The clinical course of chest computed tomography (CT) findings. (a) The tumor shrunk three months after afatinib administration. (b) The antitumor effect of afatinib was maintained in partial response at 18 months and (c) 42 months after the start of afatinib treatment. (d) The tumor was enlarged 49 months after the initiation of afatinib. The yellow arrows indicate the primary tumor
DISCUSSION
The elderly patient in our report, who presented with lung adenocarcinoma with an uncommon EGFR mutation, developed a long‐term response to afatinib with appropriate dose reduction.
An integrated analysis of LUX‐Lung 2, 3, and 6 reported the clinical benefits of afatinib, a second‐generation TKI, for treating EGFR mutation‐positive NSCLC with uncommon mutations. 5 The objective response rate (ORR) was 71.1%, and the median duration of response (mDoR) was 11.1 months among patients with lung adenocarcinoma harboring uncommon EGFR mutations, namely G719X, L861Q, and S761I. 5 The ORR for EGFR mutation‐positive NSCLC with L861Q was 56.3%. Afatinib has previously been associated with an ORR of 59.6% in EGFR mutation‐positive NSCLC with L861Q. 4 It has been reported that 6.8% of patients with major uncommon EGFR mutation‐positive NSCLC responded to afatinib for more than three years. In our case, the patient remained responsive for more than four years. 4 On the other hand, osimertinib has also been reported to have an ORR of 50% and mDoR of 9.8 months for treating EGFR mutation‐positive NSCLC patients with major uncommon EGFR mutations. 6 The frequency and pattern of compound mutations in EGFR mutations including L858R/del19, G719C/S/A, and L861Q mutations have been reported in 15.9%, 93.3%, and 36.4% of all cases, respectively. 8 Upon analyzing the association between EGFR mutation and resistance, there was no difference between afatinib and osimertinib in terms of the susceptibility of uncommon mutation‐induced cells to them. However, compound mutation‐induced cells have been reported to be most susceptible to afatinib. 8 A large number of compound mutations have been observed in uncommon mutations, suggesting the efficacy of afatinib. Cells carrying the EGFR L861Q mutation have been reported to be less sensitive to EGFR‐specific inhibitors, but more sensitive to pan ERBB inhibitors. This suggests that afatinib may be effective in treating NSCLC harboring EGFR L861Q mutations. 9
Since the proportion of elderly participants in clinical trials is small, the safety of the administration of EGFR‐TKIs, including afatinib, in the elderly population remains unclear. In the LUX‐Lung 3 and 6 analysis, the rate at which patients required dose reduction was higher in the afatinib group. However, the trend was similar among younger and elderly patients. 10 Treatment‐related adverse events are often associated with afatinib dose reductions, regardless of age. Low discontinuation rates with appropriate dose reduction protocols, and dose reductions which have reduced the incidence of grade > 3 AEs but have not significantly altered the treatment effect have been previously reported. 11 There have also been reports of clinical trials starting afatinib at low doses in patients harboring common EGFR mutations, which have shown promising clinical efficacy and good tolerability. A phase II study using low starting doses of afatinib reported that 22% of patients aged 75 years or older who started with afatinib at 20 mg/day were able to increase the dose up to 30 mg/day, and 17% were able to increase the dose to 40 mg/day, with the majority at 20 mg/day. 12 Although the number of patients was small, a phase I study investigating the optimal dose of afatinib in elderly patients recommended 30 mg/day, 13 and other phase II studies also showed that afatinib 30 mg/day was effective and feasible in elderly patients. 14 For the elderly, 20–30 mg/day is considered to be an appropriate dose. Although most reports of low‐dose afatinib are for common mutations, there has been a study reporting that low‐dose afatinib can be safely used without reducing its efficacy in elderly patients harboring uncommon mutations. 15 In this case, an appropriate reduction in the dose of afatinib resulted in a long‐term response. This suggests that the response to treatment could be maintained in elderly patients without the need to discontinue treatment due to adverse events.
In conclusion, afatinib is effective in treating NSCLC harboring uncommon EGFR mutations, and may be administered safely to elderly patients with an appropriate dose reduction.
CONFLICT OF INTEREST
All authors declare that they have no conflicts of interest.
ACKNOWLEDGMENTS
We would like to thank Editage (www.editage.com) for English language editing. | AFATINIB | DrugsGivenReaction | CC BY | 33533191 | 18,477,251 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rash'. | Long-term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation-positive lung adenocarcinoma.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Uncommon mutations, excluding exon 19 deletions and exon 21 L858R, comprise 7%-23% of EGFR mutation-positive NSCLC. The treatment of uncommon EGFR mutation-positive NSCLCs is controversial. Here, we present the case of an 81-year-old man who was diagnosed with lung adenocarcinoma cStage IVA harboring the uncommon EGFR L861Q mutation. The patient received oral afatinib treatment (40 mg/day). One month after the initiation of afatinib treatment, Common Terminology Criteria for Adverse Events version 4.0 grade 2 stomatitis was observed. It improved upon afatinib withdrawal. After 10 days of withdrawal, afatinib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, the patient continued treatment with afatinib. A partial response to afatinib treatment was maintained for 49 months until primary tumor regrowth. Afatinib treatment was continued after disease progression, but the patient died of bacterial pneumonia 59 months after initiation of afatinib treatment. Several studies have previously reported a large number of compound mutations with uncommon mutations, and that compound mutation-induced cells are most susceptible to afatinib. This suggests the efficacy of afatinib in clinical practice and that afatinib may be safely administered to elderly patients with appropriate dose reductions.
INTRODUCTION
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. 1 , 2 , 3 Common mutations account for the majority of EGFR mutation‐positive NSCLC. However, 7%–23% of EGFR mutation‐positive NSCLC, except for exon 19 deletions and exon 21 L858R, are uncommon mutations. 4 Retrospective studies discovered that uncommon EGFR mutation‐positive NSCLC developed early resistance to first‐generation EGFR‐TKIs. Afatinib, a second‐generation EGFR‐TKI, was found to have a clinical benefit for patients with NSCLC harboring uncommon EGFR mutations. 5 Osimertinib, a third‐generation TKI, was also found to be clinically effective for treating uncommon EGFR mutation‐positive NSCLC. 6 Treatment of uncommon EGFR mutation‐positive NSCLC is controversial. Moreover, the proportion of elderly participants in clinical trials is small, therefore the safety of EGFR‐TKIs, such as afatinib, in these patients remains unclear. 7
Here, we report a case of a long‐term response to afatinib in an elderly patient harboring uncommon EGFR mutation‐positive lung adenocarcinoma.
CASE REPORT
An 81‐year‐old man was referred to our hospital following chest xray which revealed an abnormal shadow, and he was subsequently diagnosed with lung adenocarcinoma cT1bN0M1a (M: PLE) Stage IVA (Figure 1).
FIGURE 1 Chest computed tomography (CT) findings before the start of afatinib treatment. The yellow arrows indicate the tumor adjacent to the cyst (a) and pleural dissemination (b)
Examination of the DNA sequence of the EGFR gene revealed an uncommon EGFR L861Q mutation. The patient received treatment with afatinib administered orally (40 mg/day). One month later, Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 2 stomatitis was observed, which improved with afatinib withdrawal. After 10 days of withdrawal, afatanib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, grade 1 skin toxicity was observed. However, the patient continued treatment with afatinib. A partial response to afatinib treatment was noted for 49 months until the primary tumor recurred (Figure 2). Treatment with afatinib was continued after disease progression, and he died of bacterial pneumonia 59 months after the initiation of afatinib treatment. The patient provided oral informed consent for the publication of this report.
FIGURE 2 The clinical course of chest computed tomography (CT) findings. (a) The tumor shrunk three months after afatinib administration. (b) The antitumor effect of afatinib was maintained in partial response at 18 months and (c) 42 months after the start of afatinib treatment. (d) The tumor was enlarged 49 months after the initiation of afatinib. The yellow arrows indicate the primary tumor
DISCUSSION
The elderly patient in our report, who presented with lung adenocarcinoma with an uncommon EGFR mutation, developed a long‐term response to afatinib with appropriate dose reduction.
An integrated analysis of LUX‐Lung 2, 3, and 6 reported the clinical benefits of afatinib, a second‐generation TKI, for treating EGFR mutation‐positive NSCLC with uncommon mutations. 5 The objective response rate (ORR) was 71.1%, and the median duration of response (mDoR) was 11.1 months among patients with lung adenocarcinoma harboring uncommon EGFR mutations, namely G719X, L861Q, and S761I. 5 The ORR for EGFR mutation‐positive NSCLC with L861Q was 56.3%. Afatinib has previously been associated with an ORR of 59.6% in EGFR mutation‐positive NSCLC with L861Q. 4 It has been reported that 6.8% of patients with major uncommon EGFR mutation‐positive NSCLC responded to afatinib for more than three years. In our case, the patient remained responsive for more than four years. 4 On the other hand, osimertinib has also been reported to have an ORR of 50% and mDoR of 9.8 months for treating EGFR mutation‐positive NSCLC patients with major uncommon EGFR mutations. 6 The frequency and pattern of compound mutations in EGFR mutations including L858R/del19, G719C/S/A, and L861Q mutations have been reported in 15.9%, 93.3%, and 36.4% of all cases, respectively. 8 Upon analyzing the association between EGFR mutation and resistance, there was no difference between afatinib and osimertinib in terms of the susceptibility of uncommon mutation‐induced cells to them. However, compound mutation‐induced cells have been reported to be most susceptible to afatinib. 8 A large number of compound mutations have been observed in uncommon mutations, suggesting the efficacy of afatinib. Cells carrying the EGFR L861Q mutation have been reported to be less sensitive to EGFR‐specific inhibitors, but more sensitive to pan ERBB inhibitors. This suggests that afatinib may be effective in treating NSCLC harboring EGFR L861Q mutations. 9
Since the proportion of elderly participants in clinical trials is small, the safety of the administration of EGFR‐TKIs, including afatinib, in the elderly population remains unclear. In the LUX‐Lung 3 and 6 analysis, the rate at which patients required dose reduction was higher in the afatinib group. However, the trend was similar among younger and elderly patients. 10 Treatment‐related adverse events are often associated with afatinib dose reductions, regardless of age. Low discontinuation rates with appropriate dose reduction protocols, and dose reductions which have reduced the incidence of grade > 3 AEs but have not significantly altered the treatment effect have been previously reported. 11 There have also been reports of clinical trials starting afatinib at low doses in patients harboring common EGFR mutations, which have shown promising clinical efficacy and good tolerability. A phase II study using low starting doses of afatinib reported that 22% of patients aged 75 years or older who started with afatinib at 20 mg/day were able to increase the dose up to 30 mg/day, and 17% were able to increase the dose to 40 mg/day, with the majority at 20 mg/day. 12 Although the number of patients was small, a phase I study investigating the optimal dose of afatinib in elderly patients recommended 30 mg/day, 13 and other phase II studies also showed that afatinib 30 mg/day was effective and feasible in elderly patients. 14 For the elderly, 20–30 mg/day is considered to be an appropriate dose. Although most reports of low‐dose afatinib are for common mutations, there has been a study reporting that low‐dose afatinib can be safely used without reducing its efficacy in elderly patients harboring uncommon mutations. 15 In this case, an appropriate reduction in the dose of afatinib resulted in a long‐term response. This suggests that the response to treatment could be maintained in elderly patients without the need to discontinue treatment due to adverse events.
In conclusion, afatinib is effective in treating NSCLC harboring uncommon EGFR mutations, and may be administered safely to elderly patients with an appropriate dose reduction.
CONFLICT OF INTEREST
All authors declare that they have no conflicts of interest.
ACKNOWLEDGMENTS
We would like to thank Editage (www.editage.com) for English language editing. | AFATINIB | DrugsGivenReaction | CC BY | 33533191 | 18,477,251 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Skin toxicity'. | Long-term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation-positive lung adenocarcinoma.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Uncommon mutations, excluding exon 19 deletions and exon 21 L858R, comprise 7%-23% of EGFR mutation-positive NSCLC. The treatment of uncommon EGFR mutation-positive NSCLCs is controversial. Here, we present the case of an 81-year-old man who was diagnosed with lung adenocarcinoma cStage IVA harboring the uncommon EGFR L861Q mutation. The patient received oral afatinib treatment (40 mg/day). One month after the initiation of afatinib treatment, Common Terminology Criteria for Adverse Events version 4.0 grade 2 stomatitis was observed. It improved upon afatinib withdrawal. After 10 days of withdrawal, afatinib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, the patient continued treatment with afatinib. A partial response to afatinib treatment was maintained for 49 months until primary tumor regrowth. Afatinib treatment was continued after disease progression, but the patient died of bacterial pneumonia 59 months after initiation of afatinib treatment. Several studies have previously reported a large number of compound mutations with uncommon mutations, and that compound mutation-induced cells are most susceptible to afatinib. This suggests the efficacy of afatinib in clinical practice and that afatinib may be safely administered to elderly patients with appropriate dose reductions.
INTRODUCTION
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. 1 , 2 , 3 Common mutations account for the majority of EGFR mutation‐positive NSCLC. However, 7%–23% of EGFR mutation‐positive NSCLC, except for exon 19 deletions and exon 21 L858R, are uncommon mutations. 4 Retrospective studies discovered that uncommon EGFR mutation‐positive NSCLC developed early resistance to first‐generation EGFR‐TKIs. Afatinib, a second‐generation EGFR‐TKI, was found to have a clinical benefit for patients with NSCLC harboring uncommon EGFR mutations. 5 Osimertinib, a third‐generation TKI, was also found to be clinically effective for treating uncommon EGFR mutation‐positive NSCLC. 6 Treatment of uncommon EGFR mutation‐positive NSCLC is controversial. Moreover, the proportion of elderly participants in clinical trials is small, therefore the safety of EGFR‐TKIs, such as afatinib, in these patients remains unclear. 7
Here, we report a case of a long‐term response to afatinib in an elderly patient harboring uncommon EGFR mutation‐positive lung adenocarcinoma.
CASE REPORT
An 81‐year‐old man was referred to our hospital following chest xray which revealed an abnormal shadow, and he was subsequently diagnosed with lung adenocarcinoma cT1bN0M1a (M: PLE) Stage IVA (Figure 1).
FIGURE 1 Chest computed tomography (CT) findings before the start of afatinib treatment. The yellow arrows indicate the tumor adjacent to the cyst (a) and pleural dissemination (b)
Examination of the DNA sequence of the EGFR gene revealed an uncommon EGFR L861Q mutation. The patient received treatment with afatinib administered orally (40 mg/day). One month later, Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 2 stomatitis was observed, which improved with afatinib withdrawal. After 10 days of withdrawal, afatanib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, grade 1 skin toxicity was observed. However, the patient continued treatment with afatinib. A partial response to afatinib treatment was noted for 49 months until the primary tumor recurred (Figure 2). Treatment with afatinib was continued after disease progression, and he died of bacterial pneumonia 59 months after the initiation of afatinib treatment. The patient provided oral informed consent for the publication of this report.
FIGURE 2 The clinical course of chest computed tomography (CT) findings. (a) The tumor shrunk three months after afatinib administration. (b) The antitumor effect of afatinib was maintained in partial response at 18 months and (c) 42 months after the start of afatinib treatment. (d) The tumor was enlarged 49 months after the initiation of afatinib. The yellow arrows indicate the primary tumor
DISCUSSION
The elderly patient in our report, who presented with lung adenocarcinoma with an uncommon EGFR mutation, developed a long‐term response to afatinib with appropriate dose reduction.
An integrated analysis of LUX‐Lung 2, 3, and 6 reported the clinical benefits of afatinib, a second‐generation TKI, for treating EGFR mutation‐positive NSCLC with uncommon mutations. 5 The objective response rate (ORR) was 71.1%, and the median duration of response (mDoR) was 11.1 months among patients with lung adenocarcinoma harboring uncommon EGFR mutations, namely G719X, L861Q, and S761I. 5 The ORR for EGFR mutation‐positive NSCLC with L861Q was 56.3%. Afatinib has previously been associated with an ORR of 59.6% in EGFR mutation‐positive NSCLC with L861Q. 4 It has been reported that 6.8% of patients with major uncommon EGFR mutation‐positive NSCLC responded to afatinib for more than three years. In our case, the patient remained responsive for more than four years. 4 On the other hand, osimertinib has also been reported to have an ORR of 50% and mDoR of 9.8 months for treating EGFR mutation‐positive NSCLC patients with major uncommon EGFR mutations. 6 The frequency and pattern of compound mutations in EGFR mutations including L858R/del19, G719C/S/A, and L861Q mutations have been reported in 15.9%, 93.3%, and 36.4% of all cases, respectively. 8 Upon analyzing the association between EGFR mutation and resistance, there was no difference between afatinib and osimertinib in terms of the susceptibility of uncommon mutation‐induced cells to them. However, compound mutation‐induced cells have been reported to be most susceptible to afatinib. 8 A large number of compound mutations have been observed in uncommon mutations, suggesting the efficacy of afatinib. Cells carrying the EGFR L861Q mutation have been reported to be less sensitive to EGFR‐specific inhibitors, but more sensitive to pan ERBB inhibitors. This suggests that afatinib may be effective in treating NSCLC harboring EGFR L861Q mutations. 9
Since the proportion of elderly participants in clinical trials is small, the safety of the administration of EGFR‐TKIs, including afatinib, in the elderly population remains unclear. In the LUX‐Lung 3 and 6 analysis, the rate at which patients required dose reduction was higher in the afatinib group. However, the trend was similar among younger and elderly patients. 10 Treatment‐related adverse events are often associated with afatinib dose reductions, regardless of age. Low discontinuation rates with appropriate dose reduction protocols, and dose reductions which have reduced the incidence of grade > 3 AEs but have not significantly altered the treatment effect have been previously reported. 11 There have also been reports of clinical trials starting afatinib at low doses in patients harboring common EGFR mutations, which have shown promising clinical efficacy and good tolerability. A phase II study using low starting doses of afatinib reported that 22% of patients aged 75 years or older who started with afatinib at 20 mg/day were able to increase the dose up to 30 mg/day, and 17% were able to increase the dose to 40 mg/day, with the majority at 20 mg/day. 12 Although the number of patients was small, a phase I study investigating the optimal dose of afatinib in elderly patients recommended 30 mg/day, 13 and other phase II studies also showed that afatinib 30 mg/day was effective and feasible in elderly patients. 14 For the elderly, 20–30 mg/day is considered to be an appropriate dose. Although most reports of low‐dose afatinib are for common mutations, there has been a study reporting that low‐dose afatinib can be safely used without reducing its efficacy in elderly patients harboring uncommon mutations. 15 In this case, an appropriate reduction in the dose of afatinib resulted in a long‐term response. This suggests that the response to treatment could be maintained in elderly patients without the need to discontinue treatment due to adverse events.
In conclusion, afatinib is effective in treating NSCLC harboring uncommon EGFR mutations, and may be administered safely to elderly patients with an appropriate dose reduction.
CONFLICT OF INTEREST
All authors declare that they have no conflicts of interest.
ACKNOWLEDGMENTS
We would like to thank Editage (www.editage.com) for English language editing. | AFATINIB | DrugsGivenReaction | CC BY | 33533191 | 18,477,251 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Stomatitis'. | Long-term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation-positive lung adenocarcinoma.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Uncommon mutations, excluding exon 19 deletions and exon 21 L858R, comprise 7%-23% of EGFR mutation-positive NSCLC. The treatment of uncommon EGFR mutation-positive NSCLCs is controversial. Here, we present the case of an 81-year-old man who was diagnosed with lung adenocarcinoma cStage IVA harboring the uncommon EGFR L861Q mutation. The patient received oral afatinib treatment (40 mg/day). One month after the initiation of afatinib treatment, Common Terminology Criteria for Adverse Events version 4.0 grade 2 stomatitis was observed. It improved upon afatinib withdrawal. After 10 days of withdrawal, afatinib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, the patient continued treatment with afatinib. A partial response to afatinib treatment was maintained for 49 months until primary tumor regrowth. Afatinib treatment was continued after disease progression, but the patient died of bacterial pneumonia 59 months after initiation of afatinib treatment. Several studies have previously reported a large number of compound mutations with uncommon mutations, and that compound mutation-induced cells are most susceptible to afatinib. This suggests the efficacy of afatinib in clinical practice and that afatinib may be safely administered to elderly patients with appropriate dose reductions.
INTRODUCTION
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. 1 , 2 , 3 Common mutations account for the majority of EGFR mutation‐positive NSCLC. However, 7%–23% of EGFR mutation‐positive NSCLC, except for exon 19 deletions and exon 21 L858R, are uncommon mutations. 4 Retrospective studies discovered that uncommon EGFR mutation‐positive NSCLC developed early resistance to first‐generation EGFR‐TKIs. Afatinib, a second‐generation EGFR‐TKI, was found to have a clinical benefit for patients with NSCLC harboring uncommon EGFR mutations. 5 Osimertinib, a third‐generation TKI, was also found to be clinically effective for treating uncommon EGFR mutation‐positive NSCLC. 6 Treatment of uncommon EGFR mutation‐positive NSCLC is controversial. Moreover, the proportion of elderly participants in clinical trials is small, therefore the safety of EGFR‐TKIs, such as afatinib, in these patients remains unclear. 7
Here, we report a case of a long‐term response to afatinib in an elderly patient harboring uncommon EGFR mutation‐positive lung adenocarcinoma.
CASE REPORT
An 81‐year‐old man was referred to our hospital following chest xray which revealed an abnormal shadow, and he was subsequently diagnosed with lung adenocarcinoma cT1bN0M1a (M: PLE) Stage IVA (Figure 1).
FIGURE 1 Chest computed tomography (CT) findings before the start of afatinib treatment. The yellow arrows indicate the tumor adjacent to the cyst (a) and pleural dissemination (b)
Examination of the DNA sequence of the EGFR gene revealed an uncommon EGFR L861Q mutation. The patient received treatment with afatinib administered orally (40 mg/day). One month later, Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 2 stomatitis was observed, which improved with afatinib withdrawal. After 10 days of withdrawal, afatanib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, grade 1 skin toxicity was observed. However, the patient continued treatment with afatinib. A partial response to afatinib treatment was noted for 49 months until the primary tumor recurred (Figure 2). Treatment with afatinib was continued after disease progression, and he died of bacterial pneumonia 59 months after the initiation of afatinib treatment. The patient provided oral informed consent for the publication of this report.
FIGURE 2 The clinical course of chest computed tomography (CT) findings. (a) The tumor shrunk three months after afatinib administration. (b) The antitumor effect of afatinib was maintained in partial response at 18 months and (c) 42 months after the start of afatinib treatment. (d) The tumor was enlarged 49 months after the initiation of afatinib. The yellow arrows indicate the primary tumor
DISCUSSION
The elderly patient in our report, who presented with lung adenocarcinoma with an uncommon EGFR mutation, developed a long‐term response to afatinib with appropriate dose reduction.
An integrated analysis of LUX‐Lung 2, 3, and 6 reported the clinical benefits of afatinib, a second‐generation TKI, for treating EGFR mutation‐positive NSCLC with uncommon mutations. 5 The objective response rate (ORR) was 71.1%, and the median duration of response (mDoR) was 11.1 months among patients with lung adenocarcinoma harboring uncommon EGFR mutations, namely G719X, L861Q, and S761I. 5 The ORR for EGFR mutation‐positive NSCLC with L861Q was 56.3%. Afatinib has previously been associated with an ORR of 59.6% in EGFR mutation‐positive NSCLC with L861Q. 4 It has been reported that 6.8% of patients with major uncommon EGFR mutation‐positive NSCLC responded to afatinib for more than three years. In our case, the patient remained responsive for more than four years. 4 On the other hand, osimertinib has also been reported to have an ORR of 50% and mDoR of 9.8 months for treating EGFR mutation‐positive NSCLC patients with major uncommon EGFR mutations. 6 The frequency and pattern of compound mutations in EGFR mutations including L858R/del19, G719C/S/A, and L861Q mutations have been reported in 15.9%, 93.3%, and 36.4% of all cases, respectively. 8 Upon analyzing the association between EGFR mutation and resistance, there was no difference between afatinib and osimertinib in terms of the susceptibility of uncommon mutation‐induced cells to them. However, compound mutation‐induced cells have been reported to be most susceptible to afatinib. 8 A large number of compound mutations have been observed in uncommon mutations, suggesting the efficacy of afatinib. Cells carrying the EGFR L861Q mutation have been reported to be less sensitive to EGFR‐specific inhibitors, but more sensitive to pan ERBB inhibitors. This suggests that afatinib may be effective in treating NSCLC harboring EGFR L861Q mutations. 9
Since the proportion of elderly participants in clinical trials is small, the safety of the administration of EGFR‐TKIs, including afatinib, in the elderly population remains unclear. In the LUX‐Lung 3 and 6 analysis, the rate at which patients required dose reduction was higher in the afatinib group. However, the trend was similar among younger and elderly patients. 10 Treatment‐related adverse events are often associated with afatinib dose reductions, regardless of age. Low discontinuation rates with appropriate dose reduction protocols, and dose reductions which have reduced the incidence of grade > 3 AEs but have not significantly altered the treatment effect have been previously reported. 11 There have also been reports of clinical trials starting afatinib at low doses in patients harboring common EGFR mutations, which have shown promising clinical efficacy and good tolerability. A phase II study using low starting doses of afatinib reported that 22% of patients aged 75 years or older who started with afatinib at 20 mg/day were able to increase the dose up to 30 mg/day, and 17% were able to increase the dose to 40 mg/day, with the majority at 20 mg/day. 12 Although the number of patients was small, a phase I study investigating the optimal dose of afatinib in elderly patients recommended 30 mg/day, 13 and other phase II studies also showed that afatinib 30 mg/day was effective and feasible in elderly patients. 14 For the elderly, 20–30 mg/day is considered to be an appropriate dose. Although most reports of low‐dose afatinib are for common mutations, there has been a study reporting that low‐dose afatinib can be safely used without reducing its efficacy in elderly patients harboring uncommon mutations. 15 In this case, an appropriate reduction in the dose of afatinib resulted in a long‐term response. This suggests that the response to treatment could be maintained in elderly patients without the need to discontinue treatment due to adverse events.
In conclusion, afatinib is effective in treating NSCLC harboring uncommon EGFR mutations, and may be administered safely to elderly patients with an appropriate dose reduction.
CONFLICT OF INTEREST
All authors declare that they have no conflicts of interest.
ACKNOWLEDGMENTS
We would like to thank Editage (www.editage.com) for English language editing. | AFATINIB | DrugsGivenReaction | CC BY | 33533191 | 18,477,251 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy partial responder'. | Long-term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation-positive lung adenocarcinoma.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Uncommon mutations, excluding exon 19 deletions and exon 21 L858R, comprise 7%-23% of EGFR mutation-positive NSCLC. The treatment of uncommon EGFR mutation-positive NSCLCs is controversial. Here, we present the case of an 81-year-old man who was diagnosed with lung adenocarcinoma cStage IVA harboring the uncommon EGFR L861Q mutation. The patient received oral afatinib treatment (40 mg/day). One month after the initiation of afatinib treatment, Common Terminology Criteria for Adverse Events version 4.0 grade 2 stomatitis was observed. It improved upon afatinib withdrawal. After 10 days of withdrawal, afatinib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, the patient continued treatment with afatinib. A partial response to afatinib treatment was maintained for 49 months until primary tumor regrowth. Afatinib treatment was continued after disease progression, but the patient died of bacterial pneumonia 59 months after initiation of afatinib treatment. Several studies have previously reported a large number of compound mutations with uncommon mutations, and that compound mutation-induced cells are most susceptible to afatinib. This suggests the efficacy of afatinib in clinical practice and that afatinib may be safely administered to elderly patients with appropriate dose reductions.
INTRODUCTION
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. 1 , 2 , 3 Common mutations account for the majority of EGFR mutation‐positive NSCLC. However, 7%–23% of EGFR mutation‐positive NSCLC, except for exon 19 deletions and exon 21 L858R, are uncommon mutations. 4 Retrospective studies discovered that uncommon EGFR mutation‐positive NSCLC developed early resistance to first‐generation EGFR‐TKIs. Afatinib, a second‐generation EGFR‐TKI, was found to have a clinical benefit for patients with NSCLC harboring uncommon EGFR mutations. 5 Osimertinib, a third‐generation TKI, was also found to be clinically effective for treating uncommon EGFR mutation‐positive NSCLC. 6 Treatment of uncommon EGFR mutation‐positive NSCLC is controversial. Moreover, the proportion of elderly participants in clinical trials is small, therefore the safety of EGFR‐TKIs, such as afatinib, in these patients remains unclear. 7
Here, we report a case of a long‐term response to afatinib in an elderly patient harboring uncommon EGFR mutation‐positive lung adenocarcinoma.
CASE REPORT
An 81‐year‐old man was referred to our hospital following chest xray which revealed an abnormal shadow, and he was subsequently diagnosed with lung adenocarcinoma cT1bN0M1a (M: PLE) Stage IVA (Figure 1).
FIGURE 1 Chest computed tomography (CT) findings before the start of afatinib treatment. The yellow arrows indicate the tumor adjacent to the cyst (a) and pleural dissemination (b)
Examination of the DNA sequence of the EGFR gene revealed an uncommon EGFR L861Q mutation. The patient received treatment with afatinib administered orally (40 mg/day). One month later, Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 2 stomatitis was observed, which improved with afatinib withdrawal. After 10 days of withdrawal, afatanib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, grade 1 skin toxicity was observed. However, the patient continued treatment with afatinib. A partial response to afatinib treatment was noted for 49 months until the primary tumor recurred (Figure 2). Treatment with afatinib was continued after disease progression, and he died of bacterial pneumonia 59 months after the initiation of afatinib treatment. The patient provided oral informed consent for the publication of this report.
FIGURE 2 The clinical course of chest computed tomography (CT) findings. (a) The tumor shrunk three months after afatinib administration. (b) The antitumor effect of afatinib was maintained in partial response at 18 months and (c) 42 months after the start of afatinib treatment. (d) The tumor was enlarged 49 months after the initiation of afatinib. The yellow arrows indicate the primary tumor
DISCUSSION
The elderly patient in our report, who presented with lung adenocarcinoma with an uncommon EGFR mutation, developed a long‐term response to afatinib with appropriate dose reduction.
An integrated analysis of LUX‐Lung 2, 3, and 6 reported the clinical benefits of afatinib, a second‐generation TKI, for treating EGFR mutation‐positive NSCLC with uncommon mutations. 5 The objective response rate (ORR) was 71.1%, and the median duration of response (mDoR) was 11.1 months among patients with lung adenocarcinoma harboring uncommon EGFR mutations, namely G719X, L861Q, and S761I. 5 The ORR for EGFR mutation‐positive NSCLC with L861Q was 56.3%. Afatinib has previously been associated with an ORR of 59.6% in EGFR mutation‐positive NSCLC with L861Q. 4 It has been reported that 6.8% of patients with major uncommon EGFR mutation‐positive NSCLC responded to afatinib for more than three years. In our case, the patient remained responsive for more than four years. 4 On the other hand, osimertinib has also been reported to have an ORR of 50% and mDoR of 9.8 months for treating EGFR mutation‐positive NSCLC patients with major uncommon EGFR mutations. 6 The frequency and pattern of compound mutations in EGFR mutations including L858R/del19, G719C/S/A, and L861Q mutations have been reported in 15.9%, 93.3%, and 36.4% of all cases, respectively. 8 Upon analyzing the association between EGFR mutation and resistance, there was no difference between afatinib and osimertinib in terms of the susceptibility of uncommon mutation‐induced cells to them. However, compound mutation‐induced cells have been reported to be most susceptible to afatinib. 8 A large number of compound mutations have been observed in uncommon mutations, suggesting the efficacy of afatinib. Cells carrying the EGFR L861Q mutation have been reported to be less sensitive to EGFR‐specific inhibitors, but more sensitive to pan ERBB inhibitors. This suggests that afatinib may be effective in treating NSCLC harboring EGFR L861Q mutations. 9
Since the proportion of elderly participants in clinical trials is small, the safety of the administration of EGFR‐TKIs, including afatinib, in the elderly population remains unclear. In the LUX‐Lung 3 and 6 analysis, the rate at which patients required dose reduction was higher in the afatinib group. However, the trend was similar among younger and elderly patients. 10 Treatment‐related adverse events are often associated with afatinib dose reductions, regardless of age. Low discontinuation rates with appropriate dose reduction protocols, and dose reductions which have reduced the incidence of grade > 3 AEs but have not significantly altered the treatment effect have been previously reported. 11 There have also been reports of clinical trials starting afatinib at low doses in patients harboring common EGFR mutations, which have shown promising clinical efficacy and good tolerability. A phase II study using low starting doses of afatinib reported that 22% of patients aged 75 years or older who started with afatinib at 20 mg/day were able to increase the dose up to 30 mg/day, and 17% were able to increase the dose to 40 mg/day, with the majority at 20 mg/day. 12 Although the number of patients was small, a phase I study investigating the optimal dose of afatinib in elderly patients recommended 30 mg/day, 13 and other phase II studies also showed that afatinib 30 mg/day was effective and feasible in elderly patients. 14 For the elderly, 20–30 mg/day is considered to be an appropriate dose. Although most reports of low‐dose afatinib are for common mutations, there has been a study reporting that low‐dose afatinib can be safely used without reducing its efficacy in elderly patients harboring uncommon mutations. 15 In this case, an appropriate reduction in the dose of afatinib resulted in a long‐term response. This suggests that the response to treatment could be maintained in elderly patients without the need to discontinue treatment due to adverse events.
In conclusion, afatinib is effective in treating NSCLC harboring uncommon EGFR mutations, and may be administered safely to elderly patients with an appropriate dose reduction.
CONFLICT OF INTEREST
All authors declare that they have no conflicts of interest.
ACKNOWLEDGMENTS
We would like to thank Editage (www.editage.com) for English language editing. | AFATINIB | DrugsGivenReaction | CC BY | 33533191 | 18,477,251 | 2021-03 |
What was the administration route of drug 'AFATINIB'? | Long-term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation-positive lung adenocarcinoma.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Uncommon mutations, excluding exon 19 deletions and exon 21 L858R, comprise 7%-23% of EGFR mutation-positive NSCLC. The treatment of uncommon EGFR mutation-positive NSCLCs is controversial. Here, we present the case of an 81-year-old man who was diagnosed with lung adenocarcinoma cStage IVA harboring the uncommon EGFR L861Q mutation. The patient received oral afatinib treatment (40 mg/day). One month after the initiation of afatinib treatment, Common Terminology Criteria for Adverse Events version 4.0 grade 2 stomatitis was observed. It improved upon afatinib withdrawal. After 10 days of withdrawal, afatinib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, the patient continued treatment with afatinib. A partial response to afatinib treatment was maintained for 49 months until primary tumor regrowth. Afatinib treatment was continued after disease progression, but the patient died of bacterial pneumonia 59 months after initiation of afatinib treatment. Several studies have previously reported a large number of compound mutations with uncommon mutations, and that compound mutation-induced cells are most susceptible to afatinib. This suggests the efficacy of afatinib in clinical practice and that afatinib may be safely administered to elderly patients with appropriate dose reductions.
INTRODUCTION
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. 1 , 2 , 3 Common mutations account for the majority of EGFR mutation‐positive NSCLC. However, 7%–23% of EGFR mutation‐positive NSCLC, except for exon 19 deletions and exon 21 L858R, are uncommon mutations. 4 Retrospective studies discovered that uncommon EGFR mutation‐positive NSCLC developed early resistance to first‐generation EGFR‐TKIs. Afatinib, a second‐generation EGFR‐TKI, was found to have a clinical benefit for patients with NSCLC harboring uncommon EGFR mutations. 5 Osimertinib, a third‐generation TKI, was also found to be clinically effective for treating uncommon EGFR mutation‐positive NSCLC. 6 Treatment of uncommon EGFR mutation‐positive NSCLC is controversial. Moreover, the proportion of elderly participants in clinical trials is small, therefore the safety of EGFR‐TKIs, such as afatinib, in these patients remains unclear. 7
Here, we report a case of a long‐term response to afatinib in an elderly patient harboring uncommon EGFR mutation‐positive lung adenocarcinoma.
CASE REPORT
An 81‐year‐old man was referred to our hospital following chest xray which revealed an abnormal shadow, and he was subsequently diagnosed with lung adenocarcinoma cT1bN0M1a (M: PLE) Stage IVA (Figure 1).
FIGURE 1 Chest computed tomography (CT) findings before the start of afatinib treatment. The yellow arrows indicate the tumor adjacent to the cyst (a) and pleural dissemination (b)
Examination of the DNA sequence of the EGFR gene revealed an uncommon EGFR L861Q mutation. The patient received treatment with afatinib administered orally (40 mg/day). One month later, Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 2 stomatitis was observed, which improved with afatinib withdrawal. After 10 days of withdrawal, afatanib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, grade 1 skin toxicity was observed. However, the patient continued treatment with afatinib. A partial response to afatinib treatment was noted for 49 months until the primary tumor recurred (Figure 2). Treatment with afatinib was continued after disease progression, and he died of bacterial pneumonia 59 months after the initiation of afatinib treatment. The patient provided oral informed consent for the publication of this report.
FIGURE 2 The clinical course of chest computed tomography (CT) findings. (a) The tumor shrunk three months after afatinib administration. (b) The antitumor effect of afatinib was maintained in partial response at 18 months and (c) 42 months after the start of afatinib treatment. (d) The tumor was enlarged 49 months after the initiation of afatinib. The yellow arrows indicate the primary tumor
DISCUSSION
The elderly patient in our report, who presented with lung adenocarcinoma with an uncommon EGFR mutation, developed a long‐term response to afatinib with appropriate dose reduction.
An integrated analysis of LUX‐Lung 2, 3, and 6 reported the clinical benefits of afatinib, a second‐generation TKI, for treating EGFR mutation‐positive NSCLC with uncommon mutations. 5 The objective response rate (ORR) was 71.1%, and the median duration of response (mDoR) was 11.1 months among patients with lung adenocarcinoma harboring uncommon EGFR mutations, namely G719X, L861Q, and S761I. 5 The ORR for EGFR mutation‐positive NSCLC with L861Q was 56.3%. Afatinib has previously been associated with an ORR of 59.6% in EGFR mutation‐positive NSCLC with L861Q. 4 It has been reported that 6.8% of patients with major uncommon EGFR mutation‐positive NSCLC responded to afatinib for more than three years. In our case, the patient remained responsive for more than four years. 4 On the other hand, osimertinib has also been reported to have an ORR of 50% and mDoR of 9.8 months for treating EGFR mutation‐positive NSCLC patients with major uncommon EGFR mutations. 6 The frequency and pattern of compound mutations in EGFR mutations including L858R/del19, G719C/S/A, and L861Q mutations have been reported in 15.9%, 93.3%, and 36.4% of all cases, respectively. 8 Upon analyzing the association between EGFR mutation and resistance, there was no difference between afatinib and osimertinib in terms of the susceptibility of uncommon mutation‐induced cells to them. However, compound mutation‐induced cells have been reported to be most susceptible to afatinib. 8 A large number of compound mutations have been observed in uncommon mutations, suggesting the efficacy of afatinib. Cells carrying the EGFR L861Q mutation have been reported to be less sensitive to EGFR‐specific inhibitors, but more sensitive to pan ERBB inhibitors. This suggests that afatinib may be effective in treating NSCLC harboring EGFR L861Q mutations. 9
Since the proportion of elderly participants in clinical trials is small, the safety of the administration of EGFR‐TKIs, including afatinib, in the elderly population remains unclear. In the LUX‐Lung 3 and 6 analysis, the rate at which patients required dose reduction was higher in the afatinib group. However, the trend was similar among younger and elderly patients. 10 Treatment‐related adverse events are often associated with afatinib dose reductions, regardless of age. Low discontinuation rates with appropriate dose reduction protocols, and dose reductions which have reduced the incidence of grade > 3 AEs but have not significantly altered the treatment effect have been previously reported. 11 There have also been reports of clinical trials starting afatinib at low doses in patients harboring common EGFR mutations, which have shown promising clinical efficacy and good tolerability. A phase II study using low starting doses of afatinib reported that 22% of patients aged 75 years or older who started with afatinib at 20 mg/day were able to increase the dose up to 30 mg/day, and 17% were able to increase the dose to 40 mg/day, with the majority at 20 mg/day. 12 Although the number of patients was small, a phase I study investigating the optimal dose of afatinib in elderly patients recommended 30 mg/day, 13 and other phase II studies also showed that afatinib 30 mg/day was effective and feasible in elderly patients. 14 For the elderly, 20–30 mg/day is considered to be an appropriate dose. Although most reports of low‐dose afatinib are for common mutations, there has been a study reporting that low‐dose afatinib can be safely used without reducing its efficacy in elderly patients harboring uncommon mutations. 15 In this case, an appropriate reduction in the dose of afatinib resulted in a long‐term response. This suggests that the response to treatment could be maintained in elderly patients without the need to discontinue treatment due to adverse events.
In conclusion, afatinib is effective in treating NSCLC harboring uncommon EGFR mutations, and may be administered safely to elderly patients with an appropriate dose reduction.
CONFLICT OF INTEREST
All authors declare that they have no conflicts of interest.
ACKNOWLEDGMENTS
We would like to thank Editage (www.editage.com) for English language editing. | Oral | DrugAdministrationRoute | CC BY | 33533191 | 18,477,251 | 2021-03 |
What was the outcome of reaction 'Pneumonia bacterial'? | Long-term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation-positive lung adenocarcinoma.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Uncommon mutations, excluding exon 19 deletions and exon 21 L858R, comprise 7%-23% of EGFR mutation-positive NSCLC. The treatment of uncommon EGFR mutation-positive NSCLCs is controversial. Here, we present the case of an 81-year-old man who was diagnosed with lung adenocarcinoma cStage IVA harboring the uncommon EGFR L861Q mutation. The patient received oral afatinib treatment (40 mg/day). One month after the initiation of afatinib treatment, Common Terminology Criteria for Adverse Events version 4.0 grade 2 stomatitis was observed. It improved upon afatinib withdrawal. After 10 days of withdrawal, afatinib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, the patient continued treatment with afatinib. A partial response to afatinib treatment was maintained for 49 months until primary tumor regrowth. Afatinib treatment was continued after disease progression, but the patient died of bacterial pneumonia 59 months after initiation of afatinib treatment. Several studies have previously reported a large number of compound mutations with uncommon mutations, and that compound mutation-induced cells are most susceptible to afatinib. This suggests the efficacy of afatinib in clinical practice and that afatinib may be safely administered to elderly patients with appropriate dose reductions.
INTRODUCTION
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. 1 , 2 , 3 Common mutations account for the majority of EGFR mutation‐positive NSCLC. However, 7%–23% of EGFR mutation‐positive NSCLC, except for exon 19 deletions and exon 21 L858R, are uncommon mutations. 4 Retrospective studies discovered that uncommon EGFR mutation‐positive NSCLC developed early resistance to first‐generation EGFR‐TKIs. Afatinib, a second‐generation EGFR‐TKI, was found to have a clinical benefit for patients with NSCLC harboring uncommon EGFR mutations. 5 Osimertinib, a third‐generation TKI, was also found to be clinically effective for treating uncommon EGFR mutation‐positive NSCLC. 6 Treatment of uncommon EGFR mutation‐positive NSCLC is controversial. Moreover, the proportion of elderly participants in clinical trials is small, therefore the safety of EGFR‐TKIs, such as afatinib, in these patients remains unclear. 7
Here, we report a case of a long‐term response to afatinib in an elderly patient harboring uncommon EGFR mutation‐positive lung adenocarcinoma.
CASE REPORT
An 81‐year‐old man was referred to our hospital following chest xray which revealed an abnormal shadow, and he was subsequently diagnosed with lung adenocarcinoma cT1bN0M1a (M: PLE) Stage IVA (Figure 1).
FIGURE 1 Chest computed tomography (CT) findings before the start of afatinib treatment. The yellow arrows indicate the tumor adjacent to the cyst (a) and pleural dissemination (b)
Examination of the DNA sequence of the EGFR gene revealed an uncommon EGFR L861Q mutation. The patient received treatment with afatinib administered orally (40 mg/day). One month later, Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 2 stomatitis was observed, which improved with afatinib withdrawal. After 10 days of withdrawal, afatanib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, grade 1 skin toxicity was observed. However, the patient continued treatment with afatinib. A partial response to afatinib treatment was noted for 49 months until the primary tumor recurred (Figure 2). Treatment with afatinib was continued after disease progression, and he died of bacterial pneumonia 59 months after the initiation of afatinib treatment. The patient provided oral informed consent for the publication of this report.
FIGURE 2 The clinical course of chest computed tomography (CT) findings. (a) The tumor shrunk three months after afatinib administration. (b) The antitumor effect of afatinib was maintained in partial response at 18 months and (c) 42 months after the start of afatinib treatment. (d) The tumor was enlarged 49 months after the initiation of afatinib. The yellow arrows indicate the primary tumor
DISCUSSION
The elderly patient in our report, who presented with lung adenocarcinoma with an uncommon EGFR mutation, developed a long‐term response to afatinib with appropriate dose reduction.
An integrated analysis of LUX‐Lung 2, 3, and 6 reported the clinical benefits of afatinib, a second‐generation TKI, for treating EGFR mutation‐positive NSCLC with uncommon mutations. 5 The objective response rate (ORR) was 71.1%, and the median duration of response (mDoR) was 11.1 months among patients with lung adenocarcinoma harboring uncommon EGFR mutations, namely G719X, L861Q, and S761I. 5 The ORR for EGFR mutation‐positive NSCLC with L861Q was 56.3%. Afatinib has previously been associated with an ORR of 59.6% in EGFR mutation‐positive NSCLC with L861Q. 4 It has been reported that 6.8% of patients with major uncommon EGFR mutation‐positive NSCLC responded to afatinib for more than three years. In our case, the patient remained responsive for more than four years. 4 On the other hand, osimertinib has also been reported to have an ORR of 50% and mDoR of 9.8 months for treating EGFR mutation‐positive NSCLC patients with major uncommon EGFR mutations. 6 The frequency and pattern of compound mutations in EGFR mutations including L858R/del19, G719C/S/A, and L861Q mutations have been reported in 15.9%, 93.3%, and 36.4% of all cases, respectively. 8 Upon analyzing the association between EGFR mutation and resistance, there was no difference between afatinib and osimertinib in terms of the susceptibility of uncommon mutation‐induced cells to them. However, compound mutation‐induced cells have been reported to be most susceptible to afatinib. 8 A large number of compound mutations have been observed in uncommon mutations, suggesting the efficacy of afatinib. Cells carrying the EGFR L861Q mutation have been reported to be less sensitive to EGFR‐specific inhibitors, but more sensitive to pan ERBB inhibitors. This suggests that afatinib may be effective in treating NSCLC harboring EGFR L861Q mutations. 9
Since the proportion of elderly participants in clinical trials is small, the safety of the administration of EGFR‐TKIs, including afatinib, in the elderly population remains unclear. In the LUX‐Lung 3 and 6 analysis, the rate at which patients required dose reduction was higher in the afatinib group. However, the trend was similar among younger and elderly patients. 10 Treatment‐related adverse events are often associated with afatinib dose reductions, regardless of age. Low discontinuation rates with appropriate dose reduction protocols, and dose reductions which have reduced the incidence of grade > 3 AEs but have not significantly altered the treatment effect have been previously reported. 11 There have also been reports of clinical trials starting afatinib at low doses in patients harboring common EGFR mutations, which have shown promising clinical efficacy and good tolerability. A phase II study using low starting doses of afatinib reported that 22% of patients aged 75 years or older who started with afatinib at 20 mg/day were able to increase the dose up to 30 mg/day, and 17% were able to increase the dose to 40 mg/day, with the majority at 20 mg/day. 12 Although the number of patients was small, a phase I study investigating the optimal dose of afatinib in elderly patients recommended 30 mg/day, 13 and other phase II studies also showed that afatinib 30 mg/day was effective and feasible in elderly patients. 14 For the elderly, 20–30 mg/day is considered to be an appropriate dose. Although most reports of low‐dose afatinib are for common mutations, there has been a study reporting that low‐dose afatinib can be safely used without reducing its efficacy in elderly patients harboring uncommon mutations. 15 In this case, an appropriate reduction in the dose of afatinib resulted in a long‐term response. This suggests that the response to treatment could be maintained in elderly patients without the need to discontinue treatment due to adverse events.
In conclusion, afatinib is effective in treating NSCLC harboring uncommon EGFR mutations, and may be administered safely to elderly patients with an appropriate dose reduction.
CONFLICT OF INTEREST
All authors declare that they have no conflicts of interest.
ACKNOWLEDGMENTS
We would like to thank Editage (www.editage.com) for English language editing. | Fatal | ReactionOutcome | CC BY | 33533191 | 18,477,251 | 2021-03 |
What was the outcome of reaction 'Stomatitis'? | Long-term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation-positive lung adenocarcinoma.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Uncommon mutations, excluding exon 19 deletions and exon 21 L858R, comprise 7%-23% of EGFR mutation-positive NSCLC. The treatment of uncommon EGFR mutation-positive NSCLCs is controversial. Here, we present the case of an 81-year-old man who was diagnosed with lung adenocarcinoma cStage IVA harboring the uncommon EGFR L861Q mutation. The patient received oral afatinib treatment (40 mg/day). One month after the initiation of afatinib treatment, Common Terminology Criteria for Adverse Events version 4.0 grade 2 stomatitis was observed. It improved upon afatinib withdrawal. After 10 days of withdrawal, afatinib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, the patient continued treatment with afatinib. A partial response to afatinib treatment was maintained for 49 months until primary tumor regrowth. Afatinib treatment was continued after disease progression, but the patient died of bacterial pneumonia 59 months after initiation of afatinib treatment. Several studies have previously reported a large number of compound mutations with uncommon mutations, and that compound mutation-induced cells are most susceptible to afatinib. This suggests the efficacy of afatinib in clinical practice and that afatinib may be safely administered to elderly patients with appropriate dose reductions.
INTRODUCTION
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. 1 , 2 , 3 Common mutations account for the majority of EGFR mutation‐positive NSCLC. However, 7%–23% of EGFR mutation‐positive NSCLC, except for exon 19 deletions and exon 21 L858R, are uncommon mutations. 4 Retrospective studies discovered that uncommon EGFR mutation‐positive NSCLC developed early resistance to first‐generation EGFR‐TKIs. Afatinib, a second‐generation EGFR‐TKI, was found to have a clinical benefit for patients with NSCLC harboring uncommon EGFR mutations. 5 Osimertinib, a third‐generation TKI, was also found to be clinically effective for treating uncommon EGFR mutation‐positive NSCLC. 6 Treatment of uncommon EGFR mutation‐positive NSCLC is controversial. Moreover, the proportion of elderly participants in clinical trials is small, therefore the safety of EGFR‐TKIs, such as afatinib, in these patients remains unclear. 7
Here, we report a case of a long‐term response to afatinib in an elderly patient harboring uncommon EGFR mutation‐positive lung adenocarcinoma.
CASE REPORT
An 81‐year‐old man was referred to our hospital following chest xray which revealed an abnormal shadow, and he was subsequently diagnosed with lung adenocarcinoma cT1bN0M1a (M: PLE) Stage IVA (Figure 1).
FIGURE 1 Chest computed tomography (CT) findings before the start of afatinib treatment. The yellow arrows indicate the tumor adjacent to the cyst (a) and pleural dissemination (b)
Examination of the DNA sequence of the EGFR gene revealed an uncommon EGFR L861Q mutation. The patient received treatment with afatinib administered orally (40 mg/day). One month later, Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 2 stomatitis was observed, which improved with afatinib withdrawal. After 10 days of withdrawal, afatanib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, grade 1 skin toxicity was observed. However, the patient continued treatment with afatinib. A partial response to afatinib treatment was noted for 49 months until the primary tumor recurred (Figure 2). Treatment with afatinib was continued after disease progression, and he died of bacterial pneumonia 59 months after the initiation of afatinib treatment. The patient provided oral informed consent for the publication of this report.
FIGURE 2 The clinical course of chest computed tomography (CT) findings. (a) The tumor shrunk three months after afatinib administration. (b) The antitumor effect of afatinib was maintained in partial response at 18 months and (c) 42 months after the start of afatinib treatment. (d) The tumor was enlarged 49 months after the initiation of afatinib. The yellow arrows indicate the primary tumor
DISCUSSION
The elderly patient in our report, who presented with lung adenocarcinoma with an uncommon EGFR mutation, developed a long‐term response to afatinib with appropriate dose reduction.
An integrated analysis of LUX‐Lung 2, 3, and 6 reported the clinical benefits of afatinib, a second‐generation TKI, for treating EGFR mutation‐positive NSCLC with uncommon mutations. 5 The objective response rate (ORR) was 71.1%, and the median duration of response (mDoR) was 11.1 months among patients with lung adenocarcinoma harboring uncommon EGFR mutations, namely G719X, L861Q, and S761I. 5 The ORR for EGFR mutation‐positive NSCLC with L861Q was 56.3%. Afatinib has previously been associated with an ORR of 59.6% in EGFR mutation‐positive NSCLC with L861Q. 4 It has been reported that 6.8% of patients with major uncommon EGFR mutation‐positive NSCLC responded to afatinib for more than three years. In our case, the patient remained responsive for more than four years. 4 On the other hand, osimertinib has also been reported to have an ORR of 50% and mDoR of 9.8 months for treating EGFR mutation‐positive NSCLC patients with major uncommon EGFR mutations. 6 The frequency and pattern of compound mutations in EGFR mutations including L858R/del19, G719C/S/A, and L861Q mutations have been reported in 15.9%, 93.3%, and 36.4% of all cases, respectively. 8 Upon analyzing the association between EGFR mutation and resistance, there was no difference between afatinib and osimertinib in terms of the susceptibility of uncommon mutation‐induced cells to them. However, compound mutation‐induced cells have been reported to be most susceptible to afatinib. 8 A large number of compound mutations have been observed in uncommon mutations, suggesting the efficacy of afatinib. Cells carrying the EGFR L861Q mutation have been reported to be less sensitive to EGFR‐specific inhibitors, but more sensitive to pan ERBB inhibitors. This suggests that afatinib may be effective in treating NSCLC harboring EGFR L861Q mutations. 9
Since the proportion of elderly participants in clinical trials is small, the safety of the administration of EGFR‐TKIs, including afatinib, in the elderly population remains unclear. In the LUX‐Lung 3 and 6 analysis, the rate at which patients required dose reduction was higher in the afatinib group. However, the trend was similar among younger and elderly patients. 10 Treatment‐related adverse events are often associated with afatinib dose reductions, regardless of age. Low discontinuation rates with appropriate dose reduction protocols, and dose reductions which have reduced the incidence of grade > 3 AEs but have not significantly altered the treatment effect have been previously reported. 11 There have also been reports of clinical trials starting afatinib at low doses in patients harboring common EGFR mutations, which have shown promising clinical efficacy and good tolerability. A phase II study using low starting doses of afatinib reported that 22% of patients aged 75 years or older who started with afatinib at 20 mg/day were able to increase the dose up to 30 mg/day, and 17% were able to increase the dose to 40 mg/day, with the majority at 20 mg/day. 12 Although the number of patients was small, a phase I study investigating the optimal dose of afatinib in elderly patients recommended 30 mg/day, 13 and other phase II studies also showed that afatinib 30 mg/day was effective and feasible in elderly patients. 14 For the elderly, 20–30 mg/day is considered to be an appropriate dose. Although most reports of low‐dose afatinib are for common mutations, there has been a study reporting that low‐dose afatinib can be safely used without reducing its efficacy in elderly patients harboring uncommon mutations. 15 In this case, an appropriate reduction in the dose of afatinib resulted in a long‐term response. This suggests that the response to treatment could be maintained in elderly patients without the need to discontinue treatment due to adverse events.
In conclusion, afatinib is effective in treating NSCLC harboring uncommon EGFR mutations, and may be administered safely to elderly patients with an appropriate dose reduction.
CONFLICT OF INTEREST
All authors declare that they have no conflicts of interest.
ACKNOWLEDGMENTS
We would like to thank Editage (www.editage.com) for English language editing. | Recovered | ReactionOutcome | CC BY | 33533191 | 18,477,251 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Sweet Syndrome precipitated by Mycobacterium abscessus in a Laotian Man with Autoantibodies to Interferon Gamma.
Autoantibodies to interferon γ, part of the first line of defense in the human immune response, constitutes a rare form of an acquired immunodeficiency in HIV-uninfected adults that can predispose to disseminated atypical mycobacterial infection. Particularly, this has been described in people of Southeast Asian origin. In this case report, we describe a previously healthy, Laotian man who presented with skin lesions consistent with Sweet syndrome that were later found to be precipitated by disseminated atypical mycobacterial disease. Extensive immunological workup revealed the patient to have autoantibodies to interferon γ, rendering him susceptible to this infection. Our report demonstrates a complex case with a multilayered diagnosis, while inviting perspective from multiple specialties. This enigmatic case emphasizes the importance of a broad differential with special attention to demographics while demonstrating the difficulty in treating certain atypical infections that are inherently multidrug resistant.
Case Presentation
A 63-year-old man presented with 2 months of cough, fever, intermittent night sweats, and 10 lbs of unintentional weight loss. Computed tomography scan showed pulmonary opacities and indeterminate mediastinal and hilar lymphadenopathy. Levofloxacin was administered without improvement, so a bronchoscopy with endobronchial ultrasound was performed. Needle aspiration of a lymph node yielded necrotic tissue without evidence of malignancy. Bacterial culture of bronchoalveolar lavage had no growth; stain for acid fast bacilli (AFB) was negative. Despite continued antibiotic administration, the fevers persisted. Skin lesions appeared, as well as pain and swelling of his wrists, elbows, knees, and ankles. A pustule developed at the site of a tuberculin purified protein derivative skin test 72 hours after placement. Two skin biopsies were nondiagnostic. The patient was transferred to our hospital for further evaluation.
The patient was born and raised in Laos where he was an irrigation engineer. He and his family immigrated to the United States decades ago and settled in Northwest Arkansas where he worked as a school custodian. His hobbies included gardening. He was not sexually active, and he never used illicit drugs. His last international travel was 6 years ago when he visited Laos and Japan.
On arrival to our hospital, the patient complained of pain related to swelling of his extremities and skin lesions. He did not have cough or other respiratory symptoms. Temperature was 102.8 °F, blood pressure was 163/85 mm Hg, heart rate was 118 beats per minute, and respiratory rate was 18 breaths per minute. There were no ocular abnormalities, oral lesions, or lymphadenopathy. Skin examination was remarkable for dusky, hemorrhagic pustules, bullae that were most prominent on bilateral proximal palms, and erythematous papules and pustules on bilateral arms, knees, ankles, and dorsal feet, with increased density proximal to joints (Figures 1 and 2). There was tight edema of all distal extremities. Previous skin biopsy sites had purulent drainage. This finding and the reaction to intradermal injection of tuberculin PPD suggested pathergy, an exaggerated inflammatory response to local skin injury.
Figure 1. Lesions of the hand.
Figure 2. Lesions of the leg.
Laboratory results showed white blood cell count of 16.2 K/mm3 with 84% polymorphonuclear leukocytes, C-reactive protein of 15.9 mg/dL, and erythrocyte sedimentation rate of >130 mm/h. Numerous blood cultures had no growth. Culture of purulent material from the site of previous skin biopsy was negative. Aspiration of the left ankle yielded 1 cc of blood-tinged fluid, which was not of sufficient quantity to send for analysis. Fourth-generation HIV testing was nonreactive. Multiple expectorated sputum specimens stained negatively for AFB and tested negatively for Mycobacterium tuberculosis DNA by polymerase chain reaction.
Diagnosis and Management
The differential diagnosis included vasculitis, reactive arthritis, hematologic malignancy, and various infections including tuberculosis, disseminated nontuberculous mycobacterial infection, the 2 mycoses that are endemic in Arkansas—blastomycosis and histoplasmosis—and one that is endemic in Southeast Asia—talaromycosis. Additionally, Sweet syndrome, Behçet disease, and pyoderma gangrenosum were considered because of their association with pathergy.
The dermatology service performed a skin biopsy. Histologic sections of the biopsy showed marked papillary edema and a dense neutrophilic infiltrate with admixed histiocytes within the papillary and superficial reticular dermis without evidence of vasculitis or leukocytoclasis (Figure 3). Special stains did not reveal fungal organisms or AFB. The patient’s clinical presentation and histopathologic findings were consistent with Sweet syndrome, also known as acute febrile neutrophilic dermatosis (Table 1),1 which is usually precipitated or preceded by a parainflammatory process such as infection, malignancy, or autoimmune disease. In our case, the patient’s fever, cutaneous lesions, and edema all responded to treatment with prednisone and dapsone, and he was discharged with plans for close follow-up.
Figure 3. Skin biopsy (hematoxylin & eosin; A, 20×; B, 200×; C, 400×). See text for description.
Table 1. Modified Diagnostic Criteria for Sweet Syndrome1.
Major criteria (must have both) Minor criteria (must have at least two)
• Abrupt onset of tender or painful erythematous plaques or nodules, occasionally with vesicles, pustules, or blisters
• Predominantly neutrophilic dermal infiltrate without leukocytoclastic vasculitis • Preceded by a nonspecific respiratory or gastrointestinal tract infection or vaccination OR associated with inflammatory diseases such as chronic autoimmune disorders or infections, hemoproliferative disorders or solid malignant tumors, or pregnancy
• Temperature > 38 °C
• Abnormal laboratory values at presentation (must have 3 of 4):
1. Erythrocyte sedimentation rate >20 mm/h
2. Elevated C-reactive protein levels
3. Leukocytosis > 8 K/mm3
4. Neutrophilia > 70% of total white blood cells
• Excellent response to treatment with systemic corticosteroids or potassium iodide
Over the ensuing weeks, all signs and symptoms worsened whenever the dose of prednisone was decreased below 20 mg/day. Bacterial, mycobacterial, and fungal cultures from the skin biopsy all returned negative. Polymerase chain reaction testing of the tissue did not detect bacterial, mycobacterial, or fungal DNA. At the initial diagnosis of Sweet syndrome, no underlying trigger was identified; but 2 months later, a microbiology report from the patient’s primary care physician revealed that a culture, from a previously obtained bronchoalveolar lavage, had grown Mycobacterium abscessus/chelonae (not otherwise differentiated). Communication of the result was delayed because the community hospital sent the isolate to a reference laboratory for identification and susceptibility testing, and the significance of the result was not appreciated at that time.
About 4 months after discharge, the patient developed cervical and supraclavicular lymphadenopathy. The nodes were approximately 1 to 2 cm, mildly tender, rubbery, and not fixed. A cervical lymph node was excised; histopathology showed marked, reactive paracortical hyperplasia with focal microabscesses without granulomas, vasculitis, or malignancy. Special stains for microorganisms, including AFB, were negative, but many colonies of Mycobacterium abscessus subsp abscessus grew in culture.
Mycobacterium abscessus subsp abscessus is a rapidly growing mycobacterium that has in vitro resistance to many antibiotics. The usual therapeutic approach for pulmonary disease, which is the most common form of infection with this bacterium, includes a combination of intravenous and oral antibiotics given for more than 6 months.2 Amikacin, which is the most active agent, is the cornerstone of therapy for M abscessus subsp abscessus infections, despite potential nephrotoxicity and ototoxicity.2 In our case, the isolate was resistant to macrolides due to the presence of a functional erm41 gene.2,3 The patient was treated for disseminated infection with 4 months of intravenous antibiotics consisting of amikacin, imipenem, and tigecycline, plus oral clofazimine, an anti-leprosy drug procured through the Food and Drug Administration via a single patient Investigational New Drug process.4 The patient tolerated 4 months of this potentially toxic and unwieldy regimen remarkably well. All signs and symptoms resolved. Once the infection was controlled, prednisone was tapered off successfully.
Discussion
Why did this patient, who was not known to be immunocompromised, develop disseminated mycobacterial infection? A previously unrecognized clinical entity of cervical lymphadenitis due to rapidly growing mycobacteria and reactive skin disease, that is Sweet syndrome, among adults in northeastern Thailand was reported in 2000.5 Additional investigations supported the existence of a non-HIV-related, adult-onset immunodeficiency syndrome in Southeast Asians.6,7 People with this disorder produce neutralizing anti-interferon γ autoantibodies, which increases the risk of mycobacterial and other opportunistic infections.7-10 Serum from our patient tested positive for the presence of these autoantibodies.
When evaluated 12 months after completion of antibiotics, he was doing well without recurrence of constitutional symptoms, cutaneous disease, or cervical lymphadenopathy. After extensive evaluation of this challenging case, we concluded that the patient’s initial diagnosis of Sweet syndrome was likely precipitated by disseminated M. abscessus subsp. abscessus infection to which he was predisposed by immunodeficiency due to anti-interferon γ autoantibodies. The complexity of this case demonstrates the importance of evaluating uncommon causes of acquired immunodeficiency in seemingly healthy patients with attention to the demographics and associated predilection for disease.
We thank Sara Shalin, MD, and Jerad Gardner, MD, for their assistance with the histologic images and description of pathologic findings.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
ORCID iD: Priyenka Thapa https://orcid.org/0000-0001-7518-1916 | PREDNISONE | DrugsGivenReaction | CC BY-NC | 33533284 | 19,084,609 | 2021 |
What was the dosage of drug 'PREDNISONE'? | Sweet Syndrome precipitated by Mycobacterium abscessus in a Laotian Man with Autoantibodies to Interferon Gamma.
Autoantibodies to interferon γ, part of the first line of defense in the human immune response, constitutes a rare form of an acquired immunodeficiency in HIV-uninfected adults that can predispose to disseminated atypical mycobacterial infection. Particularly, this has been described in people of Southeast Asian origin. In this case report, we describe a previously healthy, Laotian man who presented with skin lesions consistent with Sweet syndrome that were later found to be precipitated by disseminated atypical mycobacterial disease. Extensive immunological workup revealed the patient to have autoantibodies to interferon γ, rendering him susceptible to this infection. Our report demonstrates a complex case with a multilayered diagnosis, while inviting perspective from multiple specialties. This enigmatic case emphasizes the importance of a broad differential with special attention to demographics while demonstrating the difficulty in treating certain atypical infections that are inherently multidrug resistant.
Case Presentation
A 63-year-old man presented with 2 months of cough, fever, intermittent night sweats, and 10 lbs of unintentional weight loss. Computed tomography scan showed pulmonary opacities and indeterminate mediastinal and hilar lymphadenopathy. Levofloxacin was administered without improvement, so a bronchoscopy with endobronchial ultrasound was performed. Needle aspiration of a lymph node yielded necrotic tissue without evidence of malignancy. Bacterial culture of bronchoalveolar lavage had no growth; stain for acid fast bacilli (AFB) was negative. Despite continued antibiotic administration, the fevers persisted. Skin lesions appeared, as well as pain and swelling of his wrists, elbows, knees, and ankles. A pustule developed at the site of a tuberculin purified protein derivative skin test 72 hours after placement. Two skin biopsies were nondiagnostic. The patient was transferred to our hospital for further evaluation.
The patient was born and raised in Laos where he was an irrigation engineer. He and his family immigrated to the United States decades ago and settled in Northwest Arkansas where he worked as a school custodian. His hobbies included gardening. He was not sexually active, and he never used illicit drugs. His last international travel was 6 years ago when he visited Laos and Japan.
On arrival to our hospital, the patient complained of pain related to swelling of his extremities and skin lesions. He did not have cough or other respiratory symptoms. Temperature was 102.8 °F, blood pressure was 163/85 mm Hg, heart rate was 118 beats per minute, and respiratory rate was 18 breaths per minute. There were no ocular abnormalities, oral lesions, or lymphadenopathy. Skin examination was remarkable for dusky, hemorrhagic pustules, bullae that were most prominent on bilateral proximal palms, and erythematous papules and pustules on bilateral arms, knees, ankles, and dorsal feet, with increased density proximal to joints (Figures 1 and 2). There was tight edema of all distal extremities. Previous skin biopsy sites had purulent drainage. This finding and the reaction to intradermal injection of tuberculin PPD suggested pathergy, an exaggerated inflammatory response to local skin injury.
Figure 1. Lesions of the hand.
Figure 2. Lesions of the leg.
Laboratory results showed white blood cell count of 16.2 K/mm3 with 84% polymorphonuclear leukocytes, C-reactive protein of 15.9 mg/dL, and erythrocyte sedimentation rate of >130 mm/h. Numerous blood cultures had no growth. Culture of purulent material from the site of previous skin biopsy was negative. Aspiration of the left ankle yielded 1 cc of blood-tinged fluid, which was not of sufficient quantity to send for analysis. Fourth-generation HIV testing was nonreactive. Multiple expectorated sputum specimens stained negatively for AFB and tested negatively for Mycobacterium tuberculosis DNA by polymerase chain reaction.
Diagnosis and Management
The differential diagnosis included vasculitis, reactive arthritis, hematologic malignancy, and various infections including tuberculosis, disseminated nontuberculous mycobacterial infection, the 2 mycoses that are endemic in Arkansas—blastomycosis and histoplasmosis—and one that is endemic in Southeast Asia—talaromycosis. Additionally, Sweet syndrome, Behçet disease, and pyoderma gangrenosum were considered because of their association with pathergy.
The dermatology service performed a skin biopsy. Histologic sections of the biopsy showed marked papillary edema and a dense neutrophilic infiltrate with admixed histiocytes within the papillary and superficial reticular dermis without evidence of vasculitis or leukocytoclasis (Figure 3). Special stains did not reveal fungal organisms or AFB. The patient’s clinical presentation and histopathologic findings were consistent with Sweet syndrome, also known as acute febrile neutrophilic dermatosis (Table 1),1 which is usually precipitated or preceded by a parainflammatory process such as infection, malignancy, or autoimmune disease. In our case, the patient’s fever, cutaneous lesions, and edema all responded to treatment with prednisone and dapsone, and he was discharged with plans for close follow-up.
Figure 3. Skin biopsy (hematoxylin & eosin; A, 20×; B, 200×; C, 400×). See text for description.
Table 1. Modified Diagnostic Criteria for Sweet Syndrome1.
Major criteria (must have both) Minor criteria (must have at least two)
• Abrupt onset of tender or painful erythematous plaques or nodules, occasionally with vesicles, pustules, or blisters
• Predominantly neutrophilic dermal infiltrate without leukocytoclastic vasculitis • Preceded by a nonspecific respiratory or gastrointestinal tract infection or vaccination OR associated with inflammatory diseases such as chronic autoimmune disorders or infections, hemoproliferative disorders or solid malignant tumors, or pregnancy
• Temperature > 38 °C
• Abnormal laboratory values at presentation (must have 3 of 4):
1. Erythrocyte sedimentation rate >20 mm/h
2. Elevated C-reactive protein levels
3. Leukocytosis > 8 K/mm3
4. Neutrophilia > 70% of total white blood cells
• Excellent response to treatment with systemic corticosteroids or potassium iodide
Over the ensuing weeks, all signs and symptoms worsened whenever the dose of prednisone was decreased below 20 mg/day. Bacterial, mycobacterial, and fungal cultures from the skin biopsy all returned negative. Polymerase chain reaction testing of the tissue did not detect bacterial, mycobacterial, or fungal DNA. At the initial diagnosis of Sweet syndrome, no underlying trigger was identified; but 2 months later, a microbiology report from the patient’s primary care physician revealed that a culture, from a previously obtained bronchoalveolar lavage, had grown Mycobacterium abscessus/chelonae (not otherwise differentiated). Communication of the result was delayed because the community hospital sent the isolate to a reference laboratory for identification and susceptibility testing, and the significance of the result was not appreciated at that time.
About 4 months after discharge, the patient developed cervical and supraclavicular lymphadenopathy. The nodes were approximately 1 to 2 cm, mildly tender, rubbery, and not fixed. A cervical lymph node was excised; histopathology showed marked, reactive paracortical hyperplasia with focal microabscesses without granulomas, vasculitis, or malignancy. Special stains for microorganisms, including AFB, were negative, but many colonies of Mycobacterium abscessus subsp abscessus grew in culture.
Mycobacterium abscessus subsp abscessus is a rapidly growing mycobacterium that has in vitro resistance to many antibiotics. The usual therapeutic approach for pulmonary disease, which is the most common form of infection with this bacterium, includes a combination of intravenous and oral antibiotics given for more than 6 months.2 Amikacin, which is the most active agent, is the cornerstone of therapy for M abscessus subsp abscessus infections, despite potential nephrotoxicity and ototoxicity.2 In our case, the isolate was resistant to macrolides due to the presence of a functional erm41 gene.2,3 The patient was treated for disseminated infection with 4 months of intravenous antibiotics consisting of amikacin, imipenem, and tigecycline, plus oral clofazimine, an anti-leprosy drug procured through the Food and Drug Administration via a single patient Investigational New Drug process.4 The patient tolerated 4 months of this potentially toxic and unwieldy regimen remarkably well. All signs and symptoms resolved. Once the infection was controlled, prednisone was tapered off successfully.
Discussion
Why did this patient, who was not known to be immunocompromised, develop disseminated mycobacterial infection? A previously unrecognized clinical entity of cervical lymphadenitis due to rapidly growing mycobacteria and reactive skin disease, that is Sweet syndrome, among adults in northeastern Thailand was reported in 2000.5 Additional investigations supported the existence of a non-HIV-related, adult-onset immunodeficiency syndrome in Southeast Asians.6,7 People with this disorder produce neutralizing anti-interferon γ autoantibodies, which increases the risk of mycobacterial and other opportunistic infections.7-10 Serum from our patient tested positive for the presence of these autoantibodies.
When evaluated 12 months after completion of antibiotics, he was doing well without recurrence of constitutional symptoms, cutaneous disease, or cervical lymphadenopathy. After extensive evaluation of this challenging case, we concluded that the patient’s initial diagnosis of Sweet syndrome was likely precipitated by disseminated M. abscessus subsp. abscessus infection to which he was predisposed by immunodeficiency due to anti-interferon γ autoantibodies. The complexity of this case demonstrates the importance of evaluating uncommon causes of acquired immunodeficiency in seemingly healthy patients with attention to the demographics and associated predilection for disease.
We thank Sara Shalin, MD, and Jerad Gardner, MD, for their assistance with the histologic images and description of pathologic findings.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
ORCID iD: Priyenka Thapa https://orcid.org/0000-0001-7518-1916 | UNK (DECREASED BELOW 20 MG/DAY) | DrugDosageText | CC BY-NC | 33533284 | 19,084,609 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | LOPERAMIDE, MAGNESIUM SULFATE, SODIUM BICARBONATE | DrugsGivenReaction | CC BY-NC | 33533290 | 19,002,263 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Confusional state'. | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | LOPERAMIDE, MAGNESIUM SULFATE, SODIUM BICARBONATE | DrugsGivenReaction | CC BY-NC | 33533290 | 19,002,263 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug abuse'. | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | LOPERAMIDE, MAGNESIUM SULFATE, SODIUM BICARBONATE | DrugsGivenReaction | CC BY-NC | 33533290 | 19,036,080 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mood altered'. | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | LOPERAMIDE, MAGNESIUM SULFATE, SODIUM BICARBONATE | DrugsGivenReaction | CC BY-NC | 33533290 | 19,002,263 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Overdose'. | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | LOPERAMIDE, MAGNESIUM SULFATE, SODIUM BICARBONATE | DrugsGivenReaction | CC BY-NC | 33533290 | 19,036,080 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Torsade de pointes'. | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | LOPERAMIDE, MAGNESIUM SULFATE, SODIUM BICARBONATE | DrugsGivenReaction | CC BY-NC | 33533290 | 19,036,080 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ventricular tachycardia'. | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | LOPERAMIDE, MAGNESIUM SULFATE, SODIUM BICARBONATE | DrugsGivenReaction | CC BY-NC | 33533290 | 19,036,080 | 2021 |
What was the administration route of drug 'MAGNESIUM SULFATE'? | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33533290 | 19,036,080 | 2021 |
What was the administration route of drug 'MAGNESIUM'? | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33533290 | 19,034,632 | 2021 |
What was the administration route of drug 'SODIUM BICARBONATE'? | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | Other | DrugAdministrationRoute | CC BY-NC | 33533290 | 19,036,080 | 2021 |
What was the dosage of drug 'SODIUM BICARBONATE'? | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | 150 MILLIEQUIVALENT, QH, INFUSION | DrugDosageText | CC BY-NC | 33533290 | 19,002,263 | 2021 |
What was the outcome of reaction 'Condition aggravated'? | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | Recovering | ReactionOutcome | CC BY-NC | 33533290 | 19,002,263 | 2021 |
What was the outcome of reaction 'Confusional state'? | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | Recovering | ReactionOutcome | CC BY-NC | 33533290 | 19,002,263 | 2021 |
What was the outcome of reaction 'Drug abuse'? | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | Recovering | ReactionOutcome | CC BY-NC | 33533290 | 19,002,263 | 2021 |
What was the outcome of reaction 'Mood altered'? | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | Recovering | ReactionOutcome | CC BY-NC | 33533290 | 19,002,263 | 2021 |
What was the outcome of reaction 'Overdose'? | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | Recovering | ReactionOutcome | CC BY-NC | 33533290 | 19,002,263 | 2021 |
What was the outcome of reaction 'Torsade de pointes'? | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | Recovering | ReactionOutcome | CC BY-NC | 33533290 | 19,036,080 | 2021 |
What was the outcome of reaction 'Ventricular tachycardia'? | A Case Report of Loperamide-Induced Ventricular Storm.
Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide's mechanisms for causing toxicity as well as how to appropriately treat its complications.
Introduction
Loperamide is a common over-the-counter antidiarrheal. It primarily acts on peripheral µ-opioid receptors, but unlike other µ-receptor agonists, loperamide has less central nervous system (CNS) activity. When the medication was developed, it was initially listed as a schedule II medication but later marketed as a nonprescription medication in 1988. This was based on loperamide’s lower abuse potential relative to other medications in the same class, which is attributed to low bioavailability in the CNS.1
With the emergence of the opioid epidemic and the rising number of opioid-related deaths, there have been increasing reports of loperamide being used as alternatives to prescription opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014. At higher than recommended doses (50-300 mg), loperamide has been shown to cross the blood-brain barrier more readily, providing its consumer with both psychotropic and euphoric effects.2
In addition to its CNS effects, high doses of loperamide also act on the cardiac myocytes. Although incompletely understood, loperamide is thought to have a dose-dependent antagonistic effect on the calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported including prolonged QTc, ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, wide complex tachycardia, and even sudden cardiac death. Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the Federal Drug Administration (FDA). Of these 48, 10 patients died and 31 were hospitalized.2 This report highlights a patient admitted to Loma Linda University Medical Center for loperamide intoxication and subsequent VT storm.
Case Report
A 29-year-old female with history of heroin abuse and depression presented after being found altered and confused. At the time, the patient was known to be taking an estimated 300 tablets of loperamide daily for “chronic stomach issues” (1 tablet is 2 mg for an approximate total of 600 mg). Her husband reported that within the past year, he would witness her taking at least one entire bottle of loperamide with roughly 96 tablets up to 3 times per day. There were no other medications reported, including use of any antidepressants.
On presentation, she was tachycardic to 156 BPM (beats per minute) and hypotensive to 70/40 mm Hg. Initial electrocardiogram (ECG) showed polymorphic VT with prolonged QTc of 669 ms (Figures 1 and 2). Subsequently, she developed recurrent episodes of VT that degenerated into torsades de pointes, resulting in multiple cardioversions and her admission to the cardiac intensive care unit.
Figure 1. Electrocardiogram rhythm strip done on route showing ventricular tachycardia.
Figure 2. Continuous cardiac monitoring in the emergency room showing polymorphic ventricular tachycardia.
Preliminary laboratory findings were unremarkable except for the following: leukocytosis 18 bil/L, anion gap 16, and lactate 2.2 mmol/L. Chemistries showed a sodium 136 mmol/L, potassium 4.3 mmol/L, calcium 2.2 mmol/L, and magnesium 1.6 mmol/L. Urine drug screen was positive for cannabinoids, and her chest X-ray was normal. A serum loperamide level was ordered but would not result until after her discharge.
After cardioversion in the emergency room, the patient was stabilized. Repeat ECG shortly after demonstrated a QTc of 515 ms. Poison control was contacted immediately and recommended supportive management. Unfortunately that evening, she began having frequent episodes of nonsustained VT triggered by positional change and vomiting (Figure 3). Additional intravenous magnesium sulfate was given but symptoms persisted. A sodium bicarbonate infusion at 150 mEq/h was initiated per the recommendations of the electrophysiologist on call.
Figure 3. Recurrent nonsustained ventricular tachycardia before anti-arrhythmics.
Several hours later, the patient further decompensated into sustained VT. Electrical cardioversion with 120 J was required to maintain hemodynamic stability. Given her tenuous status and recurrent VT storm, she was intubated and sedated to suppress sympathetic overstimulation. Subsequently, an isoproterenol infusion was started at 2 µg/min to reduce the number of subsequent VT episodes.
After 8 hours without VT, isoproterenol was reduced to 1 µg/min and the bicarbonate infusion was discontinued. Her transthoracic echocardiogram was completed and shown to be normal. Isoproterenol was stopped on day 3, and the patient was extubated. By then, she was free of VT for more than 24 hours and her QTc improved to 500 ms. No additional anti-arrhythmics were started, and the patient was downgraded and later discharged from the hospital (Figure 4).
Figure 4. Sinus bradycardia after anti-arrhythmics.
The final results of her serum loperamide and desmethyl loperamide (the primary metabolite of loperamide) were elevated to 26 ng/mL (normal is <10 ng/mL) and 160 ng/dL (normal is <20 ng/dL), respectively.
Discussion
Loperamide is a common antidiarrheal that acts on peripheral µ-opioid receptors. Unlike other µ-receptor agonists, loperamide has less CNS activity.3 When it was first developed, loperamide was listed as a schedule II medication. By 1988, loperamide was marketed as a nonprescription medication because of its low abuse potential relative to other medications within its class.1
Despite its low abuse potential, there have been increasing reports of loperamide being substituted for other opioids. Between 2008 and 2016, there were 179 cases of loperamide abuse reported to the National Poison Data System with more than 50% being reported after 2014.2 Loperamide is a substrate for the P-glycoprotein transporter found in the intestine and CNS. At appropriate doses, the transporter moves loperamide from the cytosol of the vascular endothelial cells into the vascular lumen, resulting in less absorption through the blood-brain barrier. Supratherapeutic levels of loperamide (50-300 mg) cause the P-glycoprotein transporter to become overwhelmed, allowing more loperamide to be absorbed into the CNS and providing its user with a sensation of euphoria.4-6
In addition to its CNS effect, high doses of loperamide also act on the cardiac myocytes. Loperamide has a dose-dependent antagonistic effect on calcium, sodium, and inward-rectifier potassium channels, resulting in delayed repolarization. Multiple conduction abnormalities have been reported, including prolonged QTc, VT/VF, torsades de pointes, and even sudden cardiac death.3,7 Since loperamide’s approval in 1976, 48 cases of serious cardiac complications have been reported to the FDA. Of these 48, 10 patients died and 31 were hospitalized.2 As a result, the FDA placed a black box warning for torsades de pointes, cardiac arrest, QT prolongation, and death.1,3,8,9
Loperamide’s cardiotoxicity comes from inhibiting sodium and potassium channels. Two channels involved are the hERG voltage-gated potassium channel and the NaV1.5 sodium channel. The hERG voltage-gated potassium channel is responsible for the delayed rectifier current and affects repolarization. The NaV1.5 sodium channel is responsible for fast depolarization during the ventricular action potential. Inhibition of both these channels results in prolonged QT. Loperamide also affects the endothelial release of calcium by modifying calmodulin and decreasing the influx of intracellular calcium that can cause longer QT, hypotension, and bradycardia.3,8,9
Treating loperamide toxicity is mainly supportive and includes the following: advanced cardiopulmonary life support, electrolyte management, sodium bicarbonate, anti-arrhythmic medications, and potentially hemodialysis. Narcan can be used to reverse the opioid effects by competitively antagonizing the µ-receptors. Magnesium cations maintain the gradient between sodium and potassium moving through their respective channels via the magnesium-dependent Na-K-ADPase. By having an appropriate gradient, myocardial stabilization is achieved and the likelihood of arrhythmogenesis is reduced.10 Intravenous sodium bicarbonate works by decreasing sodium channel blockade. This helps drive sodium through both open and closed sodium channels. Sodium bicarbonate also increases pH levels, which inhibits loperamide’s ability to bind to sodium channels.7
As for arrhythmia suppression, amiodarone is a class III anti-arrhythmic with following properties: prolongation of the action potential by acting on electrolyte channels reduced AV conduction and inhibition of adrenergic stimulation. Lidocaine is a class Ib anti-arrhythmic that acts by inhibiting sodium channels. Isoproterenol is an inotropic and chronotropic medication that acts on both β-1 and β-2 adrenergic receptors. By increasing heart rate and decreasing repolarization, isoproterenol reduces the QT interval and accelerates atrioventricular nodal conduction.7,10 Mechanical ventilation and sedation help reduce the sympathetic surge, thereby decreasing the trigger for VT storm. In the setting of severe acidosis and other electrolyte derangement, hemodialysis can be used to directly remove loperamide.
Amiodarone and lidocaine were avoided in this scenario to minimize the risk of further QTc prolongation and additional sodium channel blockade. Isoproterenol had no effect on either and thus became the obvious treatment choice. Narcan was not used because patient’s cognition and cardiorespiratory functions were normal. Hemodialysis was never required since her cardiac function improved on isoproterenol.
Conclusion
Loperamide toxicity is a growing concern in health care due to its accessibility and abuse potential. As our case demonstrates, these patients should be closely monitored for cardiac toxicity with telemetry and serial ECGs. In these particular patients who use loperamide for its abuse potential, there is the possibility for other drugs to be in their system that could also induce cardiac arrhythmias. Although unlikely in this situation given the significant dose of loperamide ingested and her urine drug screen being positive for cannabinoid only. Initial management should include contacting poison control, correcting electrolytes, and cardiopulmonary support. Sodium bicarbonate and an appropriate anti-arrhythmic should be started immediately. Mechanical ventilation and sedation reduce sympathetic surge during the VT storm. Hemodialysis should be considered if the patient’s clinical status does not improve.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Ethical approval to report this case was obtained from the institutional review board (IRB# 5200351).
Informed Consent: Informed consent for patient information to be published in this article was not obtained because the institutional review board determined that this activity did not meet the definition of human subject research and no personal identifiers were used.
ORCID iD: Jerome De Vera
https://orcid.org/0000-0002-4970-5525 | Recovered | ReactionOutcome | CC BY-NC | 33533290 | 19,036,080 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Apnoea'. | A post-incorporation study on the use of palivizumab in the Brazilian public health system.
Respiratory syncytial virus (RSV) is the main cause of lower respiratory disease in infants and children under five years of age. As there is no specific treatment for RSV infections, prophylaxis with the specific monoclonal antibody palivizumab (PVZ) has been widely recommended for high-risk cases during the RSV season. The present study aimed to evaluate the effectiveness of a public prophylaxis program with palivizumab on the incidence of hospitalizations for lower respiratory tract infections and RSV in children at high risk for severe RSV infections. A retrospective cohort study was carried out with preterm children or children under two years of age with chronic lung disease or hemodynamically significant congenital heart disease; the children were selected on the basis of their exposure status, which was defined as the prophylactic use of palivizumab during the RSV season. Children were enrolled retrospectively in two hospitals located in Southern Brazil, from May 2009 to August 2016. In a sample of 129 children, 69 (53.5%) received palivizumab and adherence to three or more doses was observed in 78%; 60 (46.5%) children did not receive palivizumab. PVZ prophylaxis was independently associated with a 66% reduction in hospitalizations for any cause (26/69 - 37.7%) in the PVZ group and 34/60 (56.7%) in the control group). A 52% reduction in hospitalizations due to lower respiratory tract infection was observed in the PVZ group (15/69 -21.7%) and 25/60 (41.7%) in the control group. These findings suggest that, for the group of studied patients, the adoption of an RSV prophylaxis scheme reached the same effectiveness as those described in previous clinical trials.
INTRODUCTION
Respiratory syncytial virus (RSV) is one of the main etiological agents of infections affecting the lower respiratory tract among infants and children under five years of age, and it accounts for nearly 75% of bronchiolitis and 40% of pneumonia cases in infants up to one year of age during the RSV season1,2. Usually, the first infection progresses as an ordinary cold; however, severe RSV infections are responsible for hospitalization and, eventually, the need of mechanical ventilation (MV), mostly in children of less than 1 year of age1,3.
As there is no specific treatment for RSV infections, prophylaxis with the specific monoclonal antibody palivizumab (PVZ) has been widely recommended for high-risk cases during RSV season4. The groups with a higher risk of severe respiratory disease caused by RSV are premature infants, children with chronic lung disease of prematurity, immunosuppressed children and children suffering from heart conditions, especially those with hemodynamic consequences1.
The effectiveness of palivizumab in reducing hospitalizations due to RSV in infants has been demonstrated in randomized clinical trials, ranging from 39 to 78% in two pivotal clinical trials5-7. Evidence from observational studies suggests that PVZ prophylaxis reduces the incidence of recurrent wheezing over the first six years of life; however, it does not prevent the onset of atopic asthma8,9.
In December 2012, PVZ was introduced in the Brazilian public health system (SUS) for use in high-risk cases and premature infants at a gestational age equal to or less than 32 weeks10; this decision was amended in 2013, with prophylaxis being recommended for infants under one year of age who were born prematurely at a gestational age equal to or less than 28 weeks, as well as in children up to two years of age suffering from chronic lung disease or hemodynamically significant congenital heart disease11.
Since the drug was incorporated into SUS, few studies have assessed the impact of the use of palivizumab on lower respiratory tract infection rates in children at high risk for respiratory syncytial virus infections. Post-incorporation studies are crucial to monitor the outcomes achieved with the use of this approach. The present study aimed to evaluate the effectiveness of a public prophylaxis program with palivizumab on the incidence of hospitalizations for lower respiratory tract infections and RSV cases in children at high-risk for severe RSV infections.
MATERIAL AND METHODS
Study design
A retrospective cohort study was conducted. The medical records of preterm children and/or children under two years of age suffering from chronic lung disease or hemodynamically significant congenital heart disease were reviewed for data collection. Children were selected according to their exposure status, which was defined as the prophylactic use of at least one dose of palivizumab with monthly doses of palivizumab during the RSV season (between April and August). Children were retrospectively recruited at the Hospital Materno Infantil Presidente Vargas (HMIPV) and Hospital de Clinicas de Porto Alegre – RS (HCPA), both located in the city of Porto Alegre, in Southern Brazil. Although palivizumab was incorporated into the Brazilian public health system in 2013, due to the differences among Brazilian regions regarding drug acquisition and distribution and the issues of availability of electronic medical records in one of the centers, the study period started in 2014. The cases (PVZ group) were chosen from May 2014 to August 2016, a period subsequent to the incorporation of palivizumab into SUS, and controls were chosen from May 2009 to August 2016. The initial date for the controls recruitment was extended to include the period prior to PVZ incorporation due to the difficulty in gathering a sufficient number of children with indication but who did not take PVZ after 2014, in the health services assessed. The follow-up was censored in June 2017. The study period was up to two years following the first dose of palivizumab for exposed cases or up to two years after the identification of the indication criterium for the use of PVZ in the medical records, as recommended by the Ministry of Health for controls.
The study included children who met one of the following three criteria: 1) prematurity, defined as a gestational age at birth ≤ 28 weeks; 2) less than two years of age with chronic lung disease resulting from prematurity; or 3) less than two years of age with hemodynamically significant congenital heart disease.
The list of children who received palivizumab was elaborated according to palivizumab dispensation records from the hospital pharmacies. Children in the control group were identified from the medical records of children hospitalized in neonatal or pediatric units during the study period, as indicated by International Classification of Diseases codes for prematurity or chronic lung disease resulting from prematurity or congenital heart disease. Children transferred from other health services were excluded.
Outcomes were assessed by analyzing data from the medical records according to the diagnosis made in the health service unit by the attending physician. The outcomes were grouped into four categories: 1) hospitalization for any reason (hospitalization rate); 2) hospitalization for lower respiratory tract infection regardless of etiology (ICD 10: J20 – J22); 3) hospitalization for respiratory syncytial virus infection (ICD 10: B97.4, J12.1, J20.5, or J21.0) and 4) death from any cause.
Sample size and data analysis
The sample size was calculated using the EPI-INFO software, version 7.2, considering the following parameters for a cohort study: 80% test power; 95% confidence level (α = 5); an expected risk value to be detected of 0.6; and an expected emergency admission rate due to respiratory causes among the unexposed of 64% according to the pilot study conducted at the HCPA. The total sample size calculated based on these parameters was 134 (67 exposed and 67 unexposed).
A descriptive analysis on the frequency distribution of risk factors was carried out according to the exposure groups in the cohort. Student’s t test was used to compare the means for some characteristics between the PVZ and control groups.
As the cohort groups had different years of inclusion as it was difficult to find children with indications for the use that were not using prophylaxis after PVZ was incorporated into SUS, it was decided that the year of entry into the cohort would be included as an independent variable to be tested.
A logistic regression analysis was performed to identify predictors of hospitalization. The variables that were significant in the bivariate analysis (with a p-value ≤ 0.25) were included in the multivariate logistic regression model. Backward and Irtest multivariate analyses were performed after the removal of each variable to verify whether this procedure had an impact on the model. The odds ratio (OR), relative risks (RR) and 95% confidence intervals were calculated. The data were entered into and stored in REDCap (Research Electronic Data Capture) and analyzed using STATA software, version 11.2 (Stata-Corp LP, College Station,Texas, USA). The study was approved by the ethics committees of Hospital Materno Infantil Presidente Vargas and Hospital de Clinicas de Porto Alegre.
RESULTS
One hundred and twenty-nine children were included in the study; 69 (53.5%) were exposed to palivizumab (cases) and 60 (46.5%) were in the unexposed group (controls). Most children (91/129 - 70.5) were included based on a gestational age equal to or less than 28 weeks and six days, followed by those with less than two years of age and with chronic lung disease of prematurity (28/129 - 21.7%), less than two years of age and suffering from heart disease and severe lung hypertension (7/129 - 5.4%), and those with more than two years of age suffering from complex congenital heart disease (3/129 - 2.3%). Seventy nine children lived in the city of Porto Alegre (61.2%), 106 were born from single pregnancies (82.2%) and 91(70.5%) were breastfed. For the city of residence, there was a difference between the groups, as most of the unexposed (36/60 - 60%) lived in other cities, while those who received PVZ (55/69 - 79.7%) were mostly Porto Alegre residents (p<0.001). The control group children were less breastfed (38/53 - 71.7%) than the group receiving palivizumab (53/58 - 91.4%) (p<0.01). Clinical and demographic characteristics are shown in Table 1.
Table 1 Demographic and clinical characteristics of children meeting the criteria for the use of palivizumab, treated at Hospital de Clinicas de Porto Alegre and Hospital Presidente Vargas, Porto Alegre, 2017.
Characteristics Using PVZ mean Not using PVZ mean
P*
Age at PVZ indication
months 7.33 3.67
0.000
Weight at birth
grams 1.177 1.059
0.188
Gestational age at birth
weeks 29.24 29.14
0.855
Number of people in household
4.39 4.71
0.401
Length of stay in the neonatal ICU
days 78.7 77.0
0.825
*P from Student’s t test
Of the 69 children who received palivizumab, 28 (40.6%) received five doses, 13 (18.8%) received four doses, 13 (18.8%) received three doses, 13 (18.8%) received two doses, and two (2.9%) received one dose. It was noted that, in some cases, the first dose was taken up to three months after the beginning of the RSV season. Among patients who received palivizumab, 46 (66.7%) received all the necessary doses during the RSV season, 11 (15.9%) missed only one month, and the remainder 12 (17.4%) missed two months or more during the RSV season. Side effects were recorded in three (4.3%) children: a case of apnea with cyanosis, a case of low fever after the administration of the first dose (37.4 °C ), and a case of cutaneous rash.
Analysis of hospitalization for any cause
Among children who did not receive palivizumab, 34 (56.7%) were hospitalized during the follow-up, and among those who received palivizumab, 26 (37.7%) children were hospitalized (p=0.024). The mean hospital length of stay in the palivizumab group was 9.54 days, and in the control group, it was 8.75 days (p=0.81). Among hospitalized patients, only five children needed mechanical ventilation, three from the control group and two from the PVZ group. The mean mechanical ventilation time was 6.3 days for the controls and 3.0 days for those who received palivizumab (p=0.12).
The main reason for hospitalization was bronchopneumonia, which was responsible for 23.3% of the total hospitalizations (14/60), followed by acute bronchiolitis (10/60 - 16.7%), acute bronchitis (6/60 - 10%), acute bronchiolitis caused by RSV (6/60 or 10%), and asthma (5/60 - 8.3%). All other reasons for hospitalization accounted for only one case (1/60 - 1.7 %) each.
The incidence rate of hospitalization for any cause was 45.7 per 100 people/year (95% CI: 35.5-58.9). In the group of children who did not take palivizumab (control group), the density of hospitalization incidence was 59.2 per 100 people/year (95% CI: 42.3-82.9), and in the children who used palivizumab, it was 35.2 per 100 people/year (95% CI: 23.9-51.7).
Table 2 shows the bivariate analyses of variables associated with hospitalization for any cause. There was no association between the year of entry into the cohort and hospitalization for any cause, indicated by a p-value > 0.25 (p= 0.879); therefore, this variable was not included in the multivariate model (data not shown in the table).
Table 2 Bivariate analysis of parameters associated with hospitalization for any cause in children with indication for the use of palivizumab, Porto Alegre, 2017.
Hospitalization for any cause OR (95% CI)
p
Yes n (%) No n (%)
Use of prophylactic palivizumab
Yes 26 (37.7) 43 (62.3) 1.0
No 34 (56.7) 26 (43.3) 0.46 (0.23 - 0.94)
0.032
Sex
Female 32 (45.7) 38 (54.3) 1.0
Male 28 (47.5) 31 (52.5) 1.07 (0.54 - 2.15) 0.843
Place of residence
Porto Alegre 35 (44.3) 44 (55.7) 1.0
Another city 25 (50.0) 25 (50.0) 1.26 (0.62 - 2.56) 0.528
Number of people in household
Up to 3 people 09 (37.5) 15 (62.5) 1.0
4 people or more 22 (37.9) 36 (62.1) 1.02 (0.38 - 2.72) 0.971
Main reason for inclusion in the study
Prematurity 46 (50.5) 45 (49.5) 1.0
Lung or heart disease 14 (36.8) 24 (63.2) 0.57 (0.26 - 1.24) 0.157
Breastfeeding records
Yes 43 (47.2) 48 (52.8) 1.0
No 09 (45.0) 11 (55.0) 0.91 (0.34 - 2.41) 0.855
For those who used PVZ:
Number of doses administered
Three or more 21 (38.9) 33 (61.1) 1.0
Up to two 05 (33.3) 10 (66.7) 0.78 (0.23 – 2.62) 0.695
*Adjusted per year of entry into the study
Table 3 shows the final result of the multivariate model for predictors of hospitalization for any cause. The variables with p ≤ 0.25 were added to the saturated model and then removed one by one from the model as the p-value increased, until only those that were statistically significant (p < 0.05) remained. Only the use of palivizumab remained in the final model as a significant variable.
Table 3 Final multivariate analysis of the association between hospitalization for any cause and exposure elements of individuals, Porto Alegre, 2017.
Odds Ratio and 95% CI
p
Relative Risk and 95% CI
p
PAF
Use of prophylactic palivizumab
Yes 1.0 1.0
No 0.46 (0.23 - 0.94) 0.032 0.66 (0.46 -0.97) 0.031 -0.50
PAF = Population Attributable Fraction
There was no difference in the number of doses of PVZ between children hospitalized for any reason (mean of 3.73 doses) and those that were not hospitalized (mean of 3.77 doses; p= 0.91).
Analysis of hospitalization due to lower respiratory tract infections
Among the children using palivizumab, hospitalizations for lower respiratory tract infections were noted in 21.7% (15/69), while in those who did not receive palivizumab, hospitalizations were observed in 41.7% (25/60) (p=0.01). The incidence rate of hospitalization for lower respiratory tract infection was 26.0 per 100 people/year (95% CI: 19.1 - 35.5). In children who did not take palivizumab (control group), the density of hospitalization incidence was 35.3 per 100 people/year (95% CI: 23.9 - 52.2), and in the children who used palivizumab, the calculated rate was 18.1 per 100 people/year (95% CI: 10.9 - 30.0).
Table 4 shows the bivariate analyses of elements possibly associated with hospitalization for lower respiratory tract infections. The bivariate analysis of the association between the year of entry into the cohort and hospitalization for lower respiratory tract infections showed a p value > 0.25 (p = 0.43); thus, it was not a candidate for inclusion in the multivariate model (data not shown in the table).
Table 4 Bivariate analysis of parameters associated with hospitalization for lower respiratory tract infections in children with indication for the use of palivizumab, Porto Alegre, 2017.
Hospitalization for lower respiratory tract infections OR (95% CI)
p
Yes n (%) No n (%)
Use of prophylactic palivizumab
Yes 15 (21.7) 54 (78.3) 1.0
No 25 (41.7) 35 (58.3) 0.39 (0.18 - 0.84)
0.016
Sex
Female 24 (34.3) 46 (65.7) 1.0
Male 16 (27.1) 43 (72.9) 0.71 (0.33- 1.52) 0.381
Place of residence
Porto Alegre 21 (26.6) 58 (73.4) 1.0
Another city 19 (38.0) 31 (62.0) 1.69 (0.79 - 3.61) 0.174
Number of people in household
Up to 3 people 04 (16.7) 20 (83.3) 1.0
4 people or more 16 (27.6) 42 (72.4) 1.90 (0.56 - 6.44) 0.300
Main reason for inclusion in the study
Prematurity 31 (34.1) 60 (65.9) 1.0
Lung or heart disease 09 (23.7) 29 (76.3) 0.60 (0.25 - 1.42) 0.248
Breastfeeding records
Yes 29 (31.9) 62 (68.1) 1.0
No 07 (35.0) 13 (65.0) 1.15 (0.41 - 3.19) 0.787
For those who used PVZ:
Number of doses administered
Three or more 11 (20.4) 43 (79.6) 1.0
Up to two 04 (26.7) 11 (73.3) 1.42 (0.38 - 5.33) 0.602
*Adjusted per year of entry into the study
Table 5 shows the results of the final multivariate analysis model for the association between the studied parameters and hospitalization for lower respiratory tract infections. Variables were removed from the model as the p-value increased until only the statistically significant ones remained (p < 0.05).
Table 5 Final multivariate analysis of the association between hospitalization for lower respiratory tract infections and exposure elements of individuals, Porto Alegre, 2017.
Odds Ratio and 95% CI
p
Relative Risk and 95% CI
p
PAF
Use of prophylactic palivizumab
Yes 1.0 1.0
No 0.39 (0.18 - 0.84) 0.016 0.52 (0.30 - 0.89) 0.014 -0.59
Six hospitalizations with laboratory confirmation of respiratory syncytial virus infections were recorded, all of which were in the control group. The rate of respiratory syncytial virus infection in the cohort was 3.2 per 100 people/year (95% CI: 1.42-7.04). As this was a retrospective study, RSV infection was only considered when the diagnosis was recorded in the medical records, and it is not possible to know whether all the patients were actually tested for RSV, as this is a retrospective study.
General analysis of the sample
The use of palivizumab remained independently associated with hospitalization for any cause and hospitalization for lower respiratory tract infections, was a protective factor, with relative risk reductions of 66% and 52%, respectively. The population attributable fraction associated with the use of palivizumab for hospitalizations for any cause was –0.50 and for hospitalization for lower respiratory tract infections was –0.59; that is, it is estimated that palivizumab decreases hospitalizations for any cause by 50% and hospitalizations for lower respiratory tract infections by 59%.
Only one death was observed in the cohort, and it occurred 1.2 years after the date of inclusion; this child was in the control group. The death rate in the cohort was 3.7 per 1,000 people/year (95% CI: 0.53-26.6).
DISCUSSION
Palivizumab prophylaxis was independently associated with a reduction in hospitalizations for any cause and hospitalization due to lower respiratory tract infections in patients at high risk of RSV infection.
The two-year rate of hospitalization for any cause in the cohort was 46.5% and it is noteworthy that this was a more vulnerable group, given that children were premature and/ or suffered from pulmonary or cardiacdiseases. The hospitalization rate among those who did not receive palivizumab was higher for both, hospitalizations for any cause (56.7%) and hospitalizations for lower respiratory tract infections (41.7% versus 31%). These findings are corroborated by the result of the multivariate analyses as well as the calculation of the population attributable fraction, according to which, palivizumab reduced hospitalizations for any cause by 50% and hospitalizations for lower respiratory tract infections by 59%.
The rate of hospitalization for lower respiratory tract infections among those who received palivizumab (21.7%) was higher than the rate of hospitalization for acute respiratory tract infections (12.9%) described in Canada during the 2004 and 2005 seasons12. It is important to stress that regarding the children who received palivizumab that we assessed, the first dose was administered up to three months after the beginning of the RSV season, which may indicate a delay in palivizumab prescription or in the patient’s visit to the referral center after receiving the palivizumab prescription at the original hospital.
The effectiveness of palivizumab in reducing hospitalization due to respiratory syncytial virus was shown in the IMpact-RSV study6, a randomized double-blind clinical trial that included 1,502 premature children (up to 35 weeks of gestational age) or with bronchopulmonary dysplasia; the trial was conducted in the United States, United Kingdom and Canada in the late 1990s. In that trial, a 55% decrease in hospitalizations for RSV was observed in the group treated with palivizumab (4.8%) compared with the group that received placebo (10.6%). The hospitalization rate for RSV in the placebo group of the IMpact-RSV study was similar to the rate found in those unexposed to PVZ in our study, which was 10%. In another multicenter clinical trial5, a relative decrease of 45% in hospitalizations for RSV resulting from the use of palivizumab was described. A systematic review carried out in 2011 has also evaluated the RSV hospitalization rate among groups who received PVZ, the summarized measure of which was 0.35 for the premature infants group (p < 0.001)13. Although it was not possible to assess the reduction in RSV-specific hospitalizations in this study as this outcome did not occur in the exposed group, the observed data indicate that the use of palivizumab decreases hospitalizations for any cause by 50%.
The clinical trials comparing exposure to palivizumab with the use of placebo in the literature are international studies with different realities in terms of respiratory infection profiles. The studies that provided the basis for indicating the incorporation of palivizumab by CONITEC were published prior to 2010, and little has been done after this incorporation, especially in view of the ethical issue that makes it difficult to gather/ form a control group. In Brazil, studies on the topic are scarce, and our results can only be compared with the cohort study conducted by Monteiro et al.1, in 2014 with patients subjected to palivizumab prophylaxis; this study was performed without a control group for ethical reasons. Among the children who received palivizumab, the rate of hospitalization for lower respiratory tract infections was 9.1%1, a much lower rate than that found in this study (21.7%). The Southern region of the country may present a different respiratory infection profile due to climate characteristics, with a more distinct winter and lower temperatures, as well as to an increase in the seasonality of RSV and other respiratory viruses.
As this was a retrospective study, it was not possible to ensure that all patients with acute lower respiratory tract infections underwent laboratory tests for respiratory syncytial virus, which may explain the low rate of RSV-positive infections among the patients with bronchiolitis, bronchitis and bronchopneumonia (16.7%). This percentage is much lower than the rate found by Souza in Porto Alegre14, who identified RSV in 59% of samples from infants up to 12 months of age with bronchiolitis; unfortunately, these patients were recruited between September 2009 and August 2011, prior to the incorporation of PVZ by the public health system.
There was a difference in the mean age of the patients chosen for the cohort, with the group using palivizumab being in general older than the unexposed group. This difference may have resulted from the fact that the controls were included upon the observation of the indication of palivizumab in accordance with criteria specified by the Brazilian Ministry of Health, while the cases that received palivizumab were included from the date of the first dose, which indicates the date of initial exposure to the drug under study. As there is a difference between the date of prescription and the first date the drug was administered, especially because the only referral hospital for the treatment with palivizumab was the HMIPV, there may have been a delay in the patient’s visit to this specialized service. At the HCPA, the doses were administered only to hospitalized patients, while outpatients were referred to the HMIPV.
Another difference found between the exposure groups was related to the patients’ cities of residence. Most children in the group unexposed to palivizumab (60%) lived in cities other than the capital city Porto Alegre.
The hospitals included in this study are referral hospitals located in the metropolitan area of Porto Alegre. The unexposed patients from other cities may have risen questions about the prescription and the use of palivizumab in hospitals located in their home cities; however, to avoid this bias, only patients with at least two years of outpatient follow-up at the referral hospital and frequent visits were selected to ensure that their medical records really included information on medications occasionally administered in their cities of residence.
An important point in the monitoring of new components incorporated into the public health system should take into account the cost of prophylaxis in relation to the benefits it offers, ideally through a complete cost-effectiveness study. It would be important to analyze the increase in drug costs to the budget of the public health system, taking into account favorable outcomes, such as a decrease in hospitalizations and problems for patients and their families. Unfortunately, these economic issues were not analyzed in this study and should be addressed in future research.
The limitations of the study were those inherent to the retrospective cohort study design itself, such as the inability to retrospectively collect some variables that are possibly association confounders (in this case, socioeconomic variables). Regarding the external validity, this study produced specific results as it was conducted at referral hospitals and in a capital city located in the Southern region of the country, where seasonality is well defined and high incidence levels of respiratory infections are often experienced in winter, what makes this region stand out from the rest.
CONCLUSION
The use of PVZ has been approved in several countries, although its effectiveness is controversial in developing countries and in places with a low incidence of respiratory infections. In Brazil, there were many questions regarding the effectiveness of this drug for the Brazilian population at the time of its recommendation in view of sociodemographic, epidemiological and even geographical differences. This study sought to address a key aspect of monitoring the incorporation of new concepts into the public health system in an attempt to reinvigorate the process based on the successes and mistakes resulting from the decisions made. The results suggest that the adoption of this prophylactic program achieved the expected effectiveness for the studied patients corroborating the findings of previously published international clinical trials.
ACKNOWLEDGMENTS
We thank Dr. Ana Maria Araujo Cirne and Dr. Cintia Beatriz Momo Selister for their support in data collection.
FUNDING.The study was sponsored and coordinated by the Moinhos de Vento Hospital, Brazil, in partnership with the Brazilian Ministry of Health through the Program of Institutional Development of the Brazilian Unified Health System (PROADI-SUS) (Project 01553 - ATS/PROADI HMV). | PALIVIZUMAB | DrugsGivenReaction | CC BY-NC | 33533808 | 18,940,182 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cyanosis'. | A post-incorporation study on the use of palivizumab in the Brazilian public health system.
Respiratory syncytial virus (RSV) is the main cause of lower respiratory disease in infants and children under five years of age. As there is no specific treatment for RSV infections, prophylaxis with the specific monoclonal antibody palivizumab (PVZ) has been widely recommended for high-risk cases during the RSV season. The present study aimed to evaluate the effectiveness of a public prophylaxis program with palivizumab on the incidence of hospitalizations for lower respiratory tract infections and RSV in children at high risk for severe RSV infections. A retrospective cohort study was carried out with preterm children or children under two years of age with chronic lung disease or hemodynamically significant congenital heart disease; the children were selected on the basis of their exposure status, which was defined as the prophylactic use of palivizumab during the RSV season. Children were enrolled retrospectively in two hospitals located in Southern Brazil, from May 2009 to August 2016. In a sample of 129 children, 69 (53.5%) received palivizumab and adherence to three or more doses was observed in 78%; 60 (46.5%) children did not receive palivizumab. PVZ prophylaxis was independently associated with a 66% reduction in hospitalizations for any cause (26/69 - 37.7%) in the PVZ group and 34/60 (56.7%) in the control group). A 52% reduction in hospitalizations due to lower respiratory tract infection was observed in the PVZ group (15/69 -21.7%) and 25/60 (41.7%) in the control group. These findings suggest that, for the group of studied patients, the adoption of an RSV prophylaxis scheme reached the same effectiveness as those described in previous clinical trials.
INTRODUCTION
Respiratory syncytial virus (RSV) is one of the main etiological agents of infections affecting the lower respiratory tract among infants and children under five years of age, and it accounts for nearly 75% of bronchiolitis and 40% of pneumonia cases in infants up to one year of age during the RSV season1,2. Usually, the first infection progresses as an ordinary cold; however, severe RSV infections are responsible for hospitalization and, eventually, the need of mechanical ventilation (MV), mostly in children of less than 1 year of age1,3.
As there is no specific treatment for RSV infections, prophylaxis with the specific monoclonal antibody palivizumab (PVZ) has been widely recommended for high-risk cases during RSV season4. The groups with a higher risk of severe respiratory disease caused by RSV are premature infants, children with chronic lung disease of prematurity, immunosuppressed children and children suffering from heart conditions, especially those with hemodynamic consequences1.
The effectiveness of palivizumab in reducing hospitalizations due to RSV in infants has been demonstrated in randomized clinical trials, ranging from 39 to 78% in two pivotal clinical trials5-7. Evidence from observational studies suggests that PVZ prophylaxis reduces the incidence of recurrent wheezing over the first six years of life; however, it does not prevent the onset of atopic asthma8,9.
In December 2012, PVZ was introduced in the Brazilian public health system (SUS) for use in high-risk cases and premature infants at a gestational age equal to or less than 32 weeks10; this decision was amended in 2013, with prophylaxis being recommended for infants under one year of age who were born prematurely at a gestational age equal to or less than 28 weeks, as well as in children up to two years of age suffering from chronic lung disease or hemodynamically significant congenital heart disease11.
Since the drug was incorporated into SUS, few studies have assessed the impact of the use of palivizumab on lower respiratory tract infection rates in children at high risk for respiratory syncytial virus infections. Post-incorporation studies are crucial to monitor the outcomes achieved with the use of this approach. The present study aimed to evaluate the effectiveness of a public prophylaxis program with palivizumab on the incidence of hospitalizations for lower respiratory tract infections and RSV cases in children at high-risk for severe RSV infections.
MATERIAL AND METHODS
Study design
A retrospective cohort study was conducted. The medical records of preterm children and/or children under two years of age suffering from chronic lung disease or hemodynamically significant congenital heart disease were reviewed for data collection. Children were selected according to their exposure status, which was defined as the prophylactic use of at least one dose of palivizumab with monthly doses of palivizumab during the RSV season (between April and August). Children were retrospectively recruited at the Hospital Materno Infantil Presidente Vargas (HMIPV) and Hospital de Clinicas de Porto Alegre – RS (HCPA), both located in the city of Porto Alegre, in Southern Brazil. Although palivizumab was incorporated into the Brazilian public health system in 2013, due to the differences among Brazilian regions regarding drug acquisition and distribution and the issues of availability of electronic medical records in one of the centers, the study period started in 2014. The cases (PVZ group) were chosen from May 2014 to August 2016, a period subsequent to the incorporation of palivizumab into SUS, and controls were chosen from May 2009 to August 2016. The initial date for the controls recruitment was extended to include the period prior to PVZ incorporation due to the difficulty in gathering a sufficient number of children with indication but who did not take PVZ after 2014, in the health services assessed. The follow-up was censored in June 2017. The study period was up to two years following the first dose of palivizumab for exposed cases or up to two years after the identification of the indication criterium for the use of PVZ in the medical records, as recommended by the Ministry of Health for controls.
The study included children who met one of the following three criteria: 1) prematurity, defined as a gestational age at birth ≤ 28 weeks; 2) less than two years of age with chronic lung disease resulting from prematurity; or 3) less than two years of age with hemodynamically significant congenital heart disease.
The list of children who received palivizumab was elaborated according to palivizumab dispensation records from the hospital pharmacies. Children in the control group were identified from the medical records of children hospitalized in neonatal or pediatric units during the study period, as indicated by International Classification of Diseases codes for prematurity or chronic lung disease resulting from prematurity or congenital heart disease. Children transferred from other health services were excluded.
Outcomes were assessed by analyzing data from the medical records according to the diagnosis made in the health service unit by the attending physician. The outcomes were grouped into four categories: 1) hospitalization for any reason (hospitalization rate); 2) hospitalization for lower respiratory tract infection regardless of etiology (ICD 10: J20 – J22); 3) hospitalization for respiratory syncytial virus infection (ICD 10: B97.4, J12.1, J20.5, or J21.0) and 4) death from any cause.
Sample size and data analysis
The sample size was calculated using the EPI-INFO software, version 7.2, considering the following parameters for a cohort study: 80% test power; 95% confidence level (α = 5); an expected risk value to be detected of 0.6; and an expected emergency admission rate due to respiratory causes among the unexposed of 64% according to the pilot study conducted at the HCPA. The total sample size calculated based on these parameters was 134 (67 exposed and 67 unexposed).
A descriptive analysis on the frequency distribution of risk factors was carried out according to the exposure groups in the cohort. Student’s t test was used to compare the means for some characteristics between the PVZ and control groups.
As the cohort groups had different years of inclusion as it was difficult to find children with indications for the use that were not using prophylaxis after PVZ was incorporated into SUS, it was decided that the year of entry into the cohort would be included as an independent variable to be tested.
A logistic regression analysis was performed to identify predictors of hospitalization. The variables that were significant in the bivariate analysis (with a p-value ≤ 0.25) were included in the multivariate logistic regression model. Backward and Irtest multivariate analyses were performed after the removal of each variable to verify whether this procedure had an impact on the model. The odds ratio (OR), relative risks (RR) and 95% confidence intervals were calculated. The data were entered into and stored in REDCap (Research Electronic Data Capture) and analyzed using STATA software, version 11.2 (Stata-Corp LP, College Station,Texas, USA). The study was approved by the ethics committees of Hospital Materno Infantil Presidente Vargas and Hospital de Clinicas de Porto Alegre.
RESULTS
One hundred and twenty-nine children were included in the study; 69 (53.5%) were exposed to palivizumab (cases) and 60 (46.5%) were in the unexposed group (controls). Most children (91/129 - 70.5) were included based on a gestational age equal to or less than 28 weeks and six days, followed by those with less than two years of age and with chronic lung disease of prematurity (28/129 - 21.7%), less than two years of age and suffering from heart disease and severe lung hypertension (7/129 - 5.4%), and those with more than two years of age suffering from complex congenital heart disease (3/129 - 2.3%). Seventy nine children lived in the city of Porto Alegre (61.2%), 106 were born from single pregnancies (82.2%) and 91(70.5%) were breastfed. For the city of residence, there was a difference between the groups, as most of the unexposed (36/60 - 60%) lived in other cities, while those who received PVZ (55/69 - 79.7%) were mostly Porto Alegre residents (p<0.001). The control group children were less breastfed (38/53 - 71.7%) than the group receiving palivizumab (53/58 - 91.4%) (p<0.01). Clinical and demographic characteristics are shown in Table 1.
Table 1 Demographic and clinical characteristics of children meeting the criteria for the use of palivizumab, treated at Hospital de Clinicas de Porto Alegre and Hospital Presidente Vargas, Porto Alegre, 2017.
Characteristics Using PVZ mean Not using PVZ mean
P*
Age at PVZ indication
months 7.33 3.67
0.000
Weight at birth
grams 1.177 1.059
0.188
Gestational age at birth
weeks 29.24 29.14
0.855
Number of people in household
4.39 4.71
0.401
Length of stay in the neonatal ICU
days 78.7 77.0
0.825
*P from Student’s t test
Of the 69 children who received palivizumab, 28 (40.6%) received five doses, 13 (18.8%) received four doses, 13 (18.8%) received three doses, 13 (18.8%) received two doses, and two (2.9%) received one dose. It was noted that, in some cases, the first dose was taken up to three months after the beginning of the RSV season. Among patients who received palivizumab, 46 (66.7%) received all the necessary doses during the RSV season, 11 (15.9%) missed only one month, and the remainder 12 (17.4%) missed two months or more during the RSV season. Side effects were recorded in three (4.3%) children: a case of apnea with cyanosis, a case of low fever after the administration of the first dose (37.4 °C ), and a case of cutaneous rash.
Analysis of hospitalization for any cause
Among children who did not receive palivizumab, 34 (56.7%) were hospitalized during the follow-up, and among those who received palivizumab, 26 (37.7%) children were hospitalized (p=0.024). The mean hospital length of stay in the palivizumab group was 9.54 days, and in the control group, it was 8.75 days (p=0.81). Among hospitalized patients, only five children needed mechanical ventilation, three from the control group and two from the PVZ group. The mean mechanical ventilation time was 6.3 days for the controls and 3.0 days for those who received palivizumab (p=0.12).
The main reason for hospitalization was bronchopneumonia, which was responsible for 23.3% of the total hospitalizations (14/60), followed by acute bronchiolitis (10/60 - 16.7%), acute bronchitis (6/60 - 10%), acute bronchiolitis caused by RSV (6/60 or 10%), and asthma (5/60 - 8.3%). All other reasons for hospitalization accounted for only one case (1/60 - 1.7 %) each.
The incidence rate of hospitalization for any cause was 45.7 per 100 people/year (95% CI: 35.5-58.9). In the group of children who did not take palivizumab (control group), the density of hospitalization incidence was 59.2 per 100 people/year (95% CI: 42.3-82.9), and in the children who used palivizumab, it was 35.2 per 100 people/year (95% CI: 23.9-51.7).
Table 2 shows the bivariate analyses of variables associated with hospitalization for any cause. There was no association between the year of entry into the cohort and hospitalization for any cause, indicated by a p-value > 0.25 (p= 0.879); therefore, this variable was not included in the multivariate model (data not shown in the table).
Table 2 Bivariate analysis of parameters associated with hospitalization for any cause in children with indication for the use of palivizumab, Porto Alegre, 2017.
Hospitalization for any cause OR (95% CI)
p
Yes n (%) No n (%)
Use of prophylactic palivizumab
Yes 26 (37.7) 43 (62.3) 1.0
No 34 (56.7) 26 (43.3) 0.46 (0.23 - 0.94)
0.032
Sex
Female 32 (45.7) 38 (54.3) 1.0
Male 28 (47.5) 31 (52.5) 1.07 (0.54 - 2.15) 0.843
Place of residence
Porto Alegre 35 (44.3) 44 (55.7) 1.0
Another city 25 (50.0) 25 (50.0) 1.26 (0.62 - 2.56) 0.528
Number of people in household
Up to 3 people 09 (37.5) 15 (62.5) 1.0
4 people or more 22 (37.9) 36 (62.1) 1.02 (0.38 - 2.72) 0.971
Main reason for inclusion in the study
Prematurity 46 (50.5) 45 (49.5) 1.0
Lung or heart disease 14 (36.8) 24 (63.2) 0.57 (0.26 - 1.24) 0.157
Breastfeeding records
Yes 43 (47.2) 48 (52.8) 1.0
No 09 (45.0) 11 (55.0) 0.91 (0.34 - 2.41) 0.855
For those who used PVZ:
Number of doses administered
Three or more 21 (38.9) 33 (61.1) 1.0
Up to two 05 (33.3) 10 (66.7) 0.78 (0.23 – 2.62) 0.695
*Adjusted per year of entry into the study
Table 3 shows the final result of the multivariate model for predictors of hospitalization for any cause. The variables with p ≤ 0.25 were added to the saturated model and then removed one by one from the model as the p-value increased, until only those that were statistically significant (p < 0.05) remained. Only the use of palivizumab remained in the final model as a significant variable.
Table 3 Final multivariate analysis of the association between hospitalization for any cause and exposure elements of individuals, Porto Alegre, 2017.
Odds Ratio and 95% CI
p
Relative Risk and 95% CI
p
PAF
Use of prophylactic palivizumab
Yes 1.0 1.0
No 0.46 (0.23 - 0.94) 0.032 0.66 (0.46 -0.97) 0.031 -0.50
PAF = Population Attributable Fraction
There was no difference in the number of doses of PVZ between children hospitalized for any reason (mean of 3.73 doses) and those that were not hospitalized (mean of 3.77 doses; p= 0.91).
Analysis of hospitalization due to lower respiratory tract infections
Among the children using palivizumab, hospitalizations for lower respiratory tract infections were noted in 21.7% (15/69), while in those who did not receive palivizumab, hospitalizations were observed in 41.7% (25/60) (p=0.01). The incidence rate of hospitalization for lower respiratory tract infection was 26.0 per 100 people/year (95% CI: 19.1 - 35.5). In children who did not take palivizumab (control group), the density of hospitalization incidence was 35.3 per 100 people/year (95% CI: 23.9 - 52.2), and in the children who used palivizumab, the calculated rate was 18.1 per 100 people/year (95% CI: 10.9 - 30.0).
Table 4 shows the bivariate analyses of elements possibly associated with hospitalization for lower respiratory tract infections. The bivariate analysis of the association between the year of entry into the cohort and hospitalization for lower respiratory tract infections showed a p value > 0.25 (p = 0.43); thus, it was not a candidate for inclusion in the multivariate model (data not shown in the table).
Table 4 Bivariate analysis of parameters associated with hospitalization for lower respiratory tract infections in children with indication for the use of palivizumab, Porto Alegre, 2017.
Hospitalization for lower respiratory tract infections OR (95% CI)
p
Yes n (%) No n (%)
Use of prophylactic palivizumab
Yes 15 (21.7) 54 (78.3) 1.0
No 25 (41.7) 35 (58.3) 0.39 (0.18 - 0.84)
0.016
Sex
Female 24 (34.3) 46 (65.7) 1.0
Male 16 (27.1) 43 (72.9) 0.71 (0.33- 1.52) 0.381
Place of residence
Porto Alegre 21 (26.6) 58 (73.4) 1.0
Another city 19 (38.0) 31 (62.0) 1.69 (0.79 - 3.61) 0.174
Number of people in household
Up to 3 people 04 (16.7) 20 (83.3) 1.0
4 people or more 16 (27.6) 42 (72.4) 1.90 (0.56 - 6.44) 0.300
Main reason for inclusion in the study
Prematurity 31 (34.1) 60 (65.9) 1.0
Lung or heart disease 09 (23.7) 29 (76.3) 0.60 (0.25 - 1.42) 0.248
Breastfeeding records
Yes 29 (31.9) 62 (68.1) 1.0
No 07 (35.0) 13 (65.0) 1.15 (0.41 - 3.19) 0.787
For those who used PVZ:
Number of doses administered
Three or more 11 (20.4) 43 (79.6) 1.0
Up to two 04 (26.7) 11 (73.3) 1.42 (0.38 - 5.33) 0.602
*Adjusted per year of entry into the study
Table 5 shows the results of the final multivariate analysis model for the association between the studied parameters and hospitalization for lower respiratory tract infections. Variables were removed from the model as the p-value increased until only the statistically significant ones remained (p < 0.05).
Table 5 Final multivariate analysis of the association between hospitalization for lower respiratory tract infections and exposure elements of individuals, Porto Alegre, 2017.
Odds Ratio and 95% CI
p
Relative Risk and 95% CI
p
PAF
Use of prophylactic palivizumab
Yes 1.0 1.0
No 0.39 (0.18 - 0.84) 0.016 0.52 (0.30 - 0.89) 0.014 -0.59
Six hospitalizations with laboratory confirmation of respiratory syncytial virus infections were recorded, all of which were in the control group. The rate of respiratory syncytial virus infection in the cohort was 3.2 per 100 people/year (95% CI: 1.42-7.04). As this was a retrospective study, RSV infection was only considered when the diagnosis was recorded in the medical records, and it is not possible to know whether all the patients were actually tested for RSV, as this is a retrospective study.
General analysis of the sample
The use of palivizumab remained independently associated with hospitalization for any cause and hospitalization for lower respiratory tract infections, was a protective factor, with relative risk reductions of 66% and 52%, respectively. The population attributable fraction associated with the use of palivizumab for hospitalizations for any cause was –0.50 and for hospitalization for lower respiratory tract infections was –0.59; that is, it is estimated that palivizumab decreases hospitalizations for any cause by 50% and hospitalizations for lower respiratory tract infections by 59%.
Only one death was observed in the cohort, and it occurred 1.2 years after the date of inclusion; this child was in the control group. The death rate in the cohort was 3.7 per 1,000 people/year (95% CI: 0.53-26.6).
DISCUSSION
Palivizumab prophylaxis was independently associated with a reduction in hospitalizations for any cause and hospitalization due to lower respiratory tract infections in patients at high risk of RSV infection.
The two-year rate of hospitalization for any cause in the cohort was 46.5% and it is noteworthy that this was a more vulnerable group, given that children were premature and/ or suffered from pulmonary or cardiacdiseases. The hospitalization rate among those who did not receive palivizumab was higher for both, hospitalizations for any cause (56.7%) and hospitalizations for lower respiratory tract infections (41.7% versus 31%). These findings are corroborated by the result of the multivariate analyses as well as the calculation of the population attributable fraction, according to which, palivizumab reduced hospitalizations for any cause by 50% and hospitalizations for lower respiratory tract infections by 59%.
The rate of hospitalization for lower respiratory tract infections among those who received palivizumab (21.7%) was higher than the rate of hospitalization for acute respiratory tract infections (12.9%) described in Canada during the 2004 and 2005 seasons12. It is important to stress that regarding the children who received palivizumab that we assessed, the first dose was administered up to three months after the beginning of the RSV season, which may indicate a delay in palivizumab prescription or in the patient’s visit to the referral center after receiving the palivizumab prescription at the original hospital.
The effectiveness of palivizumab in reducing hospitalization due to respiratory syncytial virus was shown in the IMpact-RSV study6, a randomized double-blind clinical trial that included 1,502 premature children (up to 35 weeks of gestational age) or with bronchopulmonary dysplasia; the trial was conducted in the United States, United Kingdom and Canada in the late 1990s. In that trial, a 55% decrease in hospitalizations for RSV was observed in the group treated with palivizumab (4.8%) compared with the group that received placebo (10.6%). The hospitalization rate for RSV in the placebo group of the IMpact-RSV study was similar to the rate found in those unexposed to PVZ in our study, which was 10%. In another multicenter clinical trial5, a relative decrease of 45% in hospitalizations for RSV resulting from the use of palivizumab was described. A systematic review carried out in 2011 has also evaluated the RSV hospitalization rate among groups who received PVZ, the summarized measure of which was 0.35 for the premature infants group (p < 0.001)13. Although it was not possible to assess the reduction in RSV-specific hospitalizations in this study as this outcome did not occur in the exposed group, the observed data indicate that the use of palivizumab decreases hospitalizations for any cause by 50%.
The clinical trials comparing exposure to palivizumab with the use of placebo in the literature are international studies with different realities in terms of respiratory infection profiles. The studies that provided the basis for indicating the incorporation of palivizumab by CONITEC were published prior to 2010, and little has been done after this incorporation, especially in view of the ethical issue that makes it difficult to gather/ form a control group. In Brazil, studies on the topic are scarce, and our results can only be compared with the cohort study conducted by Monteiro et al.1, in 2014 with patients subjected to palivizumab prophylaxis; this study was performed without a control group for ethical reasons. Among the children who received palivizumab, the rate of hospitalization for lower respiratory tract infections was 9.1%1, a much lower rate than that found in this study (21.7%). The Southern region of the country may present a different respiratory infection profile due to climate characteristics, with a more distinct winter and lower temperatures, as well as to an increase in the seasonality of RSV and other respiratory viruses.
As this was a retrospective study, it was not possible to ensure that all patients with acute lower respiratory tract infections underwent laboratory tests for respiratory syncytial virus, which may explain the low rate of RSV-positive infections among the patients with bronchiolitis, bronchitis and bronchopneumonia (16.7%). This percentage is much lower than the rate found by Souza in Porto Alegre14, who identified RSV in 59% of samples from infants up to 12 months of age with bronchiolitis; unfortunately, these patients were recruited between September 2009 and August 2011, prior to the incorporation of PVZ by the public health system.
There was a difference in the mean age of the patients chosen for the cohort, with the group using palivizumab being in general older than the unexposed group. This difference may have resulted from the fact that the controls were included upon the observation of the indication of palivizumab in accordance with criteria specified by the Brazilian Ministry of Health, while the cases that received palivizumab were included from the date of the first dose, which indicates the date of initial exposure to the drug under study. As there is a difference between the date of prescription and the first date the drug was administered, especially because the only referral hospital for the treatment with palivizumab was the HMIPV, there may have been a delay in the patient’s visit to this specialized service. At the HCPA, the doses were administered only to hospitalized patients, while outpatients were referred to the HMIPV.
Another difference found between the exposure groups was related to the patients’ cities of residence. Most children in the group unexposed to palivizumab (60%) lived in cities other than the capital city Porto Alegre.
The hospitals included in this study are referral hospitals located in the metropolitan area of Porto Alegre. The unexposed patients from other cities may have risen questions about the prescription and the use of palivizumab in hospitals located in their home cities; however, to avoid this bias, only patients with at least two years of outpatient follow-up at the referral hospital and frequent visits were selected to ensure that their medical records really included information on medications occasionally administered in their cities of residence.
An important point in the monitoring of new components incorporated into the public health system should take into account the cost of prophylaxis in relation to the benefits it offers, ideally through a complete cost-effectiveness study. It would be important to analyze the increase in drug costs to the budget of the public health system, taking into account favorable outcomes, such as a decrease in hospitalizations and problems for patients and their families. Unfortunately, these economic issues were not analyzed in this study and should be addressed in future research.
The limitations of the study were those inherent to the retrospective cohort study design itself, such as the inability to retrospectively collect some variables that are possibly association confounders (in this case, socioeconomic variables). Regarding the external validity, this study produced specific results as it was conducted at referral hospitals and in a capital city located in the Southern region of the country, where seasonality is well defined and high incidence levels of respiratory infections are often experienced in winter, what makes this region stand out from the rest.
CONCLUSION
The use of PVZ has been approved in several countries, although its effectiveness is controversial in developing countries and in places with a low incidence of respiratory infections. In Brazil, there were many questions regarding the effectiveness of this drug for the Brazilian population at the time of its recommendation in view of sociodemographic, epidemiological and even geographical differences. This study sought to address a key aspect of monitoring the incorporation of new concepts into the public health system in an attempt to reinvigorate the process based on the successes and mistakes resulting from the decisions made. The results suggest that the adoption of this prophylactic program achieved the expected effectiveness for the studied patients corroborating the findings of previously published international clinical trials.
ACKNOWLEDGMENTS
We thank Dr. Ana Maria Araujo Cirne and Dr. Cintia Beatriz Momo Selister for their support in data collection.
FUNDING.The study was sponsored and coordinated by the Moinhos de Vento Hospital, Brazil, in partnership with the Brazilian Ministry of Health through the Program of Institutional Development of the Brazilian Unified Health System (PROADI-SUS) (Project 01553 - ATS/PROADI HMV). | PALIVIZUMAB | DrugsGivenReaction | CC BY-NC | 33533808 | 18,940,182 | 2021 |
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