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What was the dosage of drug 'NITROGLYCERIN'? | Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: A case report.
BACKGROUND
Toxic epidermal necrolysis (TEN) is a rare, severe mucosal response of the skin associated with a high mortality rate. TEN is most commonly caused by drugs, and is characterized by extensive skin epidermal exfoliation.
A 68-year-old woman presented with a rash that had persisted for four days. The patient who had undergone a mitral valve replacement 1 month prior and was taking atorvastatin at the time of admission.
The patient exhibited more than 30% exfoliation surfaces and the severe drug eruption was considered to be TEN. According to human leukocyte antigen (HLA) allele detection and ALDEN score, HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin.
METHODS
All drugs used prior to admission were discontinued and the patient was given antiallergic drugs.
RESULTS
After 3 weeks following Antiallergic treatment, the rash on patient's calf had subsided, the edema was relieved, and the patient was no longer experiencing pain. After 60 days following discharge, the patient's skin has regrown.
CONCLUSIONS
This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. For HLA alleles carrier, atorvastatin may need to be used with caution to avoid TEN. Future systematic research is also required to confirm this finding and avoid similar serious skin adverse reactions.
1 Introduction
Toxic epidermal necrolysis (TEN) is an acute, life-threatening, severe dermatosis characterized by epidermal loss and multi-site mucositis, and is accompanied by systemic disturbance.[1] It is rare but very serious forms of drug-induced cutaneous adverse reaction. The morbidity of TEN is approximately 2 cases per million individuals each year.[2] The average mortality rate of TEN is over 30%, and the mortality rate of critically ill patients (SCORTEN > 3) is as high as 60% to 90%.[3]
Approximately 85% of TEN cases are induced by drugs.[4] The primary sensitizing drugs associated with TEN include antibiotics, anticonvulsants, antiviral drugs, and traditional Chinese medicine.[3] Recent studies have found that the occurrence of TEN is related to the individual human leukocyte antigen (HLA) allele genotype.[5,6,7] The HLA complex consists more than 200 genes on chromosome 6 can be categorized into 3 subgroups: Class I HLA, being recognized by CD8+ T cells, consists of 3 main genes, that is HLA-A, HLA-B, and HLA-C. Class II HLA, being recognized by CD4+ T cells, consists of 6 maingenes, that is, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLADQB1, HLA-DRA, and HLA-DRB1. HLA class I molecules are expressed in almost all the cells and are responsible for presenting peptides to immune cells.[5] Studies have shown that certain drugs that cause TEN are associated with HLA alleles; for example, carbamazepine-induced TEN and the HLA-B∗ 15:02 allele are highly correlated. Moreover, TEN induced by abacavir is correlated with individuals positive for the HLA-B∗57:01 allele.[5]
2 Case report
A 68-year-old woman presented with a rash that had persisted for 4 days. She had undergone a mitral valve replacement 1 month prior. Four days before admission, the patient developed a red rash on her face, chest, and back, accompanied by itching and a fever. At the time of admission, she presented with a burgundy rash that was distributed diffusely throughout her entire body. Moreover, some of the lesions were fused together, with a few blisters, itching, tolerability, fever, without skin breakage, subcutaneous nodules, bleeding, and ulcers (Fig. 1A). The laboratory test results revealed: albumin, 34.6 g/L; gamma glutamyl transpeptidase, 45 U/L; glucose, 13.24 mmol/L; creatine kinase MB subtype, 18.0 U/L; creatine kinase, 20 U/L; lactic dehydrogenase, 398 U/L; sodium, 135.9 mmol/L; leukocyte count, 5.19∗109/L; hemoglobin, 98.0 g/L; platelet count, 267 g/L; procalcitonin, 0.130 ng/mL; and fibrinogen, 4.35 g/L. The patient was taking the following medications at the time of admission: 0.125 mg qd po digoxin; 20 mg bid po furosemide; 1 g bid po potassium chloride; 0.625 mg qn po warfarin; and 20 mg qn po atorvastatin.
Figure 1 (A) At the time of admission, a burgundy rash was distributed diffusely throughout the patient's entire body. (B) On the fifth day of admission, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel. (C) After 60 days following discharge, the patient's skin has regrown.
On Day 1 post-admission, all drugs used prior to admission were discontinued and the patient was given antiallergic drugs, including 10 mg qd po loratadine, 10 mg qd po cetirizine, 100 mg tid po vitamin C, 120 mg q12 h po methylprednisolone, 40 mg q12 h ivgtt omeprazole acid, calamine and ethacridine for external use. The following day, the patient developed a large number of blisters that began to rupture over a large area of skin, and was accompanied by a fever. On Day 4, human immunoglobulin was intravenously administered. On Day 5, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel, which was associated with obvious pain. Mupirocin ointment was applied externally as treatment (Fig. 1B). On Day 11, the patient developed a new red patchy rash on both of her lower extremities accompanied by mild edema, as well as moderate blister formation near the thigh (Fig. 2). On Day 17, after developing erythema, blisters, rupture and peeling, the face and trunk skin were basically healed. On Day 22, the rash on her calf had subsided, the edema was relieved, and she was no longer experiencing pain. Then he was discharged from hospital. After 60 days following discharge, the patient's skin has regrown (Fig. 1C). During hospitalization, the location and exfoliation site of the rash were observed (Fig. 3); since the patient exhibited more than 30% exfoliation surfaces, the severe drug eruption was considered to be TEN rather than Stevens-Johnson Syndrome (SJS).
Figure 2 On Day 11 of admission, the patient developed a new red patchy rash on both lower extremities, which was accompanied by mild edema, and moderate blister formation near the thigh.
Figure 3 The location and exfoliation site of the rash were observed during hospitalization.
3 Investigations
Since more than 80% of TEN cases are caused by a drug allergy, timely cessation of the sensitizing drugs is the first step in treatment. Screening for suspected drug allergies relies primarily on medical history and previous reports of adverse drug reactions, however, for patients who have used multiple drugs before the onset of TEN, it is often difficult to identify the sensitizing drug.[4] The 2016 British Adult Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Symptoms Management Guide recommends using the ALDEN score (drug causality algorithm for epidermal necrolysis) to retrospectively evaluate sensitizing drugs for TEN.[8] The ALDEN score was designed based on the results of the Severe Cutaneous Adverse Reaction case-control study conducted from 1989 to 1993. Therefore, we analyzed all of the drugs used in this patient according to the ALDEN score in order to identify those that induce TEN (Table 1). Atorvastatin had an ALDEN score of 4 (the highest score of all drugs taken; Table 1) and was judged to be “probable” for sensitization. Furthermore, the patient had taken warfarin for venous thrombosis of lower extremities 2 years ago and did not induce TEN. Thus, the patient's TEN was most likely caused by atorvastatin.
Table 1 Possible sensitizing drugs ALDEN score.
Values
Drugs the duration of use Criterion1 Criterion2 Criterion3 Criterion 4 Criterion 5 Final score Sensitization possibility∗
Aspirin 9/15–9/30 2a −3c 0e 0g −1i −2 Very unlikely
Atorvastatin calcium 9/20–10/16 3b 0d 0e 0g 1j 4 probable
Cefazolin sodium 9/14–9/15 2b −3c 0e 0g 1j 0 unlikely
Compound ammonia barbital 9/15–9/16 2a −3c 0e 0g 0k −1 Very unlikely
Furosemide 9/11–9/15,9/20–9/30, 10/1–10/16 3b 0d −2f −2h 0k −1 Very unlikely
Isosorbide mononitrate 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Nitroglycerin 9/15–9/22 2a −3c 0e 0g 0k −1 Very unlikely
Cefoperazone Sulbactam Sodium 9/16–9/30 3b −3c −2f 0g 1j −1 Very unlikely
Warfarin 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Tramadol 9/20–9/30 3b −3c 0e 0g 0k 0 unlikely
3.1 HLA allele detection
A 2-mL sample of peripheral venous blood was collected from the patient. Genomic DNA was extracted using a DNA extraction kit (Shanghai Baio Co., Ltd.) in accordance with the manufacturer's protocol. The exons of the HLA-A, -B, and-C loci were sequenced using sanger.[5] The results showed that the patient carried the HLA-A∗02:07, HLA-A∗11:01, HLA-B∗15:02, HLA-B∗40:01, HLA-C∗03:04, and HLA-C∗08:01 alleles.
4 Discussion
TEN is a serious skin mucosal disease characterized by large areas of erythema, blisters, epidermal exfoliation, and multi-site mucositis, that is often accompanied by systemic dysfunction.[1] The onset is urgent, progresses rapidly, and is associated with a high mortality rate. Thus, there is an urgent need to identify drugs that induce TEN. By using ALDEN to score all the drugs the patient had used, we were able to determine that atorvastatin was most likely associated with TEN in this patient. There have been 6 reports of statin-induced exfoliative dermatitis in the literature, including TEN, but none of the studies tested for HLA-related genes.[9,10,11,12,13,14] In addition, it is mentioned on the atorvastatin drug label that it may cause TEN in extremely rare cases.[15]
Genetic factors are also closely related to the occurrence of SJS/TEN. In this study, the patient's HLA exon was sequenced and found to carry multiple mutant HLA genotypes, that may have the correlation with SJS and TEN. A thorough review of the literature reveals that, among these alleles, HLA-B∗15:02, HLA-A∗02:07 and TEN may have the correlation.[16,17,18] The correlation between other alleles and TEN has not been reported, but their association cannot be ruled out, it need to be further investigated. HLA alleles have been proposed as markers of SJS/TEN. Studies revealed a high prevalence of pharmacogenetic markers of drug-induced SJS/TEN e.g., B∗13:01 for dapsone; B∗15:02 for carbamazepine and oxcarbazepine; B∗58:01, A∗33:03 and C∗03:02 for allopurinol; C∗08:01, C∗14:02 and DRB1∗12:02 for co-trimoxazole.[18] HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin. Previous studies have found that HLA-B∗15:02 is an cause of serious adverse reactions in the skin induced by anti-epileptic drugs.[16] Carbamazepine non-covalently bind to proteins or peptides and are presented by MHC molecules after cellular processing, resulting in the HLA–restricted T cell activation.[17,19] Perhaps the mechanism of atorvastatin-induced TEN could be studied in the light of this study.
Atorvastatin is the most common drug for lipid lowering in patients with dyslipidemia, and the proportion of dyslipidemia in Chinese population is as high as 40.40%.[20] Therefore, the population of atorvastatin is very large, but SJS/TEN is very rare, HLA alleles may be a genetic factor. This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. Future systematic research is required to confirm this finding and avoid similar serious skin adverse reactions.
Author contributions
Conceptualization: Meina Lv, Yuxin Liu, Jinhua Zhang.
Data curation: Shaojun Jiang, Jinglan Fu.
Formal analysis: Yuxin Liu, Siheng Lian.
Project administration: Meina Lv, Jinhua Zhang.
Writing – original draft: Meina Lv.
Writing – review & editing: Shaojun Jiang, Jinglan Fu, Yuxin Liu, Siheng Lian, Jinhua Zhang.
Abbreviations: HLA = human leukocyte antigen, SJS = stevens-johnson syndrome, TEN = toxic epidermal necrolysis.
How to cite this article: Lv M, Jiang S, Fu J, Liu Y, Lian S, Zhang J. Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: a case report. Medicine. 2021;100:3(e24392).
This study was supported by the Natural Science Foundation of Fujian Province of China [grant number 2018Y0037].
Informed consent was obtained from the patient for publication of this case report. Approval of the study by our hospital's ethics committee was not required because it was a case report.
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
∗ < 0, very unlikely; 0 – 1, unlikely; 2 – 3, possible; 4 – 5, probable; ≥ 6, very probable.
a Delay from initial drug component intake to onset of reaction: from 29 to 56 days.
b Delay from initial drug component intake to onset of reaction: from 5 to 28 days.
c Drug present in the body on index day: drug stopped at a time point prior to the index day by more than 5 times the elimination half-life, without liver or kidney function alterations or suspected drug interactions.
d Drug present in the body on index day: drug continued up to index day or stopped at a time point less than 5 times the elimination half-life before the index day.
e Prechallenge/rechanllenge: no known previous exposure to this drug.
f Prechallenge/rechanllenge: Exposure to this drug without any reaction (before or after reaction).
g Dechallenge: Drug stopped (or unknown).
h Dechallenge: Drug continued without harm.
i Type of drug (notoriety):No evidence of association from previous epidemiology study with sufficient number of exposed control.
j Type of drug (notoriety): Several previous reports, ambiguous epidemiology results (drug “under surveillance”).
k Type of drug (notoriety): All other drugs including newly released ones. | DURATION OF USE: 9/15?9/22 | DrugDosageText | CC BY | 33546081 | 18,901,737 | 2021-01-22 |
What was the dosage of drug 'TRAMADOL'? | Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: A case report.
BACKGROUND
Toxic epidermal necrolysis (TEN) is a rare, severe mucosal response of the skin associated with a high mortality rate. TEN is most commonly caused by drugs, and is characterized by extensive skin epidermal exfoliation.
A 68-year-old woman presented with a rash that had persisted for four days. The patient who had undergone a mitral valve replacement 1 month prior and was taking atorvastatin at the time of admission.
The patient exhibited more than 30% exfoliation surfaces and the severe drug eruption was considered to be TEN. According to human leukocyte antigen (HLA) allele detection and ALDEN score, HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin.
METHODS
All drugs used prior to admission were discontinued and the patient was given antiallergic drugs.
RESULTS
After 3 weeks following Antiallergic treatment, the rash on patient's calf had subsided, the edema was relieved, and the patient was no longer experiencing pain. After 60 days following discharge, the patient's skin has regrown.
CONCLUSIONS
This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. For HLA alleles carrier, atorvastatin may need to be used with caution to avoid TEN. Future systematic research is also required to confirm this finding and avoid similar serious skin adverse reactions.
1 Introduction
Toxic epidermal necrolysis (TEN) is an acute, life-threatening, severe dermatosis characterized by epidermal loss and multi-site mucositis, and is accompanied by systemic disturbance.[1] It is rare but very serious forms of drug-induced cutaneous adverse reaction. The morbidity of TEN is approximately 2 cases per million individuals each year.[2] The average mortality rate of TEN is over 30%, and the mortality rate of critically ill patients (SCORTEN > 3) is as high as 60% to 90%.[3]
Approximately 85% of TEN cases are induced by drugs.[4] The primary sensitizing drugs associated with TEN include antibiotics, anticonvulsants, antiviral drugs, and traditional Chinese medicine.[3] Recent studies have found that the occurrence of TEN is related to the individual human leukocyte antigen (HLA) allele genotype.[5,6,7] The HLA complex consists more than 200 genes on chromosome 6 can be categorized into 3 subgroups: Class I HLA, being recognized by CD8+ T cells, consists of 3 main genes, that is HLA-A, HLA-B, and HLA-C. Class II HLA, being recognized by CD4+ T cells, consists of 6 maingenes, that is, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLADQB1, HLA-DRA, and HLA-DRB1. HLA class I molecules are expressed in almost all the cells and are responsible for presenting peptides to immune cells.[5] Studies have shown that certain drugs that cause TEN are associated with HLA alleles; for example, carbamazepine-induced TEN and the HLA-B∗ 15:02 allele are highly correlated. Moreover, TEN induced by abacavir is correlated with individuals positive for the HLA-B∗57:01 allele.[5]
2 Case report
A 68-year-old woman presented with a rash that had persisted for 4 days. She had undergone a mitral valve replacement 1 month prior. Four days before admission, the patient developed a red rash on her face, chest, and back, accompanied by itching and a fever. At the time of admission, she presented with a burgundy rash that was distributed diffusely throughout her entire body. Moreover, some of the lesions were fused together, with a few blisters, itching, tolerability, fever, without skin breakage, subcutaneous nodules, bleeding, and ulcers (Fig. 1A). The laboratory test results revealed: albumin, 34.6 g/L; gamma glutamyl transpeptidase, 45 U/L; glucose, 13.24 mmol/L; creatine kinase MB subtype, 18.0 U/L; creatine kinase, 20 U/L; lactic dehydrogenase, 398 U/L; sodium, 135.9 mmol/L; leukocyte count, 5.19∗109/L; hemoglobin, 98.0 g/L; platelet count, 267 g/L; procalcitonin, 0.130 ng/mL; and fibrinogen, 4.35 g/L. The patient was taking the following medications at the time of admission: 0.125 mg qd po digoxin; 20 mg bid po furosemide; 1 g bid po potassium chloride; 0.625 mg qn po warfarin; and 20 mg qn po atorvastatin.
Figure 1 (A) At the time of admission, a burgundy rash was distributed diffusely throughout the patient's entire body. (B) On the fifth day of admission, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel. (C) After 60 days following discharge, the patient's skin has regrown.
On Day 1 post-admission, all drugs used prior to admission were discontinued and the patient was given antiallergic drugs, including 10 mg qd po loratadine, 10 mg qd po cetirizine, 100 mg tid po vitamin C, 120 mg q12 h po methylprednisolone, 40 mg q12 h ivgtt omeprazole acid, calamine and ethacridine for external use. The following day, the patient developed a large number of blisters that began to rupture over a large area of skin, and was accompanied by a fever. On Day 4, human immunoglobulin was intravenously administered. On Day 5, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel, which was associated with obvious pain. Mupirocin ointment was applied externally as treatment (Fig. 1B). On Day 11, the patient developed a new red patchy rash on both of her lower extremities accompanied by mild edema, as well as moderate blister formation near the thigh (Fig. 2). On Day 17, after developing erythema, blisters, rupture and peeling, the face and trunk skin were basically healed. On Day 22, the rash on her calf had subsided, the edema was relieved, and she was no longer experiencing pain. Then he was discharged from hospital. After 60 days following discharge, the patient's skin has regrown (Fig. 1C). During hospitalization, the location and exfoliation site of the rash were observed (Fig. 3); since the patient exhibited more than 30% exfoliation surfaces, the severe drug eruption was considered to be TEN rather than Stevens-Johnson Syndrome (SJS).
Figure 2 On Day 11 of admission, the patient developed a new red patchy rash on both lower extremities, which was accompanied by mild edema, and moderate blister formation near the thigh.
Figure 3 The location and exfoliation site of the rash were observed during hospitalization.
3 Investigations
Since more than 80% of TEN cases are caused by a drug allergy, timely cessation of the sensitizing drugs is the first step in treatment. Screening for suspected drug allergies relies primarily on medical history and previous reports of adverse drug reactions, however, for patients who have used multiple drugs before the onset of TEN, it is often difficult to identify the sensitizing drug.[4] The 2016 British Adult Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Symptoms Management Guide recommends using the ALDEN score (drug causality algorithm for epidermal necrolysis) to retrospectively evaluate sensitizing drugs for TEN.[8] The ALDEN score was designed based on the results of the Severe Cutaneous Adverse Reaction case-control study conducted from 1989 to 1993. Therefore, we analyzed all of the drugs used in this patient according to the ALDEN score in order to identify those that induce TEN (Table 1). Atorvastatin had an ALDEN score of 4 (the highest score of all drugs taken; Table 1) and was judged to be “probable” for sensitization. Furthermore, the patient had taken warfarin for venous thrombosis of lower extremities 2 years ago and did not induce TEN. Thus, the patient's TEN was most likely caused by atorvastatin.
Table 1 Possible sensitizing drugs ALDEN score.
Values
Drugs the duration of use Criterion1 Criterion2 Criterion3 Criterion 4 Criterion 5 Final score Sensitization possibility∗
Aspirin 9/15–9/30 2a −3c 0e 0g −1i −2 Very unlikely
Atorvastatin calcium 9/20–10/16 3b 0d 0e 0g 1j 4 probable
Cefazolin sodium 9/14–9/15 2b −3c 0e 0g 1j 0 unlikely
Compound ammonia barbital 9/15–9/16 2a −3c 0e 0g 0k −1 Very unlikely
Furosemide 9/11–9/15,9/20–9/30, 10/1–10/16 3b 0d −2f −2h 0k −1 Very unlikely
Isosorbide mononitrate 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Nitroglycerin 9/15–9/22 2a −3c 0e 0g 0k −1 Very unlikely
Cefoperazone Sulbactam Sodium 9/16–9/30 3b −3c −2f 0g 1j −1 Very unlikely
Warfarin 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Tramadol 9/20–9/30 3b −3c 0e 0g 0k 0 unlikely
3.1 HLA allele detection
A 2-mL sample of peripheral venous blood was collected from the patient. Genomic DNA was extracted using a DNA extraction kit (Shanghai Baio Co., Ltd.) in accordance with the manufacturer's protocol. The exons of the HLA-A, -B, and-C loci were sequenced using sanger.[5] The results showed that the patient carried the HLA-A∗02:07, HLA-A∗11:01, HLA-B∗15:02, HLA-B∗40:01, HLA-C∗03:04, and HLA-C∗08:01 alleles.
4 Discussion
TEN is a serious skin mucosal disease characterized by large areas of erythema, blisters, epidermal exfoliation, and multi-site mucositis, that is often accompanied by systemic dysfunction.[1] The onset is urgent, progresses rapidly, and is associated with a high mortality rate. Thus, there is an urgent need to identify drugs that induce TEN. By using ALDEN to score all the drugs the patient had used, we were able to determine that atorvastatin was most likely associated with TEN in this patient. There have been 6 reports of statin-induced exfoliative dermatitis in the literature, including TEN, but none of the studies tested for HLA-related genes.[9,10,11,12,13,14] In addition, it is mentioned on the atorvastatin drug label that it may cause TEN in extremely rare cases.[15]
Genetic factors are also closely related to the occurrence of SJS/TEN. In this study, the patient's HLA exon was sequenced and found to carry multiple mutant HLA genotypes, that may have the correlation with SJS and TEN. A thorough review of the literature reveals that, among these alleles, HLA-B∗15:02, HLA-A∗02:07 and TEN may have the correlation.[16,17,18] The correlation between other alleles and TEN has not been reported, but their association cannot be ruled out, it need to be further investigated. HLA alleles have been proposed as markers of SJS/TEN. Studies revealed a high prevalence of pharmacogenetic markers of drug-induced SJS/TEN e.g., B∗13:01 for dapsone; B∗15:02 for carbamazepine and oxcarbazepine; B∗58:01, A∗33:03 and C∗03:02 for allopurinol; C∗08:01, C∗14:02 and DRB1∗12:02 for co-trimoxazole.[18] HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin. Previous studies have found that HLA-B∗15:02 is an cause of serious adverse reactions in the skin induced by anti-epileptic drugs.[16] Carbamazepine non-covalently bind to proteins or peptides and are presented by MHC molecules after cellular processing, resulting in the HLA–restricted T cell activation.[17,19] Perhaps the mechanism of atorvastatin-induced TEN could be studied in the light of this study.
Atorvastatin is the most common drug for lipid lowering in patients with dyslipidemia, and the proportion of dyslipidemia in Chinese population is as high as 40.40%.[20] Therefore, the population of atorvastatin is very large, but SJS/TEN is very rare, HLA alleles may be a genetic factor. This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. Future systematic research is required to confirm this finding and avoid similar serious skin adverse reactions.
Author contributions
Conceptualization: Meina Lv, Yuxin Liu, Jinhua Zhang.
Data curation: Shaojun Jiang, Jinglan Fu.
Formal analysis: Yuxin Liu, Siheng Lian.
Project administration: Meina Lv, Jinhua Zhang.
Writing – original draft: Meina Lv.
Writing – review & editing: Shaojun Jiang, Jinglan Fu, Yuxin Liu, Siheng Lian, Jinhua Zhang.
Abbreviations: HLA = human leukocyte antigen, SJS = stevens-johnson syndrome, TEN = toxic epidermal necrolysis.
How to cite this article: Lv M, Jiang S, Fu J, Liu Y, Lian S, Zhang J. Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: a case report. Medicine. 2021;100:3(e24392).
This study was supported by the Natural Science Foundation of Fujian Province of China [grant number 2018Y0037].
Informed consent was obtained from the patient for publication of this case report. Approval of the study by our hospital's ethics committee was not required because it was a case report.
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
∗ < 0, very unlikely; 0 – 1, unlikely; 2 – 3, possible; 4 – 5, probable; ≥ 6, very probable.
a Delay from initial drug component intake to onset of reaction: from 29 to 56 days.
b Delay from initial drug component intake to onset of reaction: from 5 to 28 days.
c Drug present in the body on index day: drug stopped at a time point prior to the index day by more than 5 times the elimination half-life, without liver or kidney function alterations or suspected drug interactions.
d Drug present in the body on index day: drug continued up to index day or stopped at a time point less than 5 times the elimination half-life before the index day.
e Prechallenge/rechanllenge: no known previous exposure to this drug.
f Prechallenge/rechanllenge: Exposure to this drug without any reaction (before or after reaction).
g Dechallenge: Drug stopped (or unknown).
h Dechallenge: Drug continued without harm.
i Type of drug (notoriety):No evidence of association from previous epidemiology study with sufficient number of exposed control.
j Type of drug (notoriety): Several previous reports, ambiguous epidemiology results (drug “under surveillance”).
k Type of drug (notoriety): All other drugs including newly released ones. | DURATION OF USE: 9/20?9/30 | DrugDosageText | CC BY | 33546081 | 18,901,737 | 2021-01-22 |
What was the outcome of reaction 'Toxic epidermal necrolysis'? | Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: A case report.
BACKGROUND
Toxic epidermal necrolysis (TEN) is a rare, severe mucosal response of the skin associated with a high mortality rate. TEN is most commonly caused by drugs, and is characterized by extensive skin epidermal exfoliation.
A 68-year-old woman presented with a rash that had persisted for four days. The patient who had undergone a mitral valve replacement 1 month prior and was taking atorvastatin at the time of admission.
The patient exhibited more than 30% exfoliation surfaces and the severe drug eruption was considered to be TEN. According to human leukocyte antigen (HLA) allele detection and ALDEN score, HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin.
METHODS
All drugs used prior to admission were discontinued and the patient was given antiallergic drugs.
RESULTS
After 3 weeks following Antiallergic treatment, the rash on patient's calf had subsided, the edema was relieved, and the patient was no longer experiencing pain. After 60 days following discharge, the patient's skin has regrown.
CONCLUSIONS
This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. For HLA alleles carrier, atorvastatin may need to be used with caution to avoid TEN. Future systematic research is also required to confirm this finding and avoid similar serious skin adverse reactions.
1 Introduction
Toxic epidermal necrolysis (TEN) is an acute, life-threatening, severe dermatosis characterized by epidermal loss and multi-site mucositis, and is accompanied by systemic disturbance.[1] It is rare but very serious forms of drug-induced cutaneous adverse reaction. The morbidity of TEN is approximately 2 cases per million individuals each year.[2] The average mortality rate of TEN is over 30%, and the mortality rate of critically ill patients (SCORTEN > 3) is as high as 60% to 90%.[3]
Approximately 85% of TEN cases are induced by drugs.[4] The primary sensitizing drugs associated with TEN include antibiotics, anticonvulsants, antiviral drugs, and traditional Chinese medicine.[3] Recent studies have found that the occurrence of TEN is related to the individual human leukocyte antigen (HLA) allele genotype.[5,6,7] The HLA complex consists more than 200 genes on chromosome 6 can be categorized into 3 subgroups: Class I HLA, being recognized by CD8+ T cells, consists of 3 main genes, that is HLA-A, HLA-B, and HLA-C. Class II HLA, being recognized by CD4+ T cells, consists of 6 maingenes, that is, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLADQB1, HLA-DRA, and HLA-DRB1. HLA class I molecules are expressed in almost all the cells and are responsible for presenting peptides to immune cells.[5] Studies have shown that certain drugs that cause TEN are associated with HLA alleles; for example, carbamazepine-induced TEN and the HLA-B∗ 15:02 allele are highly correlated. Moreover, TEN induced by abacavir is correlated with individuals positive for the HLA-B∗57:01 allele.[5]
2 Case report
A 68-year-old woman presented with a rash that had persisted for 4 days. She had undergone a mitral valve replacement 1 month prior. Four days before admission, the patient developed a red rash on her face, chest, and back, accompanied by itching and a fever. At the time of admission, she presented with a burgundy rash that was distributed diffusely throughout her entire body. Moreover, some of the lesions were fused together, with a few blisters, itching, tolerability, fever, without skin breakage, subcutaneous nodules, bleeding, and ulcers (Fig. 1A). The laboratory test results revealed: albumin, 34.6 g/L; gamma glutamyl transpeptidase, 45 U/L; glucose, 13.24 mmol/L; creatine kinase MB subtype, 18.0 U/L; creatine kinase, 20 U/L; lactic dehydrogenase, 398 U/L; sodium, 135.9 mmol/L; leukocyte count, 5.19∗109/L; hemoglobin, 98.0 g/L; platelet count, 267 g/L; procalcitonin, 0.130 ng/mL; and fibrinogen, 4.35 g/L. The patient was taking the following medications at the time of admission: 0.125 mg qd po digoxin; 20 mg bid po furosemide; 1 g bid po potassium chloride; 0.625 mg qn po warfarin; and 20 mg qn po atorvastatin.
Figure 1 (A) At the time of admission, a burgundy rash was distributed diffusely throughout the patient's entire body. (B) On the fifth day of admission, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel. (C) After 60 days following discharge, the patient's skin has regrown.
On Day 1 post-admission, all drugs used prior to admission were discontinued and the patient was given antiallergic drugs, including 10 mg qd po loratadine, 10 mg qd po cetirizine, 100 mg tid po vitamin C, 120 mg q12 h po methylprednisolone, 40 mg q12 h ivgtt omeprazole acid, calamine and ethacridine for external use. The following day, the patient developed a large number of blisters that began to rupture over a large area of skin, and was accompanied by a fever. On Day 4, human immunoglobulin was intravenously administered. On Day 5, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel, which was associated with obvious pain. Mupirocin ointment was applied externally as treatment (Fig. 1B). On Day 11, the patient developed a new red patchy rash on both of her lower extremities accompanied by mild edema, as well as moderate blister formation near the thigh (Fig. 2). On Day 17, after developing erythema, blisters, rupture and peeling, the face and trunk skin were basically healed. On Day 22, the rash on her calf had subsided, the edema was relieved, and she was no longer experiencing pain. Then he was discharged from hospital. After 60 days following discharge, the patient's skin has regrown (Fig. 1C). During hospitalization, the location and exfoliation site of the rash were observed (Fig. 3); since the patient exhibited more than 30% exfoliation surfaces, the severe drug eruption was considered to be TEN rather than Stevens-Johnson Syndrome (SJS).
Figure 2 On Day 11 of admission, the patient developed a new red patchy rash on both lower extremities, which was accompanied by mild edema, and moderate blister formation near the thigh.
Figure 3 The location and exfoliation site of the rash were observed during hospitalization.
3 Investigations
Since more than 80% of TEN cases are caused by a drug allergy, timely cessation of the sensitizing drugs is the first step in treatment. Screening for suspected drug allergies relies primarily on medical history and previous reports of adverse drug reactions, however, for patients who have used multiple drugs before the onset of TEN, it is often difficult to identify the sensitizing drug.[4] The 2016 British Adult Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Symptoms Management Guide recommends using the ALDEN score (drug causality algorithm for epidermal necrolysis) to retrospectively evaluate sensitizing drugs for TEN.[8] The ALDEN score was designed based on the results of the Severe Cutaneous Adverse Reaction case-control study conducted from 1989 to 1993. Therefore, we analyzed all of the drugs used in this patient according to the ALDEN score in order to identify those that induce TEN (Table 1). Atorvastatin had an ALDEN score of 4 (the highest score of all drugs taken; Table 1) and was judged to be “probable” for sensitization. Furthermore, the patient had taken warfarin for venous thrombosis of lower extremities 2 years ago and did not induce TEN. Thus, the patient's TEN was most likely caused by atorvastatin.
Table 1 Possible sensitizing drugs ALDEN score.
Values
Drugs the duration of use Criterion1 Criterion2 Criterion3 Criterion 4 Criterion 5 Final score Sensitization possibility∗
Aspirin 9/15–9/30 2a −3c 0e 0g −1i −2 Very unlikely
Atorvastatin calcium 9/20–10/16 3b 0d 0e 0g 1j 4 probable
Cefazolin sodium 9/14–9/15 2b −3c 0e 0g 1j 0 unlikely
Compound ammonia barbital 9/15–9/16 2a −3c 0e 0g 0k −1 Very unlikely
Furosemide 9/11–9/15,9/20–9/30, 10/1–10/16 3b 0d −2f −2h 0k −1 Very unlikely
Isosorbide mononitrate 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Nitroglycerin 9/15–9/22 2a −3c 0e 0g 0k −1 Very unlikely
Cefoperazone Sulbactam Sodium 9/16–9/30 3b −3c −2f 0g 1j −1 Very unlikely
Warfarin 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Tramadol 9/20–9/30 3b −3c 0e 0g 0k 0 unlikely
3.1 HLA allele detection
A 2-mL sample of peripheral venous blood was collected from the patient. Genomic DNA was extracted using a DNA extraction kit (Shanghai Baio Co., Ltd.) in accordance with the manufacturer's protocol. The exons of the HLA-A, -B, and-C loci were sequenced using sanger.[5] The results showed that the patient carried the HLA-A∗02:07, HLA-A∗11:01, HLA-B∗15:02, HLA-B∗40:01, HLA-C∗03:04, and HLA-C∗08:01 alleles.
4 Discussion
TEN is a serious skin mucosal disease characterized by large areas of erythema, blisters, epidermal exfoliation, and multi-site mucositis, that is often accompanied by systemic dysfunction.[1] The onset is urgent, progresses rapidly, and is associated with a high mortality rate. Thus, there is an urgent need to identify drugs that induce TEN. By using ALDEN to score all the drugs the patient had used, we were able to determine that atorvastatin was most likely associated with TEN in this patient. There have been 6 reports of statin-induced exfoliative dermatitis in the literature, including TEN, but none of the studies tested for HLA-related genes.[9,10,11,12,13,14] In addition, it is mentioned on the atorvastatin drug label that it may cause TEN in extremely rare cases.[15]
Genetic factors are also closely related to the occurrence of SJS/TEN. In this study, the patient's HLA exon was sequenced and found to carry multiple mutant HLA genotypes, that may have the correlation with SJS and TEN. A thorough review of the literature reveals that, among these alleles, HLA-B∗15:02, HLA-A∗02:07 and TEN may have the correlation.[16,17,18] The correlation between other alleles and TEN has not been reported, but their association cannot be ruled out, it need to be further investigated. HLA alleles have been proposed as markers of SJS/TEN. Studies revealed a high prevalence of pharmacogenetic markers of drug-induced SJS/TEN e.g., B∗13:01 for dapsone; B∗15:02 for carbamazepine and oxcarbazepine; B∗58:01, A∗33:03 and C∗03:02 for allopurinol; C∗08:01, C∗14:02 and DRB1∗12:02 for co-trimoxazole.[18] HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin. Previous studies have found that HLA-B∗15:02 is an cause of serious adverse reactions in the skin induced by anti-epileptic drugs.[16] Carbamazepine non-covalently bind to proteins or peptides and are presented by MHC molecules after cellular processing, resulting in the HLA–restricted T cell activation.[17,19] Perhaps the mechanism of atorvastatin-induced TEN could be studied in the light of this study.
Atorvastatin is the most common drug for lipid lowering in patients with dyslipidemia, and the proportion of dyslipidemia in Chinese population is as high as 40.40%.[20] Therefore, the population of atorvastatin is very large, but SJS/TEN is very rare, HLA alleles may be a genetic factor. This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. Future systematic research is required to confirm this finding and avoid similar serious skin adverse reactions.
Author contributions
Conceptualization: Meina Lv, Yuxin Liu, Jinhua Zhang.
Data curation: Shaojun Jiang, Jinglan Fu.
Formal analysis: Yuxin Liu, Siheng Lian.
Project administration: Meina Lv, Jinhua Zhang.
Writing – original draft: Meina Lv.
Writing – review & editing: Shaojun Jiang, Jinglan Fu, Yuxin Liu, Siheng Lian, Jinhua Zhang.
Abbreviations: HLA = human leukocyte antigen, SJS = stevens-johnson syndrome, TEN = toxic epidermal necrolysis.
How to cite this article: Lv M, Jiang S, Fu J, Liu Y, Lian S, Zhang J. Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: a case report. Medicine. 2021;100:3(e24392).
This study was supported by the Natural Science Foundation of Fujian Province of China [grant number 2018Y0037].
Informed consent was obtained from the patient for publication of this case report. Approval of the study by our hospital's ethics committee was not required because it was a case report.
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
∗ < 0, very unlikely; 0 – 1, unlikely; 2 – 3, possible; 4 – 5, probable; ≥ 6, very probable.
a Delay from initial drug component intake to onset of reaction: from 29 to 56 days.
b Delay from initial drug component intake to onset of reaction: from 5 to 28 days.
c Drug present in the body on index day: drug stopped at a time point prior to the index day by more than 5 times the elimination half-life, without liver or kidney function alterations or suspected drug interactions.
d Drug present in the body on index day: drug continued up to index day or stopped at a time point less than 5 times the elimination half-life before the index day.
e Prechallenge/rechanllenge: no known previous exposure to this drug.
f Prechallenge/rechanllenge: Exposure to this drug without any reaction (before or after reaction).
g Dechallenge: Drug stopped (or unknown).
h Dechallenge: Drug continued without harm.
i Type of drug (notoriety):No evidence of association from previous epidemiology study with sufficient number of exposed control.
j Type of drug (notoriety): Several previous reports, ambiguous epidemiology results (drug “under surveillance”).
k Type of drug (notoriety): All other drugs including newly released ones. | Recovered | ReactionOutcome | CC BY | 33546081 | 18,901,737 | 2021-01-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | TP53 Mutations as a Driver of Metastasis Signaling in Advanced Cancer Patients.
Molecular profiling with next generation sequencing (NGS) delivers key information on mutant gene sequences, copy number alterations, gene-fusions, and with immunohistochemistry (IHC), is a valuable tool in clinical decision making for patients entering investigational agent trials. Our objective was to elucidate mutational profiles from primary versus metastatic sites from advanced cancer patients to guide rational therapy. All phase I patients (n = 203) with advanced cancer were profiled by commercially available NGS platforms. The samples were annotated by histology, primary and metastatic site, biopsy site, gene mutations, mutation count/gene, and mutant TP53. A molecular profile of each patient was categorized into common and unique mutations, signaling pathways for each profile and TP53 mutations mapped to 3D-structure of p53 bound to DNA and pre/post therapy molecular response. Of the 171 patients analyzed, 145 had genetic alterations from primary and metastatic sites. The predominant histology was adenocarcinoma followed by squamous cell carcinoma, carcinoma of unknown primary site (CUPS), and melanoma. Of 790 unique mutations, TP53 is the most common followed by APC, KRAS, PIK3CA, ATM, PTEN, NOTCH1, BRCA2, BRAF, KMT2D, LRP1B, and CDKN2A. TP53 was found in most metastatic sites and appears to be a key driver of acquired drug resistance. We highlight examples of acquired mutational profiles pre-/post- targeted therapy in multiple tumor types with a menu of potential targeted agents. Conclusion: The mutational profiling of primary and metastatic lesions in cancer patients provides an opportunity to identify TP53 driver 'pathways' that may predict for drug sensitivity/resistance and guide rational drug combinations in clinical trials.
1. Introduction
‘Precision oncology’ or ‘cancer genome medicine’ is the seamless application of the Watson–Crick ‘central dogma’ to every patient with cancer (personalized therapy), where their tumor molecular profile (genome, proteome, epigenome, immunome, micro-environmentome, metabolome, etc.) may inform diagnosis, prognosis, and treatments. ‘Precision therapeutics’ of cancer implies mechanism of action-based targeting of the ‘hallmarks’ of cancer utilizing molecular taxonomy, genomic, proteomic in diagnosis and guiding therapeutics in well-designed innovative trials. The large-scale whole genome sequencing (WGS) of cancer such as the ICGC (International Cancer Genome Consortium) and TCGA (The Cancer Genome Atlas) have cataloged prevalent genomic alterations across a myriad of human malignancies [1,2], identifying recurrent genetic mutations that drive aberrant signaling pathways controlled by master regulators that lead to acquired targetable phenotypic characteristics [3]. With the advent of new molecular and cellular technologies, oncology has evolved from treating cancer patients with non-specific DNA-damaging and microtubule-targeted combination chemotherapy to molecular pathology-stratified histology agnostic immune checkpoint and targeted therapies.
Intra-tumor and spatially separated multiple sub-clone heterogeneity elegantly described in clear cell renal cancer and other malignancies are major contributors to the understanding of tumor evolution and drug resistance. Branched ‘Darwinian’ evolution [4] is a significant challenge to current therapies but should provide insights to mitigate or disrupt anticipated genetic alterations by a rationalized approach to precision therapeutics. Elucidating the mechanism of genomic alterations is likely to identify master regulators [5] once longitudinal tumor sampling with minimally invasive methods become a reality. Solid and liquid tumor biopsies during the course of therapy of a given cancer subtype are likely to inform decisions to switch tailored therapies that make mechanistic sense (e.g., TRACERx-Tracking Cancer Evolution through Therapy [6] in lung cancer [7]) and advanced cancer [8]. The current practice of stratifying patients to a single-diagnostic/single-drug will change as multiple biomarkers has become clinically actionable. The development of multi-biomarker assays coupled to NGS (DNA and RNA sequencing and single cell transcriptomics) will complement ‘precision’ diagnostics, prognostics, and therapeutics [9].
A major requirement of ‘precision oncology’ is hypothesis-driven research to improve patient outcomes [10]. NGS data have been utilized to conduct histology-agnostic ‘umbrella’ or ‘basket’ trials and one such trial sponsored by the NCI (MATCH trial) [11] where multiple histologies are matched by biomarkers to a targeted agent. A second approach uses a master protocol (S1400) within a single histology (e.g., squamous cell lung cancer) to test multiple omic-drug matches based on a defined set of genes. A third approach is a ‘strategy’ trial where patients are assigned a therapy based on their omics profile or physician’s choice. The NCI has launched the ‘The Molecular Profiling-based Assignment of Cancer Therapeutics’ (M-PACT) [12] trial where patients are screened for actionable gene alterations and randomized to a drug that targets a mutated oncogene product or a drug chosen by a physician that does not correspond to a mutation or amplification. The primary endpoint is response rate and four-month progression-free survival. A fourth approach is an ‘observational’ trial utilizing off-label targeted therapies (Targeted Agent and Profiling Utilization Registry–TAPUR) [13]. A major challenge is analysis of large-scale genomic data for clinical application [14]. Whole-genome sequencing is an excellent strategy for comprehensive molecular profiling but requires validation for clinical utility. The currently available gene-capture platforms, when used to match therapies with whole exome, whole genome, and transcriptome (RNA-Seq), are in the domain of discovery research [15].
In unmatched and matched paired analysis of primary and metastatic tumors, TP53 appears to enrich to metastasis [16]. However, whether the cause and/or effect is due to chromosomal instability and/or drug resistance remains to be established [16]. In our ‘New Therapeutics Program’ all advanced cancer patients were molecularly profiled by NGS for mutations, copy number alterations (CNA), translocations (FISH/CISH), and IHC to inform clinical decisions for investigational agent trials. We hypothesized that for primary and metastatic sites, TP53 mutations are more frequent and appear to be a key driver of acquired drug resistance in advanced cancer patients. Mutation in TP53 is heterogeneous and are known to induce complex transcriptional changes effecting multiple biological responses [17]. Cellular responses to a specific TP53 mutation may depend on the tissue type, tumor stage and co-mutated genes. Thus, investigating the underlying p53 driven signaling pathways is predicted to provide opportunities to not only understand evolving pathobiology but also provide better guidance to rational drug therapies.
2. Results
2.1. Primary and Metastatic NGS Profiling of Advanced Cancer Patients
Of the 171 patients entering phase I clinical trials, 145 had genetic alterations with respect to the primary and metastatic site, histology, and total number of clinically relevant mutated genes (Table 1). In our cohort of patients, utilizing large NGS platforms probing 300 (Foundation One: 25% Patients, 421 (Precipio: 36% Patients), and 600 (Caris MI: 39% Patients) cancer-related genes identified (a) common tumor types with a myriad of total unique mutations e.g., non-small cell lung cancer 85 mutations (n = 20), colon cancer 87 mutations (n = 28), breast cancer 79 mutations (n = 17), and ovarian cancer 51 mutations (n = 14); (b) common tumor types with a lower average number of uniquely mutated genes per patient e.g., non-small cell lung cancer (n = 3), colon cancer (n = 3), breast cancer (n = 4), and ovarian cancer (n = 3); (c) some tumor types have a higher number of unique mutated genes per patient e.g., anus (n = 27 mutations), CUPS (n = 90 mutations), esophagus (n = 54), prostate (n = 49 mutations) and uterus (n = 38 mutations); (d) common driver mutations per histologic type were for e.g., for colon cancer (TP53, APC, KRAS, PIK3CA, BRAF, SMAD4, SPTA1), non-small cell lung cancer (TP53, EGFR, KRAS, PTEN, CDKN2A, NOTCH1, NTRK1), breast cancer (TP53, NOTCH1, PIK3CA, ARID1A, BRCA2, NF1, ABL1) and ovarian cancer (TP53, FLT4, ALK, ATM, BRAF, BRIP1, C11orf30) respectively.
Of the 171 phase I cancer patients with mutations, adenocarcinoma is the most common (n = 111), followed by squamous cell carcinoma (n = 17), CUPS (n = 11) and melanoma (n = 6). We determined the average number of unique mutations per patient for adenocarcinoma (n = 7), squamous cell carcinoma (n = 6), CUPS (n = 10), and melanoma (n = 8). In our patient cohort, mutation frequency among the drivers of malignancy, TP53 had the highest frequency (92, ~54%), followed by APC (47, ~27%), KRAS (36, ~27%), PIK3CA (31, ~18%), ATM (25, ~15%), NOTCH1 (23, ~7%), PTEN (22, ~13%), BRCA2 (20, 12%), BRAF (20, ~12%), KMT2D (19, ~11%), LRP1B (18, ~11%) and CDKN2A (16, ~9%) (Figure 1A). Our study identified gene mutations unique to primary and metastatic sites that track with common mutations. Individual patient data was further screened for accurate and unique identification of primary or metastatic biopsy sites resulting in 145 patient samples. The frequency of individual gene mutations in primary and metastatic samples of 145 patients across all tumor types was estimated. Some of the gene mutations were found to be prevalent with significance to both primary and metastatic tissues, while others occurred with higher frequency in primary or metastatic sites (Figure 1B,C).
The relative frequency of TP53 mutations amongst other genes was 0.54 in primary (p value (val) = 7.9 × 10−28) and 0.45 (p val = 1.42 × 10−41) in metastatic tissue samples (Figure 2) respectively. TP53 was the most frequent gene in both primary and metastatic sites followed by KRAS, APC, PTEN, PIK3CA, ATM, and NOTCH1. In addition, Figure 2 shows that metastatic sites carry several new mutations with higher frequency (KMT2D, BRAF, BRCA2, KMT2C, PRKDC) along with the top driver mutations found in primary sites. There is a combination of cell signaling genes, DNA damage repair, and histone methyltransferase genes that are common to primary and metastatic sites and some unique to metastatic sites. The enrichment of multiple DNA damage repair proteins in metastatic sites suggest potential for investigating the safety and efficacy of PARP inhibitors therapy in a ‘basket’ trial. It is well known that there is an interplay between epigenetic pathways and TP53 mutations. We see a statistically significant enrichment of mutations of the KMT2 family of histone modifying genes. These proteins are part of multimeric complexes that bind with other proteins to target enhancers across the genome that impact complex gene regulation. Their mutated frequencies in tumors have been reported [18] and are critical co-occurring mutations which opens possibilities for pharmacologic intervention that target cofactors in gene regulation complexes.
2.2. Gene Mutation Networks in Lung and Colon Cancer
The system-wide profiling of pathogenic mutations in human cancer produces lists of genes that can be evaluated for their collective functions in order to garner new knowledge. Well annotated lists of genes can be input for enrichment into existing lists from prior knowledge. This methodology was applied to the overrepresented gene mutations across all primary and metastatic sites in lung and colon cancer cohorts of patients. Lung cancer patients were divided into adenocarcinoma, squamous cell carcinoma, and small cell lung cancer for this analysis. Figure 3A shows the site of biopsy for each subtype of lung cancer with their mutational profile, frequency and significant enrichments of genes. Node sizes reflect the abundance of a particular gene mutation. Although metastatic tumors harbor an increased number of genetic alterations, some of the alterations found in the primary tumor are preserved. Cytoscape analysis demonstrate that TP53 mutations are a major central node with combined Frequency (F) of 0.8 in primary and metastatic tumors, dictating the 3 subtypes of lung cancer pathogenesis. Statistical analysis shows TP53 enrichment with significance in both primary (p value = 0.01) and metastatic sites but a higher frequency and significance in metastatic patients (p value = 5.75 × 10−13) (Figure 3B). For adenocarcinoma of the lung, the TP53 oncogenic program impacts genetic aberrancies in all the hallmarks of cancer which includes alterations in the cell cycle, DNA repair, epigenetic regulation, growth factor receptor RAS-MAPK signaling, GPCR signaling, apoptosis, and stemness pathways. We evaluated the top mutated genes (Figure 3A) for significant enrichment of Kegg pathways, Figure 3C shows the altered signaling pathways based on the top mutations and many of the pathways known for alteration in TP53 mutated tumors are prevalent. For squamous cell carcinoma of the lung, the mutational burden is less than that for adenocarcinoma, however, TP53 mutations are a driver and associate with several known oncogenes (KRAS, BRAF, and PI3KCA). For small cell lung cancer, TP53 mutations associate with angiogenic factors (KDR, PDGFRB, EPHB6), stem cell markers (NOTCH1, 4 and PTCH1), and a novel NTRK1 mutation.
For colon cancer, statistical analysis showed the primary site mutations with combined frequency in primary and metastatic sites of 0.8 in APC and TP53 that are the major drivers followed by KRAS (F = 0.4), PIK3CA (F = 0.32), BRAF (F = 0.2) and SMAD4 (F = 0.17) pathogenic mutations respectively (Figure 4A). TP53 mutations are higher in metastatic sites but new co-mutations become prevalent in metastatic colon tumor. Statistical analysis shows TP53 enrichment with significance occurs in both primary (p value = 4.2 × 10−9) and metastatic sites (p value = 3.5 × 10−5). In a study [19] that evaluated p53 mutations in primary and metastatic tumors and CTCs from colorectal cancer (CRC) patients reported identical TP53 mutations in both sites. However, in another study TP53 mutations were shown to enrich to metastatic sites [16]. Of the metastatic sites, lung cancer shows the most diverse profile compared to colon. All other metastatic sites have only a few unique mutations (Figure 4A). As known from previous studies, the top 4 driver mutations in our colon cancer cohort with statistical significance are TP53, KRAS, and APC with PIK3CA (Figure 4B) mutations that are more prevalent in metastatic sites as these are late occurring mutations in CRC. Figure 4C shows signal transduction pathways affected by significant mutations in colon cancer (Figure 4A). Signaling pathway changes known in TP53 mutated tumors are overrepresented in the list of pathways. A RAS wild type colon cancer patient with HER2+ by CISH and IHC 3+ had 2 pathogenic TP53 mutations affecting both alleles indicating a rare and novel event. Similar profiles have also been generated for breast cancer (ER/PR, HER2/Neu, TNBC, TPBC), ovarian cancer, and CUPS. Data provides information for potential targeted functional studies.
2.3. Distribution of TP53 Mutations among Tumor Types
In our cohort of patients, TP53 is mutated more often in lung (80%), colon = pancreas (75%), CUPS (63%), and breast (41%) cancers. No TP53 mutations were detected in the rectum, anus, appendix and melanoma (Table 2). The type of TP53 mutation is variable with most affecting the central DNA-binding core domain and to a lesser degree the C-terminal domain that down-regulates DNA binding to the central domain and the acidic N-terminus transcription-activation domain. We hypothesized that distinct TP53 mutations may track with unique co-mutations that orchestrate distinct transcriptional programs and signaling pathways.
We evaluated TP53 in the context of other oncogenes that track with it at metastatic sites in each tumor site (Figure 5A). Some TP53 mutations are conserved in both primary and metastatic sites, while new mutations are acquired in metastatic samples. Loss of p53 function via missense or truncating mutations occurs in many human tumors. Over 75% of TP53 mutations result in the loss of wild-type function which exerts dominant-negative regulatory effects over co-expressed wild-type p53. Mutant p53 may be oncogenic in ways not related to those associated with wild type p53 functions [20,21] which include cell invasion, migration, scattering, survival, proliferation, angiogenesis, stem cell expansion, and tissue remodeling. We characterized individual TP53 mutations in each tumor type to better understand the diversity of mutant sites (Figure 5B).
In lung cancer, TP53 mutations are spread across the DNA binding domain (DBD). In the colon, TP53 mutations are clustered toward the c-terminal end of the DBD which directly interacts with DNA (Figure S1). For breast and ovarian cancer, TP53 mutations are clustered more in the middle of the DBD (Figure 5B). It is known that small changes in p53 protein do not necessarily preclude expression with some wild-type activities. Analyses of TP53 mutation-site clustering indicate that DNA-binding activity direct versus indirect, may alter the target gene transcription affecting p53-dependent signaling pathways.
TP53 mutations are divided into 2 categories: structural mutants, where protein folding is altered and DNA-contact mutants, where changes in critical amino acids affect DNA binding. Well characterized structural mutants such as R175H are highly unfolded under physiological conditions. Contact mutants such as R248Q exhibit decreased structural stability compared to wild type p53 [22]. We cataloged common and unique TP53 mutations for lung cancer (Table 3, Figure 5B) and colon cancer (Table 4, Figure 5B) with respect to aberrations documented from functional studies. In lung adenocarcinoma, mutations are observed in exon 4 (n = 3), exon 5 (n = 8), exon 6 (n = 4), exon 7 (n = 6), and exon 8 (n = 3). In colon adenocarcinoma, mutations occur in exon 5 (n = 2), exon 6 (n = 1), exon 7 (n = 8) and exon 8 (n = 6). Mutations in exon 4 affect transactivation while mutations in exon 5, 6 and 7 are buried within the p53 structure and affect DNA binding. Mutation in exon 5 (lung cancer) and two mutations in exon 7 (colon cancer), affect zinc binding while exon 8 mutations partially expose DNA binding.
Tetramers of p53 bind to DNA targets through two decameric half-sites separated by a variable nucleotide spacer. The spacer length (contiguous versus non-contiguous) determines affinity of protein–protein and protein-DNA interactions [20]. A crystal structure of p53 bound to DNA (Watson–Crick and Hoogsteen) was utilized to map various p53 DNA-binding domain mutations detected in our cohort of patients (Figure S1). For example, R248W (lung cancer) or R248Q (colon cancer) interfere with DNA binding affinity. H179L (lung cancer) and C238S (colon cancer) disrupt zinc binding and stabilization of a loop-sheet-helix motif necessary for protein–protein interactions. TP53 mutations away from DNA and protein–protein interaction sites enhance structural disruption of the p53 protein that dysregulate affinity of binding to DNA targets, thus potentially driving different oncogenic signaling pathways. In addition, TP53 mutations may be truncal or acquired at metastatic sites.
Protein–protein interaction data from Stringdb show that the p53 protein strongly interacts with multiple proteins (Figure S2A). Different mutated TP53 sites may affect binding and interactions and in turn dysregulate p53-dependent signaling pathways. We searched for protein-interaction networks for top key mutated genes in lung and colon metastatic samples (Figure S2B,C) which showed two different networks for colon and lung with TP53 as one of the central nodes. Some of the nodes are preserved between the two tissue types, but additional nodes produce new interactions and possible changes to integrated signaling mechanisms.
2.4. Pre- and Post-Targeted Therapy Response
Finally, we report on the molecular profiles pre- and/or post-treatment of 10 advanced cancer patients undergoing targeted (small molecule and monoclonal antibodies) and immune checkpoint therapy to highlight unique pathways with insights to molecular responses (Table 5). The most intriguing is the effect of targeted therapies on epistasis, a phenomenon where the effect of one gene depends upon the genetic background or presence of other modifier genes. Moreover, in contrast to individual mutations, combinations of epistatic mutations may have unique effects including unexpected phenotypes and inherent resistance to single agent therapies.
Case #9 is of a patient with an EML4-ALK inversion non-small cell adenocarcinoma of the lung treated with crizotinib and highlights persistence of the target EML4-ALK on initial chronic crizotinib with a complete remission but then slow relapse on crizotinib without a resistant mutation. The patient enrolled on a phase Ib study of crizotinib plus an HSP90 inhibitor [23] and had a near complete remission, however, a persistent pleural effusion led to withdrawal from the study. Cell and molecular analysis of the pleural fluid was positive for adenocarcinoma but FISH confirmed the loss of EML4-ALK inversion, respectively. Moreover, NGS showed the tumor had acquired several novel gene mutations that may be targetable (Figure 6). The potential therapies suggested include CDK46 inhibitor or immune checkpoint therapy (Table 5).
Case #3 is a patient with CUPS harboring a rare CCNE1 mutation treated with a CDK4/6 inhibitor on a clinical trial. The patient achieved stable disease for 11 months. In the cell cycle, cyclin E1 complexes with and activates CDK2 driving cells through the G1/S phase and is degraded as cells progress through S phase. Over-expression of CCNE1 has been found in many tumor types and can cause chromosome instability with enhanced proliferation. CCNE1/CDK2 phosphorylates NPAT (nuclear protein mapped to the ATM locus), a transcriptional activator of the cell cycle regulated histone gene expression promoting cell cycle progression in the absence of pRB [24]. In case #3, mutated CCNE1 with a high proliferative index suggests that CDK4/6 inhibition could prevent G1 progression and halt cell cycling. In addition to a CCNE1 mutation, concurrent mutations in AKT3 and PTEN were present, suggesting co-targeting with a PI3K or mTOR inhibitor.
Case #10 is a patient with triple-hit diffuse large B-cell lymphoma (MYC/BCL2/BCL6 translocated). The patient received dose-adjusted R-EPOCH immuno-chemotherapy with rapid progression and was enrolled on a novel-novel investigational trial of a BTK inhibitor + fourth generation IMiD + rituximab. The molecular profile prior to initiating therapy (Table 5) indicated multiple pathway defects including a TP53 dependent G1-aberrant DNA damage response. Drugs targeting epigenetics (e.g., EZH2 or DNMT3A inhibitor), DNA damage response and aberrant cell cycle may have benefitted this patient.
3. Discussion
The frequency and distribution of mutant oncogenes and tumor suppressors have redefined taxonomy for most tumor types. The mutational landscape of cancer is made up of a few mutated genes in a high fraction of tumors (‘mountains’) and most genes are altered at relatively low frequencies (‘hills’) [25]. Precision medicine approaches have been evaluated as novel tailored therapies and current trends emphasize characterizing the mutational repertoire. The questions remain as to what constitutes the ‘driver pathways’ that should be targeted. We focused our efforts on a heterogeneous group of cancer patients with metastasis entering early phase investigational agent trials. These patients have had >3 prior therapies. We provide an analysis of TP53 mutations present at primary and metastatic sites with other genomic aberrations that may guide rational targeted therapeutics. Tp53 current state-of-the-art precludes testing of TP53 mutant driven transcriptional programs with selective agent (s), since there is a lack of knowledge of these signaling pathways. Individual patients treated on targeted trials are subject to potential selection bias, however, our analyses highlight examples of decision complexity based on molecular profiling.
The mutational profiling of metastatic sites by NGS identify unique genetic aberrations absent at the primary site. Hence, to fully decipher pathobiology and therapeutic response, clonal and sub-clonal genotypes of individual tumors need characterization. Large-scale NGS projects require integration with functional screens to better develop strategies for novel therapeutic combinations. For functional screening to be useful, key metastatic drivers need to be identified to better define driver pathways that can be optimally targeted in anticipation of drug resistance and tumor evolution [26]. We utilized TP53 mutations as a critical driver at primary and metastatic sites and hypothesized that mutant p53 protein (s) activate unique signaling pathways within a background of epistasis [27]. Our study demonstrates that the enrichment of TP53 mutations occur at both primary and metastatic sites. This indicates both truncal and acquired TP53 mutations are most likely from prior therapies. The premise we surmised was that multiple epistatic mutations can have a combination effect, which differs from those they may elaborate individually. We identified TP53 mutations that may partner with unique co-mutations in colon and lung cancer. There has been a significant effort to restore wild type p53 function [28] in tumors with mutant TP53. Phase 1/II clinical trials are ongoing investigating small molecule inhibitors APR-246 (eprenetapopt binds to p53 at two cysteine residues in the DNA-binding domain and stabilizes mutant p53), PRIMA-1 (p53 reactivation and induction of apoptosis) and MDM2 inhibitor AMG 232 that restores p53 tumor suppression by blocking the MDM2-p53 interaction [29]. These p53 targeted small molecular inhibitors are being developed in both solid and hematologic malignancies. These inhibitors are available for testing in TP53 mutant cell lines and preclinical models to evaluate combination treatments targeting co-occurring gene mutations identified in our study.
In our analyses, we found co-mutations in the DNA damage repair genes (ATM, BRCA2, PRCKDC, PMS2) that highlight consideration for targeting with PARP inhibitors. Mutation in genes that activate multiple signaling pathways for e.g., mTOR and its inhibition by everolimus is a pharmacologic approach to target mutant TP53 reported to be activated in breast and pancreatic cancer cell lines. Similarly, histone lysine methyltransferases are known to modulate the methylation status of TP53 at distinct sites. Mutations in KMT2C/KMT2D can be targeted with specific methyltransferase small molecule inhibitors that disrupt the WDR5-KMT2 interaction [30]. Some of these core complex mutations along with TP53 mutations that upregulate the activation of specific cellular pathways can only be investigated by whole genome transcription assays in the backdrop of specific TP53 mutations. We believe that this is a basis for the transcriptomic studies of primary versus metastasis that could translate into unique ‘pathway’ focused therapies.
The current practice focus has been on mutations considered to be clinically ‘actionable’. Comparative analyses of unmatched and matched primary and metastatic sites have shown depletion versus enrichment of certain oncogenic and tumor suppressor mutations respectively [16]. There appears to be a paucity of universal mutations limited to metastatic sites. However, focusing on distinct non-actionable TP53 mutations that drive unique signaling pathways may address context of vulnerability and define improved methods for rational therapies. These improved methods of rational combinations may help overcome acquired drug resistance at both primary and metastatic sites. It is prudent to develop transcriptional models to identify signaling pathway drivers. Tumor vulnerabilities differ based on specific TP53 mutations and tumor type, thus multi-mutant, multi-omics strategies are needed to elucidate cancer protecting activities that can be targeted. The goal of precision medicine in oncology will then move a step closer to the realization of implementing unique clinical trials personalized to each patient’s malignancy. These trials will be key to assess targetable and non-targetable genomic aberrations and provide a handle on moving the needle to enhance survival in patients with metastatic disease.
4. Materials and Methods
4.1. Patient Population
Patients with advanced solid and hematologic malignancies that were referred to the New Therapeutics Program (n = 203) were routinely profiled as a standard of care utilizing commercial next generation sequencing (NGS) platforms. Tumor samples taken from primary and metastatic sites (liver, lung, lymph nodes, pleural fluid, etc.) were formalin-fixed and paraffin-embedded (FFPE). Ten case studies of patients’ pre-/post-targeted treatment biopsies were available for analysis. All patient information was de-identified.
4.2. Profiling Platforms
We utilized Precipio 421-NGS (includes FISH) (Precipio Diagnostics, New Haven, CT, USA), Caris-Molecular Intelligence (600-NGS, IHC, FISH/CISH) (Caris Life Sciences, Irving, TX, USA), and Foundation One (300-NGS/CNV) (Foundation Medicine, Cambridge, MA, USA) platforms for NGS analysis. Each commercially available platform cannot be compared to each other as they are propriety encrypted; however, all the actionable genes are represented in each of the platforms. Biopsy samples were annotated by histology, primary and metastatic site, biopsy location, gene mutation, mutation count/gene and TP53 mutations. We focused on mutations that co-occur with mutant TP53 type at primary and metastatic sites. NGS molecular profiles from each patient and tumor type were categorized into common and unique mutations.
4.3. Mutation Analysis in Primary and Metastatic Tissue Samples
Out of 171 cases, gene mutations from 145 unique patient cases (94 with metastatic tumors and 51 with primary tumor) were analyzed. The mutation frequency and enrichment of mutation was estimated independently in primary and metastatic tumors. Relative frequency was calculated, and binomial exact test was performed to estimate the probability of enrichment of gene mutations in primary or metastatic tumors. For each gene mutation, the odds ratio was calculated as relative frequency of a gene mutation to the reference as average relative frequency of all genes. For all analysis p value < 0.05 was considered significant. Data was also stratified for organ specific mutations and similar analysis was performed to estimate frequency and enrichment. All analysis and plots were done utilizing R (v 3.4.3).
4.4. Gene Mutation Pathways and Protein Interaction
Cytoscape (http://www.cytoscape.org/) was used for the mapping of gene mutation frequencies and enrichment probability to cancer histology and primary site. We utilized Enrichr [31] to estimate enrichment of Reactome pathways [32] for gene mutations with significant representation across all patients. Signaling pathways were also estimated for primary and metastatic samples from specific primary sites using the enrichKEGG and cluster profiler package from Bioconductor (https://Bioconductor.org). Top genes with mutations that were significant in tissue sites were analyzed for enriched Kegg pathways to find out which cellular pathways are altered by co-occurring gene mutations. Patients enrolled in targeted therapy trials were profiled pre-and/or post-treatment for pathway to ascertain response to therapy. Protein interaction analysis was performed using the String database [33].
4.5. Three-Dimensional Mapping
The crystal structure of p53 bound to DNA from Protein Data bank (pdb: 3KZ8) was utilized to map TP53 mutations [20]. The International Agency for Research on Cancer (IARC—Version R 19) TP53 database was used to help analyze data on human cancer TP53 gene variations [21].
5. Conclusions
The mutational profiling of primary and metastatic sites of cancer patients participating in early phase therapeutic trials provide an opportunity to identify distinct TP53 mutations that drive unique signaling pathways, which should guide rational drug combinations to abrogate oncogene addiction and drug resistance, hopefully with minimal toxicity to normal tissue.
Acknowledgments
We wish to thank the West Clinic and the University of Tennessee Health Science Center for support and seed funding.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/4/597/s1. Figure S1: The crystal structures of p53 bound to DNA was utilized to map common and rare p53 mutations detected in our cohort of patients. Figure S2: TP53 protein interaction network from String db.
Click here for additional data file.
Author Contributions
D.M.—Design, execution, analysis, and writing of the manuscript; R.P.—Data Analysis, Bioinformatics, statistical analysis, wrote part of the manuscript; Y.C.—Data and statistical Analysis, N.J.—Methodology and analysis of data; B.J.—Methodology and wrote part of the manuscript; M.P.—Reviewed molecular profiling data and wrote sections of the manuscript; J.C.—Reviewed molecular profiling data and wrote sections of the manuscript; L.C.—Wrote parts of the manuscript, generated Tables, structural models of p5 and pathway analysis. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by discretionary funds from University of TN Health Science Center.
Institutional Review Board Statement
Ethical review and approval were waived for this study, due to the fact that commercially available platforms were used to research tumor profiling with de-identified samples which does not require ethics committee approval as no patient information is used.
Informed Consent Statement
Patient consent was waived due to: No patient information was used and de-identified patient samples were used for tumor profiling.
Data Availability Statement
The data presented in this study are available within the article or supplementary material.
Conflicts of Interest
The authors listed have no conflict of interest or financial disclosures.
Figure 1 The mutation frequency of the common drivers of malignancy. (A) Most frequently mutated genes for 171 advanced cancer patients in study. Top 12 mutated genes labeled with gene name. Plot showing representation of gene mutations with significance (p-values < 0.05) across (B) primary samples and (C) metastatic samples. Y-axis is p-value and X-axis is the odds ratio. Significant genes are labeled and highlighted.
Figure 2 Scatter plot of frequencies of gene mutations in primary and metastatic samples. Genes that are enriched in primary, metastatic or both samples with p value < 0.05 are labeled.
Figure 3 (A) Map of mutation frequencies in lung cancer patients. “Gene” node sizes positively correlate with total mutation frequency (F) of the gene among all primary/metastatic sites. Rectangular nodes: Primary/metastatic sites colored by histology type. Pink-colored gene nodes: Genes mutated in multiple primary/histology types. Gray-colored genes nodes: Mutated genes unique to a particular site. (B) Plot of relative frequency of gene mutations in primary and metastatic and gene enriched are highlighted. (C) Signaling pathways altered by significant gene mutation. Genes with significant mutations were analyzed for enrichment of Kegg pathways. Pathways with adjusted p value < 0.05 were selected. The plot shows the significant pathways with bar height as gene counts.
Figure 4 (A) Map of mutation frequencies (F) in colon cancer patients with adenocarcinoma histology type. “Gene” node sizes positively correlate with gene mutation frequency. Pink-colored gene nodes: genes mutated in multiple primary/metastatic sites. Gray-colored gene nodes: mutated genes unique to the particular primary/metastatic site. (B) Plot of relative frequency of gene mutations in primary and metastatic and gene enriched are highlighted. (C) Signaling pathways altered by significant gene mutation. Genes with significant mutations were analyzed for enrichment of Kegg pathways. Pathways with adjusted p value < 0.05 were selected. The bar plot shows the significant pathways with bar height as gene counts.
Figure 5 (A) Mutational profile of all patients from all tumor types. The figure shows frequency of mutations and differences in primary and metastatic tissue for different tumor types. (B) Schematic diagram of TP53 gene and its site-specific mutations in lung, colon, breast, and ovarian tumor tissues.
Figure 6 Targetable signaling pathways with of loss EML4-ALK in a patient (Case #9) with non-small cell adenocarcinoma of the lung cancer (Case #9) progressing on crizotinib plus an HSP90 inhibitor.
cancers-13-00597-t001_Table 1Table 1 Molecular profiles of advanced cancer patients enrolling in phase I trials.
Primary Number of Patients Histology Number of Mutated Genes Mutated Gene ID′s
Anus 2 Squamous Cell Carcinoma 27
APC, ARID2, ASXL1, ATRX, CCND1, CDKN1B, CDKN2A, EPHA5, ERBB2, ERBB4, FANCA, FGF19, FGF4, FLT1, INHBA, MED12, KMT2D, MYCN, NKX2-1, PALB2, PIK3CA, POLE, RARA, RB1, SMARCA4, TERT, TSHR
Appendix 2 Adenocarcinoma 13
AR, CDK12, FGFR1, FLT3, GATA6, GNAS, KRAS, KMT2A, KMT2C, NOTCH1, PRKDC, SMAD4, SPEN
- 1 Mucinous Adenocarcinoma 1
KRAS
Bladder 2 Transitional Cell Carcinoma 24
ATM, CSMD3, EP400, EPHB4, FGFR3, FN1, LTF, MAF, KMT2A, MSH6, MTR, MYH9, NUMA1, PDE4DIP, PDGFB, PDGFRa, PIK3C2B, PIK3CA, PRKAR1A, PTEN, SF3B1, THBS1, TP53, WRN
Brain 1 Astrocytoma 2
IDH1, TP53
- 3 Glioblastoma Multiforme 16
AKT3, BRAF, EGFR, EGFRvIII, ERBB2, ETV4, FLT3, KRAS, NF1, NOTCH2, PTEN, SMAD2, SMO, TNFAIP3, TRRAP, UBR5
- 1 Medulloblastoma 10
BCOR, CARD11, FAM123B, GNAS, LZTR1, KMT2D, NRAS, RARA, SMO, TERT
- 1 Meningioma 5
FAT1, FGF19, LRP1B, KMT2D, NF2
Breast 17 Adenocarcinoma 79
ABL1, ABL2, AKT1, AR, ARFRP1, ARID1A, ASXL1, ATM, BARD1, BCL2L2, BCL9, BRCA2, CCNE1, CDH1, CDK12, CDKN2A, CHD4, CHEK2, CIC, CREBBP, CSMD3, DAXX, DDR2, DST, EGFR, EPHA3, ERBB4, ESR1, FAM123B, FAT1, FGFR1, FGFR3, FH, FLT1, FLT3, GATA3, GRIN2A, HSP90AB1, Her2/Neu, IDH2, JAK1, JAK2, JAK3, KDM6A, KIT, KRAS, MAP2K4, MAPK8, MST1R, MYCL1, MYST3, NF1, NFKB1, NOTCH1, PARP1, PBRM1, PDGFRA, PDGFRB, PDGFRa, PIK3CA, PIK3R2, PMS2, PRKCI, PTCH1, PTEN, PTPN11, PTPRD, RET, RPS6KA2, RUNX1, SDHA, SGK1, TGM7, TLR4, TNK2, TOP2A, TP53, TPR, TSC1
CUP 8 Carcinoma 90
ABL2, ACVR2A, AFF1, AKT2, AKT3, APC, AR, ARFRP1, ARID1A, ARID1B, ASXL1, ATM, ATR, ATRX, AXL, BCORL1, BCR, BRCA2, BTK, CCND2, CCNE1, CDH5, CDK12, CDK8, CDKN1B, CHD2, CHD4, CREBBP, CSMD3, CTNNB1, DNMT3A, EPHA3, EPHB1, ERCC1, EZH2, FANCA, FANCE, FAT1, FGF23, FGF6, FGFR2, GATA2, HGF, IL7R, IRS2, KDM5A, KEAP1, KEL, KRAS, LRP1B, MAP2K2, MAP3K1, MDM4, MET, KMT2C, MRE11A, MSH2, MSH6, MUTYH, MYCL1, MYST3, NOTCH1, NOTCH2, NTRK1, NTRK3, PAK3, PDCD1LG2, PIK3CG, PIK3R2, POLD1, PPP2R1A, PRKDC, PTCH1, PTEN, PTGS2, RALGDS, RANBP2, ROS1, RPTOR, SETD2, SMARCA4, SMARCB1, SNCAIP, STK36, SYK, TCF7L2, TP53, TSC2, ZNF217, ZNF703
Cervix 1 Adenocarcinoma 5
APC, PIK3CA, PTEN, RB1, TP53
- 6 Squamous Cell Carcinoma 45
ABL2, AKT1, ARID1A, ATM, ATRX, AURKB, BCORL1, CASP8, CCNE1, CDH5, CEBPA, CHEK2, CIC, CYLD, EPHA5, FGF23, FLCN, FLT3, GDNF, IDH1, IGF1R, LRP1B, MAP2K4, MAPK8, MED12, KMT2C, MYC, MYH9, MYST3, NOTCH1, NOTCH2, PALB2, PIK3CA, PIK3CG, PIK3R1, PMS2, PRKDC, RAD51, RANBP2, ROS1, SOCS1, TAL1, TCF7L1, TET2, TOP2A
Colon 28 Adenocarcinoma 87
ABL1, AKT1, ALK, APC, ARAF, ARID1A, ARID1B, ASXL1, ATM, BRAF, BRCA2, BTG1, CCND2, CCND3, CDK8, CDKN2A, CSF1R, DDR2, DNMT3A, EGFR, ERBB3, ERCC5, FAM123B, FANCA, FANCC, FANCD2, FAS, FAT1, FBXW7, FGFR1, FGFR2, FLT1, FLT3, FLT4, GATA4, GNA11, GNAS, GPR124, Her2/Neu, JAK2, KDR, KLHL6, KRAS, LRP1B, MAP2K2, MAP2K4, MED12, MET, KMT2A, KMT2D, KMT2C, MYC, NOTCH1, NRAS, NTRK1, NTRK2, NTRK3, PDGFRA, PDGFRB, PIK3CA, PIK3R2, PMS2, POLD1, PPP2R1A, PREX2, PRKDC, PTCH1, PTEN, RB1, RET, RICTOR, ROS1, SMAD2, SMAD3, SMAD4, SPTA1, SRC, TAF1, TGFBR2, TNFAIP3, TOP1, TP53, TSC1, TSC2, VEGFA, XPO1, ZNF703
Endometrium 6 Adenocarcinoma 24
ABL1, ABL2, APC, AURKA, AURKB, BRCA1, CYLD, EPHA5, ERBB3, ERCC1, FGFR2, IDH1, JAK3, MAP2K4, NF1, NOTCH1, NRAS, NTRK1, PIK3CA, PTCH1, PTEN, TGM7, TP53, TSC2
Esophagus 3 Adenocarcinoma 54
ACVR1B, ASXL1, ATM, ATR, AXIN1, BCL2L1, BRIP1, CARD11, CCND2, CCND3, CCNE1, CDKN2C, CEBPA, CREBBP, CTNNB1, DST, EGFR, EP300, EPHA3, FANCC, FANCL, FH, FLT1, GATA4, GATA6, GLI1, IKZF1, INHBA, JAK1, KDM5C, KEAP1, KRAS, LRP1B, MAGI1, KMT2C, MTOR, MYC, NKX2-1, NTRK3, PMS2, RNF43, RUNX1, RUNX1T1, SLIT2, SMARCA4, SPEN, STAG2, TAF1, TOP1, TP53, TSHR, VEGFA, WT1, XPO1
Head & Neck 1 Carcinoma 3
ATM, BRCA2, CDKN2A
- 1 Mucoepidermoid Carcinoma 11
CDKN2A, CDKN2B, CJD2, CREBBP, EWSR1, KDM6A, KMT2D, NOTCH1, NOTCH3, SPTA1, TBX3
- 2 Squamous Cell Carcinoma 8
BRCA2, CDK4, FLT3, KDR, MET, MSH2, NOTCH2, TP53
Kidney 1 Clear Cell Adenocarcinoma 3
BRAF, MEK2, NF1
- 4 Clear Cell Carcinoma 24
ACVR1B, ATM, AXL, CD79A, CDK4, EPHA3, EPHA5, FGFR1, FRS2, GLI1, HSP90AA1, KEAP1, MDM2, MSH2, PBRM1, PIK3CA, PMS2, POT1, PRKDC, SETD2, SMARCA4, SPEN, TET2, VHL
Liver 1 Adenocarcinoma 4
CDKN2A, Her2/Neu, KRAS, TP53
- 1 Cholangiocarcinoma 15
APC, ATR, CDH2, CDKN2A, CSF1R, ERCC1, EZH2, FANCD2, FLT1, IL21R, KIT, NOTCH2, NOTCH4, SRC, XPC
Lung 20 Adenocarcinoma 85
ABL1, ALK, APC, ARID1A, ARID1B, ATM, BCL6, BCOR, BRAF, BRCA1, BRCA2, CBL, CCNE1, CDKN2A, CDKN2B, CIC, CSF1R, CSMD3, DICER1, DOT1L, DST, EGFR, EP300, EPHA3, EPHA5, ERBB2, ERBB3, ERRFI1, EXT1, FANCG, FGFR2, FLT1, GNA11, HGF, HRAS, Her2/Neu, IRF2, ITGA10, KDR, KEAP1, KIT, KRAS, LRP1B, MAGI2, MAP2K2, MAP3K1, MAP3K7, MET, MLH1, KMT2D, MSH2, MYC, NF1, NOTCH1, NOTCH2, NOTCH3, NSD1, NTRK1, NTRK3, PARP1, PDGFRB, PIK3CA, PKHD1, PMS2, POLE, PRKDC, PTCH1, PTEN, PTPN11, PTPRT, RAD50, RB1, RET, RPTOR, SETD2, SMARCB1, SMO, SOX9, SRC, TP53, TPR, UBR5, VEGFR2, WT1, ZNF703
- 1 Neuroendocrine Carcinoma 7
CDKN2A, CREBBP, CSMD3, DOT1L, MAGI1, PBX1, PRKDC
- 2 Small Cell Carcinoma 12
EPHB6, JAK1, KDR, MUTYH, NOTCH1, NOTCH4, NTRK1, PDGFRB, PTCH1, SMARCB1, SYK, TP53
- 3 Squamous Cell Carcinoma 13
APC, ATM, BRAF, EGFR, GRIK5, IGF1R, KDR, KRAS, LRP1B, NOTCH1, PIK3CA, PTEN, TP53
Lymph Node 1 Diffuse Large B-Cell Lymphoma 9
ABL2, AFF1, DNMT3A, EZH2, PIK3R2, PRKDC, PTGS2, STK36, TP53
- 1 Mantle Cell Lymphoma 6
ATM, NOTCH2, PTPRT, RPS6KA2, TP53, TSC2
Not Specified 1 Adenocarcinoma 1
PDGFRA
- 1 Diffuse Large B-Cell Lymphoma 15
BCL2, CBL, DUSP2, GNA13, HIST1H1D, IGH, KDM4C, MAP3K1, KMT2D, MYC, PIM1, PLCG2, RAD50, RB1, TNGRSF14
- 2 Melanoma 17
APC, BRCA2, CCND2, CSF1R, EPHA5, GNA13, IDH1, LRP1B, MAP3K1, KMT2C, MYC, NRAS, PMS2, PRKDC, PTEN, TSC1, TSHR
- 1 Sarcoma 22
APC, ARHGAP26, ATRX, C17orf39, CREBBP, ELP2, EP300, FANCG, FANCL, FBXW7, FGF10, GNA13, IL7R, KMT2A, KMT2D, NKX2-1, RB1, RICTOR, SDHB, SMARCA4, TP53, ZNF24
- 1 Squamous Cell Carcinoma 8
ALK, ATM, BRAF, BRCA1, JAK2, NOTCH1, NTRK1, TP53
Ovary 14 Adenocarcinoma 51
ABL1, ALK, APC, ARAF, ARID1A, ARID1B, ATM, ATRX, AXIN1, BAP1, BARD1, BCR, BLM, BRAF, BRCA1, BRIP1, C11orf30, CCNE1, CDH2, CRKL, CSF1R, CTNNB1, DNMT3A, EP300, ERBB2, ERBB3, ERBB4, FANCD2, FBXW7, FLT4, HRAS, KDM5A, KEAP1, KRAS, LRP1B, MAML2, NOTCH1, NOTCH2, NOTCH4, PALB2, PAX8, PDGFRA, PDGFRB, PMS2, PTEN, RET, SDHA, SLIT2, TAF1, TBX3, TP53
Pancreas 8 Adenocarcinoma 35
AKT2, APC, ARID1B, BARD1, BRAF, BRCA1, CDH2, CDK6, CDKN2A, CDKN2B, CTNNB1, ERCC4, FBX27, GNAS, HGF, HNF1A, HRAS, KRAS, MEK2, MET, MUTYH, MYST3, PALB2, PDGFRA, PIK3CA, PIK3R3, PMS1, PMS2, RET, RICTOR, ROS1, SMO, STK11, TP53, TSC1
Peritoneum 1 Carcinoma 2
EGFR, TP53
Pharynx 2 Squamous Cell Carcinoma 8
CHEK2, EPHA7, KDR, MET, PALB2, RAF1, TP53, TSC1
Pleura 1 Mesothelioma 6
BAP1, FOXL2, MYCN, NF2, POLD1, SETD2
Prostate 5 Adenocarcinoma 49
ABL1, APC, ARID1A, ARID1B, BCL2L2, BCL6, BRCA2, CDKN1B, CIC, ERBB4, FANCC, FAS, FGF6, FGFR2, FGFR3, FLT1, FLT4, GABRA6, GNAS, IDH2, IRF2, LRP1B, LYN, MAGI2, MAP2K4, MAP3K1, KMT2D, KMT2C, NF1, NIN, NTRK1, PIK3C2B, PIK3CA, POLD1, POLE, PRDM1, PREX2, PTCH1, PTEN, RET, RUNX1T1, SDHD, SETD2, SMAD3, TAF1, TCF7L1, TMPRSS2, TP53, ZNF217
Rectum 2 Adenocarcinoma 20
APC, ATM, ATRX, FAT1, FGF23, GPR124, IDH1, KLHL6, KRAS, KMT2D, KMT2C, MYST3, NRAS, PDGFRA, PIK3CA, PRKDC, PTEN, RANBP2, SMAD4, ZNF703
- 1 Melanoma 6
DAXX, FANCA, NRAS, PMS2, SUFU, TRRAP
- 1 Squamous Cell Carcinoma 1
PIK3CA
Skin 3 Melanoma 26
ALK, ARID1A, ATM, ATR, BCL2, BRAF, BRCA2, CARD11, CYLD, DDR2, DNMT3A, FLT1, GNAS, IDH1, INPP4B, MAGI2, KMT2A, KMT2C, NRAS, PDK1, PRKCI, RPTOR, SOX10, SPTA1, TERT, TET2
- 1 Sarcoma 2
FGFR1, NOTCH1
Soft Tissue 1 Sarcoma 23
CCND2, CD36, CDKN2A, CDKN2B, DOT1L, EP300, FANCA, FANCE, FGFR2, GNA12, KIT, LRP1B, MKI67, KMT2A, KMT2C, PRKDC, RAD21, RUNX1T1, TCF3, TP53, TRAF5, TSC2, WDR90
Uterus 3 Adenocarcinoma 38
APC, ATR, BCL11A, CATA6, CBL, CDKN2A, DOT1L, ERBB4, FANCD2, FANCF, FAT1, FBXW7, FGF19, FLT4, FRS2, GATA6, IGF1R, KDM5C, KDM6A, KRAS, LRP1B, MAP2K4, MED12, KMT2C, MST1R, MTOR, PDGFRa, PIK3CA, PMS2, PRDM1, PRKDC, PTCH1, RANBP2, RB1, RICTOR, RPTOR, SRC, TP53
- 1 Leiomyosarcoma 4
EPHB6, GID4, TET2, TP53
Combined patient gene mutation profiles showing genes mutated in at least one patient. Profiles obtained with NGS using Precipio-421-NGS, Caris-Molecular Intelligence, and Foundation One platforms. Total patients: 171.
cancers-13-00597-t002_Table 2Table 2 Distribution of TP53 mutations among tumor types.
Primary Histology Number of Patients Number of Patients with mutTP53 Fraction Patients with mutTP53
Breast Adenocarcinoma 17 7 0.41
Colon Adenocarcinoma 28 21 0.75
CUP Carcinoma 8 5 0.63
Endometrium Adenocarcinoma 6 2 0.33
Lung Adenocarcinoma 20 16 0.80
Ovary Adenocarcinoma 14 7 0.50
Pancreas Adenocarcinoma 8 6 0.75
Fraction of patients with mutated TP53 by primary site and histology.
cancers-13-00597-t003_Table 3Table 3 Catalog of common and unique TP53 mutations for lung cancer.
Protein Mutation Exon/Intron Residue Function Domain Function Structural Motif
P47S 4 exon na Transactivation N-terminal Transactivation
P58R 4 exon na na N-term
Q100 * 4 exon na na N-term
K132M 5 exon Buried DNA binding L1/S/H2
C141Y 5 exon Buried DNA binding NDBL/beta-sheets
V143M 5 exon Buried DNA binding NDBL/beta-sheets
Y163N 5 exon Buried DNA binding NDBL/beta-sheets
Y163C 5 exon Buried DNA binding NDBL/beta-sheets
R174W 5 exon Partially exposed DNA binding L2/L3
H179L 5 exon Zn binding DNA bindin L2/L3
R181P 5 exon Exposed DNA binding L2/L3
H193R 6 exon Buried DNA binding L2/L3
R196G 6 exon Buried DNA binding NDBL/beta-sheets
S215I 6 exon Buried DNA binding NDBL/beta-sheets
Y220C 6 exon Buried DNA binding NDBL/beta-sheets
M237I 7 exon Buried DNA binding L2/L3
M237I 7 exon Buried DNA binding L2/L3
M237I 7 exon Buried DNA binding L2/L3
R248W 7 exon DNA binding DNA binding L2/L3
R248W 7 exon DNA binding DNA binding L2/L3
E258G 7 exon Buried DNA binding NDBL/beta-sheets
R273L 8 exon DNA binding DNA binding L1/S/H2
P278A 8 exon Buried DNA binding L1/S/H2
R283P 8 exon DNA binding DNA binding L1/S/H2
IARC TP53 Database search results for TP53 mutations in lung cancer patients. Most mutations are in exons 4, 5, 6, 7, and 8 located in the DNA binding domain. * represents unknown.
cancers-13-00597-t004_Table 4Table 4 Catalog of common and unique TP53 mutations for colon cancer.
Protein Mutation Exon/Intron Residue Function Domain Function Structural Motif
C141Y 5 exon Buried DNA binding NDBL/beta-sheets
R175H 5 exon Buried DNA binding L2/L3
R213L 6 exon Buried DNA binding NDBL/beta-sheets
I232S 7 exon Buried DNA binding NDBL/beta-sheets
M237K 7 exon Buried DNA binding L2/L3
C238S 7 exon Zn binding DNA binding L2/L3
C238S 7 exon Zn binding DNA binding L2/L3
G244S 7 exon Exposed DNA binding L2/L3
G245S 7 exon Buried DNA binding L2/L3
R248Q 7 exon DNA binding DNA binding L2/L3
R248Q 7 exon DNA binding DNA binding L2/L3
R273C 8 exon DNA binding DNA binding L1/S/H2
R273H 8 exon DNA binding DNA binding L1/S/H2
E286K 8 exon Partially exposed DNA binding L1/S/H2
E286K 8 exon Partially exposed DNA binding L1/S/H2
E286G 8 exon Partially exposed DNA binding L1/S/H2
E286G 8 exon Partially exposed DNA binding L1/S/H2
IARC TP53 Database search results for TP53 mutations in colon cancer patients. Most mutations are in exon 5, 7, and 8 located in the DNA binding domain.
cancers-13-00597-t005_Table 5Table 5 Mutational signatures and pathway analysis of pre- and/or post- targeted therapies individualized in advanced cancer patients entering phase I therapeutic trials.
Index Case Prior Therapy Targeted or Immunotherapy Site of Biopsy Mutational Signature Pathway Analysis Clinical Decisions
64 y F with KRAS WT metastatic rectal adenoCA FOLFIRI/Avastin; Panitumumab; FOLFOX/Avastin CDK4/6 Inhibitor B/L pulmonary metastasis → adenoCA of rectal origin
NRAS, FLT3, KMT2A, TP53, CDK8, BRCA2, DDR2, EGFR, FLT1, GPR124, KMT2C, PRKDC, SMAD4, SPTA1
EGFR, HER2 &
SMAD2/SMAD3:
SMAD4 signaling Double-strand break repair 1. NRAS mutation explains lack of response to EGFR therapy
2. FLT3 mutation → Regorafenib
3. PARP inhibitor or CDK8 inhibitor
64 y F with metastatic uterine adenoCA Carboplatin Taxol
Doxil PI3K inhibitor
CDK4/6 Inhibitor Uterus
ERBB2, BFBXW7, FLT3, NF1, PIK3CA, PTEN, TSC1, DNMT3A, SMARCB1, TET2, ARID1A, ESR1, MDM4, MSH6, ATRX, FGF3, RAD51
HER2, PI3K/AKT & PI3K events in ERRB4 signaling
PIP3 activates AKT signaling
DNA Repair Aberrations 1. ERBB2 mutation identified however IHC was negative and HER2 not amplified → deferred monoclonal antibody therapy
2. PI3K is as an active pathway
3. FLT3 mutation → off label Sorafenib recommended
4. Epigenetic therapy with PARP inhibitor or Aurora kinase inhibitor
66 y F with hx of early stage breast cancer develops L supraclavicular LAD biopsy proven -Neuroendocrine Carcinoma, unknown primary Carboplatin & Etoposide CDK4/6 Inhibitor Diffuse LAD
NTRK3, PTEN, TCF7L2, SMARCA4, AKT3, CCNE1, ERCC1, FANCE
FGFR, BCR, PI3K, ERBB2 and ERBB4 signaling
Negative regulation of the PI3K/AKT network
Active Cell Cycle 1. Due to CCNE1 mutation → CDK4/6 inhibitor trial. Stable disease at C11.
2. PI3K pathway is active suggesting next therapy if patient progresses
69 y F with stage IV (T4N0M1b) NSCLC Carboplatin & Pemetrexed
Anti PD-L1 CKD4/6 inhibitor + anti-VEGFR2 Lung Nodule KRAS, TP53, CDKN2A, BRCA2,
[cMET,
EGFR, PD-1+,
PD-LI-] IHC. EGFR, ERBB2 &
FGFR signaling
Oncogene induced senescence
Immune Checkpoint 1. CDKN2A mutation → CDK4/6 inhibitor trial + anti-VEGFR2
2. Immune checkpoint therapy
52 y F with metastatic EML4-ALK NSCLC Crizotinib; Crizotinib + HSP90 Inhibitor
ChemoRT to the R hilum Crizotinib L supraclavicular node Persistent ALK + by IHC & FISH. No ALK mutation within EML4-ALK translocation; PD-1 and PD-L1 negative, BRCA2, FGFR1, NOTCH1 FGFR and FGFR1 ligand binding, activation &
signaling
Receptor-ligand binding initiates second proteolytic cleavage of NOTCH receptor
Double-strand break repair 1. Continue Crizotinib as there is no new mutation acquired in the ALK domain.
2. Investigate FGFR1 mutation as an active driver of potential clinical relevance and laboratory focus.
60 y M with metastatic squamous cell carcinoma of the lung ChemoRT Anti-PDL1 antibody Lung
PD-1+, APC
PTCH1, c-MET; TL3, TOPO1; TUBB3
Beta-catenin phosphorylation cascadeTruncated APC mutants & deletions of AMER1 destabilize the destruction complex 1. AMER1 mutation, a tumor suppressor gene resulting over-activity of the Wnt signaling pathway.
2. Immune checkpoint
61 y F with metastatic lung adenocarcinoma with EGFR exon 19 deletion and HER2 amplification by CISH/IHC Tarceva
Afatinib Monoclonal antibody to HER2 Lung
Pleural fluid Pre-targeted therapy: EGFR Exon 19 Deletion (L747_S752 del)
ERBB2 amplification
(FISH/CISH 6.4)
PIK3CA
TOPO2A
TP53
KEL intron 3
Rearrangement
Post-targeted therapy:
Loss of ERBB2 amplification by FISH and IHC
EGFR Exon 19 deletion
Loss of PIK3CA
FLT3 (V194M)
TP53
TOPO2A
PD-1 negative
PD-L1 negative EGFR, ERBB2, FGFR & PI3K Signaling
PI3K/AKT activation
G1/S DNA Damage Checkpoints 1.Tumor evolution across therapy—Loss of target
2. Network analysis reveals alternate activated pathways- PI3K and DNA repair
60 y F with metastatic adenocarcinoma of the lung with EGFR INDEL (exon 19) mutation Carboplatin
Pemetrexed
Bevacizumab Tarceva
Afatinib Lung nodule Pre-targeted therapy:
EGFR (INDEL) exon 19
TP53
CSF-1R
PMS2
ARID1A
PKHD1
PTPRT
TPR
Post-targeted therapy:
EGFR (INDEL) exon19
EGFR (T790M)
TP53
CSF-1R
PD-1 positive
PD-L1 negative
c-MET positive
M237I p-53 dependent G1/S DNA Damage Checkpoint
EGFR & ERBB2 signaling 1. Recommend AZD9291 ± Mab to PD-L1 or Mab to MET
2. Consider MEK inhibitor3. Consider Osimertinib
52 y F with Stage IV EML4-ALK NSCLC Crizotinib HSP90 inhibitor + crizotinib Persistent R pleural effusion→ moderately differentiated adenocarcinoma Loss of EML4-ALK by FISH, CDKN2A,
CSMD3, MAGI1, CREBBP, DOT1L, PBX1, PRKDC Pre-NOTCH Transcription and Translation
Double Strand Break Repair
Notch-HLH transcription
pathway 1. Loss of ALK (inversion)
2. Alternate activated pathways for future targeting with epigenetic therapy, DNA repair inhibitors and cell cycle inhibitors
3. Anti-PD-1 Mab
10. 74 y F with stage IVA triple hit DLBCL R-EPOCH X 6 cycles IMid + BTK inhibitor + Rituximab Axillary Lymph Node
TP53
PIK3R2
PTGS2
STK36
EZH2
DNMT3A
PRKDC
ABL2
AFF1
BCL-2
BCL-6
c-MYC
Epigenetic regulation of gene expression
Double-strand Break Repair
CD28 dependent PI3K/Akt signaling
Pre-NOTCH Transcription and Translation
TP53 Dependent G1 DNA Damage Response 1. Epigenetic Therapy (e.g., EZH2 or DNMT3A inhibitor)
2. PI3K inhibitor + anti-CD20 Mab
3. STK36 Hedgehog pathway3. CAR-T | FLUOROURACIL, IRINOTECAN, LEUCOVORIN, OXALIPLATIN, PANITUMUMAB | DrugsGivenReaction | CC BY | 33546249 | 19,024,276 | 2021-02-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cataract'. | Suprachoroidal CLS-TA for non-infectious uveitis: an open-label, safety trial (AZALEA).
OBJECTIVE
To evaluate local and systemic safety of suprachoroidal (SC) triamcinolone acetonide injectable suspension (CLS-TA) injections in subjects with non-infectious uveitis (NIU).
METHODS
Open-label, prospective multicentre safety study.
METHODS
Thirty-eight subjects with NIU, with and without macular oedema (MO).
METHODS
Treatment consisted of two suprachoroidal injections of CLS-TA 4 mg, 12 weeks apart. Best-corrected visual acuity (BCVA), adverse event (AE) assessment, ophthalmic examinations and optical coherence tomography (OCT) were conducted every 4 weeks for 24 weeks. Blood samples were analysed for plasma triamcinolone acetonide (TA) concentrations.
METHODS
The main outcome measure was frequency of AEs. Other endpoints included plasma TA concentrations, change in signs of inflammation, BCVA and retinal central subfield thickness (CST).
RESULTS
Based on a CST of >300 µm, 20 out of 38 subjects had MO at baseline. Mean intraocular pressure (IOP) was 13.3 mm Hg at baseline and 15.2 mm Hg at week 24 in the study eye. A total of six (15.8%) subjects had an IOP rise >10 mm Hg compared with baseline, in the study eye, and two (5.3%) subjects had IOP >30 mm Hg (maximum 34 mm Hg at week 8 and 38 mm Hg at week 20). Cataract formation AEs were reported in four study eyes; one of which was deemed treatment-related. No serious ocular AEs in the study eye occurred in the study. Quantifiable post-injection TA plasma concentration was <1 ng/mL. Efficacy parameters showed improvement over the 24-week study period.
CONCLUSIONS
Suprachoroidally administered CLS-TA was safe and well tolerated over the 24-week, open-label study in NIU subjects with and without MO.
pmcUveitis is a group of inflammatory ocular diseases that is responsible for 5%–20% of cases of legal blindness in the USA and Europe and up to 25% of cases of blindness in the developing world. Uveitis frequently occurs between the ages of 20 and 60, affecting patients during their most productive earning years.1 2 While some uveitis cases are infectious in origin, non-infectious uveitis (NIU) comprises up to 90% of cases, affecting nearly 300 000 adults and 22 000 children in the USA.2
The primary goals of NIU treatment are to control inflammation, preserve vision and minimise risk of treatment-related sequelae. Corticosteroids have remained a mainstay of treatment for NIU but are associated with significant limitations. Topical steroid drops have limited intraocular penetration and are used most frequently in anterior uveitis. Periocular or intravitreal steroids, including intravitreal corticosteroid implants, are often used for non-infectious intermediate, posterior and panuveitis, but are associated with relatively high rates of cataract and intraocular pressure (IOP) elevations. Systemic corticosteroids, used long term, have well-established systemic side effects, including weight gain, hypertension, hyperglycaemia, osteoporosis and psychiatric disturbances. For these reasons, guidelines and recommendations by expert panels have advised using steroid-sparing immunomodulatory therapy for chronic or severe NIU when long-term treatment with systemic corticosteroids would otherwise be necessary. These immunosuppressive agents carry their own set of systemic risks, such as haematotoxicity, liver/kidney injury and an increased incidence of certain malignancies.
Suprachoroidal (SC) administration of an investigational corticosteroid formulation (triamcinolone acetonide injectable suspension (CLS-TA)) via a microinjector is a minimally invasive, alternative therapeutic approach to macular oedema (MO) associated with NIU.3 In preclinical studies, SC CLS-TA demonstrated improved bioavailability to the posterior segment and reduced exposure of anterior segment structures. Proof of concept of the efficacy and safety of SC triamcinolone acetonide (TA) treatment for posterior uveitis was established in a porcine animal model.4 Human clinical trials validated the utility of this approach, culminating in the successful phase III PEACHTREE trial using SC CLS-TA to treat MO associated with NIU. MO is the leading cause of uveitic vision loss for which there is no specific approved treatment.3 PEACHTREE demonstrated clinically meaningful ≥15 ETDRS letter gain for nearly half of the subjects treated, marked reduction of central subfield thickness (CST), and clinically and statistically significant resolution of anterior and posterior segment inflammation in approximately 70% of subjects. Furthermore, CLS-TA had a favourable adverse event (AE) profile, inclusive of events related to IOP increase and cataracts.
Herein, we report results of a companion study (AZALEA) designed to assess the safety of 4 mg of CLS-TA administered via SC injection for the treatment of subjects with NIU, both with and without the presence of MO. This study provides new information regarding the use of CLS-TA in NIU subjects without MO, while corroborating PEACHTREE results in NIU subjects with MO, and also reporting systemic pharmacokinetic (PK) outcomes for the first time.
Methods
Study participants
Institutional Review Board approval was obtained for this study (ClinicalTrials.gov identifier NCT03097315), which adhered to the tenets of the Declaration of Helsinki. Subjects ≥18 years of age were eligible if they had a diagnosis of active or inactive NIU of any aetiology in any anatomic location and an ETDRS best-corrected visual acuity (BCVA) score of ≥5 letters in the study eye. Subjects were excluded if they had any active ocular disease other than uveitis or infection in the study eye; IOP>22 mm Hg; severe or uncontrolled glaucoma; or recent use of topical, intraocular or periocular steroids. Systemic corticosteroids at doses of ≤20 mg/day for oral prednisone (or equivalent for other corticosteroids) as well as non-steroidal anti-inflammatory drugs and/or systemic immunomodulatory therapies at stable doses for the previous two or more weeks were permissible. In subjects with IOP ≤22 mm Hg, use of up to two IOP-lowering medications was allowed. All subjects provided informed consent for the study and separately for PK sampling.
Study design
This open-label, prospective multicentre safety study was conducted at 11 sites in the USA from April 2017 to January 2018. Subject eligibility was established up to 30 days prior to baseline (day 0). If both eyes met the study criteria, the right eye was designated the study eye.
Eligible subjects returned to the clinic for treatment at day 0; screening and treatment could occur on the same day. Qualified subjects received a single unilateral SC injection of CLS-TA, 4 mg (0.1 mL of 40 mg/mL), at day 0 and at week 12. SC injection was administered via a proprietary microinjector (Clearside Biomedical, Alpharetta, Georgia, USA) with a 900 or 1100 µm needle length, approximately 4 mm posterior from the limbus, in the temporal hemisphere.
Follow-up visits, consisting of AE assessment, BCVA, slit lamp examination, IOP measurement, indirect ophthalmoscopy and spectral-domain optical coherence tomography (SD-OCT), were conducted every 4 weeks up to 24 weeks for a total of 8 visits. Subjects providing consent for PK analysis had blood samples collected at day 0, week 4, week 12 and week 24. On day 0 and week 12, the blood samples were obtained prior to CLS-TA injection administration.
Beginning at week 4, a rescue treatment could be introduced if any of the following criteria were met in the study eye: (1) decrease of 10 or more ETDRS BCVA letters read from baseline; (2) increase in CST of ≥100 µm or 20%, whichever was lower, from baseline; (3) a ≥1.5 step increase from baseline in the level of inflammation (eg, anterior chamber (AC) cells, AC flare or vitreous haze) or an increase from 3+ to 4+; (4) decrease of 10 or more ETDRS BCVA letters read compared with the best ETDRS BCVA data observed during the study, along with an increase in other signs or complications associated with uveitis; or (5) the uveitic complications in the study eye had not improved and the condition needed to be addressed according to the investigator’s medical judgement.
Safety endpoints
The main safety outcome assessed was the incidence of treatment-emergent AEs (TEAEs) and serious AEs (SAEs) in the safety population. Additional safety outcomes included frequency of vision loss in the study eye, elevated IOP, frequency and severity of cataract formation, and plasma TA concentrations post-treatment.
Visual and anatomical outcomes
Efficacy measures included change in grade from baseline of AC cells, AC flare and vitreous haze as measured by Standardization of Uveitis Nomenclature (SUN) working group criteria5 at each visit; mean change from baseline in ETDRS BCVA; mean change from baseline in CST assessed by spectral-domain optical coherence tomography; the percentage of subjects with a decrease in systemic concomitant uveitis medications; and the percentage of subjects in whom any additional therapy was initiated to manage uveitis.
Statistical analysis
Statistical analyses were descriptive in nature. Continuous variables were summarised by descriptive statistics, and categorical variables were summarised by counts and percentages. The safety population included all subjects who entered this study and were administered at least 1 dose of CLS-TA. All safety analyses were performed for the safety population. The intent-to-treat (ITT) population included all subjects eligible to be treated with CLS-TA who did not fail screening. Values for missing data were imputed using the method of last observation carried forward. Subjects given additional treatment for uveitis had all data following the administration of additional treatment set to missing and imputed using the Last Observation Carried Forward (LOCF) method. The ITT population was used for efficacy assessments. The PK population included all subjects who were administered at least 1 dose of CLS-TA and provided a blood sample for the measurement of TA concentrations. Analyses were conducted on all samples collected during the study. A sample size of 35 subjects would provide approximately 80% probability of detecting at least one subject with an IOP >30 mm Hg over the 24-week follow-up period if the true incidence is 5% based on a binomial distribution.
Results
Forty-three subjects consented to screening, and 38 enrolled in the study, comprising the ITT population. The same 38 subjects received at least 1 dose of CLS-TA and were therefore included in the safety population. Thus, the safety population and ITT population were identical. Six subjects had significant protocol deviations, leaving 32 subjects in the per-protocol population. Four were related to the injection procedure, and two were schedule-related deviations per the protocol; 37 subjects completed the study. Subjects were predominantly female and white (table 1). Uveitis was bilateral in 81.6% of cases. The most common anatomical classification was intermediate uveitis, followed by anterior uveitis, and then posterior and panuveitis (table 1), and 20 out of 38 subjects had MO based on a CST of >300 µm.
Table 1 Subject and disease characteristics (safety population)
Subject characteristic Safety population (N=38)
Age at screening (years)
Mean (SD) 52.4 (15.80)
Min, Max 22, 77
Sex, n (%)
Male 13 (34.2%)
Female 25 (65.8%)
Race/Ethnicity, n (%)
White—not Hispanic or Latino 26 (68.4%)
Black/African American—not Hispanic or Latino 7 (18.4%)
White—Hispanic or Latino 5 (13.2%)
Disease characteristic (N=38) Study eye* Fellow eye†
Uveitis type, n (%)
Anterior uveitis 12 (31.6%) 10 (26.3%)
Intermediate uveitis 15 (39.5%) 12 (31.6%)
Posterior uveitis 10 (26.3%) 8 (21.1%)
Panuveitis 10 (26.3%) 7 (18.4%)
Uveitis onset, n (%)
Sudden 16 (42.1%) 4 (10.5%)
Insidious 20 (52.6%) 10 (26.5%)
Uveitis duration, n (%)
Limited (≤3 months duration) 5 (13.2%) 3 (7.9%)
Persistent (>3 months duration) 31 (81.6%) 11 (28.9%)
Uveitis course, n (%)
Acute 1 (2.6%) 1 (2.6%)
Recurrent 11 (28.9%) 1 (2.6%)
Chronic 24 (63.2%) 12 (31.6%)
Aetiology of uveitis, n (%)
Idiopathic or not specified 21 (55.3%) 15 (39.5%)
Sarcoidosis 8 (21.1%) 8 (21.1%)
HLA-B27 related 3 (7.9%) 2 (5.3%)
Reactive arthritis 2 (5.3%) 2 (5.3%)
Vogt-Koyanagi-Harada syndrome 1 (2.6%) 1 (2.6%)
Birdshot retinochoroidopathy 3 (7.9%) 3 (7.9%)
*Two study eyes were not assessed for disease characteristics.
†Thirty-one out of 38 fellow eyes were diagnosed with uveitis.
A total of six subjects were receiving one or more systemic corticosteroids or immunosuppressants at baseline, and six subjects were receiving inhaled or nasal corticosteroids. Systemic medications included adalimumab (n=3), methotrexate (n=2), mycophenolate mofetil (n=1), prednisone (n=4), rituximab (n=1), secukinumab (n=1) and vedolizumab (n=1). Each of these patients remained on at least one systemic medication for the duration of the study. A total of seven subjects were receiving IOP-lowering medication(s) in their study eye at baseline. Topical IOP-lowering medications included brimonidine (n=3), dorzolamide (n=2), timolol (n=1), combination brimonidine/timolol (n=1), combination brinzolamide/brimonidine (n=1) and combination dorzolamide/timolol (n=2). All patients remained on at least one medication for the duration of the study. No patients were on systemic IOP-lowering medications.
Safety
Treatment with CLS-TA was well tolerated over 24 weeks. Eye pain at the time of the injection procedure was reported in three (7.9%) subjects. Study eye TEAEs from AZALEA are summarised in table 2.
Table 2 Ocular adverse events
Study eye, n (%) CLS-TA 4.0 mg
(N=38)
Total number of ocular adverse events 41
Number of patients with ≥1 ocular AE 19 (50.0)
Treatment-related ocular AEs 7 (18.4)
Serious ocular AEs 0
Treatment-related serious AEs 0
TEAEs leading to study drug discontinuation 0
Adverse events
Cataract* 4 (10.5)
Cystoid macular oedema 0
Endophthalmitis 0
Eye pain†: time of procedure 3 (7.9)
Eye pain†: any time post procedure 1 (2.6)
Elevated IOP‡: time of procedure 1 (2.6)
Elevated IOP‡: pertaining to corticosteroid§ 5 (13.2)
Retinal detachment 0
Suprachoroidal haemorrhage 0
Worsening of uveitis 1 (2.6)
Vitreous detachment 1 (2.6)
*Cataract includes the medDRA preferred terms (a) cataract, (b) cataract subcapsular and (c) cataract nuclear.
†‘Eye pain’ includes the preferred terms (a) eye pain and (b) injection site pain.
‡‘Elevated IOP’ includes the preferred terms (a) IOP increased and (b) ocular hypertension.
§Includes all events of elevated IOP that did not occur on the day of the procedure.
AE, adverse event; CLS-TA, investigational triamcinolone acetonide injectable suspension; IOP, intraocular pressure.
There were no TEAEs leading to study discontinuation or death, and no SAEs involving the study eye. Seven subjects (18.4%) experienced a TEAE that was considered by the investigator to be related to the study drug. One subject (2.6%) had a TEAE immediately following the injection procedure at baseline and five (13.2%) subjects had a TEAE associated with the corticosteroid. At the conclusion of the study, all causally related events were resolved, except one event of increased IOP, two events of ocular hypertension and one event of posterior subcapsular cataract. MedDRA preferred terms ‘IOP increased’ and ‘ocular hypertension’ were grouped together under ‘Elevated IOP’ in table 2.
With respect to IOP, mean values were 13.3 mm Hg at baseline to 15.2 mm Hg at week 24 in the study eye (figure 1). A total of six (15.8%) subjects had an IOP rise >10 mm Hg compared with baseline, in the study eye, and two (5.3%) subjects had an IOP >30 mm Hg (maximum 34 mm Hg at week 8 and 38 mm Hg at week 20). Four subjects were treated with one additional IOP-lowering medication and three subjects were treated with two additional IOP-lowering medications. Of the seven subjects receiving IOP-lowering medications at baseline, three subjects experienced a sponsor-defined IOP event (eg, an increase from baseline >10 mm Hg), and two of the three were treated with additional topical IOP-lowering medications. No subjects discontinued the study because of elevated IOP or required surgery related to elevated IOP.
Figure 1 Mean (SEM) intraocular pressure. CLS-TA, investigational triamcinolone acetonide injectable suspension; IOP, intraocular pressure.
The formation or worsening of cataracts occurred in four (10.5%) subjects, one of which was considered to be treatment-related. No cases of cataract were related to the injection procedure itself; furthermore, penetration of the sclera to the lens would not be possible based on the length of the microneedle. Investigator descriptions of cataract progression included worsening of posterior subcapsular cataract, worsening of nuclear sclerosis, trace nuclear sclerosis and worsening of cataract. No patients required cataract surgery. Of note, two of these subjects developed cataracts, in the fellow eye, either concurrently or subsequently, during the trial. No patients experienced endophthalmitis or suprachoroidal haemorrhage.
Thirty-seven of 38 subjects contributed at least 1 PK sample for analysis and were included in the PK population. Analyses were conducted on all 91 samples collected during the study. Thirty-eight of 91 samples had no quantifiable TA levels, or <10.00 pg/mL (below the limit of quantitation (BLQ)) TA plasma concentration values. The quantifiable TA plasma concentration values for post-injection samples were all lower than 1 ng/mL and were no higher than those observed with intravitreal injected TA as reported in the product label.
Vision and anatomical outcomes
Figure 2 summarises the effect of CLS-TA on the grading of AC cells, AC flare and vitreous haze in study eyes of the ITT population. The number of subjects with AC cell grade of 0 improved from 17 (44.7%) at baseline to 31 (81.6%) at week 24. Over the same timeframe, the number of subjects with AC flare grade of 0 improved from 27 (71.1%) at baseline to 34 (89.5%) at week 24. The number of subjects with a vitreous haze grade of 0 improved from 17 (44.7%) at baseline to 34 (89.5%) at week 24. Per predefined criteria, four subjects received rescue therapy including nepafenac, triamcinolone acetonide, aflibercept, prednisolone or prednisolone acetate. No subjects had a decrease in systemic concomitant uveitis medications during the study.
Figure 2 Percentage of subjects with resolution of anterior chamber cells, anterior chamber flare and vitreous haze (safety population). CLS-TA, investigational triamcinolone acetonide injectable suspension
At baseline, the mean BCVA in the study eye was 68.9 (SD 19.07) for the ITT population. The mean BCVA improved at all post-baseline visits, measuring 75.0 (SD 16.93) at week 8 and 75.9 (SD 15.82) at week 24. In subjects with a baseline BCVA of ≤80 letters (27 subjects), 17 subjects (63.0%) had a gain of at least 5 letters at visit 8 (week 24).
MO was not required for inclusion in this trial. At baseline, the mean CST in the study eye was 335.9 µm (SD 85.00) in the ITT population. At all post-baseline visits, mean CST improved, and at week 24, mean CST was 284.0 µm (SD 76.44), a decrease of 15%. Excess retinal thickness, an estimate of the amount of edematous tissue in the retina, was defined as the observed thickness minus a ‘normal’ subfield thickness of 300 µm. At baseline, 20 subjects in the ITT population had excess retinal thickness >300 µm in the study eye. Over time, between 70% and 85% of subjects with MO at baseline experienced a decrease in excess retinal thickness of 20% or more compared with baseline. CST results are summarised in figure 3.
Figure 3 Mean (SEM) change from central subfield retinal thickness (intent-to-treat population).
Discussion
The goal of suprachoroidal delivery of corticosteroid is to provide a targeted therapy compartmentalised for safety and with the potential for prolonged PK for durability. AZALEA corroborates and augments the successful phase III PEACHTREE trial using SC CLS-TA for MO associated with NIU, assessing CLS-TA in NIU subjects both with and without MO, as well as reporting systemic PK outcomes for the first time. In preclinical studies involving a rabbit model, TA concentrations in plasma peaked 1 day after bilateral CLS-TA injection (4 mg/0.1 mL), with mean maximal serum concentrations of 12 ng/mL. Plasma TA concentrations were still quantifiable at very low levels in individual animals 60 days after each injection, and were undetectable in most animals 90 days after each injection. In this open-label trial, after treatment with 4 mg CLS-TA, quantifiable TA plasma concentration was <1 ng/mL in all samples and therapy was well tolerated over 24 weeks. There were no TEAEs leading to study discontinuation or death, and no ocular SAEs. Of note, this novel delivery method showed AEs related to pain which was similar to the previous PEACHTREE study3 and compared favourably with intravitreal injection of other corticosteroids.6
Although the primary objective of this study was to assess safety of SC CLS-TA in NIU, visual and anatomical outcomes were also explored. Overall, all efficacy parameters showed improvement over the 24-week AZALEA study, with the majority of subjects demonstrating improvement in the signs of inflammation (AC cells, flare and vitreous haze). The majority of patients did not require rescue therapy, similar to the PEACHTREE trial.
BCVA and CST showed modest improvement in this trial. Unlike the PEACHTREE trial, AZALEA had broader inclusion criteria and allowed subjects with active and inactive NIU to participate regardless of the presence of MO. The lack of MO among AZALEA subjects is consistent with better baseline mean BCVA and CST than in PEACHTREE subjects, potentially creating a relative ceiling effect for improvement in AZALEA compared with PEACHTREE.
The AZALEA study has several limitations, including the small number of subjects, the open-label study design and the lack of a control group. Nevertheless, CLS-TA shows meaningful promise, noted from preclinical testing through clinical studies, including AZALEA. In preclinical studies, suprachoroidal injection of TA demonstrated favourable ocular distribution with greater concentrations in the chorioretinal tissues than anterior tissues, along with prolonged therapeutic tissue levels. Also, preclinical uveitis models demonstrated the potential benefits of targeted delivery to affected tissue, as suprachoroidal injection of TA was as effective as intravitreal injection of TA at 1/10th the dose. This prolonged targeted compartmentalisation and preclinical efficacy correlated to results from AZALEA and its companion study, PEACHTREE, demonstrating clinically meaningful efficacy and safety manifested by both low IOP and cataract adverse events. In the future, CLS-TA may represent an additional promising local corticosteroid option for NIU.
Data availability statement
No data are available. Additional context can be found in the PEACHTREE manuscript (https://pubmed.ncbi.nlm.nih.gov/32173113/).
Ethics statements
Patient consent for publication
Not required.
Twitter: @ThomasCiullaMD
Presented at: Data from this manuscript were presented at the American Uveitis Society, held January 2019, in Park City, Utah, USA, the American Society of Retina Specialists (ASRS), held in July 2019, in Chicago, Illinois, USA, the Retina World Congress, held in March 2019, in Fort Lauderdale, Florida, USA, and the Macula Society, held in February 2019, in Bonita Springs, Florida, USA.
Correction notice: This article has been corrected since it was published online. An error was introduced during the production process in the results section of the abstract. In the Abstract results, first sentence: ‘Based on a CST of ≥300 µm, 20 out of 38 subjects had MO at baseline.’ has been changed to: ‘Based on a CST of >300 µm, 20 out of 38 subjects had MO at baseline.’ Further, in the Abstract results, fourth sentence: ‘Cataract formation AEs were reported in four study eyes; two of which were deemed treatment-related.’ should be: ‘Cataract formation AEs were reported in four study eyes; one of which was deemed treatment-related.’
Contributors: All coauthors contributed to the data acquisition and/or research execution, data analysis and/or interpretation, and manuscript preparation.
Funding: This study was funded by Clearside Biomedical (Alpharetta, Georgia, USA). The sponsor participated in the design of the study, conducting the study, data collection, data management, data analysis, interpretation of the data, preparation and review of the manuscript.
Competing interests: CRH reports receiving consulting fees from Clearside Biomedical and Bausch & Lomb. MS reports receiving grant support from Clearside Biomedical. MRB reports receiving consulting fees from Allegro, Allergan, Alimera, Bausch & Lomb, Genentech, Novartis and Regenxbio. RNK reports receiving consulting fees from Allergan, Clearside Biomedical, Genentech and Regeneron. He also reports receiving grant support from Allergan, Chengdu Kanghong, Clearside Biomedical, Roche and Santen. LR reports receiving consulting fees from Bausch & Lomb. SY reports receiving consulting fees from Clearside Biomedical and Santen. He also reports receiving grant funding from Clearside Biomedical. CH and TC are employees of Clearside Biomedical.
Provenance and peer review: Not commissioned; externally peer reviewed. | TRIAMCINOLONE ACETONIDE | DrugsGivenReaction | CC BY-NC | 33547034 | 20,980,219 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bradycardia foetal'. | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ATROPINE, CALCIUM CHLORIDE\POTASSIUM CHLORIDE\SODIUM CHLORIDE\SODIUM LACTATE, FENTANYL, NITROGLYCERIN, ROCURONIUM BROMIDE, TERBUTALINE SULFATE | DrugsGivenReaction | CC BY-NC | 33547119 | 19,679,527 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal exposure during delivery'. | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ATROPINE, CALCIUM CHLORIDE\POTASSIUM CHLORIDE\SODIUM CHLORIDE, FENTANYL, NITROGLYCERIN, ROCURONIUM BROMIDE, TERBUTALINE | DrugsGivenReaction | CC BY-NC | 33547119 | 19,678,018 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal exposure during pregnancy'. | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ATROPINE, CALCIUM CHLORIDE\POTASSIUM CHLORIDE\SODIUM CHLORIDE\SODIUM LACTATE, FENTANYL, NITROGLYCERIN, ROCURONIUM BROMIDE, TERBUTALINE SULFATE | DrugsGivenReaction | CC BY-NC | 33547119 | 19,679,527 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maternal exposure during pregnancy'. | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ATROPINE, CALCIUM CHLORIDE\POTASSIUM CHLORIDE\SODIUM CHLORIDE, FENTANYL, NITROGLYCERIN, ROCURONIUM BROMIDE, TERBUTALINE | DrugsGivenReaction | CC BY-NC | 33547119 | 19,680,706 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Premature baby'. | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ATROPINE, CALCIUM CHLORIDE\POTASSIUM CHLORIDE\SODIUM CHLORIDE, FENTANYL, NITROGLYCERIN, ROCURONIUM BROMIDE, TERBUTALINE | DrugsGivenReaction | CC BY-NC | 33547119 | 19,678,018 | 2021-02-05 |
What was the administration route of drug 'CALCIUM CHLORIDE\POTASSIUM CHLORIDE\SODIUM CHLORIDE\SODIUM LACTATE'? | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Transplacental | DrugAdministrationRoute | CC BY-NC | 33547119 | 19,679,527 | 2021-02-05 |
What was the administration route of drug 'NITROGLYCERIN'? | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Transplacental | DrugAdministrationRoute | CC BY-NC | 33547119 | 19,679,527 | 2021-02-05 |
What was the administration route of drug 'TERBUTALINE SULFATE'? | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Transplacental | DrugAdministrationRoute | CC BY-NC | 33547119 | 19,679,527 | 2021-02-05 |
What was the administration route of drug 'TERBUTALINE'? | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Transplacental | DrugAdministrationRoute | CC BY-NC | 33547119 | 19,678,018 | 2021-02-05 |
What was the dosage of drug 'ATROPINE'? | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | MATERNAL DOSE: UNK | DrugDosageText | CC BY-NC | 33547119 | 19,678,018 | 2021-02-05 |
What was the dosage of drug 'FENTANYL'? | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | MATERNAL DOSE: UNK | DrugDosageText | CC BY-NC | 33547119 | 19,678,018 | 2021-02-05 |
What was the dosage of drug 'NITROGLYCERIN'? | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | MATERNAL DOSE: UNK | DrugDosageText | CC BY-NC | 33547119 | 19,678,018 | 2021-02-05 |
What was the dosage of drug 'ROCURONIUM BROMIDE'? | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | MATERENAL DOSE: UNK | DrugDosageText | CC BY-NC | 33547119 | 19,678,018 | 2021-02-05 |
What was the dosage of drug 'TERBUTALINE'? | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | MATERNAL DOSE: UNK | DrugDosageText | CC BY-NC | 33547119 | 19,678,018 | 2021-02-05 |
What was the outcome of reaction 'Bradycardia foetal'? | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33547119 | 19,679,527 | 2021-02-05 |
What was the outcome of reaction 'Drug ineffective'? | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33547119 | 19,679,527 | 2021-02-05 |
What was the outcome of reaction 'Foetal exposure during pregnancy'? | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33547119 | 19,679,527 | 2021-02-05 |
What was the outcome of reaction 'Maternal exposure during pregnancy'? | A Graceful EXIT impeded by obstetrical complications.
We report an ex utero intrapartum therapy-to-airway procedure in which obstetric factors dramatically influenced the sequence of events necessary to complete the procedure.
Background
Successful ex utero intrapartum therapy (EXIT) procedures are predicated on several factors, including a highly skilled and collaborative multidisciplinary team, optimal maternal and fetal anaesthesia management, maximum uterine quiescence and relaxation with maintenance of uterine volume, creation of a haemostatic hysterotomy with adequate exposure, real-time fetal monitoring, successful fetal intervention and, lastly, a seamless transition to neonatal intensive care and definitive surgical therapy.1–4 While fetal outcomes following an EXIT procedure have been well described, lesser emphasis has been placed on maternal obstetrical considerations that may heavily impact the successful completion of the procedure. We therefore report an EXIT-to-airway procedure in which obstetrical complicating factors dramatically altered the sequence of events necessary to complete the procedure.
Case presentation
A 36-year-old gravida 5 para 3013 was referred to our fetal treatment centre at 24 weeks of gestation with a fetal diagnosis of congenital high airway obstruction syndrome (CHAOS) without additional anomalies (figures 1 and 2). Fetal imaging revealed a gap in the trachea, but sufficient tracheal length was present to permit access for tracheostomy. Fetal cytogenetics from an amniotic fluid sample revealed a normal karyotype and microarray. In a multidisciplinary conference involving the family, options were discussed to include termination of pregnancy, delivery with neonatal comfort care and an EXIT-to-airway procedure. The family was well informed that without an established airway at the time of delivery, a neonatal demise would be imminent. Fetoscopic laser decompression of CHAOS, feasible in select cases,5 was not considered in this scenario secondary to the long gap defect noted on fetal imaging, which would result in a low likelihood of a successful procedure, as well as the associated risks of surrounding tissue injury. Prematurity is also higher following fetoscopic procedures, and an EXIT procedure remains necessary regardless of decompression to develop an adequate airway at delivery. The family elected for a re-evaluation in the third trimester and returned at 31 weeks of gestational age for a repeat ultrasound and fetal MRI. She received weekly ultrasounds at the referring centre to determine fetal viability, monitor amniotic fluid volume and assess for signs of premature labour until she relocated to our centre. Findings on follow-up remained stable when compared with her earlier evaluation, with the exception of asymptomatic polyhydramnios.
Figure 1 Ultrasound image with blue arrow pointing to the abrupt termination of the dilated trachea within the neck in the fetus with CHAOS. The white arrow is at the level of the trachea within the thorax surrounded by bilateral hyperechoic lung.
Figure 2 Fetal MRI showing the dilated fetal airway (blue arrow), everted diaphragm (yellow arrow) and ascites (white arrow) typical of fetal CHAOS.
After follow-up counselling, the family elected to undergo an EXIT-to-airway procedure scheduled for 37 weeks of gestation. At this point, a call tree was established placing all key specialties on 24-hour availability until the procedure was completed. The gestational age chosen for the procedure was established to allow for further fetal growth and to promote fetal lung maturity.
At 34 weeks 5 days of gestation, she presented to labour and delivery at 03:00 on a Sunday morning with the complaint of gross rupture of membranes. On examination, her cervix was noted to be 4 cm dilated; there was gross pooling of amniotic fluid; and the umbilical cord was prolapsed through the cervix up to the level of the introitus (figure 3). The fetus was in the breech presentation. Contractions were occurring regularly at 4 min intervals with persistent variable fetal heart rate decelerations down to 80 beats/min. The call tree was activated. The patient was taken to the operating room and underwent general anaesthesia with endotracheal intubation, while the multidisciplinary team congregated to discuss adjustments to the procedure. The time from patient presentation in labour and delivery triage to induction of general anaesthesia was 59 min, with all essential team members present.
Figure 3 Colour Doppler on abdominal ultrasound demonstrating umbilical cord prolapse to within the vagina (blue arrow) at time of exit procedure, maternal lower uterine segment (white arrow) and maternal bladder (yellow arrow).
The decision was made to make a maternal midline laparotomy to provide sufficient access to completely exteriorise the late-preterm gravid uterus and to make a fundal hysterotomy to deliver the fetal head and neck first. The placenta was anterior, and the fetus was in the breech presentation in the setting of anhydramnios secondary to rupture of membranes. An attempt at external cephalic version was not deemed safe in the setting of anhydramnios, active labour and existing cord prolapse. For these reasons, the original plan to perform a maternal abdominal transverse skin incision with a low transverse uterine hysterotomy was therefore abandoned. The midline skin incision was made to just below the umbilicus with placement of a large Olexis O retractor (Applied Medical, Rancho Santa Margarita, Californis, USA) allowing the uterus to be exteriorised. The anaesthesiologist provided maximal halogenated agents with a mean alveolar concentration of 3, along with both nitroglycerin and terbutaline. Unfortunately, uterine relaxation was not sufficient to maintain optimal placental perfusion to the fetus. In an effort to expedite the procedure, the surgical team proceeded by placing a haemostatic myometrial box stitch at the fundus placed well away from the placental edge. The uterus was incised within the box stitch with electrocautery, and the amniotic sac was entered. Bainbridge clamps were used to compress the myometrium prior to placing uterine haemostatic staplers. Due to inadequate uterine relaxation, the thickened myometrium prohibited sufficient compression of tissue to allow for stapling. At this point, the uterine entry point was extended with electrocautery, and Allis clamps were used along the length of the hysterotomy to provide haemostasis. The fetal head and neck were then delivered followed immediately by an intramuscular injection of a cocktail containing atropine, rocuronium and fentanyl. A rapid intravenous infusion device was used to infuse warm lactated Ringer’s solution through the hysterotomy to assist in maintaining uterine volume. Fetal monitoring performed throughout the procedure by fetal cardiology demonstrated intermittent bradycardia with rate as low as 88 beats/min and as high as 129 beats/min with depressed biventricular function. At this time, the paediatric surgeon and paediatric otolaryngologist worked in concert and established an airway via an endotracheal tube through a tracheostomy incision. The time from delivery of the head and neck until airway establishment was 3 min. The remainder of the baby was delivered; the umbilical cord was clamped and cut; and the infant was passed off to the neonatology team.
The neonatal response to initial resuscitation was an immediate return to a heart rate in the 150’s bpm with an oxygen saturation of 100%. After stabilisation, bronchoscopy revealed laryngeal atresia below the level of the vocal cords with an intact trachea (figure 4).
Figure 4 Upper left image demonstrates zoomed-in supraglottic view with normal anatomy with medialised vocal cords. Upper right image is the glottic view with medialised normal vocal cords. Bottom left image is the glottic view with cords spread demonstrating laryngeal atresia starting in the infraglottis. Bottom right image is the infraglottic view with laryngeal atresia.
The parturient was extubated after the placement of bilateral transversus abdominus plane blocks for postoperative pain control. Unfortunately, during the first 24 hours postpartum, the mother developed uterine atony necessitating the use of uterotonics and uterine balloon tamponade. She received a transfusion of 2 units of packed red blood cells. Subsequently, the mother remained inpatient for three postoperative days and was discharged in good condition without further complications from the surgical procedure.
Outcome and follow-up
The infant is doing well and remains with a tracheostomy awaiting definitive repair of the laryngeal atresia.
Discussion
Despite meticulous planning, the EXIT procedure was performed in a suboptimal scenario secondary to multiple obstetrical factors. The patient presented to labour and delivery unscheduled on an early Sunday morning with a complex presentation including an umbilical cord prolapse with category II fetal heart rate tracing. In normal circumstances, an umbilical cord prolapse results in an emergent caesarean delivery. Because the fetus lacked a patent airway, an emergent caesarean would have resulted in a neonatal demise or, in the best-case scenario, prolonged hypoxia during an attempt to establish an emergent airway immediately following delivery.
Maternal safety is of paramount importance when considering the option for an EXIT procedure. If maternal safety is compromised, the EXIT procedure should be abandoned to ensure an optimal maternal outcome. Fetal health follows second to the mother’s well-being. Throughout this case, extensive monitoring of the patient’s status was undertaken by both the anaesthesiology and surgical teams. Fetal compromise was certainly a concern with the non-patent airway, as well as an umbilical cord prolapse and suboptimal placental perfusion. Our team was able to assure maternal safety, and, therefore, the EXIT was allowed to proceed as planned but with notable deviations. Due to anhydramnios, cord prolapse, breech presentation and inadequate uterine relaxation, an external cephalic version and a low transverse uterine incision were not feasible, and access to the uterine fundus was needed to deliver the head and neck first. This necessitated a maternal midline incision sufficient to exteriorise the uterus to enable fundal access for the hysterotomy.
Once the uterus was exteriorised, uterine relaxation was attempted with an anaesthetic cocktail (halogenated agent, terbutaline and nitroglycerin) while maintaining stable maternal cardiovascular status with pressor infusions. Uterine relaxation was unfortunately never obtained despite maximal anaesthetic agents. As a result, the myometrial thickness compromised compression of the tissue with Bainbridge clamps, and use of the hysterotomy staples was rendered futile. Also, as a result of lack of uterine relaxation, optimisation of uteroplacental circulation was not achieved. Whether fetal bradycardia was secondary to the existing cord prolapse, increased uterine tone and/or loss of optimal uterine volume is not clear. Fortunately, there were no signs of placental abruption at any point, which would have terminated the EXIT procedure. Infusion of warm Ringer’s lactate was not effective to maintain optimal uterine volume due to the myometrial contractile force in this circumstance, and the only volume maintained was secondary to the lower half of the fetus remaining within the uterus.
Fortunately, the tracheostomy was performed expeditiously without any issue. There was minimal time spent on uteroplacental bypass, which was present but suboptimal secondary to the aforementioned complicating factors. In addition, once the airway was secured, an awaiting neonatal team optimised oxygenation and ventilation.
Quality review performed after the procedure highlighted an important area for improvement, establishing the optimal gestational age to schedule an EXIT procedure. In one series of 31 EXIT procedures, the gestational age range at the time of delivery was quite variable at 29–40 weeks. There is no existing consensus as to when timing is optimal.6 With the diagnosis of CHAOS, polyhydramnios is common and is associated with a high risk of premature rupture of membranes and premature labour. Our EXIT occurred at 34 weeks and 5 days. An amnioreduction could have been performed prophylactically to try to avoid this complication or the EXIT could have been scheduled earlier than the planned 37 weeks of gestation. Admission to the hospital is another consideration to maximise efficient movement to the operating room in the setting of spontaneous labour. In this case, the patient did have asymptomatic polyhydramnios with a long cervix, and the risks of a late amnioreduction was considered by the team to be higher than the benefits. Active labour following an amnioreduction can certainly occur.7 The benefit of waiting longer to promote fetal maturity was desired, although the ability to achieve this in the setting of CHAOS is unknown.
A critical component of the procedure is an established, experienced and highly collaborative multidisciplinary team within a quaternary care system.8 This asset cannot be understated and likely contributed to this case proceeding stepwise through the critical steps despite complicating factors and concluding with the efficient placement of a patent airway. The procedure was planned several weeks in advance and a walk-through was performed with all key stake holders, which is standard protocol for every EXIT procedure at our institution. Simulation prior to each procedure results in a higher success rate, especially when it occurs unscheduled with few personnel on site.9
The literature on EXIT procedures primarily focuses on the technical aspects of the procedure and case series of its use for various fetal diagnoses, including CHAOS. Only in select few instances are maternal complications described and even fewer instances of cases where the EXIT procedure was abandoned prematurely due to maternal or fetal complications. The case series describe the fetal diagnosis and success or failure of establishing the airway. Maternal complications from EXIT procedures include longer operative times, higher blood loss and higher rates of wound complications compared with those undergoing caesarean delivery.2 10–12 In addition, uterine dehiscence and rupture in a subsequent pregnancy is a real risk.12 In an anaesthesia review of the largest case series of 65 patients, 32% of cases occurred prior to the planned date for reasons including prelabour premature rupture of membranes, and 18% of cases were emergently performed. In 6% of the cases, the procedure was ‘rushed’ due to either identified placental abruption or what was identified as impending abruption.13 In these cases, as in ours, the definitive therapy was expeditious control of the fetal airway followed by delivery. Refractory elevated uterine tone is mentioned; however, the rate of this complicating factor is not known from the available literature, and there are likely many contributing factors. The key to success in these complicated cases appears to be the experience and the coordination of the surgical team.
In summary, we have described an EXIT procedure complicated by significant obstetrical factors. In the absence of maternal complications, obstetrical complications, which can be multiple in nature, can be ameliorated and addressed such that an EXIT procedure can be successfully completed.
Learning points
Lesser emphasis has been placed on obstetrical considerations during ex utero intrapartum therapy (EXIT) procedures; however, these factors may significantly affect the surgical procedure as well as the clinical outcome.
In the absence of maternal complications and when maternal safety is ensured, an EXIT procedure may proceed despite significant obstetrical complications.
An established and experienced multidisciplinary team with extensive surgical planning is essential for the successful completion of an EXIT procedure.
A standard protocol for EXIT procedures should include a preoperative walk-through to rehearse all the critical steps for its successful completion.
We thank Henry L Galan, Kenneth W Liechty and Nicholas Behrendt for their contribution in the surgical management of the patient, as well as in the preparation and review of this article.
Contributors: MZ, MB and SCD, CF and CW contributed significantly to the conception and design, drafting and revision, as well as the final approval of this article, and are accountable to the accuracy and integrity of the article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33547119 | 19,680,706 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug interaction'. | Fever in a patient with osteomyelitis: the diagnosis could be serotonin syndrome.
Awareness of rare differential diagnoses of common clinical presentations helps promote early detection and prompt management of serious conditions. A 54-year-old man, with an infected non-union following a high tibial osteotomy, presented with an acutely discharging abscess to his proximal tibia. He was generally unwell with a Staphylococcus aureus bacteraemia. The tibia was debrided, CERAMENT G used as dead space management and a spanning external fixator applied. Postoperatively, pregabalin and tapentadol were commenced in addition to amitriptyline and sertraline, which the patient was taking regularly. Overnight, the patient developed hyperthermia, inducible clonus, hyperreflexia, agitation, confusion and rigors. Prompt recognition of the possibility of serotonin syndrome resulted in early cessation of serotonergic medications and a positive outcome. From this case an important message is that fever in a patient taking serotonergic medications should prompt a screening neurological examination. Clinicians should also be wary when patients are commenced on multimodal analgesia, including tapentadol.
Background
An awareness of rare differential diagnoses of common clinical presentations helps promote the early detection and prompt management of serious conditions. The following case report describes the presentation of serotonin syndrome postoperatively on an orthopaedic ward, which with prompt diagnosis was managed effectively with good outcomes for the patient.
Serotonin syndrome is a rare, unpredictable and potentially fatal cause of fever. It is a drug-induced condition caused by too much serotonin within the synapses of the nervous system. Generally, it results from the combination of at least two drugs that increase serotonin levels or sometimes an overdose with a single drug that raises serotonin.1 Its incidence among 15 million patients in the USA who were taking serotonergic agents was around 0.07% to 0.19%.2 The true incidence of serotonin syndrome is thought to be unknown, due to it being under-recognised and under-reported.3
Currently, the Hunter Serotonin Toxicity Criteria (84% sensitive and 97% specific) is the most widely accepted diagnostic tool, with an emphasis on the following signs in the presence of a serotonergic agent: spontaneous or inducible clonus, agitation, tremor, diaphoresis, ocular clonus, hypertonia, hyperthermia and hyperreflexia (figure 1).4 The critical management step following diagnosis is identification and discontinuation of causative agents. In severe cases complications can include seizures, disseminated intravascular coagulopathy, metabolic acidosis, rhabdomyolysis, renal failure and death. Consequently patients with more severe cases may require management in critical care.5
Figure 1 The Hunter Serotonin Toxicity Criteria (adapted).
Case presentation
A 54-year-old man presented with an acutely discharging sinus with abscess to his right proximal tibia on the background of a complex orthopaedic history involving an infected non-union from an elective right tibial osteotomy. Past medical history included well-controlled asthma, obstructive sleep apnoea, hypertension, deep vein thrombosis and pericarditis.
At presentation, the patient was generally unwell with swinging fever and was found to have a Staphylococcus aureus bacteraemia. He was started on flucloxacillin intravenously and an echocardiogram requested.
Right knee radiographs showed non-union of the proximal tibia and evidence of a sequestrum, confirmed by CT scan. Right tibial exploration and debridement was conducted with tissue sampling, instillation of CERAMENT G (antibiotic laden synthetic bone substitute) and application of a spanning external fixator. All six tissue samples grew methicillin-sensitive S. aureus, with Proteus mirabilis and Enterobacter growing in one tissue sample.
Following the operation, oral rifampicin was added. A transthoracic echo showed an echogenic mobile structure behind the mitral valve leaflet, which was queried as an endocarditis vegetation. Flucloxacillin was increased to six times per day.
Postoperative complications included significant pain and acute kidney injury stage III, the latter deemed secondary to hypovolaemia and improved following intravenous fluid administration. The episodes of fever had resolved at this stage.
On the 5th day after the operation, following a difficult night with pain, 75 mg pregabalin (given two times per day) and subsequently 100 mg tapentadol modified release (given every 12 hours) were commenced for analgesia. The pregabalin was later increased to 150 mg (given two times per day). This was in addition to 25 mg amitriptyline (given one time per day), 150 mg sertraline (given one time per day) and 20 mg ketamine (given up to four times per day as required) which the patient was already taking.
The following day the patient deteriorated, and the initial impression was of sepsis secondary to tibial infection and/or infective endocarditis. However, following a review of the patient’s medications, the possibility of serotonin syndrome was raised, as it was noted that he had been commenced on tapentadol (one dose given) and pregabalin within the previous 48 hours and was already taking sertraline and amitriptyline. On examination he had hyperthermia (41°C at highest), tachycardia and tachypnoea. The patient also had neurological findings of tremor, hyperreflexia, agitation and bilateral inducible ankle clonus. These findings in the context of his recent medication history, supported a diagnosis of serotonin syndrome. Therefore, all serotoninergic medications were suspended and critical care involvement was requested.
The patient was admitted to the critical care unit for careful monitoring. Blood cultures that were taken at the time of the initial temperature rise grew P. mirabilis. Meropenem was added and flucloxacillin increased to every four hours. The patient’s creatine kinase (CK) rose to 6490 U/L over the next few days. The patient did have some tenderness to the mid anterior thigh and an urgent MRI of the right thigh ruled out myositis as a cause of the rising CK.
Vital and neurological signs settled after cessation of the medications in question, with the last significant temperature rise of 39.5°C recorded around 72 hours from the initial clinical deterioration. On day 7 the patient’s CK had dropped to 205 U/L. The patient was stepped down to the ward and avoided requiring any level 2 or 3 interventions. A transoesophageal echo, conducted when the patient was discharged from the intensive care unit, concluded that there were no criteria present for infective endocarditis and the previously reported abnormality was not significant.
Investigations
Laboratory investigations at that time showed a C-reactive protein (CRP) of 276 mg/L (which rose to 354 mg/L), a white cell count (WCC) of 7.8×109/L, neutrophils of 6.7×109/L, lymphocytes 0.6×109/L, creatinine 138 µmol/L and an alkaline phosphatase of 138 U/L.
Differential diagnosis
With the preceding history of S. aureus bacteraemia, possible infective endocarditis and a positive blood culture for P. mirabilis, the initial diagnosis, considered following the patient’s deterioration postoperatively, was sepsis. Indeed, he was concomitantly treated as sepsis during his stay on the critical care unit, with an escalation of antibiotic therapy.
The ultimate diagnosis of serotonin syndrome was first suspected due to the rapid deterioration following commencement of tapentadol and pregabalin (figure 2), alongside the examination findings present at this time, most notably the substantial hyperthermia of up to 41°C, inducible clonus, confusion, agitation and hyperreflexia. The combination of agitation and inducible clonus, in the presence of serotonergic medications, confirmed the clinical diagnosis of serotonin syndrome as per the Hunter classification system.4 Laboratory results also illustrated a raised CRP without any raise in WCC or neutrophils to suggest an overwhelming bacterial infection was present.
Figure 2 Patient’s vital signs leading up to intensive care unit admission. Pregabalin was started at a dose of 75 mg two times per day (BD) (blue arrow) and increased to 150 mg BD (second blue arrow). A single dose of tapentadol was given (green arrow).
Neuroleptic malignant syndrome (NMS) and malignant hyperthermia (MH) both also cause a drug-induced hyperthermia. Within this case NMS was effectively ruled out on the basis that the patient was not taking any anti-dopaminergic medications.6 With MH, the presentation would have been perioperatively or immediately postoperatively had a volatile anaesthetic agent or the depolarising muscle relaxant succinylcholine been used.7
Outcome and follow-up
The patient was discharged on a 6-week course of antibiotics. In the past 6 months he underwent a further orthopaedic procedure on the right knee and currently has a circular fixator in place. There have been several pin site infections, ongoing issues with pain and an episode of deep vein thrombosis in the right leg. Currently, he is walking, fully weight bearing on his leg with the help of crutches and has been listed for removal of the external fixator and application of a cast.
Discussion
Serotonin is synthesised from the essential amino acid tryptophan in both the midline raphe nuclei of the brainstem and enterochromaffin cells of the gastrointestinal (GI) tract.8 Around 40% to 80% of the body’s serotonin is stored in the enterochromaffin cells of the GI tract, with the remainder found in the central nervous system and also on platelets.8 Within the central nervous system and GI tract serotonin has numerous functions including attention, affective behaviour, thermoregulation, motor tone, GI motility, vasoconstriction, bronchoconstriction and platelet aggregation.9 Serotonin syndrome is the clinical manifestation of over activation of these central and peripheral serotonin receptors.9
Serotonin syndrome typically occurs when two or more drugs that elevate serotonin are used together, especially if they elevate serotonin in different ways.1 Monoamine oxidase inhibitors (MAOI) carry the highest risk profile due to their action to slow the breakdown of serotonin by blocking monoamine oxidase.1 Serotonin reuptake inhibitors (SSRI, such as sertraline in this case) and serotonin-norepinephrine reuptake inhibitors (SNRI) carry the next most significant risk due to their action to prevent the reuptake of serotonin from synapses.1 A combination of an MAOI with another MAOI or an SSRI or SNRI is the most dangerous combination of drugs and most likely to result in serotonin syndrome.9 Tricyclic antidepressants (such as amitriptyline in this case), opioids, drugs of abuse and selected other prescription and herbal drugs also carry a significant risk profile.9
Within this case, the initial episode of fever developed following initiation of pregabalin (figure 2), with the patient already regularly taking sertraline and amitriptyline, before a more significant deterioration overnight following the single dose of tapentadol. It is possible that this initial fever was due to sepsis. The blood culture taken around this time grew P. mirabilis, which was also present on a single tissue sample taken operatively. Pregabalin in the literature is not thought to have any effect on serotonin receptors or any inhibition of serotonin reuptake.10 However three case reports were identified where initiation of pregabalin was thought to have resulted in serotonin syndrome.11–13 A small double blind randomised controlled trial has also shown that gabapentin, an analogue of pregabalin, increases serotonin levels when used at a therapeutic range.14 However, without any substantial evidence it is difficult to draw any conclusions in this case about whether the initiation of pregabalin played any part in the development of serotonin syndrome.
Tapentadol is a centrally acting opioid. It acts as a µ-opioid receptor agonist, a norepinephrine receptor inhibitor and a weak serotonin uptake blocker in the rat.15 A review of post marketing safety data, undertaken by the tapentadol manufacturing pharmaceutical company, Grünenthal, concluded that it is unlikely that tapentadol has a clinically significant influence on the development of serotonin syndrome.16 Of the 151 cases identified, only 4 were deemed to be robustly diagnosed and of these other serotonergic medications were taken which could have caused serotonin syndrome. However, figures from the WHO VigiBase database rank tapentadol third on the list of serotonin syndrome individual case safety reports associated with an opioid alone or with another drug(s) (115 out of 1641 cases; 7%), and second when the opioid was the only suspected cause (42 out of 147 cases; 28.6%).15 17 Following the administration of tapentadol at 00:30 a.m., the patient in this case suffered a considerable clinical deterioration which started around 04:44 a.m. As mentioned, this fulfilled the Hunter classification criteria and would therefore seem to strongly suggest that tapentadol, in combination with sertraline and amitriptyline, caused serotonin syndrome in this patient. Case reports exist of serotonin syndrome following tapentadol overdose, however this patient received just one dose of tapentadol.18
Prompt diagnosis in this case likely had a significant impact on the patient outcome, which illustrates the importance of keeping an open mind when clinical signs do not fully support the more commonly encountered presentation of sepsis. The key message to highlight here is that fever in a patient with serotonergic drugs should prompt a screening neurological examination. The most important sign to be aware of is clonus, be it spontaneous, inducible or ocular, as this has been found to be strongly associated with serotonin syndrome.4 Therefore, the presence of clonus with serotonergic polypharmacy should act as a red flag for clinicians.
Patient’s perspective
In 2018 I had a routine HTO (high tibia osteotomy) on my right leg to correct my stance due to knee pain. I was informed that I was too young to have a knee replacement and that this operation would solve my problem. Unfortunately, some 2 years later I am still using crutches to get around and have a metal fixator from above the knee down to my ankle.
In 2019, I had severe pain in my leg, swelling and redness so I took myself to A&E. I was admitted and put in a single room. From that time, I cannot remember that much. I know I was hallucinating, and I was feeling irritable and restless. My wife recalls that I was asking all sorts of random questions. I was having extreme hot sweats and high temperatures. It is all quite hazy but my son, who works for our family business, had some amount of verbal abuse from me. I apparently telephoned him at 3 in the morning asking where he was and accused him of not finishing a job off because he was too busy smoking. I have no recollection of this.
It all seemed so surreal like living in a different dimension. I was admitted to the ICU and remember feeling anxious and irritated. I remember my wife stood at my bedside crying and still I had little idea of what was occurring or where I was!
Thankfully, the care and the expertise of the ICU staff saw me through whatever I was experiencing. I was later told that I had serotonin syndrome and that it was quite rare for this to occur. I really do not remember much about the entire chain of events. I was happy that I came through it.
Learning points
Fever in surgical patients is not always secondary to infection.
Clinicians should be wary when patients are commenced on multimodal analgesia as inpatients. Specific care should be taken when prescribing tapentadol with other serotonergic agents due to an increased risk of serotonin syndrome.
As part of a neurological examination, clonus is a useful clinical sign to be aware of when assessing for serotonin syndrome.
Contributors: MG obtained the case details and wrote the first draft of the case report. WDH re-drafted the case report and ensured the orthopaedic details in the case report were accurate. AC-K re-drafted the case report and ensured the critical care details of the case were accurate. GB offered insights into the pharmaceutical side of the case report and ensured the accuracy of the discussion around the different serotonergic medications included in the case report.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | AMITRIPTYLINE, FLUCLOXACILLIN, KETAMINE, PREGABALIN, RIFAMPIN, SERTRALINE HYDROCHLORIDE, TAPENTADOL | DrugsGivenReaction | CC BY-NC | 33547128 | 19,009,765 | 2021-02-05 |
What was the administration route of drug 'FLUCLOXACILLIN'? | Fever in a patient with osteomyelitis: the diagnosis could be serotonin syndrome.
Awareness of rare differential diagnoses of common clinical presentations helps promote early detection and prompt management of serious conditions. A 54-year-old man, with an infected non-union following a high tibial osteotomy, presented with an acutely discharging abscess to his proximal tibia. He was generally unwell with a Staphylococcus aureus bacteraemia. The tibia was debrided, CERAMENT G used as dead space management and a spanning external fixator applied. Postoperatively, pregabalin and tapentadol were commenced in addition to amitriptyline and sertraline, which the patient was taking regularly. Overnight, the patient developed hyperthermia, inducible clonus, hyperreflexia, agitation, confusion and rigors. Prompt recognition of the possibility of serotonin syndrome resulted in early cessation of serotonergic medications and a positive outcome. From this case an important message is that fever in a patient taking serotonergic medications should prompt a screening neurological examination. Clinicians should also be wary when patients are commenced on multimodal analgesia, including tapentadol.
Background
An awareness of rare differential diagnoses of common clinical presentations helps promote the early detection and prompt management of serious conditions. The following case report describes the presentation of serotonin syndrome postoperatively on an orthopaedic ward, which with prompt diagnosis was managed effectively with good outcomes for the patient.
Serotonin syndrome is a rare, unpredictable and potentially fatal cause of fever. It is a drug-induced condition caused by too much serotonin within the synapses of the nervous system. Generally, it results from the combination of at least two drugs that increase serotonin levels or sometimes an overdose with a single drug that raises serotonin.1 Its incidence among 15 million patients in the USA who were taking serotonergic agents was around 0.07% to 0.19%.2 The true incidence of serotonin syndrome is thought to be unknown, due to it being under-recognised and under-reported.3
Currently, the Hunter Serotonin Toxicity Criteria (84% sensitive and 97% specific) is the most widely accepted diagnostic tool, with an emphasis on the following signs in the presence of a serotonergic agent: spontaneous or inducible clonus, agitation, tremor, diaphoresis, ocular clonus, hypertonia, hyperthermia and hyperreflexia (figure 1).4 The critical management step following diagnosis is identification and discontinuation of causative agents. In severe cases complications can include seizures, disseminated intravascular coagulopathy, metabolic acidosis, rhabdomyolysis, renal failure and death. Consequently patients with more severe cases may require management in critical care.5
Figure 1 The Hunter Serotonin Toxicity Criteria (adapted).
Case presentation
A 54-year-old man presented with an acutely discharging sinus with abscess to his right proximal tibia on the background of a complex orthopaedic history involving an infected non-union from an elective right tibial osteotomy. Past medical history included well-controlled asthma, obstructive sleep apnoea, hypertension, deep vein thrombosis and pericarditis.
At presentation, the patient was generally unwell with swinging fever and was found to have a Staphylococcus aureus bacteraemia. He was started on flucloxacillin intravenously and an echocardiogram requested.
Right knee radiographs showed non-union of the proximal tibia and evidence of a sequestrum, confirmed by CT scan. Right tibial exploration and debridement was conducted with tissue sampling, instillation of CERAMENT G (antibiotic laden synthetic bone substitute) and application of a spanning external fixator. All six tissue samples grew methicillin-sensitive S. aureus, with Proteus mirabilis and Enterobacter growing in one tissue sample.
Following the operation, oral rifampicin was added. A transthoracic echo showed an echogenic mobile structure behind the mitral valve leaflet, which was queried as an endocarditis vegetation. Flucloxacillin was increased to six times per day.
Postoperative complications included significant pain and acute kidney injury stage III, the latter deemed secondary to hypovolaemia and improved following intravenous fluid administration. The episodes of fever had resolved at this stage.
On the 5th day after the operation, following a difficult night with pain, 75 mg pregabalin (given two times per day) and subsequently 100 mg tapentadol modified release (given every 12 hours) were commenced for analgesia. The pregabalin was later increased to 150 mg (given two times per day). This was in addition to 25 mg amitriptyline (given one time per day), 150 mg sertraline (given one time per day) and 20 mg ketamine (given up to four times per day as required) which the patient was already taking.
The following day the patient deteriorated, and the initial impression was of sepsis secondary to tibial infection and/or infective endocarditis. However, following a review of the patient’s medications, the possibility of serotonin syndrome was raised, as it was noted that he had been commenced on tapentadol (one dose given) and pregabalin within the previous 48 hours and was already taking sertraline and amitriptyline. On examination he had hyperthermia (41°C at highest), tachycardia and tachypnoea. The patient also had neurological findings of tremor, hyperreflexia, agitation and bilateral inducible ankle clonus. These findings in the context of his recent medication history, supported a diagnosis of serotonin syndrome. Therefore, all serotoninergic medications were suspended and critical care involvement was requested.
The patient was admitted to the critical care unit for careful monitoring. Blood cultures that were taken at the time of the initial temperature rise grew P. mirabilis. Meropenem was added and flucloxacillin increased to every four hours. The patient’s creatine kinase (CK) rose to 6490 U/L over the next few days. The patient did have some tenderness to the mid anterior thigh and an urgent MRI of the right thigh ruled out myositis as a cause of the rising CK.
Vital and neurological signs settled after cessation of the medications in question, with the last significant temperature rise of 39.5°C recorded around 72 hours from the initial clinical deterioration. On day 7 the patient’s CK had dropped to 205 U/L. The patient was stepped down to the ward and avoided requiring any level 2 or 3 interventions. A transoesophageal echo, conducted when the patient was discharged from the intensive care unit, concluded that there were no criteria present for infective endocarditis and the previously reported abnormality was not significant.
Investigations
Laboratory investigations at that time showed a C-reactive protein (CRP) of 276 mg/L (which rose to 354 mg/L), a white cell count (WCC) of 7.8×109/L, neutrophils of 6.7×109/L, lymphocytes 0.6×109/L, creatinine 138 µmol/L and an alkaline phosphatase of 138 U/L.
Differential diagnosis
With the preceding history of S. aureus bacteraemia, possible infective endocarditis and a positive blood culture for P. mirabilis, the initial diagnosis, considered following the patient’s deterioration postoperatively, was sepsis. Indeed, he was concomitantly treated as sepsis during his stay on the critical care unit, with an escalation of antibiotic therapy.
The ultimate diagnosis of serotonin syndrome was first suspected due to the rapid deterioration following commencement of tapentadol and pregabalin (figure 2), alongside the examination findings present at this time, most notably the substantial hyperthermia of up to 41°C, inducible clonus, confusion, agitation and hyperreflexia. The combination of agitation and inducible clonus, in the presence of serotonergic medications, confirmed the clinical diagnosis of serotonin syndrome as per the Hunter classification system.4 Laboratory results also illustrated a raised CRP without any raise in WCC or neutrophils to suggest an overwhelming bacterial infection was present.
Figure 2 Patient’s vital signs leading up to intensive care unit admission. Pregabalin was started at a dose of 75 mg two times per day (BD) (blue arrow) and increased to 150 mg BD (second blue arrow). A single dose of tapentadol was given (green arrow).
Neuroleptic malignant syndrome (NMS) and malignant hyperthermia (MH) both also cause a drug-induced hyperthermia. Within this case NMS was effectively ruled out on the basis that the patient was not taking any anti-dopaminergic medications.6 With MH, the presentation would have been perioperatively or immediately postoperatively had a volatile anaesthetic agent or the depolarising muscle relaxant succinylcholine been used.7
Outcome and follow-up
The patient was discharged on a 6-week course of antibiotics. In the past 6 months he underwent a further orthopaedic procedure on the right knee and currently has a circular fixator in place. There have been several pin site infections, ongoing issues with pain and an episode of deep vein thrombosis in the right leg. Currently, he is walking, fully weight bearing on his leg with the help of crutches and has been listed for removal of the external fixator and application of a cast.
Discussion
Serotonin is synthesised from the essential amino acid tryptophan in both the midline raphe nuclei of the brainstem and enterochromaffin cells of the gastrointestinal (GI) tract.8 Around 40% to 80% of the body’s serotonin is stored in the enterochromaffin cells of the GI tract, with the remainder found in the central nervous system and also on platelets.8 Within the central nervous system and GI tract serotonin has numerous functions including attention, affective behaviour, thermoregulation, motor tone, GI motility, vasoconstriction, bronchoconstriction and platelet aggregation.9 Serotonin syndrome is the clinical manifestation of over activation of these central and peripheral serotonin receptors.9
Serotonin syndrome typically occurs when two or more drugs that elevate serotonin are used together, especially if they elevate serotonin in different ways.1 Monoamine oxidase inhibitors (MAOI) carry the highest risk profile due to their action to slow the breakdown of serotonin by blocking monoamine oxidase.1 Serotonin reuptake inhibitors (SSRI, such as sertraline in this case) and serotonin-norepinephrine reuptake inhibitors (SNRI) carry the next most significant risk due to their action to prevent the reuptake of serotonin from synapses.1 A combination of an MAOI with another MAOI or an SSRI or SNRI is the most dangerous combination of drugs and most likely to result in serotonin syndrome.9 Tricyclic antidepressants (such as amitriptyline in this case), opioids, drugs of abuse and selected other prescription and herbal drugs also carry a significant risk profile.9
Within this case, the initial episode of fever developed following initiation of pregabalin (figure 2), with the patient already regularly taking sertraline and amitriptyline, before a more significant deterioration overnight following the single dose of tapentadol. It is possible that this initial fever was due to sepsis. The blood culture taken around this time grew P. mirabilis, which was also present on a single tissue sample taken operatively. Pregabalin in the literature is not thought to have any effect on serotonin receptors or any inhibition of serotonin reuptake.10 However three case reports were identified where initiation of pregabalin was thought to have resulted in serotonin syndrome.11–13 A small double blind randomised controlled trial has also shown that gabapentin, an analogue of pregabalin, increases serotonin levels when used at a therapeutic range.14 However, without any substantial evidence it is difficult to draw any conclusions in this case about whether the initiation of pregabalin played any part in the development of serotonin syndrome.
Tapentadol is a centrally acting opioid. It acts as a µ-opioid receptor agonist, a norepinephrine receptor inhibitor and a weak serotonin uptake blocker in the rat.15 A review of post marketing safety data, undertaken by the tapentadol manufacturing pharmaceutical company, Grünenthal, concluded that it is unlikely that tapentadol has a clinically significant influence on the development of serotonin syndrome.16 Of the 151 cases identified, only 4 were deemed to be robustly diagnosed and of these other serotonergic medications were taken which could have caused serotonin syndrome. However, figures from the WHO VigiBase database rank tapentadol third on the list of serotonin syndrome individual case safety reports associated with an opioid alone or with another drug(s) (115 out of 1641 cases; 7%), and second when the opioid was the only suspected cause (42 out of 147 cases; 28.6%).15 17 Following the administration of tapentadol at 00:30 a.m., the patient in this case suffered a considerable clinical deterioration which started around 04:44 a.m. As mentioned, this fulfilled the Hunter classification criteria and would therefore seem to strongly suggest that tapentadol, in combination with sertraline and amitriptyline, caused serotonin syndrome in this patient. Case reports exist of serotonin syndrome following tapentadol overdose, however this patient received just one dose of tapentadol.18
Prompt diagnosis in this case likely had a significant impact on the patient outcome, which illustrates the importance of keeping an open mind when clinical signs do not fully support the more commonly encountered presentation of sepsis. The key message to highlight here is that fever in a patient with serotonergic drugs should prompt a screening neurological examination. The most important sign to be aware of is clonus, be it spontaneous, inducible or ocular, as this has been found to be strongly associated with serotonin syndrome.4 Therefore, the presence of clonus with serotonergic polypharmacy should act as a red flag for clinicians.
Patient’s perspective
In 2018 I had a routine HTO (high tibia osteotomy) on my right leg to correct my stance due to knee pain. I was informed that I was too young to have a knee replacement and that this operation would solve my problem. Unfortunately, some 2 years later I am still using crutches to get around and have a metal fixator from above the knee down to my ankle.
In 2019, I had severe pain in my leg, swelling and redness so I took myself to A&E. I was admitted and put in a single room. From that time, I cannot remember that much. I know I was hallucinating, and I was feeling irritable and restless. My wife recalls that I was asking all sorts of random questions. I was having extreme hot sweats and high temperatures. It is all quite hazy but my son, who works for our family business, had some amount of verbal abuse from me. I apparently telephoned him at 3 in the morning asking where he was and accused him of not finishing a job off because he was too busy smoking. I have no recollection of this.
It all seemed so surreal like living in a different dimension. I was admitted to the ICU and remember feeling anxious and irritated. I remember my wife stood at my bedside crying and still I had little idea of what was occurring or where I was!
Thankfully, the care and the expertise of the ICU staff saw me through whatever I was experiencing. I was later told that I had serotonin syndrome and that it was quite rare for this to occur. I really do not remember much about the entire chain of events. I was happy that I came through it.
Learning points
Fever in surgical patients is not always secondary to infection.
Clinicians should be wary when patients are commenced on multimodal analgesia as inpatients. Specific care should be taken when prescribing tapentadol with other serotonergic agents due to an increased risk of serotonin syndrome.
As part of a neurological examination, clonus is a useful clinical sign to be aware of when assessing for serotonin syndrome.
Contributors: MG obtained the case details and wrote the first draft of the case report. WDH re-drafted the case report and ensured the orthopaedic details in the case report were accurate. AC-K re-drafted the case report and ensured the critical care details of the case were accurate. GB offered insights into the pharmaceutical side of the case report and ensured the accuracy of the discussion around the different serotonergic medications included in the case report.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33547128 | 18,955,414 | 2021-02-05 |
What was the administration route of drug 'RIFAMPIN'? | Fever in a patient with osteomyelitis: the diagnosis could be serotonin syndrome.
Awareness of rare differential diagnoses of common clinical presentations helps promote early detection and prompt management of serious conditions. A 54-year-old man, with an infected non-union following a high tibial osteotomy, presented with an acutely discharging abscess to his proximal tibia. He was generally unwell with a Staphylococcus aureus bacteraemia. The tibia was debrided, CERAMENT G used as dead space management and a spanning external fixator applied. Postoperatively, pregabalin and tapentadol were commenced in addition to amitriptyline and sertraline, which the patient was taking regularly. Overnight, the patient developed hyperthermia, inducible clonus, hyperreflexia, agitation, confusion and rigors. Prompt recognition of the possibility of serotonin syndrome resulted in early cessation of serotonergic medications and a positive outcome. From this case an important message is that fever in a patient taking serotonergic medications should prompt a screening neurological examination. Clinicians should also be wary when patients are commenced on multimodal analgesia, including tapentadol.
Background
An awareness of rare differential diagnoses of common clinical presentations helps promote the early detection and prompt management of serious conditions. The following case report describes the presentation of serotonin syndrome postoperatively on an orthopaedic ward, which with prompt diagnosis was managed effectively with good outcomes for the patient.
Serotonin syndrome is a rare, unpredictable and potentially fatal cause of fever. It is a drug-induced condition caused by too much serotonin within the synapses of the nervous system. Generally, it results from the combination of at least two drugs that increase serotonin levels or sometimes an overdose with a single drug that raises serotonin.1 Its incidence among 15 million patients in the USA who were taking serotonergic agents was around 0.07% to 0.19%.2 The true incidence of serotonin syndrome is thought to be unknown, due to it being under-recognised and under-reported.3
Currently, the Hunter Serotonin Toxicity Criteria (84% sensitive and 97% specific) is the most widely accepted diagnostic tool, with an emphasis on the following signs in the presence of a serotonergic agent: spontaneous or inducible clonus, agitation, tremor, diaphoresis, ocular clonus, hypertonia, hyperthermia and hyperreflexia (figure 1).4 The critical management step following diagnosis is identification and discontinuation of causative agents. In severe cases complications can include seizures, disseminated intravascular coagulopathy, metabolic acidosis, rhabdomyolysis, renal failure and death. Consequently patients with more severe cases may require management in critical care.5
Figure 1 The Hunter Serotonin Toxicity Criteria (adapted).
Case presentation
A 54-year-old man presented with an acutely discharging sinus with abscess to his right proximal tibia on the background of a complex orthopaedic history involving an infected non-union from an elective right tibial osteotomy. Past medical history included well-controlled asthma, obstructive sleep apnoea, hypertension, deep vein thrombosis and pericarditis.
At presentation, the patient was generally unwell with swinging fever and was found to have a Staphylococcus aureus bacteraemia. He was started on flucloxacillin intravenously and an echocardiogram requested.
Right knee radiographs showed non-union of the proximal tibia and evidence of a sequestrum, confirmed by CT scan. Right tibial exploration and debridement was conducted with tissue sampling, instillation of CERAMENT G (antibiotic laden synthetic bone substitute) and application of a spanning external fixator. All six tissue samples grew methicillin-sensitive S. aureus, with Proteus mirabilis and Enterobacter growing in one tissue sample.
Following the operation, oral rifampicin was added. A transthoracic echo showed an echogenic mobile structure behind the mitral valve leaflet, which was queried as an endocarditis vegetation. Flucloxacillin was increased to six times per day.
Postoperative complications included significant pain and acute kidney injury stage III, the latter deemed secondary to hypovolaemia and improved following intravenous fluid administration. The episodes of fever had resolved at this stage.
On the 5th day after the operation, following a difficult night with pain, 75 mg pregabalin (given two times per day) and subsequently 100 mg tapentadol modified release (given every 12 hours) were commenced for analgesia. The pregabalin was later increased to 150 mg (given two times per day). This was in addition to 25 mg amitriptyline (given one time per day), 150 mg sertraline (given one time per day) and 20 mg ketamine (given up to four times per day as required) which the patient was already taking.
The following day the patient deteriorated, and the initial impression was of sepsis secondary to tibial infection and/or infective endocarditis. However, following a review of the patient’s medications, the possibility of serotonin syndrome was raised, as it was noted that he had been commenced on tapentadol (one dose given) and pregabalin within the previous 48 hours and was already taking sertraline and amitriptyline. On examination he had hyperthermia (41°C at highest), tachycardia and tachypnoea. The patient also had neurological findings of tremor, hyperreflexia, agitation and bilateral inducible ankle clonus. These findings in the context of his recent medication history, supported a diagnosis of serotonin syndrome. Therefore, all serotoninergic medications were suspended and critical care involvement was requested.
The patient was admitted to the critical care unit for careful monitoring. Blood cultures that were taken at the time of the initial temperature rise grew P. mirabilis. Meropenem was added and flucloxacillin increased to every four hours. The patient’s creatine kinase (CK) rose to 6490 U/L over the next few days. The patient did have some tenderness to the mid anterior thigh and an urgent MRI of the right thigh ruled out myositis as a cause of the rising CK.
Vital and neurological signs settled after cessation of the medications in question, with the last significant temperature rise of 39.5°C recorded around 72 hours from the initial clinical deterioration. On day 7 the patient’s CK had dropped to 205 U/L. The patient was stepped down to the ward and avoided requiring any level 2 or 3 interventions. A transoesophageal echo, conducted when the patient was discharged from the intensive care unit, concluded that there were no criteria present for infective endocarditis and the previously reported abnormality was not significant.
Investigations
Laboratory investigations at that time showed a C-reactive protein (CRP) of 276 mg/L (which rose to 354 mg/L), a white cell count (WCC) of 7.8×109/L, neutrophils of 6.7×109/L, lymphocytes 0.6×109/L, creatinine 138 µmol/L and an alkaline phosphatase of 138 U/L.
Differential diagnosis
With the preceding history of S. aureus bacteraemia, possible infective endocarditis and a positive blood culture for P. mirabilis, the initial diagnosis, considered following the patient’s deterioration postoperatively, was sepsis. Indeed, he was concomitantly treated as sepsis during his stay on the critical care unit, with an escalation of antibiotic therapy.
The ultimate diagnosis of serotonin syndrome was first suspected due to the rapid deterioration following commencement of tapentadol and pregabalin (figure 2), alongside the examination findings present at this time, most notably the substantial hyperthermia of up to 41°C, inducible clonus, confusion, agitation and hyperreflexia. The combination of agitation and inducible clonus, in the presence of serotonergic medications, confirmed the clinical diagnosis of serotonin syndrome as per the Hunter classification system.4 Laboratory results also illustrated a raised CRP without any raise in WCC or neutrophils to suggest an overwhelming bacterial infection was present.
Figure 2 Patient’s vital signs leading up to intensive care unit admission. Pregabalin was started at a dose of 75 mg two times per day (BD) (blue arrow) and increased to 150 mg BD (second blue arrow). A single dose of tapentadol was given (green arrow).
Neuroleptic malignant syndrome (NMS) and malignant hyperthermia (MH) both also cause a drug-induced hyperthermia. Within this case NMS was effectively ruled out on the basis that the patient was not taking any anti-dopaminergic medications.6 With MH, the presentation would have been perioperatively or immediately postoperatively had a volatile anaesthetic agent or the depolarising muscle relaxant succinylcholine been used.7
Outcome and follow-up
The patient was discharged on a 6-week course of antibiotics. In the past 6 months he underwent a further orthopaedic procedure on the right knee and currently has a circular fixator in place. There have been several pin site infections, ongoing issues with pain and an episode of deep vein thrombosis in the right leg. Currently, he is walking, fully weight bearing on his leg with the help of crutches and has been listed for removal of the external fixator and application of a cast.
Discussion
Serotonin is synthesised from the essential amino acid tryptophan in both the midline raphe nuclei of the brainstem and enterochromaffin cells of the gastrointestinal (GI) tract.8 Around 40% to 80% of the body’s serotonin is stored in the enterochromaffin cells of the GI tract, with the remainder found in the central nervous system and also on platelets.8 Within the central nervous system and GI tract serotonin has numerous functions including attention, affective behaviour, thermoregulation, motor tone, GI motility, vasoconstriction, bronchoconstriction and platelet aggregation.9 Serotonin syndrome is the clinical manifestation of over activation of these central and peripheral serotonin receptors.9
Serotonin syndrome typically occurs when two or more drugs that elevate serotonin are used together, especially if they elevate serotonin in different ways.1 Monoamine oxidase inhibitors (MAOI) carry the highest risk profile due to their action to slow the breakdown of serotonin by blocking monoamine oxidase.1 Serotonin reuptake inhibitors (SSRI, such as sertraline in this case) and serotonin-norepinephrine reuptake inhibitors (SNRI) carry the next most significant risk due to their action to prevent the reuptake of serotonin from synapses.1 A combination of an MAOI with another MAOI or an SSRI or SNRI is the most dangerous combination of drugs and most likely to result in serotonin syndrome.9 Tricyclic antidepressants (such as amitriptyline in this case), opioids, drugs of abuse and selected other prescription and herbal drugs also carry a significant risk profile.9
Within this case, the initial episode of fever developed following initiation of pregabalin (figure 2), with the patient already regularly taking sertraline and amitriptyline, before a more significant deterioration overnight following the single dose of tapentadol. It is possible that this initial fever was due to sepsis. The blood culture taken around this time grew P. mirabilis, which was also present on a single tissue sample taken operatively. Pregabalin in the literature is not thought to have any effect on serotonin receptors or any inhibition of serotonin reuptake.10 However three case reports were identified where initiation of pregabalin was thought to have resulted in serotonin syndrome.11–13 A small double blind randomised controlled trial has also shown that gabapentin, an analogue of pregabalin, increases serotonin levels when used at a therapeutic range.14 However, without any substantial evidence it is difficult to draw any conclusions in this case about whether the initiation of pregabalin played any part in the development of serotonin syndrome.
Tapentadol is a centrally acting opioid. It acts as a µ-opioid receptor agonist, a norepinephrine receptor inhibitor and a weak serotonin uptake blocker in the rat.15 A review of post marketing safety data, undertaken by the tapentadol manufacturing pharmaceutical company, Grünenthal, concluded that it is unlikely that tapentadol has a clinically significant influence on the development of serotonin syndrome.16 Of the 151 cases identified, only 4 were deemed to be robustly diagnosed and of these other serotonergic medications were taken which could have caused serotonin syndrome. However, figures from the WHO VigiBase database rank tapentadol third on the list of serotonin syndrome individual case safety reports associated with an opioid alone or with another drug(s) (115 out of 1641 cases; 7%), and second when the opioid was the only suspected cause (42 out of 147 cases; 28.6%).15 17 Following the administration of tapentadol at 00:30 a.m., the patient in this case suffered a considerable clinical deterioration which started around 04:44 a.m. As mentioned, this fulfilled the Hunter classification criteria and would therefore seem to strongly suggest that tapentadol, in combination with sertraline and amitriptyline, caused serotonin syndrome in this patient. Case reports exist of serotonin syndrome following tapentadol overdose, however this patient received just one dose of tapentadol.18
Prompt diagnosis in this case likely had a significant impact on the patient outcome, which illustrates the importance of keeping an open mind when clinical signs do not fully support the more commonly encountered presentation of sepsis. The key message to highlight here is that fever in a patient with serotonergic drugs should prompt a screening neurological examination. The most important sign to be aware of is clonus, be it spontaneous, inducible or ocular, as this has been found to be strongly associated with serotonin syndrome.4 Therefore, the presence of clonus with serotonergic polypharmacy should act as a red flag for clinicians.
Patient’s perspective
In 2018 I had a routine HTO (high tibia osteotomy) on my right leg to correct my stance due to knee pain. I was informed that I was too young to have a knee replacement and that this operation would solve my problem. Unfortunately, some 2 years later I am still using crutches to get around and have a metal fixator from above the knee down to my ankle.
In 2019, I had severe pain in my leg, swelling and redness so I took myself to A&E. I was admitted and put in a single room. From that time, I cannot remember that much. I know I was hallucinating, and I was feeling irritable and restless. My wife recalls that I was asking all sorts of random questions. I was having extreme hot sweats and high temperatures. It is all quite hazy but my son, who works for our family business, had some amount of verbal abuse from me. I apparently telephoned him at 3 in the morning asking where he was and accused him of not finishing a job off because he was too busy smoking. I have no recollection of this.
It all seemed so surreal like living in a different dimension. I was admitted to the ICU and remember feeling anxious and irritated. I remember my wife stood at my bedside crying and still I had little idea of what was occurring or where I was!
Thankfully, the care and the expertise of the ICU staff saw me through whatever I was experiencing. I was later told that I had serotonin syndrome and that it was quite rare for this to occur. I really do not remember much about the entire chain of events. I was happy that I came through it.
Learning points
Fever in surgical patients is not always secondary to infection.
Clinicians should be wary when patients are commenced on multimodal analgesia as inpatients. Specific care should be taken when prescribing tapentadol with other serotonergic agents due to an increased risk of serotonin syndrome.
As part of a neurological examination, clonus is a useful clinical sign to be aware of when assessing for serotonin syndrome.
Contributors: MG obtained the case details and wrote the first draft of the case report. WDH re-drafted the case report and ensured the orthopaedic details in the case report were accurate. AC-K re-drafted the case report and ensured the critical care details of the case were accurate. GB offered insights into the pharmaceutical side of the case report and ensured the accuracy of the discussion around the different serotonergic medications included in the case report.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33547128 | 18,955,414 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Leukopenia'. | Paliperidone induced neutropenia in first episode psychosis: a case report.
Neutropenia, a decrease in total number of neutrophils below 1500/mm3 and particularly severe neutropenia, defined as neutrophils less than 500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections and death. However, much of the attention on the potential adverse effect is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work. We demonstrate here that paliperidone can also cause neutropenia and therefore clinicians should be aware of this possibility especially during initiation of treatment.
The following report presents the case of a 23-year-old African American male with first episode psychosis who developed neutropenia after initiation of paliperidone. Neutropenia resolved after discontinuation of paliperidone and initiation of an alternative antipsychotic, haloperidol.
This case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. We conclude that when initiating paliperidone, clinicians should be more aware of the risk of neutropenia. Moreover, neutropenia may be a more common and overlooked issue in patients on antipsychotic medications other than clozapine and increased awareness of comparative risk across antipsychotics could help direct treatment.
Background
Neutropenia, a decrease in total number of neutrophils below 1500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections. However, much of the attention on the potential for neutropenia and severe neutropenia, defined as neutrophils less than 500/mm3, is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work [1–3].
In the following case report, we describe a relatively treatment-naïve patient with new onset psychosis whose absolute neutrophil count (ANC) dropped significantly with the initiation of the atypical antipsychotic, paliperidone. We later discuss the future implications of neutropenia in antipsychotic medications other than clozapine.
Case presentation
A 23-year-old African American male with previous high level of social and academic functioning, family history of depression, and no past medical or psychiatric history was admitted to an inpatient psychiatric unit for treatment of several months of uncharacteristic, odd behavior and disorganized thought process. On presentation, the patient could not provide a coherent narrative. His family and friends reported gradual onset of odd behavior within the year prior to admission. These behaviors included wearing his rugby helmet around his college campus, discarding clothes in the trash, and becoming increasingly disheveled in appearance. He drove across the state, in the middle of the night, to his mother’s home to then fearfully claim he was being pursued and his mother was trying to kill him.
Several weeks prior to admission, the patient was hospitalized, diagnosed with schizophrenia, and prescribed perphenazine 8 mg twice daily and doxepin 50 mg nightly. After 7 days of inpatient care he was discharged. His disorganized behavior returned 3 days after discharge, prompting his mother to bring him for inpatient psychiatric admission.
On presentation, he was responding to internal stimuli, regularly glancing around the room during the interview. His speech was latent with intermittent thought blocking. He reported somatic delusions regarding his heart and a general delusional atmosphere feeling that everything around him was connected. He reported an auditory hallucination of the devil’s voice.
Admission labs (WBC 5300, ANC 2100), urine toxicity, and head CT were all unremarkable. He was diagnosed with schizophrenia and started on aripiprazole 10 mg, which was increased to 20 mg. He was also treated with escitalopram 10 mg daily given concern for possible affective component and clonazepam 0.25 mg twice daily for anxiety. After nearly 2 weeks, the patient demonstrated little improvement on mental status exam.
Given lack of response to aripiprazole, he was transitioned to oral paliperidone 6 mg. His ANC prior to paliperidone initiation was 4120. Following 15 days of paliperidone 6 mg, he started to respond with improvement in his psychotic symptoms. However, his complete blood count at day fifteen of paliperidone revealed an ANC of 1210 with a nadir of 960 (WBC nadir of 3720) on serial monitoring. Aside from neutropenia, there were no other lab abnormalities. Peripheral smear showed mild leucopenia with neutropenia and relative lymphocytosis. Antinuclear antibody (ANA) and human immunodeficiency virus (HIV) were both negative. Physical exam was unremarkable. Hematology specialists concluded that the timeline and negative work-up were most consistent with drug-induced neutropenia. Paliperidone was discontinued after 20 days of treatment and haloperidol 10 mg nightly was started. ANC was monitored three times weekly. Gradually, his counts improved and 16 days after discontinuation of paliperidone, returned to normal with an ANC of 2070 (WBC 5220). While on haloperidol, the patient showed progressive improvement of his symptoms. By discharge he demonstrated spontaneity of speech and greatly improved content and organization of thoughts.
Discussion and conclusions
In our case, neutropenia developed after initiation of paliperidone and resolved within 16 days of discontinuation. Neutrophil levels remained normal after the initiation of haloperidol, indicating that neutropenia was most likely related to the initiation of paliperidone.
We also considered other contributing factors to his neutropenia. He was also treated with clonazepam and escitalopram during his course but with no evidence of temporal relationship to his neutropenia. However, there are reports of clonazepam induced neutropenia [4]. Though clonazepam had been discontinued by the time the patient developed neutropenia, we cannot rule out a possible synergistic effect from both paliperidone and clonazepam. Additionally, while there are no agreed upon risk factors for antipsychotic induced neutropenia (particularly paliperidone-induced), one might reasonably apply risk factors for clozapine induced neutropenia to this case. And in this case, neuroleptic naivety, higher doses of neuroleptics, African American race, male gender, and younger age all may have placed him at greater risk of developing neuroleptic induced neutropenia [5, 6]. Furthermore, we considered the role of benign ethnic neutropenia (BEN); however, hematology consultants did not consider this a factor given his ANC counts being consistently greater than 1500 prior to initiation of neuroleptics.
To date, we are only aware of three other case reports on neutropenia induced by paliperidone. In all three cases, neutropenia resolved within several days to weeks after discontinuation of paliperidone [7–9]. In one case, lithium was successfully added temporarily to counteract the neutropenia [7]. Two of the reports suggested that neutropenia was dose related and concomitant psychiatric medications (divalproex sodium and quetiapine in one case, risperidone in the other) could have also synergistically contributed to development of neutropenia [7, 8]. In all cases, patients had been on their previous regimens without neutropenia prior to initiation of paliperidone. The patient described here highlights that the decrease in ANC may occur at low to middle doses of paliperidone since the Food and Drug Administration FDA maximum dosage is 12 mg and early in the course of treatment. Of note, paliperidone (9-hydroxyrisperidone) is a metabolite of risperidone. A literature review demonstrates evidence of risperidone induced blood dyscrasias, including neutropenia [10, 11]. Thus, it stands to reason that risperidone’s metabolite could also lead to neutropenia.
Our case report highlights the potential for antipsychotics other than clozapine to cause neutropenia. Although clozapine is the antipsychotic most commonly associated with agranulocytosis or severe neutropenia (term now used by the Clozapine Risk Evaluation and Mitigation Strategies program) with an estimated risk of approximately 0.68%, other antipsychotics have also been linked to neutropenia and severe neutropenia including the majority of second generation antipsychotics [12–14]. We now present evidence for paliperidone causing neutropenia in a case of first episode psychosis (occurring within the first year of treatment). While there are no guidelines for routine ANC monitoring when using any antipsychotic other than clozapine, our case suggests the potential risk of neutropenia when initiating paliperidone. If we had failed to recognize the precipitous fall in our patient’s neutrophil count, he may have remained on paliperidone indefinitely with increased risk for medication-related morbidity and mortality.
Currently, clozapine is widely recognized as one of the most effective antipsychotic medications available but is underutilized largely due to the barriers to prescribers and heavy burden placed on patients with required regular blood monitoring [2]. After many years of implementation, the utility of long-term clozapine monitoring is still debated. Some evidence suggests that there is not a significant increase in risk for developing neutropenia while on clozapine compared to other medications [12–15] and following the ANC after the first 6 months of treatment may not be as beneficial in preventing fatalities as previously thought [12, 15]. Based on the experiences with clozapine, it would likely be counterproductive to spread this monitoring burden to even more antipsychotics, such as paliperidone, in efforts to mitigate this side effect risk. Further evaluation of how high the risk of neutropenia and severe neutropenia is in the population treated with paliperidone, as well as other newer antipsychotics, would be necessary to fully appreciate the true risk. Ultimately, striking a balance between safely prescribing antipsychotics while still providing effective and accessible treatment will be crucial in the future as newer medications like paliperidone become more widely used. However, this case report highlights the importance of clinicians being aware of the risk and considering obtaining routine ANCs when initiating paliperidone and other antipsychotics.
This case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. In general, we conclude that there is sufficient and mounting evidence that most antipsychotics can cause neutropenia and that there may be value in monitoring ANCs early in the course of treatment to ensure stability. However, we would caution against mandatory monitoring with a national registry as this has contributed to the underutilization of clozapine, and thus could disrupt effective utilization of antipsychotics in general. This could also help make the argument to relax mandatory monitoring of clozapine since neutropenia may not be specific to clozapine. The hope is that this case will add to clinicians’ awareness that neutropenia is a risk with neuroleptic treatment, and that it will also spur further studies regarding comparative risk for neutropenia among all neuroleptics and a re-thinking of a mandatory registry for clozapine.
Abbreviations
ANCAbsolute Neutrophil Count
ANAAntinuclear Antibody
HIVHuman Immunodeficiency Virus
FDAFood and Drug Administration
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Natalie Martos and William Hall contributed equally to this work.
Acknowledgements
None.
Authors’ contributions
FCN was the primary clinician involved in the assessment, management, and follow-up of the patient. NM, WH, AM and TWS were involved in the patient follow-up. FCN conceived the case report. NM, WH, AM and TWS contributed to the literature review. All authors contributed to the manuscript preparation. FCN and WH wrote the revisions. All authors read and approved the final manuscript.
Funding
No funding sources.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Written informed consent was obtained from the individual to participate and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.
Consent for publication
Written informed consent was obtained from the individual for the publication of this manuscript and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.
Competing interests
The authors have no competing interests to declare. | ARIPIPRAZOLE, CLONAZEPAM, DOXEPIN, ESCITALOPRAM OXALATE, PALIPERIDONE, PERPHENAZINE | DrugsGivenReaction | CC BY | 33549083 | 18,921,011 | 2021-02-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lymphocytosis'. | Paliperidone induced neutropenia in first episode psychosis: a case report.
Neutropenia, a decrease in total number of neutrophils below 1500/mm3 and particularly severe neutropenia, defined as neutrophils less than 500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections and death. However, much of the attention on the potential adverse effect is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work. We demonstrate here that paliperidone can also cause neutropenia and therefore clinicians should be aware of this possibility especially during initiation of treatment.
The following report presents the case of a 23-year-old African American male with first episode psychosis who developed neutropenia after initiation of paliperidone. Neutropenia resolved after discontinuation of paliperidone and initiation of an alternative antipsychotic, haloperidol.
This case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. We conclude that when initiating paliperidone, clinicians should be more aware of the risk of neutropenia. Moreover, neutropenia may be a more common and overlooked issue in patients on antipsychotic medications other than clozapine and increased awareness of comparative risk across antipsychotics could help direct treatment.
Background
Neutropenia, a decrease in total number of neutrophils below 1500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections. However, much of the attention on the potential for neutropenia and severe neutropenia, defined as neutrophils less than 500/mm3, is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work [1–3].
In the following case report, we describe a relatively treatment-naïve patient with new onset psychosis whose absolute neutrophil count (ANC) dropped significantly with the initiation of the atypical antipsychotic, paliperidone. We later discuss the future implications of neutropenia in antipsychotic medications other than clozapine.
Case presentation
A 23-year-old African American male with previous high level of social and academic functioning, family history of depression, and no past medical or psychiatric history was admitted to an inpatient psychiatric unit for treatment of several months of uncharacteristic, odd behavior and disorganized thought process. On presentation, the patient could not provide a coherent narrative. His family and friends reported gradual onset of odd behavior within the year prior to admission. These behaviors included wearing his rugby helmet around his college campus, discarding clothes in the trash, and becoming increasingly disheveled in appearance. He drove across the state, in the middle of the night, to his mother’s home to then fearfully claim he was being pursued and his mother was trying to kill him.
Several weeks prior to admission, the patient was hospitalized, diagnosed with schizophrenia, and prescribed perphenazine 8 mg twice daily and doxepin 50 mg nightly. After 7 days of inpatient care he was discharged. His disorganized behavior returned 3 days after discharge, prompting his mother to bring him for inpatient psychiatric admission.
On presentation, he was responding to internal stimuli, regularly glancing around the room during the interview. His speech was latent with intermittent thought blocking. He reported somatic delusions regarding his heart and a general delusional atmosphere feeling that everything around him was connected. He reported an auditory hallucination of the devil’s voice.
Admission labs (WBC 5300, ANC 2100), urine toxicity, and head CT were all unremarkable. He was diagnosed with schizophrenia and started on aripiprazole 10 mg, which was increased to 20 mg. He was also treated with escitalopram 10 mg daily given concern for possible affective component and clonazepam 0.25 mg twice daily for anxiety. After nearly 2 weeks, the patient demonstrated little improvement on mental status exam.
Given lack of response to aripiprazole, he was transitioned to oral paliperidone 6 mg. His ANC prior to paliperidone initiation was 4120. Following 15 days of paliperidone 6 mg, he started to respond with improvement in his psychotic symptoms. However, his complete blood count at day fifteen of paliperidone revealed an ANC of 1210 with a nadir of 960 (WBC nadir of 3720) on serial monitoring. Aside from neutropenia, there were no other lab abnormalities. Peripheral smear showed mild leucopenia with neutropenia and relative lymphocytosis. Antinuclear antibody (ANA) and human immunodeficiency virus (HIV) were both negative. Physical exam was unremarkable. Hematology specialists concluded that the timeline and negative work-up were most consistent with drug-induced neutropenia. Paliperidone was discontinued after 20 days of treatment and haloperidol 10 mg nightly was started. ANC was monitored three times weekly. Gradually, his counts improved and 16 days after discontinuation of paliperidone, returned to normal with an ANC of 2070 (WBC 5220). While on haloperidol, the patient showed progressive improvement of his symptoms. By discharge he demonstrated spontaneity of speech and greatly improved content and organization of thoughts.
Discussion and conclusions
In our case, neutropenia developed after initiation of paliperidone and resolved within 16 days of discontinuation. Neutrophil levels remained normal after the initiation of haloperidol, indicating that neutropenia was most likely related to the initiation of paliperidone.
We also considered other contributing factors to his neutropenia. He was also treated with clonazepam and escitalopram during his course but with no evidence of temporal relationship to his neutropenia. However, there are reports of clonazepam induced neutropenia [4]. Though clonazepam had been discontinued by the time the patient developed neutropenia, we cannot rule out a possible synergistic effect from both paliperidone and clonazepam. Additionally, while there are no agreed upon risk factors for antipsychotic induced neutropenia (particularly paliperidone-induced), one might reasonably apply risk factors for clozapine induced neutropenia to this case. And in this case, neuroleptic naivety, higher doses of neuroleptics, African American race, male gender, and younger age all may have placed him at greater risk of developing neuroleptic induced neutropenia [5, 6]. Furthermore, we considered the role of benign ethnic neutropenia (BEN); however, hematology consultants did not consider this a factor given his ANC counts being consistently greater than 1500 prior to initiation of neuroleptics.
To date, we are only aware of three other case reports on neutropenia induced by paliperidone. In all three cases, neutropenia resolved within several days to weeks after discontinuation of paliperidone [7–9]. In one case, lithium was successfully added temporarily to counteract the neutropenia [7]. Two of the reports suggested that neutropenia was dose related and concomitant psychiatric medications (divalproex sodium and quetiapine in one case, risperidone in the other) could have also synergistically contributed to development of neutropenia [7, 8]. In all cases, patients had been on their previous regimens without neutropenia prior to initiation of paliperidone. The patient described here highlights that the decrease in ANC may occur at low to middle doses of paliperidone since the Food and Drug Administration FDA maximum dosage is 12 mg and early in the course of treatment. Of note, paliperidone (9-hydroxyrisperidone) is a metabolite of risperidone. A literature review demonstrates evidence of risperidone induced blood dyscrasias, including neutropenia [10, 11]. Thus, it stands to reason that risperidone’s metabolite could also lead to neutropenia.
Our case report highlights the potential for antipsychotics other than clozapine to cause neutropenia. Although clozapine is the antipsychotic most commonly associated with agranulocytosis or severe neutropenia (term now used by the Clozapine Risk Evaluation and Mitigation Strategies program) with an estimated risk of approximately 0.68%, other antipsychotics have also been linked to neutropenia and severe neutropenia including the majority of second generation antipsychotics [12–14]. We now present evidence for paliperidone causing neutropenia in a case of first episode psychosis (occurring within the first year of treatment). While there are no guidelines for routine ANC monitoring when using any antipsychotic other than clozapine, our case suggests the potential risk of neutropenia when initiating paliperidone. If we had failed to recognize the precipitous fall in our patient’s neutrophil count, he may have remained on paliperidone indefinitely with increased risk for medication-related morbidity and mortality.
Currently, clozapine is widely recognized as one of the most effective antipsychotic medications available but is underutilized largely due to the barriers to prescribers and heavy burden placed on patients with required regular blood monitoring [2]. After many years of implementation, the utility of long-term clozapine monitoring is still debated. Some evidence suggests that there is not a significant increase in risk for developing neutropenia while on clozapine compared to other medications [12–15] and following the ANC after the first 6 months of treatment may not be as beneficial in preventing fatalities as previously thought [12, 15]. Based on the experiences with clozapine, it would likely be counterproductive to spread this monitoring burden to even more antipsychotics, such as paliperidone, in efforts to mitigate this side effect risk. Further evaluation of how high the risk of neutropenia and severe neutropenia is in the population treated with paliperidone, as well as other newer antipsychotics, would be necessary to fully appreciate the true risk. Ultimately, striking a balance between safely prescribing antipsychotics while still providing effective and accessible treatment will be crucial in the future as newer medications like paliperidone become more widely used. However, this case report highlights the importance of clinicians being aware of the risk and considering obtaining routine ANCs when initiating paliperidone and other antipsychotics.
This case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. In general, we conclude that there is sufficient and mounting evidence that most antipsychotics can cause neutropenia and that there may be value in monitoring ANCs early in the course of treatment to ensure stability. However, we would caution against mandatory monitoring with a national registry as this has contributed to the underutilization of clozapine, and thus could disrupt effective utilization of antipsychotics in general. This could also help make the argument to relax mandatory monitoring of clozapine since neutropenia may not be specific to clozapine. The hope is that this case will add to clinicians’ awareness that neutropenia is a risk with neuroleptic treatment, and that it will also spur further studies regarding comparative risk for neutropenia among all neuroleptics and a re-thinking of a mandatory registry for clozapine.
Abbreviations
ANCAbsolute Neutrophil Count
ANAAntinuclear Antibody
HIVHuman Immunodeficiency Virus
FDAFood and Drug Administration
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Natalie Martos and William Hall contributed equally to this work.
Acknowledgements
None.
Authors’ contributions
FCN was the primary clinician involved in the assessment, management, and follow-up of the patient. NM, WH, AM and TWS were involved in the patient follow-up. FCN conceived the case report. NM, WH, AM and TWS contributed to the literature review. All authors contributed to the manuscript preparation. FCN and WH wrote the revisions. All authors read and approved the final manuscript.
Funding
No funding sources.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Written informed consent was obtained from the individual to participate and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.
Consent for publication
Written informed consent was obtained from the individual for the publication of this manuscript and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.
Competing interests
The authors have no competing interests to declare. | ARIPIPRAZOLE, CLONAZEPAM, DOXEPIN, ESCITALOPRAM OXALATE, PALIPERIDONE, PERPHENAZINE | DrugsGivenReaction | CC BY | 33549083 | 18,921,011 | 2021-02-06 |
What was the administration route of drug 'PALIPERIDONE'? | Paliperidone induced neutropenia in first episode psychosis: a case report.
Neutropenia, a decrease in total number of neutrophils below 1500/mm3 and particularly severe neutropenia, defined as neutrophils less than 500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections and death. However, much of the attention on the potential adverse effect is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work. We demonstrate here that paliperidone can also cause neutropenia and therefore clinicians should be aware of this possibility especially during initiation of treatment.
The following report presents the case of a 23-year-old African American male with first episode psychosis who developed neutropenia after initiation of paliperidone. Neutropenia resolved after discontinuation of paliperidone and initiation of an alternative antipsychotic, haloperidol.
This case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. We conclude that when initiating paliperidone, clinicians should be more aware of the risk of neutropenia. Moreover, neutropenia may be a more common and overlooked issue in patients on antipsychotic medications other than clozapine and increased awareness of comparative risk across antipsychotics could help direct treatment.
Background
Neutropenia, a decrease in total number of neutrophils below 1500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections. However, much of the attention on the potential for neutropenia and severe neutropenia, defined as neutrophils less than 500/mm3, is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work [1–3].
In the following case report, we describe a relatively treatment-naïve patient with new onset psychosis whose absolute neutrophil count (ANC) dropped significantly with the initiation of the atypical antipsychotic, paliperidone. We later discuss the future implications of neutropenia in antipsychotic medications other than clozapine.
Case presentation
A 23-year-old African American male with previous high level of social and academic functioning, family history of depression, and no past medical or psychiatric history was admitted to an inpatient psychiatric unit for treatment of several months of uncharacteristic, odd behavior and disorganized thought process. On presentation, the patient could not provide a coherent narrative. His family and friends reported gradual onset of odd behavior within the year prior to admission. These behaviors included wearing his rugby helmet around his college campus, discarding clothes in the trash, and becoming increasingly disheveled in appearance. He drove across the state, in the middle of the night, to his mother’s home to then fearfully claim he was being pursued and his mother was trying to kill him.
Several weeks prior to admission, the patient was hospitalized, diagnosed with schizophrenia, and prescribed perphenazine 8 mg twice daily and doxepin 50 mg nightly. After 7 days of inpatient care he was discharged. His disorganized behavior returned 3 days after discharge, prompting his mother to bring him for inpatient psychiatric admission.
On presentation, he was responding to internal stimuli, regularly glancing around the room during the interview. His speech was latent with intermittent thought blocking. He reported somatic delusions regarding his heart and a general delusional atmosphere feeling that everything around him was connected. He reported an auditory hallucination of the devil’s voice.
Admission labs (WBC 5300, ANC 2100), urine toxicity, and head CT were all unremarkable. He was diagnosed with schizophrenia and started on aripiprazole 10 mg, which was increased to 20 mg. He was also treated with escitalopram 10 mg daily given concern for possible affective component and clonazepam 0.25 mg twice daily for anxiety. After nearly 2 weeks, the patient demonstrated little improvement on mental status exam.
Given lack of response to aripiprazole, he was transitioned to oral paliperidone 6 mg. His ANC prior to paliperidone initiation was 4120. Following 15 days of paliperidone 6 mg, he started to respond with improvement in his psychotic symptoms. However, his complete blood count at day fifteen of paliperidone revealed an ANC of 1210 with a nadir of 960 (WBC nadir of 3720) on serial monitoring. Aside from neutropenia, there were no other lab abnormalities. Peripheral smear showed mild leucopenia with neutropenia and relative lymphocytosis. Antinuclear antibody (ANA) and human immunodeficiency virus (HIV) were both negative. Physical exam was unremarkable. Hematology specialists concluded that the timeline and negative work-up were most consistent with drug-induced neutropenia. Paliperidone was discontinued after 20 days of treatment and haloperidol 10 mg nightly was started. ANC was monitored three times weekly. Gradually, his counts improved and 16 days after discontinuation of paliperidone, returned to normal with an ANC of 2070 (WBC 5220). While on haloperidol, the patient showed progressive improvement of his symptoms. By discharge he demonstrated spontaneity of speech and greatly improved content and organization of thoughts.
Discussion and conclusions
In our case, neutropenia developed after initiation of paliperidone and resolved within 16 days of discontinuation. Neutrophil levels remained normal after the initiation of haloperidol, indicating that neutropenia was most likely related to the initiation of paliperidone.
We also considered other contributing factors to his neutropenia. He was also treated with clonazepam and escitalopram during his course but with no evidence of temporal relationship to his neutropenia. However, there are reports of clonazepam induced neutropenia [4]. Though clonazepam had been discontinued by the time the patient developed neutropenia, we cannot rule out a possible synergistic effect from both paliperidone and clonazepam. Additionally, while there are no agreed upon risk factors for antipsychotic induced neutropenia (particularly paliperidone-induced), one might reasonably apply risk factors for clozapine induced neutropenia to this case. And in this case, neuroleptic naivety, higher doses of neuroleptics, African American race, male gender, and younger age all may have placed him at greater risk of developing neuroleptic induced neutropenia [5, 6]. Furthermore, we considered the role of benign ethnic neutropenia (BEN); however, hematology consultants did not consider this a factor given his ANC counts being consistently greater than 1500 prior to initiation of neuroleptics.
To date, we are only aware of three other case reports on neutropenia induced by paliperidone. In all three cases, neutropenia resolved within several days to weeks after discontinuation of paliperidone [7–9]. In one case, lithium was successfully added temporarily to counteract the neutropenia [7]. Two of the reports suggested that neutropenia was dose related and concomitant psychiatric medications (divalproex sodium and quetiapine in one case, risperidone in the other) could have also synergistically contributed to development of neutropenia [7, 8]. In all cases, patients had been on their previous regimens without neutropenia prior to initiation of paliperidone. The patient described here highlights that the decrease in ANC may occur at low to middle doses of paliperidone since the Food and Drug Administration FDA maximum dosage is 12 mg and early in the course of treatment. Of note, paliperidone (9-hydroxyrisperidone) is a metabolite of risperidone. A literature review demonstrates evidence of risperidone induced blood dyscrasias, including neutropenia [10, 11]. Thus, it stands to reason that risperidone’s metabolite could also lead to neutropenia.
Our case report highlights the potential for antipsychotics other than clozapine to cause neutropenia. Although clozapine is the antipsychotic most commonly associated with agranulocytosis or severe neutropenia (term now used by the Clozapine Risk Evaluation and Mitigation Strategies program) with an estimated risk of approximately 0.68%, other antipsychotics have also been linked to neutropenia and severe neutropenia including the majority of second generation antipsychotics [12–14]. We now present evidence for paliperidone causing neutropenia in a case of first episode psychosis (occurring within the first year of treatment). While there are no guidelines for routine ANC monitoring when using any antipsychotic other than clozapine, our case suggests the potential risk of neutropenia when initiating paliperidone. If we had failed to recognize the precipitous fall in our patient’s neutrophil count, he may have remained on paliperidone indefinitely with increased risk for medication-related morbidity and mortality.
Currently, clozapine is widely recognized as one of the most effective antipsychotic medications available but is underutilized largely due to the barriers to prescribers and heavy burden placed on patients with required regular blood monitoring [2]. After many years of implementation, the utility of long-term clozapine monitoring is still debated. Some evidence suggests that there is not a significant increase in risk for developing neutropenia while on clozapine compared to other medications [12–15] and following the ANC after the first 6 months of treatment may not be as beneficial in preventing fatalities as previously thought [12, 15]. Based on the experiences with clozapine, it would likely be counterproductive to spread this monitoring burden to even more antipsychotics, such as paliperidone, in efforts to mitigate this side effect risk. Further evaluation of how high the risk of neutropenia and severe neutropenia is in the population treated with paliperidone, as well as other newer antipsychotics, would be necessary to fully appreciate the true risk. Ultimately, striking a balance between safely prescribing antipsychotics while still providing effective and accessible treatment will be crucial in the future as newer medications like paliperidone become more widely used. However, this case report highlights the importance of clinicians being aware of the risk and considering obtaining routine ANCs when initiating paliperidone and other antipsychotics.
This case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. In general, we conclude that there is sufficient and mounting evidence that most antipsychotics can cause neutropenia and that there may be value in monitoring ANCs early in the course of treatment to ensure stability. However, we would caution against mandatory monitoring with a national registry as this has contributed to the underutilization of clozapine, and thus could disrupt effective utilization of antipsychotics in general. This could also help make the argument to relax mandatory monitoring of clozapine since neutropenia may not be specific to clozapine. The hope is that this case will add to clinicians’ awareness that neutropenia is a risk with neuroleptic treatment, and that it will also spur further studies regarding comparative risk for neutropenia among all neuroleptics and a re-thinking of a mandatory registry for clozapine.
Abbreviations
ANCAbsolute Neutrophil Count
ANAAntinuclear Antibody
HIVHuman Immunodeficiency Virus
FDAFood and Drug Administration
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Natalie Martos and William Hall contributed equally to this work.
Acknowledgements
None.
Authors’ contributions
FCN was the primary clinician involved in the assessment, management, and follow-up of the patient. NM, WH, AM and TWS were involved in the patient follow-up. FCN conceived the case report. NM, WH, AM and TWS contributed to the literature review. All authors contributed to the manuscript preparation. FCN and WH wrote the revisions. All authors read and approved the final manuscript.
Funding
No funding sources.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Written informed consent was obtained from the individual to participate and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.
Consent for publication
Written informed consent was obtained from the individual for the publication of this manuscript and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.
Competing interests
The authors have no competing interests to declare. | Oral | DrugAdministrationRoute | CC BY | 33549083 | 18,999,467 | 2021-02-06 |
What was the dosage of drug 'PALIPERIDONE'? | Paliperidone induced neutropenia in first episode psychosis: a case report.
Neutropenia, a decrease in total number of neutrophils below 1500/mm3 and particularly severe neutropenia, defined as neutrophils less than 500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections and death. However, much of the attention on the potential adverse effect is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work. We demonstrate here that paliperidone can also cause neutropenia and therefore clinicians should be aware of this possibility especially during initiation of treatment.
The following report presents the case of a 23-year-old African American male with first episode psychosis who developed neutropenia after initiation of paliperidone. Neutropenia resolved after discontinuation of paliperidone and initiation of an alternative antipsychotic, haloperidol.
This case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. We conclude that when initiating paliperidone, clinicians should be more aware of the risk of neutropenia. Moreover, neutropenia may be a more common and overlooked issue in patients on antipsychotic medications other than clozapine and increased awareness of comparative risk across antipsychotics could help direct treatment.
Background
Neutropenia, a decrease in total number of neutrophils below 1500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections. However, much of the attention on the potential for neutropenia and severe neutropenia, defined as neutrophils less than 500/mm3, is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work [1–3].
In the following case report, we describe a relatively treatment-naïve patient with new onset psychosis whose absolute neutrophil count (ANC) dropped significantly with the initiation of the atypical antipsychotic, paliperidone. We later discuss the future implications of neutropenia in antipsychotic medications other than clozapine.
Case presentation
A 23-year-old African American male with previous high level of social and academic functioning, family history of depression, and no past medical or psychiatric history was admitted to an inpatient psychiatric unit for treatment of several months of uncharacteristic, odd behavior and disorganized thought process. On presentation, the patient could not provide a coherent narrative. His family and friends reported gradual onset of odd behavior within the year prior to admission. These behaviors included wearing his rugby helmet around his college campus, discarding clothes in the trash, and becoming increasingly disheveled in appearance. He drove across the state, in the middle of the night, to his mother’s home to then fearfully claim he was being pursued and his mother was trying to kill him.
Several weeks prior to admission, the patient was hospitalized, diagnosed with schizophrenia, and prescribed perphenazine 8 mg twice daily and doxepin 50 mg nightly. After 7 days of inpatient care he was discharged. His disorganized behavior returned 3 days after discharge, prompting his mother to bring him for inpatient psychiatric admission.
On presentation, he was responding to internal stimuli, regularly glancing around the room during the interview. His speech was latent with intermittent thought blocking. He reported somatic delusions regarding his heart and a general delusional atmosphere feeling that everything around him was connected. He reported an auditory hallucination of the devil’s voice.
Admission labs (WBC 5300, ANC 2100), urine toxicity, and head CT were all unremarkable. He was diagnosed with schizophrenia and started on aripiprazole 10 mg, which was increased to 20 mg. He was also treated with escitalopram 10 mg daily given concern for possible affective component and clonazepam 0.25 mg twice daily for anxiety. After nearly 2 weeks, the patient demonstrated little improvement on mental status exam.
Given lack of response to aripiprazole, he was transitioned to oral paliperidone 6 mg. His ANC prior to paliperidone initiation was 4120. Following 15 days of paliperidone 6 mg, he started to respond with improvement in his psychotic symptoms. However, his complete blood count at day fifteen of paliperidone revealed an ANC of 1210 with a nadir of 960 (WBC nadir of 3720) on serial monitoring. Aside from neutropenia, there were no other lab abnormalities. Peripheral smear showed mild leucopenia with neutropenia and relative lymphocytosis. Antinuclear antibody (ANA) and human immunodeficiency virus (HIV) were both negative. Physical exam was unremarkable. Hematology specialists concluded that the timeline and negative work-up were most consistent with drug-induced neutropenia. Paliperidone was discontinued after 20 days of treatment and haloperidol 10 mg nightly was started. ANC was monitored three times weekly. Gradually, his counts improved and 16 days after discontinuation of paliperidone, returned to normal with an ANC of 2070 (WBC 5220). While on haloperidol, the patient showed progressive improvement of his symptoms. By discharge he demonstrated spontaneity of speech and greatly improved content and organization of thoughts.
Discussion and conclusions
In our case, neutropenia developed after initiation of paliperidone and resolved within 16 days of discontinuation. Neutrophil levels remained normal after the initiation of haloperidol, indicating that neutropenia was most likely related to the initiation of paliperidone.
We also considered other contributing factors to his neutropenia. He was also treated with clonazepam and escitalopram during his course but with no evidence of temporal relationship to his neutropenia. However, there are reports of clonazepam induced neutropenia [4]. Though clonazepam had been discontinued by the time the patient developed neutropenia, we cannot rule out a possible synergistic effect from both paliperidone and clonazepam. Additionally, while there are no agreed upon risk factors for antipsychotic induced neutropenia (particularly paliperidone-induced), one might reasonably apply risk factors for clozapine induced neutropenia to this case. And in this case, neuroleptic naivety, higher doses of neuroleptics, African American race, male gender, and younger age all may have placed him at greater risk of developing neuroleptic induced neutropenia [5, 6]. Furthermore, we considered the role of benign ethnic neutropenia (BEN); however, hematology consultants did not consider this a factor given his ANC counts being consistently greater than 1500 prior to initiation of neuroleptics.
To date, we are only aware of three other case reports on neutropenia induced by paliperidone. In all three cases, neutropenia resolved within several days to weeks after discontinuation of paliperidone [7–9]. In one case, lithium was successfully added temporarily to counteract the neutropenia [7]. Two of the reports suggested that neutropenia was dose related and concomitant psychiatric medications (divalproex sodium and quetiapine in one case, risperidone in the other) could have also synergistically contributed to development of neutropenia [7, 8]. In all cases, patients had been on their previous regimens without neutropenia prior to initiation of paliperidone. The patient described here highlights that the decrease in ANC may occur at low to middle doses of paliperidone since the Food and Drug Administration FDA maximum dosage is 12 mg and early in the course of treatment. Of note, paliperidone (9-hydroxyrisperidone) is a metabolite of risperidone. A literature review demonstrates evidence of risperidone induced blood dyscrasias, including neutropenia [10, 11]. Thus, it stands to reason that risperidone’s metabolite could also lead to neutropenia.
Our case report highlights the potential for antipsychotics other than clozapine to cause neutropenia. Although clozapine is the antipsychotic most commonly associated with agranulocytosis or severe neutropenia (term now used by the Clozapine Risk Evaluation and Mitigation Strategies program) with an estimated risk of approximately 0.68%, other antipsychotics have also been linked to neutropenia and severe neutropenia including the majority of second generation antipsychotics [12–14]. We now present evidence for paliperidone causing neutropenia in a case of first episode psychosis (occurring within the first year of treatment). While there are no guidelines for routine ANC monitoring when using any antipsychotic other than clozapine, our case suggests the potential risk of neutropenia when initiating paliperidone. If we had failed to recognize the precipitous fall in our patient’s neutrophil count, he may have remained on paliperidone indefinitely with increased risk for medication-related morbidity and mortality.
Currently, clozapine is widely recognized as one of the most effective antipsychotic medications available but is underutilized largely due to the barriers to prescribers and heavy burden placed on patients with required regular blood monitoring [2]. After many years of implementation, the utility of long-term clozapine monitoring is still debated. Some evidence suggests that there is not a significant increase in risk for developing neutropenia while on clozapine compared to other medications [12–15] and following the ANC after the first 6 months of treatment may not be as beneficial in preventing fatalities as previously thought [12, 15]. Based on the experiences with clozapine, it would likely be counterproductive to spread this monitoring burden to even more antipsychotics, such as paliperidone, in efforts to mitigate this side effect risk. Further evaluation of how high the risk of neutropenia and severe neutropenia is in the population treated with paliperidone, as well as other newer antipsychotics, would be necessary to fully appreciate the true risk. Ultimately, striking a balance between safely prescribing antipsychotics while still providing effective and accessible treatment will be crucial in the future as newer medications like paliperidone become more widely used. However, this case report highlights the importance of clinicians being aware of the risk and considering obtaining routine ANCs when initiating paliperidone and other antipsychotics.
This case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. In general, we conclude that there is sufficient and mounting evidence that most antipsychotics can cause neutropenia and that there may be value in monitoring ANCs early in the course of treatment to ensure stability. However, we would caution against mandatory monitoring with a national registry as this has contributed to the underutilization of clozapine, and thus could disrupt effective utilization of antipsychotics in general. This could also help make the argument to relax mandatory monitoring of clozapine since neutropenia may not be specific to clozapine. The hope is that this case will add to clinicians’ awareness that neutropenia is a risk with neuroleptic treatment, and that it will also spur further studies regarding comparative risk for neutropenia among all neuroleptics and a re-thinking of a mandatory registry for clozapine.
Abbreviations
ANCAbsolute Neutrophil Count
ANAAntinuclear Antibody
HIVHuman Immunodeficiency Virus
FDAFood and Drug Administration
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Natalie Martos and William Hall contributed equally to this work.
Acknowledgements
None.
Authors’ contributions
FCN was the primary clinician involved in the assessment, management, and follow-up of the patient. NM, WH, AM and TWS were involved in the patient follow-up. FCN conceived the case report. NM, WH, AM and TWS contributed to the literature review. All authors contributed to the manuscript preparation. FCN and WH wrote the revisions. All authors read and approved the final manuscript.
Funding
No funding sources.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Written informed consent was obtained from the individual to participate and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.
Consent for publication
Written informed consent was obtained from the individual for the publication of this manuscript and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.
Competing interests
The authors have no competing interests to declare. | 6 mg (milligrams). | DrugDosage | CC BY | 33549083 | 18,999,467 | 2021-02-06 |
What was the dosage of drug 'PERPHENAZINE'? | Paliperidone induced neutropenia in first episode psychosis: a case report.
Neutropenia, a decrease in total number of neutrophils below 1500/mm3 and particularly severe neutropenia, defined as neutrophils less than 500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections and death. However, much of the attention on the potential adverse effect is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work. We demonstrate here that paliperidone can also cause neutropenia and therefore clinicians should be aware of this possibility especially during initiation of treatment.
The following report presents the case of a 23-year-old African American male with first episode psychosis who developed neutropenia after initiation of paliperidone. Neutropenia resolved after discontinuation of paliperidone and initiation of an alternative antipsychotic, haloperidol.
This case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. We conclude that when initiating paliperidone, clinicians should be more aware of the risk of neutropenia. Moreover, neutropenia may be a more common and overlooked issue in patients on antipsychotic medications other than clozapine and increased awareness of comparative risk across antipsychotics could help direct treatment.
Background
Neutropenia, a decrease in total number of neutrophils below 1500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections. However, much of the attention on the potential for neutropenia and severe neutropenia, defined as neutrophils less than 500/mm3, is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work [1–3].
In the following case report, we describe a relatively treatment-naïve patient with new onset psychosis whose absolute neutrophil count (ANC) dropped significantly with the initiation of the atypical antipsychotic, paliperidone. We later discuss the future implications of neutropenia in antipsychotic medications other than clozapine.
Case presentation
A 23-year-old African American male with previous high level of social and academic functioning, family history of depression, and no past medical or psychiatric history was admitted to an inpatient psychiatric unit for treatment of several months of uncharacteristic, odd behavior and disorganized thought process. On presentation, the patient could not provide a coherent narrative. His family and friends reported gradual onset of odd behavior within the year prior to admission. These behaviors included wearing his rugby helmet around his college campus, discarding clothes in the trash, and becoming increasingly disheveled in appearance. He drove across the state, in the middle of the night, to his mother’s home to then fearfully claim he was being pursued and his mother was trying to kill him.
Several weeks prior to admission, the patient was hospitalized, diagnosed with schizophrenia, and prescribed perphenazine 8 mg twice daily and doxepin 50 mg nightly. After 7 days of inpatient care he was discharged. His disorganized behavior returned 3 days after discharge, prompting his mother to bring him for inpatient psychiatric admission.
On presentation, he was responding to internal stimuli, regularly glancing around the room during the interview. His speech was latent with intermittent thought blocking. He reported somatic delusions regarding his heart and a general delusional atmosphere feeling that everything around him was connected. He reported an auditory hallucination of the devil’s voice.
Admission labs (WBC 5300, ANC 2100), urine toxicity, and head CT were all unremarkable. He was diagnosed with schizophrenia and started on aripiprazole 10 mg, which was increased to 20 mg. He was also treated with escitalopram 10 mg daily given concern for possible affective component and clonazepam 0.25 mg twice daily for anxiety. After nearly 2 weeks, the patient demonstrated little improvement on mental status exam.
Given lack of response to aripiprazole, he was transitioned to oral paliperidone 6 mg. His ANC prior to paliperidone initiation was 4120. Following 15 days of paliperidone 6 mg, he started to respond with improvement in his psychotic symptoms. However, his complete blood count at day fifteen of paliperidone revealed an ANC of 1210 with a nadir of 960 (WBC nadir of 3720) on serial monitoring. Aside from neutropenia, there were no other lab abnormalities. Peripheral smear showed mild leucopenia with neutropenia and relative lymphocytosis. Antinuclear antibody (ANA) and human immunodeficiency virus (HIV) were both negative. Physical exam was unremarkable. Hematology specialists concluded that the timeline and negative work-up were most consistent with drug-induced neutropenia. Paliperidone was discontinued after 20 days of treatment and haloperidol 10 mg nightly was started. ANC was monitored three times weekly. Gradually, his counts improved and 16 days after discontinuation of paliperidone, returned to normal with an ANC of 2070 (WBC 5220). While on haloperidol, the patient showed progressive improvement of his symptoms. By discharge he demonstrated spontaneity of speech and greatly improved content and organization of thoughts.
Discussion and conclusions
In our case, neutropenia developed after initiation of paliperidone and resolved within 16 days of discontinuation. Neutrophil levels remained normal after the initiation of haloperidol, indicating that neutropenia was most likely related to the initiation of paliperidone.
We also considered other contributing factors to his neutropenia. He was also treated with clonazepam and escitalopram during his course but with no evidence of temporal relationship to his neutropenia. However, there are reports of clonazepam induced neutropenia [4]. Though clonazepam had been discontinued by the time the patient developed neutropenia, we cannot rule out a possible synergistic effect from both paliperidone and clonazepam. Additionally, while there are no agreed upon risk factors for antipsychotic induced neutropenia (particularly paliperidone-induced), one might reasonably apply risk factors for clozapine induced neutropenia to this case. And in this case, neuroleptic naivety, higher doses of neuroleptics, African American race, male gender, and younger age all may have placed him at greater risk of developing neuroleptic induced neutropenia [5, 6]. Furthermore, we considered the role of benign ethnic neutropenia (BEN); however, hematology consultants did not consider this a factor given his ANC counts being consistently greater than 1500 prior to initiation of neuroleptics.
To date, we are only aware of three other case reports on neutropenia induced by paliperidone. In all three cases, neutropenia resolved within several days to weeks after discontinuation of paliperidone [7–9]. In one case, lithium was successfully added temporarily to counteract the neutropenia [7]. Two of the reports suggested that neutropenia was dose related and concomitant psychiatric medications (divalproex sodium and quetiapine in one case, risperidone in the other) could have also synergistically contributed to development of neutropenia [7, 8]. In all cases, patients had been on their previous regimens without neutropenia prior to initiation of paliperidone. The patient described here highlights that the decrease in ANC may occur at low to middle doses of paliperidone since the Food and Drug Administration FDA maximum dosage is 12 mg and early in the course of treatment. Of note, paliperidone (9-hydroxyrisperidone) is a metabolite of risperidone. A literature review demonstrates evidence of risperidone induced blood dyscrasias, including neutropenia [10, 11]. Thus, it stands to reason that risperidone’s metabolite could also lead to neutropenia.
Our case report highlights the potential for antipsychotics other than clozapine to cause neutropenia. Although clozapine is the antipsychotic most commonly associated with agranulocytosis or severe neutropenia (term now used by the Clozapine Risk Evaluation and Mitigation Strategies program) with an estimated risk of approximately 0.68%, other antipsychotics have also been linked to neutropenia and severe neutropenia including the majority of second generation antipsychotics [12–14]. We now present evidence for paliperidone causing neutropenia in a case of first episode psychosis (occurring within the first year of treatment). While there are no guidelines for routine ANC monitoring when using any antipsychotic other than clozapine, our case suggests the potential risk of neutropenia when initiating paliperidone. If we had failed to recognize the precipitous fall in our patient’s neutrophil count, he may have remained on paliperidone indefinitely with increased risk for medication-related morbidity and mortality.
Currently, clozapine is widely recognized as one of the most effective antipsychotic medications available but is underutilized largely due to the barriers to prescribers and heavy burden placed on patients with required regular blood monitoring [2]. After many years of implementation, the utility of long-term clozapine monitoring is still debated. Some evidence suggests that there is not a significant increase in risk for developing neutropenia while on clozapine compared to other medications [12–15] and following the ANC after the first 6 months of treatment may not be as beneficial in preventing fatalities as previously thought [12, 15]. Based on the experiences with clozapine, it would likely be counterproductive to spread this monitoring burden to even more antipsychotics, such as paliperidone, in efforts to mitigate this side effect risk. Further evaluation of how high the risk of neutropenia and severe neutropenia is in the population treated with paliperidone, as well as other newer antipsychotics, would be necessary to fully appreciate the true risk. Ultimately, striking a balance between safely prescribing antipsychotics while still providing effective and accessible treatment will be crucial in the future as newer medications like paliperidone become more widely used. However, this case report highlights the importance of clinicians being aware of the risk and considering obtaining routine ANCs when initiating paliperidone and other antipsychotics.
This case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. In general, we conclude that there is sufficient and mounting evidence that most antipsychotics can cause neutropenia and that there may be value in monitoring ANCs early in the course of treatment to ensure stability. However, we would caution against mandatory monitoring with a national registry as this has contributed to the underutilization of clozapine, and thus could disrupt effective utilization of antipsychotics in general. This could also help make the argument to relax mandatory monitoring of clozapine since neutropenia may not be specific to clozapine. The hope is that this case will add to clinicians’ awareness that neutropenia is a risk with neuroleptic treatment, and that it will also spur further studies regarding comparative risk for neutropenia among all neuroleptics and a re-thinking of a mandatory registry for clozapine.
Abbreviations
ANCAbsolute Neutrophil Count
ANAAntinuclear Antibody
HIVHuman Immunodeficiency Virus
FDAFood and Drug Administration
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Natalie Martos and William Hall contributed equally to this work.
Acknowledgements
None.
Authors’ contributions
FCN was the primary clinician involved in the assessment, management, and follow-up of the patient. NM, WH, AM and TWS were involved in the patient follow-up. FCN conceived the case report. NM, WH, AM and TWS contributed to the literature review. All authors contributed to the manuscript preparation. FCN and WH wrote the revisions. All authors read and approved the final manuscript.
Funding
No funding sources.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Written informed consent was obtained from the individual to participate and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.
Consent for publication
Written informed consent was obtained from the individual for the publication of this manuscript and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.
Competing interests
The authors have no competing interests to declare. | 8 mg (milligrams). | DrugDosage | CC BY | 33549083 | 18,921,011 | 2021-02-06 |
What was the outcome of reaction 'Leukopenia'? | Paliperidone induced neutropenia in first episode psychosis: a case report.
Neutropenia, a decrease in total number of neutrophils below 1500/mm3 and particularly severe neutropenia, defined as neutrophils less than 500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections and death. However, much of the attention on the potential adverse effect is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work. We demonstrate here that paliperidone can also cause neutropenia and therefore clinicians should be aware of this possibility especially during initiation of treatment.
The following report presents the case of a 23-year-old African American male with first episode psychosis who developed neutropenia after initiation of paliperidone. Neutropenia resolved after discontinuation of paliperidone and initiation of an alternative antipsychotic, haloperidol.
This case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. We conclude that when initiating paliperidone, clinicians should be more aware of the risk of neutropenia. Moreover, neutropenia may be a more common and overlooked issue in patients on antipsychotic medications other than clozapine and increased awareness of comparative risk across antipsychotics could help direct treatment.
Background
Neutropenia, a decrease in total number of neutrophils below 1500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections. However, much of the attention on the potential for neutropenia and severe neutropenia, defined as neutrophils less than 500/mm3, is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work [1–3].
In the following case report, we describe a relatively treatment-naïve patient with new onset psychosis whose absolute neutrophil count (ANC) dropped significantly with the initiation of the atypical antipsychotic, paliperidone. We later discuss the future implications of neutropenia in antipsychotic medications other than clozapine.
Case presentation
A 23-year-old African American male with previous high level of social and academic functioning, family history of depression, and no past medical or psychiatric history was admitted to an inpatient psychiatric unit for treatment of several months of uncharacteristic, odd behavior and disorganized thought process. On presentation, the patient could not provide a coherent narrative. His family and friends reported gradual onset of odd behavior within the year prior to admission. These behaviors included wearing his rugby helmet around his college campus, discarding clothes in the trash, and becoming increasingly disheveled in appearance. He drove across the state, in the middle of the night, to his mother’s home to then fearfully claim he was being pursued and his mother was trying to kill him.
Several weeks prior to admission, the patient was hospitalized, diagnosed with schizophrenia, and prescribed perphenazine 8 mg twice daily and doxepin 50 mg nightly. After 7 days of inpatient care he was discharged. His disorganized behavior returned 3 days after discharge, prompting his mother to bring him for inpatient psychiatric admission.
On presentation, he was responding to internal stimuli, regularly glancing around the room during the interview. His speech was latent with intermittent thought blocking. He reported somatic delusions regarding his heart and a general delusional atmosphere feeling that everything around him was connected. He reported an auditory hallucination of the devil’s voice.
Admission labs (WBC 5300, ANC 2100), urine toxicity, and head CT were all unremarkable. He was diagnosed with schizophrenia and started on aripiprazole 10 mg, which was increased to 20 mg. He was also treated with escitalopram 10 mg daily given concern for possible affective component and clonazepam 0.25 mg twice daily for anxiety. After nearly 2 weeks, the patient demonstrated little improvement on mental status exam.
Given lack of response to aripiprazole, he was transitioned to oral paliperidone 6 mg. His ANC prior to paliperidone initiation was 4120. Following 15 days of paliperidone 6 mg, he started to respond with improvement in his psychotic symptoms. However, his complete blood count at day fifteen of paliperidone revealed an ANC of 1210 with a nadir of 960 (WBC nadir of 3720) on serial monitoring. Aside from neutropenia, there were no other lab abnormalities. Peripheral smear showed mild leucopenia with neutropenia and relative lymphocytosis. Antinuclear antibody (ANA) and human immunodeficiency virus (HIV) were both negative. Physical exam was unremarkable. Hematology specialists concluded that the timeline and negative work-up were most consistent with drug-induced neutropenia. Paliperidone was discontinued after 20 days of treatment and haloperidol 10 mg nightly was started. ANC was monitored three times weekly. Gradually, his counts improved and 16 days after discontinuation of paliperidone, returned to normal with an ANC of 2070 (WBC 5220). While on haloperidol, the patient showed progressive improvement of his symptoms. By discharge he demonstrated spontaneity of speech and greatly improved content and organization of thoughts.
Discussion and conclusions
In our case, neutropenia developed after initiation of paliperidone and resolved within 16 days of discontinuation. Neutrophil levels remained normal after the initiation of haloperidol, indicating that neutropenia was most likely related to the initiation of paliperidone.
We also considered other contributing factors to his neutropenia. He was also treated with clonazepam and escitalopram during his course but with no evidence of temporal relationship to his neutropenia. However, there are reports of clonazepam induced neutropenia [4]. Though clonazepam had been discontinued by the time the patient developed neutropenia, we cannot rule out a possible synergistic effect from both paliperidone and clonazepam. Additionally, while there are no agreed upon risk factors for antipsychotic induced neutropenia (particularly paliperidone-induced), one might reasonably apply risk factors for clozapine induced neutropenia to this case. And in this case, neuroleptic naivety, higher doses of neuroleptics, African American race, male gender, and younger age all may have placed him at greater risk of developing neuroleptic induced neutropenia [5, 6]. Furthermore, we considered the role of benign ethnic neutropenia (BEN); however, hematology consultants did not consider this a factor given his ANC counts being consistently greater than 1500 prior to initiation of neuroleptics.
To date, we are only aware of three other case reports on neutropenia induced by paliperidone. In all three cases, neutropenia resolved within several days to weeks after discontinuation of paliperidone [7–9]. In one case, lithium was successfully added temporarily to counteract the neutropenia [7]. Two of the reports suggested that neutropenia was dose related and concomitant psychiatric medications (divalproex sodium and quetiapine in one case, risperidone in the other) could have also synergistically contributed to development of neutropenia [7, 8]. In all cases, patients had been on their previous regimens without neutropenia prior to initiation of paliperidone. The patient described here highlights that the decrease in ANC may occur at low to middle doses of paliperidone since the Food and Drug Administration FDA maximum dosage is 12 mg and early in the course of treatment. Of note, paliperidone (9-hydroxyrisperidone) is a metabolite of risperidone. A literature review demonstrates evidence of risperidone induced blood dyscrasias, including neutropenia [10, 11]. Thus, it stands to reason that risperidone’s metabolite could also lead to neutropenia.
Our case report highlights the potential for antipsychotics other than clozapine to cause neutropenia. Although clozapine is the antipsychotic most commonly associated with agranulocytosis or severe neutropenia (term now used by the Clozapine Risk Evaluation and Mitigation Strategies program) with an estimated risk of approximately 0.68%, other antipsychotics have also been linked to neutropenia and severe neutropenia including the majority of second generation antipsychotics [12–14]. We now present evidence for paliperidone causing neutropenia in a case of first episode psychosis (occurring within the first year of treatment). While there are no guidelines for routine ANC monitoring when using any antipsychotic other than clozapine, our case suggests the potential risk of neutropenia when initiating paliperidone. If we had failed to recognize the precipitous fall in our patient’s neutrophil count, he may have remained on paliperidone indefinitely with increased risk for medication-related morbidity and mortality.
Currently, clozapine is widely recognized as one of the most effective antipsychotic medications available but is underutilized largely due to the barriers to prescribers and heavy burden placed on patients with required regular blood monitoring [2]. After many years of implementation, the utility of long-term clozapine monitoring is still debated. Some evidence suggests that there is not a significant increase in risk for developing neutropenia while on clozapine compared to other medications [12–15] and following the ANC after the first 6 months of treatment may not be as beneficial in preventing fatalities as previously thought [12, 15]. Based on the experiences with clozapine, it would likely be counterproductive to spread this monitoring burden to even more antipsychotics, such as paliperidone, in efforts to mitigate this side effect risk. Further evaluation of how high the risk of neutropenia and severe neutropenia is in the population treated with paliperidone, as well as other newer antipsychotics, would be necessary to fully appreciate the true risk. Ultimately, striking a balance between safely prescribing antipsychotics while still providing effective and accessible treatment will be crucial in the future as newer medications like paliperidone become more widely used. However, this case report highlights the importance of clinicians being aware of the risk and considering obtaining routine ANCs when initiating paliperidone and other antipsychotics.
This case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. In general, we conclude that there is sufficient and mounting evidence that most antipsychotics can cause neutropenia and that there may be value in monitoring ANCs early in the course of treatment to ensure stability. However, we would caution against mandatory monitoring with a national registry as this has contributed to the underutilization of clozapine, and thus could disrupt effective utilization of antipsychotics in general. This could also help make the argument to relax mandatory monitoring of clozapine since neutropenia may not be specific to clozapine. The hope is that this case will add to clinicians’ awareness that neutropenia is a risk with neuroleptic treatment, and that it will also spur further studies regarding comparative risk for neutropenia among all neuroleptics and a re-thinking of a mandatory registry for clozapine.
Abbreviations
ANCAbsolute Neutrophil Count
ANAAntinuclear Antibody
HIVHuman Immunodeficiency Virus
FDAFood and Drug Administration
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Natalie Martos and William Hall contributed equally to this work.
Acknowledgements
None.
Authors’ contributions
FCN was the primary clinician involved in the assessment, management, and follow-up of the patient. NM, WH, AM and TWS were involved in the patient follow-up. FCN conceived the case report. NM, WH, AM and TWS contributed to the literature review. All authors contributed to the manuscript preparation. FCN and WH wrote the revisions. All authors read and approved the final manuscript.
Funding
No funding sources.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Written informed consent was obtained from the individual to participate and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.
Consent for publication
Written informed consent was obtained from the individual for the publication of this manuscript and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.
Competing interests
The authors have no competing interests to declare. | Recovered | ReactionOutcome | CC BY | 33549083 | 18,921,011 | 2021-02-06 |
What was the outcome of reaction 'Lymphocytosis'? | Paliperidone induced neutropenia in first episode psychosis: a case report.
Neutropenia, a decrease in total number of neutrophils below 1500/mm3 and particularly severe neutropenia, defined as neutrophils less than 500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections and death. However, much of the attention on the potential adverse effect is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work. We demonstrate here that paliperidone can also cause neutropenia and therefore clinicians should be aware of this possibility especially during initiation of treatment.
The following report presents the case of a 23-year-old African American male with first episode psychosis who developed neutropenia after initiation of paliperidone. Neutropenia resolved after discontinuation of paliperidone and initiation of an alternative antipsychotic, haloperidol.
This case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. We conclude that when initiating paliperidone, clinicians should be more aware of the risk of neutropenia. Moreover, neutropenia may be a more common and overlooked issue in patients on antipsychotic medications other than clozapine and increased awareness of comparative risk across antipsychotics could help direct treatment.
Background
Neutropenia, a decrease in total number of neutrophils below 1500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections. However, much of the attention on the potential for neutropenia and severe neutropenia, defined as neutrophils less than 500/mm3, is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work [1–3].
In the following case report, we describe a relatively treatment-naïve patient with new onset psychosis whose absolute neutrophil count (ANC) dropped significantly with the initiation of the atypical antipsychotic, paliperidone. We later discuss the future implications of neutropenia in antipsychotic medications other than clozapine.
Case presentation
A 23-year-old African American male with previous high level of social and academic functioning, family history of depression, and no past medical or psychiatric history was admitted to an inpatient psychiatric unit for treatment of several months of uncharacteristic, odd behavior and disorganized thought process. On presentation, the patient could not provide a coherent narrative. His family and friends reported gradual onset of odd behavior within the year prior to admission. These behaviors included wearing his rugby helmet around his college campus, discarding clothes in the trash, and becoming increasingly disheveled in appearance. He drove across the state, in the middle of the night, to his mother’s home to then fearfully claim he was being pursued and his mother was trying to kill him.
Several weeks prior to admission, the patient was hospitalized, diagnosed with schizophrenia, and prescribed perphenazine 8 mg twice daily and doxepin 50 mg nightly. After 7 days of inpatient care he was discharged. His disorganized behavior returned 3 days after discharge, prompting his mother to bring him for inpatient psychiatric admission.
On presentation, he was responding to internal stimuli, regularly glancing around the room during the interview. His speech was latent with intermittent thought blocking. He reported somatic delusions regarding his heart and a general delusional atmosphere feeling that everything around him was connected. He reported an auditory hallucination of the devil’s voice.
Admission labs (WBC 5300, ANC 2100), urine toxicity, and head CT were all unremarkable. He was diagnosed with schizophrenia and started on aripiprazole 10 mg, which was increased to 20 mg. He was also treated with escitalopram 10 mg daily given concern for possible affective component and clonazepam 0.25 mg twice daily for anxiety. After nearly 2 weeks, the patient demonstrated little improvement on mental status exam.
Given lack of response to aripiprazole, he was transitioned to oral paliperidone 6 mg. His ANC prior to paliperidone initiation was 4120. Following 15 days of paliperidone 6 mg, he started to respond with improvement in his psychotic symptoms. However, his complete blood count at day fifteen of paliperidone revealed an ANC of 1210 with a nadir of 960 (WBC nadir of 3720) on serial monitoring. Aside from neutropenia, there were no other lab abnormalities. Peripheral smear showed mild leucopenia with neutropenia and relative lymphocytosis. Antinuclear antibody (ANA) and human immunodeficiency virus (HIV) were both negative. Physical exam was unremarkable. Hematology specialists concluded that the timeline and negative work-up were most consistent with drug-induced neutropenia. Paliperidone was discontinued after 20 days of treatment and haloperidol 10 mg nightly was started. ANC was monitored three times weekly. Gradually, his counts improved and 16 days after discontinuation of paliperidone, returned to normal with an ANC of 2070 (WBC 5220). While on haloperidol, the patient showed progressive improvement of his symptoms. By discharge he demonstrated spontaneity of speech and greatly improved content and organization of thoughts.
Discussion and conclusions
In our case, neutropenia developed after initiation of paliperidone and resolved within 16 days of discontinuation. Neutrophil levels remained normal after the initiation of haloperidol, indicating that neutropenia was most likely related to the initiation of paliperidone.
We also considered other contributing factors to his neutropenia. He was also treated with clonazepam and escitalopram during his course but with no evidence of temporal relationship to his neutropenia. However, there are reports of clonazepam induced neutropenia [4]. Though clonazepam had been discontinued by the time the patient developed neutropenia, we cannot rule out a possible synergistic effect from both paliperidone and clonazepam. Additionally, while there are no agreed upon risk factors for antipsychotic induced neutropenia (particularly paliperidone-induced), one might reasonably apply risk factors for clozapine induced neutropenia to this case. And in this case, neuroleptic naivety, higher doses of neuroleptics, African American race, male gender, and younger age all may have placed him at greater risk of developing neuroleptic induced neutropenia [5, 6]. Furthermore, we considered the role of benign ethnic neutropenia (BEN); however, hematology consultants did not consider this a factor given his ANC counts being consistently greater than 1500 prior to initiation of neuroleptics.
To date, we are only aware of three other case reports on neutropenia induced by paliperidone. In all three cases, neutropenia resolved within several days to weeks after discontinuation of paliperidone [7–9]. In one case, lithium was successfully added temporarily to counteract the neutropenia [7]. Two of the reports suggested that neutropenia was dose related and concomitant psychiatric medications (divalproex sodium and quetiapine in one case, risperidone in the other) could have also synergistically contributed to development of neutropenia [7, 8]. In all cases, patients had been on their previous regimens without neutropenia prior to initiation of paliperidone. The patient described here highlights that the decrease in ANC may occur at low to middle doses of paliperidone since the Food and Drug Administration FDA maximum dosage is 12 mg and early in the course of treatment. Of note, paliperidone (9-hydroxyrisperidone) is a metabolite of risperidone. A literature review demonstrates evidence of risperidone induced blood dyscrasias, including neutropenia [10, 11]. Thus, it stands to reason that risperidone’s metabolite could also lead to neutropenia.
Our case report highlights the potential for antipsychotics other than clozapine to cause neutropenia. Although clozapine is the antipsychotic most commonly associated with agranulocytosis or severe neutropenia (term now used by the Clozapine Risk Evaluation and Mitigation Strategies program) with an estimated risk of approximately 0.68%, other antipsychotics have also been linked to neutropenia and severe neutropenia including the majority of second generation antipsychotics [12–14]. We now present evidence for paliperidone causing neutropenia in a case of first episode psychosis (occurring within the first year of treatment). While there are no guidelines for routine ANC monitoring when using any antipsychotic other than clozapine, our case suggests the potential risk of neutropenia when initiating paliperidone. If we had failed to recognize the precipitous fall in our patient’s neutrophil count, he may have remained on paliperidone indefinitely with increased risk for medication-related morbidity and mortality.
Currently, clozapine is widely recognized as one of the most effective antipsychotic medications available but is underutilized largely due to the barriers to prescribers and heavy burden placed on patients with required regular blood monitoring [2]. After many years of implementation, the utility of long-term clozapine monitoring is still debated. Some evidence suggests that there is not a significant increase in risk for developing neutropenia while on clozapine compared to other medications [12–15] and following the ANC after the first 6 months of treatment may not be as beneficial in preventing fatalities as previously thought [12, 15]. Based on the experiences with clozapine, it would likely be counterproductive to spread this monitoring burden to even more antipsychotics, such as paliperidone, in efforts to mitigate this side effect risk. Further evaluation of how high the risk of neutropenia and severe neutropenia is in the population treated with paliperidone, as well as other newer antipsychotics, would be necessary to fully appreciate the true risk. Ultimately, striking a balance between safely prescribing antipsychotics while still providing effective and accessible treatment will be crucial in the future as newer medications like paliperidone become more widely used. However, this case report highlights the importance of clinicians being aware of the risk and considering obtaining routine ANCs when initiating paliperidone and other antipsychotics.
This case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. In general, we conclude that there is sufficient and mounting evidence that most antipsychotics can cause neutropenia and that there may be value in monitoring ANCs early in the course of treatment to ensure stability. However, we would caution against mandatory monitoring with a national registry as this has contributed to the underutilization of clozapine, and thus could disrupt effective utilization of antipsychotics in general. This could also help make the argument to relax mandatory monitoring of clozapine since neutropenia may not be specific to clozapine. The hope is that this case will add to clinicians’ awareness that neutropenia is a risk with neuroleptic treatment, and that it will also spur further studies regarding comparative risk for neutropenia among all neuroleptics and a re-thinking of a mandatory registry for clozapine.
Abbreviations
ANCAbsolute Neutrophil Count
ANAAntinuclear Antibody
HIVHuman Immunodeficiency Virus
FDAFood and Drug Administration
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Natalie Martos and William Hall contributed equally to this work.
Acknowledgements
None.
Authors’ contributions
FCN was the primary clinician involved in the assessment, management, and follow-up of the patient. NM, WH, AM and TWS were involved in the patient follow-up. FCN conceived the case report. NM, WH, AM and TWS contributed to the literature review. All authors contributed to the manuscript preparation. FCN and WH wrote the revisions. All authors read and approved the final manuscript.
Funding
No funding sources.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Written informed consent was obtained from the individual to participate and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.
Consent for publication
Written informed consent was obtained from the individual for the publication of this manuscript and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.
Competing interests
The authors have no competing interests to declare. | Recovered | ReactionOutcome | CC BY | 33549083 | 18,921,011 | 2021-02-06 |
What was the outcome of reaction 'Neutropenia'? | Paliperidone induced neutropenia in first episode psychosis: a case report.
Neutropenia, a decrease in total number of neutrophils below 1500/mm3 and particularly severe neutropenia, defined as neutrophils less than 500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections and death. However, much of the attention on the potential adverse effect is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work. We demonstrate here that paliperidone can also cause neutropenia and therefore clinicians should be aware of this possibility especially during initiation of treatment.
The following report presents the case of a 23-year-old African American male with first episode psychosis who developed neutropenia after initiation of paliperidone. Neutropenia resolved after discontinuation of paliperidone and initiation of an alternative antipsychotic, haloperidol.
This case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. We conclude that when initiating paliperidone, clinicians should be more aware of the risk of neutropenia. Moreover, neutropenia may be a more common and overlooked issue in patients on antipsychotic medications other than clozapine and increased awareness of comparative risk across antipsychotics could help direct treatment.
Background
Neutropenia, a decrease in total number of neutrophils below 1500/mm3, is a potential adverse effect of antipsychotic medications that can lead to increased risk of infections. However, much of the attention on the potential for neutropenia and severe neutropenia, defined as neutrophils less than 500/mm3, is centered exclusively on clozapine, which remains the only antipsychotic medication in the United States requiring standardized monitoring of blood work [1–3].
In the following case report, we describe a relatively treatment-naïve patient with new onset psychosis whose absolute neutrophil count (ANC) dropped significantly with the initiation of the atypical antipsychotic, paliperidone. We later discuss the future implications of neutropenia in antipsychotic medications other than clozapine.
Case presentation
A 23-year-old African American male with previous high level of social and academic functioning, family history of depression, and no past medical or psychiatric history was admitted to an inpatient psychiatric unit for treatment of several months of uncharacteristic, odd behavior and disorganized thought process. On presentation, the patient could not provide a coherent narrative. His family and friends reported gradual onset of odd behavior within the year prior to admission. These behaviors included wearing his rugby helmet around his college campus, discarding clothes in the trash, and becoming increasingly disheveled in appearance. He drove across the state, in the middle of the night, to his mother’s home to then fearfully claim he was being pursued and his mother was trying to kill him.
Several weeks prior to admission, the patient was hospitalized, diagnosed with schizophrenia, and prescribed perphenazine 8 mg twice daily and doxepin 50 mg nightly. After 7 days of inpatient care he was discharged. His disorganized behavior returned 3 days after discharge, prompting his mother to bring him for inpatient psychiatric admission.
On presentation, he was responding to internal stimuli, regularly glancing around the room during the interview. His speech was latent with intermittent thought blocking. He reported somatic delusions regarding his heart and a general delusional atmosphere feeling that everything around him was connected. He reported an auditory hallucination of the devil’s voice.
Admission labs (WBC 5300, ANC 2100), urine toxicity, and head CT were all unremarkable. He was diagnosed with schizophrenia and started on aripiprazole 10 mg, which was increased to 20 mg. He was also treated with escitalopram 10 mg daily given concern for possible affective component and clonazepam 0.25 mg twice daily for anxiety. After nearly 2 weeks, the patient demonstrated little improvement on mental status exam.
Given lack of response to aripiprazole, he was transitioned to oral paliperidone 6 mg. His ANC prior to paliperidone initiation was 4120. Following 15 days of paliperidone 6 mg, he started to respond with improvement in his psychotic symptoms. However, his complete blood count at day fifteen of paliperidone revealed an ANC of 1210 with a nadir of 960 (WBC nadir of 3720) on serial monitoring. Aside from neutropenia, there were no other lab abnormalities. Peripheral smear showed mild leucopenia with neutropenia and relative lymphocytosis. Antinuclear antibody (ANA) and human immunodeficiency virus (HIV) were both negative. Physical exam was unremarkable. Hematology specialists concluded that the timeline and negative work-up were most consistent with drug-induced neutropenia. Paliperidone was discontinued after 20 days of treatment and haloperidol 10 mg nightly was started. ANC was monitored three times weekly. Gradually, his counts improved and 16 days after discontinuation of paliperidone, returned to normal with an ANC of 2070 (WBC 5220). While on haloperidol, the patient showed progressive improvement of his symptoms. By discharge he demonstrated spontaneity of speech and greatly improved content and organization of thoughts.
Discussion and conclusions
In our case, neutropenia developed after initiation of paliperidone and resolved within 16 days of discontinuation. Neutrophil levels remained normal after the initiation of haloperidol, indicating that neutropenia was most likely related to the initiation of paliperidone.
We also considered other contributing factors to his neutropenia. He was also treated with clonazepam and escitalopram during his course but with no evidence of temporal relationship to his neutropenia. However, there are reports of clonazepam induced neutropenia [4]. Though clonazepam had been discontinued by the time the patient developed neutropenia, we cannot rule out a possible synergistic effect from both paliperidone and clonazepam. Additionally, while there are no agreed upon risk factors for antipsychotic induced neutropenia (particularly paliperidone-induced), one might reasonably apply risk factors for clozapine induced neutropenia to this case. And in this case, neuroleptic naivety, higher doses of neuroleptics, African American race, male gender, and younger age all may have placed him at greater risk of developing neuroleptic induced neutropenia [5, 6]. Furthermore, we considered the role of benign ethnic neutropenia (BEN); however, hematology consultants did not consider this a factor given his ANC counts being consistently greater than 1500 prior to initiation of neuroleptics.
To date, we are only aware of three other case reports on neutropenia induced by paliperidone. In all three cases, neutropenia resolved within several days to weeks after discontinuation of paliperidone [7–9]. In one case, lithium was successfully added temporarily to counteract the neutropenia [7]. Two of the reports suggested that neutropenia was dose related and concomitant psychiatric medications (divalproex sodium and quetiapine in one case, risperidone in the other) could have also synergistically contributed to development of neutropenia [7, 8]. In all cases, patients had been on their previous regimens without neutropenia prior to initiation of paliperidone. The patient described here highlights that the decrease in ANC may occur at low to middle doses of paliperidone since the Food and Drug Administration FDA maximum dosage is 12 mg and early in the course of treatment. Of note, paliperidone (9-hydroxyrisperidone) is a metabolite of risperidone. A literature review demonstrates evidence of risperidone induced blood dyscrasias, including neutropenia [10, 11]. Thus, it stands to reason that risperidone’s metabolite could also lead to neutropenia.
Our case report highlights the potential for antipsychotics other than clozapine to cause neutropenia. Although clozapine is the antipsychotic most commonly associated with agranulocytosis or severe neutropenia (term now used by the Clozapine Risk Evaluation and Mitigation Strategies program) with an estimated risk of approximately 0.68%, other antipsychotics have also been linked to neutropenia and severe neutropenia including the majority of second generation antipsychotics [12–14]. We now present evidence for paliperidone causing neutropenia in a case of first episode psychosis (occurring within the first year of treatment). While there are no guidelines for routine ANC monitoring when using any antipsychotic other than clozapine, our case suggests the potential risk of neutropenia when initiating paliperidone. If we had failed to recognize the precipitous fall in our patient’s neutrophil count, he may have remained on paliperidone indefinitely with increased risk for medication-related morbidity and mortality.
Currently, clozapine is widely recognized as one of the most effective antipsychotic medications available but is underutilized largely due to the barriers to prescribers and heavy burden placed on patients with required regular blood monitoring [2]. After many years of implementation, the utility of long-term clozapine monitoring is still debated. Some evidence suggests that there is not a significant increase in risk for developing neutropenia while on clozapine compared to other medications [12–15] and following the ANC after the first 6 months of treatment may not be as beneficial in preventing fatalities as previously thought [12, 15]. Based on the experiences with clozapine, it would likely be counterproductive to spread this monitoring burden to even more antipsychotics, such as paliperidone, in efforts to mitigate this side effect risk. Further evaluation of how high the risk of neutropenia and severe neutropenia is in the population treated with paliperidone, as well as other newer antipsychotics, would be necessary to fully appreciate the true risk. Ultimately, striking a balance between safely prescribing antipsychotics while still providing effective and accessible treatment will be crucial in the future as newer medications like paliperidone become more widely used. However, this case report highlights the importance of clinicians being aware of the risk and considering obtaining routine ANCs when initiating paliperidone and other antipsychotics.
This case report demonstrates an example of paliperidone induced neutropenia which resolved with a switch to haloperidol. In general, we conclude that there is sufficient and mounting evidence that most antipsychotics can cause neutropenia and that there may be value in monitoring ANCs early in the course of treatment to ensure stability. However, we would caution against mandatory monitoring with a national registry as this has contributed to the underutilization of clozapine, and thus could disrupt effective utilization of antipsychotics in general. This could also help make the argument to relax mandatory monitoring of clozapine since neutropenia may not be specific to clozapine. The hope is that this case will add to clinicians’ awareness that neutropenia is a risk with neuroleptic treatment, and that it will also spur further studies regarding comparative risk for neutropenia among all neuroleptics and a re-thinking of a mandatory registry for clozapine.
Abbreviations
ANCAbsolute Neutrophil Count
ANAAntinuclear Antibody
HIVHuman Immunodeficiency Virus
FDAFood and Drug Administration
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Natalie Martos and William Hall contributed equally to this work.
Acknowledgements
None.
Authors’ contributions
FCN was the primary clinician involved in the assessment, management, and follow-up of the patient. NM, WH, AM and TWS were involved in the patient follow-up. FCN conceived the case report. NM, WH, AM and TWS contributed to the literature review. All authors contributed to the manuscript preparation. FCN and WH wrote the revisions. All authors read and approved the final manuscript.
Funding
No funding sources.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
Written informed consent was obtained from the individual to participate and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.
Consent for publication
Written informed consent was obtained from the individual for the publication of this manuscript and of any potentially identifiable data included in this article. This study was carried out in accordance with the recommendations of Institutional Review Board of Johns Hopkins University School of Medicine with written informed consent from all subjects.
Competing interests
The authors have no competing interests to declare. | Recovered | ReactionOutcome | CC BY | 33549083 | 18,999,467 | 2021-02-06 |
What was the outcome of reaction 'Drug ineffective'? | Selumetinib side effects in children treated for plexiform neurofibromas: first case reports of peripheral edema and hair color change.
Plexiform neurofibromas (PNs) are congenital tumors that affect around 50 % of the subjects with neurofibromatosis type 1. Despite being histologically benign, PNs can grow rapidly, especially in the pediatric age, and cause severe morbidities. In the past, various therapeutic approaches have been proposed to treat these masses, none of which obtained valuable results. Selumetinib, an inhibitor of mitogen-activated protein kinase (MEK) 1 and 2, has been the first molecule to demonstrate the ability of tackling the growth of PNs. The drug's most common side effects, which usually are mild or moderate, include gastrointestinal symptoms (diarrhea, abdominal pain), dermatologic manifestations (maculo-papular and acneiform rash, paronychia, mucositis), and various laboratory test abnormalities (elevation of creatine kinase and aminotransferase).
We report two previously undescribed adverse events in pediatric patients: peripheral edema and hair color change. The first case of peripheral edema occurred in a 7-year-old boy affected by a severe form of NF1, after two years of treatment with selumetinib at the standard dose (25 mg/m2twice a day). The edema involved the right leg, and the patient did not complain of pain. The second case of peripheral edema occurred in a 12-year-old girl after six months of therapy with selumetinib at the standard dose, involving her lower left leg. The patient initially complained of pain in that area, but it gradually and spontaneously resolved. In both patients, all the radiological exams, including lymphoscintigraphy, pelvic and abdominal ultrasound, and doppler ultrasound of the affected limb, as well as blood tests, revealed no abnormalities. Hair color change appeared in a 4-year-old boy after six months of therapy at the standard dose. The boy's hair, whose natural color was dark blonde, became lighter in some areas. Despite the appearance of these side effects, all the patients and their families decided to continue the treatment with selumetinib, in considerations of its clinical benefits.
Since the use of selumetinib to treat plexiform neurofibromas is increasing in the pediatric population, clinicians should be aware of its side effects, so to decide whether continuing the treatment, reducing the dose or even interrupting it, when appropriate.
Background
Neurofibromatosis type 1 (NF1) is a common genetic disorder that affects around 1/3000 subjects. This condition is characterized by the presence of pigmented lesions (café au lait spots, axillary, inguinal freckling, Lisch nodules of the iris, choroidal freckling), multiple cutaneous neurofibromas, brain tumors (optic nerve and central nervous system glioma), and peripheral nerve tumors (plexiform neurofibromas and malignant peripheral nerve sheath tumors). Other features include skeletal abnormalities, such as tibial dysplasia and scoliosis, renovascular hypertension, and learning disabilities.
Plexiform neurofibromas (PNs) affect around 50 % of the individuals with NF1 at some point in their life. Being congenital, PNs tend to appear in the pediatric age, reaching their peak of growth during adolescence. Although histologically benign, these tumors can generate severe morbidities, including pain, functional limitations, neurological deficits, disfigurement, and internal organs’ compression. Various medical approaches have been proposed in the past, including interferon alfa2β and imatinib, without tangible results. Complete surgical resection is often unattainable, and the persistence of tumor remnants can result in the regrowth of the mass.
Selumetinib is an ATP-independent inhibitor of mitogen-activated protein kinase (MEK or MAPK/ERK kinase) 1 and 2, which are key mediators of the RAS/RAF/MEK/ERK pathway, that is upregulated in NF-1. The drug has already been used in adult oncology in different protocols, such as in non-small cell lung cell carcinoma and uveal melanoma, with positive results. Selumenitib showed the capacity to tackle plexiform neurofibromas’ growth in pediatric patients, obtaining a reduction of the original size of the mass of at least 20 % in most of the patients [1–4]. A decrease in tumor-related pain, disfigurement, and functional impairment was also described. In consideration of these results, on April 10, 2020, selumetinib has been approved by the Food and Drug Administration (FDA) for the treatment of inoperable plexiform neurofibromas. Furthermore, it has also demonstrated a valuable, although preliminary role, in the treatment of low-grade glioma, so to represent a promising alternative to standard chemotherapy [5].
The drug’s recommended maximum posology is currently 25 mg/m2 twice a day, approximately 60 % of the standard adult dosage. In terms of safety profile and pharmacological toxicity, the drug is usually well tolerated. The most common side effects are mild or moderate, and they include gastrointestinal symptoms (diarrhea, abdominal pain), dermatologic manifestations (maculo-papular and acneiform rash, paronychia, mucositis), and various lab test anomalies (elevation of creatine kinase and aminotransferase elevation, neutropenia). Potentially serious adverse events of the drug, which have been observed in adult patients receiving selumetinib in combination with other chemotherapeutical agents, are rare and include ocular (retinal detachment), pneumological (pulmonary fibrosis) and cardiological manifestations (asymptomatic and reversible decrease of the left ventricular ejection fraction).
This paper reports two previously undescribed adverse effects in pediatric patients: peripheral edema and hair color change.
Cases presentation
The first case of peripheral edema occurred to a 7-year-old boy affected by a severe form of NF1, characterized by multiple inoperable plexiform neurofibromas in the neck, thorax, dorsum, and right leg. The masses caused compression of numerous organs and nerves, resulting in dysphagia, dyspnea, and chronic pain with inadequate response to analgesic medications. The boy also presented severe renovascular hypertension that led to two episodes of stroke, from which he gradually recovered. Based on his severe symptoms and poor quality of life, at the age of 5 selumetinib was started, with a significant shrinkage of the PNs after six months of therapy, and a remarkable and constant improvement in performance status. The maximum drug dosage was 25 mg/m2 twice a day. After two years of treatment, in approximately three months, the boy slowly developed a unilateral swelling of the right leg. He did not complain of symptoms originating from the edematous area, nor developed any skin complications. Clinically, no other new abnormalities were found. For example, there was no evidence of palpable abdominal masses, and lymphadenopathy was not found. Ultrasonography demonstrated that the PN was in stable remission, and a doppler study showed no signs of deep venous thrombosis. Lymphoscintigraphy was normal as well. No masses were found on abdominal and pelvic ultrasonography. Routine blood laboratory tests did not reveal abnormalities. An echocardiogram also appeared normal. Therefore, since all possible causes of edema were excluded, the right leg’s swelling was attributed to the drug itself. In consideration of the absence of symptoms and the drugs’ remarkable benefits, we decided to continue the treatment with selumetinib, which is still daily taken by the patient. Peripheral edema is still present, but it has remained stable through the following months.
The second case of peripheral edema occurred to a 12-year-old girl that was diagnosed with NF-1 at birth. At the age of two, she underwent an MRI, which detected multiple plexiform neurofibromas in her left leg. Due to her health condition’s severity, treatment with imatinib and eventually with interferon alfa2 was started, without clinical and radiological improvement. Selumetinib was then introduced when she was 11. The maximum drug dosage was 25 mg/m2 twice a day. After 6 months of therapy, in which a reduction of the plexiform neurofibroma’s size was clinically and radiologically noticed, her lower left leg gradually became swollen and painful (Fig. 1). Abdominal and pelvic ultrasonography, lower limbs’ doppler ultrasound and lymphoscintigraphy, as well as echocardiogram and blood laboratory values, were all standard. The parents and the patient decided to continue the MEK inhibitor treatment as it caused a shrinkage of the original mass. Nowadays the limb’s edema is still present, but it has remained clinically stable, and the local pain gradually and spontaneously resolved.
The third patient is a 4-year-old boy with multiple PNs, one of whom was surgically removed from the abdomen at one year of age. A second mass was identified during his follow up visits, located in the paravertebral region. Since the tumor appeared to be continually growing, selumetinib was started when the boy was 3-years old. Apart from some mild gastrointestinal symptoms (abdominal cramps without diarrhea), the treatment was well tolerated. After six months of therapy, the patient’s parents began to notice a discoloration of their son’s hair (Fig. 2). The boy’s hair, whose natural color was dark blonde, became light-blonde and almost white in some areas. The patient’s parents considered the symptom trivial, and the patient continued the treatment due to the good results on the mass reduction. At present the boy still has some patch of hair lighter than his original color.
Fig. 1 Lower left leg edema after the treatment with selumetinib
Fig. 2 Hair color change after treatment with selumetinib
Discussion and conclusion
This is the first case report of pediatric subjects developing peripheral edema and hair color change while treated with selumetinib.
Selumetinib, like other MEK inhibitors, has already been associated with the onset of peripheral edema in adult patients. A 2017 metanalysis evaluated the incidence of peripheral edema in patients with cancer treated with MEK inhibitors [6]. Among all the studies included in the paper, peripheral edema was reported in 13 RCTs and appeared in a total of 284 patients, with an incidence ranging from 11–47.8 % in the various cohorts examined. The degree of swelling was usually mild or moderate, and it didn’t interfere with the prosecution of the treatment. High-grade peripheral edema, possibly requiring a dose reduction or even the suspension of the drug, was reported in 8 studies, with an incidence that ranged from 0 to 4.3 %. As for the timing of appearance of the symptom in adult patients, no conclusive data are available at the moment. Peripheral edema was more common in patients treated with selumetinib, rather than with trametinib or other MEK inhibitors, and it has not been influenced by the presence of other concurrent medical therapies. Apart from the involvement of lower extremities, facial edema has also been reported [7]. The mechanism through which selumetinib causes this clinical feature is not well understood. Peripheral edema is a complex process that involves numerous variables, including hydrostatic and oncotic forces, and vascular permeability. However, none of these elements, alone or combined, appears sufficient, at the moment, to explain the pathophysiology of this process. For example, none of the patients whose cases were described above presented heart, kidney or liver failure, nor a deep vein thrombosis or an ongoing malignant process. Furthermore, no significant abnormalities were found on laboratory tests.
Hair color change was never reported in pediatric patients treated with selumetinib in the past [8]. Systemic drugs are often associated with changes in hair’s quantity and quality, such as alopecia and hypertrichosis, while they rarely modify their color (i.e. depigmentation and repigmentation). The mechanism of hair depigmentation in patients treated with selumetinib is only partially understood. The MAPK pathway is utilized by physiologic c-KIT-MITF signaling in promoting pigment production [9]. In adults, hair depigmentation, like all the other dermatological side effects of selumetinib, is completely reversible once treatment is discontinued [10]. The application of hair dye might be considered in order to restore the patient’s original color.
In light of selumetinib’s positive results in reducing plexiform neurofibromas’ growth, it can be assumed that this drug will be used more frequently in the near future. Physicians should be aware of all its possible adverse events and how to deal with them. Awareness that peripheral edema and hair color change are uncommon, yet not disturbing, manifestations, may help clinicians opt for the continuation of the treatment, rather than a dose reduction or even the drug interruption, allowing for growth control of plexiform neurofibromas. However, further studies are needed to determine the frequency of these side effects in longer follow-up protocols, to understand their origin and to find an appropriate treatment.
Abbreviations
NF1Neurofibromatosis type 1
PNPlexiform neurofibroma
MEKMitogen-activated protein kinase
ERKExtracellular-signal-regulated
RAFRapid accelerated fibrosarcoma
FDAFood and Drug Administration
MRIMagnetic resonance imaging
MIFTMelanocyte inducing transcription factor
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Acknowledgements
The authors thank Martina Bradaschia for the English revision of the manuscript.
Authors’ contributions
FB wrote the manuscript and reviewed the literature. FB and IB collected the photographs. AM, EB and IB reviewed the manuscript. All authors have read and approved the manuscript.
Funding
The authors received no specific funding for this work.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Consent for publication
Written consent was obtained from parents for participants under 18 years old. Written consent was obtained for the publication of potentially identifying images and clinical details.
Competing interests
Francesco Baldo declares that he has no conflict of interest. Andrea Magnolato declares that he has no conflict of interest. Egidio Barbi declares that he has no conflict of interest. Irene Bruno declares that she has no conflict of interest. | Recovered | ReactionOutcome | CC BY | 33549085 | 19,119,735 | 2021-02-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Diagnostic bias during the COVID-19 era: COVID-19 or renal abscess?
The Coronavirus disease-2019 (COVID-19) has been declared as a pandemic in March 2020 by the World Health Organization (WHO). Since then, this pandemic has dramatically affected the entire world, even radically influencing the way patients are framed at triage. Symptoms and tests in most cases lead to a correct diagnosis; however, error may be around the corner.
A 60 years old patient was referred with weight loss, fatigue and mild fever for 3 weeks as he was working in a COVID-19 ward. After a positive swab and chest CT scan, he was admitted in the hospital and treated as mild COVID-19 patient. A CT scan performed after the patient was discharged revealed a renal lesion misidentified as a tumor then clarified to be an abscess which retrospectively appears to be the main cause of his symptoms.
Clinicians should consider other life-threatening disease in the differential diagnosis of patients presenting with similar symptoms to minimize mistakes and avoid further unnecessary investigations.
Introduction
Coronavirus disease-2019 (COVID-19) pandemic has spread rapidly all over the world, putting COVID-19 in the spotlight, being the “pathology of the hour.” With approximately 20 million positive cases and 730 thousand deaths, all national healthcare systems were put to the test.1,2
The clinical spectrum can vary from mild symptoms (cough and loss of taste and smell) to severe respiratory failure. Even with mild symptoms, our level of suspicion should be high in risky groups.3–5 Noteworthy, symptoms alone may be deceiving, and other life-threatening pathologies should not be underestimated, even in times of a pandemic where generalized fear can be deceptive. We present a case report of a 60-year old patient, admitted to the hospital with mild respiratory symptoms, fever and COVID-19 positive swab treated as SARS-CoV-2, who was found to have another potentially life-threatening disease.
Case report
A 60-year-old diabetic man, with a history of regular medical follow-up, was admitted to the hospital by the beginning of March 2020. Mild fever, malaise, and weight loss occurred about 3 weeks before hospitalization without any other symptoms. As the patient was an anesthetist working in an Italian COVID-19 ward, and complying with a strict testing protocol, he had two negative COVID-19 swabs in the last weeks. However, due to the persistence of general malaise and one episode of fever, he had a third swab that demonstrated positive results for COVID-19. A chest CT scan showed left basal interstitial pneumonia (Figure 1), so the patient was hospitalized with COVID-19 diagnosis. At admission his vital signs were stable. On physical examination there was abdominal distension and rebounding pain on the left upper quadrant of the abdomen. Laboratory tests are summarized in Table 1. Being labeled as “COVID-19 positive” patient, he received intravenous ceftriaxone and clarithromycin, hydroxychloroquine, enoxaparin, vitamin D and tocilizumab for 2 weeks. During the hospital stay the patient remained stable showing no exacerbation of respiratory symptoms (minimum O2ps 94%) but only mild fever for three consecutive days. No further medications were administered nor support with oxygen was needed. After 15 days and two consecutive negative swabs the patient was discharged. The last blood tests are showed in the Table 1. A CT scan was performed 2 days after discharge (Figure 2) showed persistent interstitial pneumonia and also an incidental unclear shape of the left kidney, that motivated a third thoraco-abdomin-pelvic CT scan. The total body CT showed a 5.4 × 4.5 cm mass with thick walls and central colliquation, involving the renal parenchyma and the renal fat but without involving the renal sinus, suspicious for advanced malignant tumor. A previous CT done 1 year earlier for other purpose (diverticulitis) did not show any pathology in the left kidney. An MRI scan was then performed to better clarify the nature of the lesion, but no certain diagnosis was achieved (Figure 3). After urological consultation done in another hospital, the initial decision was to perform radical nephrectomy for suspicious of an advanced malignant renal disease. However, after a second opinion of an expert, considering the reported symptoms previously attributed exclusively to the virus, renal abscess was suspected and a renal biopsy was recommended. This lesion was then drained and specimens were sent to cytologic examination showing it was a renal abscess (presence of inflammatory cells and no bacteria) which did not require surgical removal. The patient started oral antibiotic treatment and performed a follow-up ultrasound at 3 months that revealed reduction in the diameter of the renal abscess.
Figure 1. Thorax CT scan: left apical interstitial pneumonia.
Table 1. Blood tests at 1st day and at 15th day.
Blood tests Reference values First day 15th day
Hemoglobin (g/dL) 13.5–17.5 16 15.4
Platelet 150–400 103/uL 235 103/uL 347 103/uL
White blood cells 4.00–10.0 103/uL 14 103/uL 9 103/uL
Neutrophils (%) 41–73 70 75
Lymphocytes (%) 19.4–44.9 21 12
Creatinine (mg/dL) 0.72–1.25 1.29 0.97
Hs-C-reactive protein (mg/dL) <0.5 2.17 0.06
Glucose (mg/dL) 70–105 108 150
Procalcitonin (ng/mL) 0.00–0.08 0.05 –
Interleuchyn-6 (pg/mL) <3.4 16.1 12.6
VES (mm) 0–20 37 12
Sars-CoV-2 IgM (AU/mL) <10 42.03 21.92
Sars-CoV-2 IgG (AU/mL) <10 71 67
Urine-culture Negative Negative –
Figure 2. Abdominal CT scan: (a) no contrast, (b) arteriosus phase, (c) venous phase, and (d) excretory phase.
Figure 3. Abdominal MRI: (a) T1-weighted axial image and (b) coronal image.
Discussion
COVID-19 pandemic is an unprecedented medical emergency, where, the healthcare systems all over the world took extreme measures, stopping all non-urgent elective surgeries, increasing the financial support and the number of personal protective devices, and directing all the available medical resources to face this pandemic.1 Considering the highly contagious nature of SARS-COV-2, healthcare personnel were classified among the groups at high risk of getting infected as they are in close contact with confirmed COVID-19 patients.6 Furthermore, the most severe cases were surprisingly manifested in younger medical staff with fever and cough as main symptoms. This could be due to the longer working hours of younger personnel, but data to support this is not yet available.7 Importantly, the massive increase in the number of patients beyond the capacity of the healthcare systems and the increased risk of infection amongst the medical workforce result in workers burnout that can lead to error.8 Moreover, pitfall of judgment because COVID-19 is a more attractive diagnosis could direct the physician in the wrong direction.9
Renal abscess is a relatively uncommon debilitating and potentially fatal disease (1–10 in 10,000 hospital admissions) with mortality rates historically ranging from 12% to 50% and diabetes appears to be the leading risk factor. Fever and flank pain are usually the main symptoms, however nonspecific symptoms have been observed, such as weight loss, fatigue and rarely lower respiratory tract symptoms.10 Urinary tract infections are usually the cause of a renal abscess, however in our case both urine culture and aspirate were negative. In the literature according to our knowledge there are no cases of aseptic renal abscesses of unknown etiology. A case report was recently published on a renal abscess in a patient suffering from Chron disease, often associated with aseptic abscesses.11 In our case there is no pathology that can explain the onset of sterile abscesses. However, diabetes is the most important predisposing factor for renal abscesses which are generally infectious. We think that the bacterial load of the pathogen responsible for the renal abscess in our case has been eliminated by the use of broad-spectrum antibiotics according to the pharmacological COVID-19 protocol used. In the current clinical case, the symptoms were ambiguous, but positivity of the swab and the chest CT scan resulted in the underestimations of other symptoms that are more likely related to the abscess. However, it was reasonable to focus on COVID-19 because of history, other main symptoms and work category risk that have been misleading. Moreover, in the first instance according to CT and MRI images and negative urine culture, malignancy of the lesion suitable for nephrectomy was the main hypothesis and not abscess, but only kidney biopsy unveiled the real nature of the lesion sparing an invasive surgery.12 On the other hand, we cannot exclude the overlapping of two pathologies at the same time.13,14 Acute renal injuries from COVID have been described in the literature,1 but no cases of virus-related abscess. However, the impact on immune system due to COVID can be a predisposing factor for infectious diseases.15 In the same setting, the absence of symptoms and fully recovery of blood tests even with CT signs of pneumonia suggests more for abscess-related initial illness rather than COVID. This case must be contextualized in the historical moment of maximum criticality for the healthcare systems.16 The fear of contagion, the harmful consequences of the COVID-19 and the small knowledge at that time, added to the subsequent fear of a potential advanced tumor were smoke and mirrors for clinicians who have over diagnosed and overtreated the patient.
Conclusion
COVID 19 is a tremendous problem that is affecting the economic system and the health system around the world, however overdiagnosis can lead to error. Other pathologies can have symptoms similar to moderate forms of COVID and accurate examination should be carried out before running to conclusion. This is an example of how a kidney disease can mislead the clinician for pitfall of judgment.
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.
ORCID iDs: Ahmed Eissa https://orcid.org/0000-0001-6817-6887
Bernardo Rocco https://orcid.org/0000-0001-7211-0485
Stefano Puliatti https://orcid.org/0000-0002-3098-2899 | CEFTRIAXONE, CLARITHROMYCIN, ENOXAPARIN, HYDROXYCHLOROQUINE, TOCILIZUMAB, VITAMIN D NOS | DrugsGivenReaction | CC BY | 33550944 | 20,254,410 | 2021-08 |
What was the administration route of drug 'CEFTRIAXONE'? | Diagnostic bias during the COVID-19 era: COVID-19 or renal abscess?
The Coronavirus disease-2019 (COVID-19) has been declared as a pandemic in March 2020 by the World Health Organization (WHO). Since then, this pandemic has dramatically affected the entire world, even radically influencing the way patients are framed at triage. Symptoms and tests in most cases lead to a correct diagnosis; however, error may be around the corner.
A 60 years old patient was referred with weight loss, fatigue and mild fever for 3 weeks as he was working in a COVID-19 ward. After a positive swab and chest CT scan, he was admitted in the hospital and treated as mild COVID-19 patient. A CT scan performed after the patient was discharged revealed a renal lesion misidentified as a tumor then clarified to be an abscess which retrospectively appears to be the main cause of his symptoms.
Clinicians should consider other life-threatening disease in the differential diagnosis of patients presenting with similar symptoms to minimize mistakes and avoid further unnecessary investigations.
Introduction
Coronavirus disease-2019 (COVID-19) pandemic has spread rapidly all over the world, putting COVID-19 in the spotlight, being the “pathology of the hour.” With approximately 20 million positive cases and 730 thousand deaths, all national healthcare systems were put to the test.1,2
The clinical spectrum can vary from mild symptoms (cough and loss of taste and smell) to severe respiratory failure. Even with mild symptoms, our level of suspicion should be high in risky groups.3–5 Noteworthy, symptoms alone may be deceiving, and other life-threatening pathologies should not be underestimated, even in times of a pandemic where generalized fear can be deceptive. We present a case report of a 60-year old patient, admitted to the hospital with mild respiratory symptoms, fever and COVID-19 positive swab treated as SARS-CoV-2, who was found to have another potentially life-threatening disease.
Case report
A 60-year-old diabetic man, with a history of regular medical follow-up, was admitted to the hospital by the beginning of March 2020. Mild fever, malaise, and weight loss occurred about 3 weeks before hospitalization without any other symptoms. As the patient was an anesthetist working in an Italian COVID-19 ward, and complying with a strict testing protocol, he had two negative COVID-19 swabs in the last weeks. However, due to the persistence of general malaise and one episode of fever, he had a third swab that demonstrated positive results for COVID-19. A chest CT scan showed left basal interstitial pneumonia (Figure 1), so the patient was hospitalized with COVID-19 diagnosis. At admission his vital signs were stable. On physical examination there was abdominal distension and rebounding pain on the left upper quadrant of the abdomen. Laboratory tests are summarized in Table 1. Being labeled as “COVID-19 positive” patient, he received intravenous ceftriaxone and clarithromycin, hydroxychloroquine, enoxaparin, vitamin D and tocilizumab for 2 weeks. During the hospital stay the patient remained stable showing no exacerbation of respiratory symptoms (minimum O2ps 94%) but only mild fever for three consecutive days. No further medications were administered nor support with oxygen was needed. After 15 days and two consecutive negative swabs the patient was discharged. The last blood tests are showed in the Table 1. A CT scan was performed 2 days after discharge (Figure 2) showed persistent interstitial pneumonia and also an incidental unclear shape of the left kidney, that motivated a third thoraco-abdomin-pelvic CT scan. The total body CT showed a 5.4 × 4.5 cm mass with thick walls and central colliquation, involving the renal parenchyma and the renal fat but without involving the renal sinus, suspicious for advanced malignant tumor. A previous CT done 1 year earlier for other purpose (diverticulitis) did not show any pathology in the left kidney. An MRI scan was then performed to better clarify the nature of the lesion, but no certain diagnosis was achieved (Figure 3). After urological consultation done in another hospital, the initial decision was to perform radical nephrectomy for suspicious of an advanced malignant renal disease. However, after a second opinion of an expert, considering the reported symptoms previously attributed exclusively to the virus, renal abscess was suspected and a renal biopsy was recommended. This lesion was then drained and specimens were sent to cytologic examination showing it was a renal abscess (presence of inflammatory cells and no bacteria) which did not require surgical removal. The patient started oral antibiotic treatment and performed a follow-up ultrasound at 3 months that revealed reduction in the diameter of the renal abscess.
Figure 1. Thorax CT scan: left apical interstitial pneumonia.
Table 1. Blood tests at 1st day and at 15th day.
Blood tests Reference values First day 15th day
Hemoglobin (g/dL) 13.5–17.5 16 15.4
Platelet 150–400 103/uL 235 103/uL 347 103/uL
White blood cells 4.00–10.0 103/uL 14 103/uL 9 103/uL
Neutrophils (%) 41–73 70 75
Lymphocytes (%) 19.4–44.9 21 12
Creatinine (mg/dL) 0.72–1.25 1.29 0.97
Hs-C-reactive protein (mg/dL) <0.5 2.17 0.06
Glucose (mg/dL) 70–105 108 150
Procalcitonin (ng/mL) 0.00–0.08 0.05 –
Interleuchyn-6 (pg/mL) <3.4 16.1 12.6
VES (mm) 0–20 37 12
Sars-CoV-2 IgM (AU/mL) <10 42.03 21.92
Sars-CoV-2 IgG (AU/mL) <10 71 67
Urine-culture Negative Negative –
Figure 2. Abdominal CT scan: (a) no contrast, (b) arteriosus phase, (c) venous phase, and (d) excretory phase.
Figure 3. Abdominal MRI: (a) T1-weighted axial image and (b) coronal image.
Discussion
COVID-19 pandemic is an unprecedented medical emergency, where, the healthcare systems all over the world took extreme measures, stopping all non-urgent elective surgeries, increasing the financial support and the number of personal protective devices, and directing all the available medical resources to face this pandemic.1 Considering the highly contagious nature of SARS-COV-2, healthcare personnel were classified among the groups at high risk of getting infected as they are in close contact with confirmed COVID-19 patients.6 Furthermore, the most severe cases were surprisingly manifested in younger medical staff with fever and cough as main symptoms. This could be due to the longer working hours of younger personnel, but data to support this is not yet available.7 Importantly, the massive increase in the number of patients beyond the capacity of the healthcare systems and the increased risk of infection amongst the medical workforce result in workers burnout that can lead to error.8 Moreover, pitfall of judgment because COVID-19 is a more attractive diagnosis could direct the physician in the wrong direction.9
Renal abscess is a relatively uncommon debilitating and potentially fatal disease (1–10 in 10,000 hospital admissions) with mortality rates historically ranging from 12% to 50% and diabetes appears to be the leading risk factor. Fever and flank pain are usually the main symptoms, however nonspecific symptoms have been observed, such as weight loss, fatigue and rarely lower respiratory tract symptoms.10 Urinary tract infections are usually the cause of a renal abscess, however in our case both urine culture and aspirate were negative. In the literature according to our knowledge there are no cases of aseptic renal abscesses of unknown etiology. A case report was recently published on a renal abscess in a patient suffering from Chron disease, often associated with aseptic abscesses.11 In our case there is no pathology that can explain the onset of sterile abscesses. However, diabetes is the most important predisposing factor for renal abscesses which are generally infectious. We think that the bacterial load of the pathogen responsible for the renal abscess in our case has been eliminated by the use of broad-spectrum antibiotics according to the pharmacological COVID-19 protocol used. In the current clinical case, the symptoms were ambiguous, but positivity of the swab and the chest CT scan resulted in the underestimations of other symptoms that are more likely related to the abscess. However, it was reasonable to focus on COVID-19 because of history, other main symptoms and work category risk that have been misleading. Moreover, in the first instance according to CT and MRI images and negative urine culture, malignancy of the lesion suitable for nephrectomy was the main hypothesis and not abscess, but only kidney biopsy unveiled the real nature of the lesion sparing an invasive surgery.12 On the other hand, we cannot exclude the overlapping of two pathologies at the same time.13,14 Acute renal injuries from COVID have been described in the literature,1 but no cases of virus-related abscess. However, the impact on immune system due to COVID can be a predisposing factor for infectious diseases.15 In the same setting, the absence of symptoms and fully recovery of blood tests even with CT signs of pneumonia suggests more for abscess-related initial illness rather than COVID. This case must be contextualized in the historical moment of maximum criticality for the healthcare systems.16 The fear of contagion, the harmful consequences of the COVID-19 and the small knowledge at that time, added to the subsequent fear of a potential advanced tumor were smoke and mirrors for clinicians who have over diagnosed and overtreated the patient.
Conclusion
COVID 19 is a tremendous problem that is affecting the economic system and the health system around the world, however overdiagnosis can lead to error. Other pathologies can have symptoms similar to moderate forms of COVID and accurate examination should be carried out before running to conclusion. This is an example of how a kidney disease can mislead the clinician for pitfall of judgment.
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.
ORCID iDs: Ahmed Eissa https://orcid.org/0000-0001-6817-6887
Bernardo Rocco https://orcid.org/0000-0001-7211-0485
Stefano Puliatti https://orcid.org/0000-0002-3098-2899 | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33550944 | 20,254,410 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaemia'. | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | ACETAMINOPHEN, ATORVASTATIN, BISOPROLOL, CELECOXIB, CITALOPRAM HYDROBROMIDE, CLOZAPINE, CYANOCOBALAMIN, FLURAZEPAM HYDROCHLORIDE, OXYBUTYNIN CHLORIDE, PANTOPRAZOLE, PROCYCLIDINE | DrugsGivenReaction | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Colitis ischaemic'. | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | ACETAMINOPHEN, ATORVASTATIN, BISOPROLOL, CELECOXIB, CITALOPRAM HYDROBROMIDE, CLOZAPINE, CYANOCOBALAMIN, FLURAZEPAM HYDROCHLORIDE, OXYBUTYNIN CHLORIDE, PANTOPRAZOLE, PROCYCLIDINE | DrugsGivenReaction | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Colitis'. | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
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Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | ACETAMINOPHEN, ATORVASTATIN, BISOPROLOL, CALCIUM\CHOLECALCIFEROL, CELECOXIB, CITALOPRAM HYDROBROMIDE, CLOZAPINE, CYANOCOBALAMIN, FLURAZEPAM HYDROCHLORIDE, OXYBUTYNIN CHLORIDE, PANTOPRAZOLE, PROCYCLIDINE | DrugsGivenReaction | CC BY | 33550992 | 18,921,014 | 2021-02-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | ACETAMINOPHEN, ATORVASTATIN, BISOPROLOL, CELECOXIB, CITALOPRAM HYDROBROMIDE, CLOZAPINE, CYANOCOBALAMIN, FLURAZEPAM HYDROCHLORIDE, OXYBUTYNIN CHLORIDE, PANTOPRAZOLE, PROCYCLIDINE | DrugsGivenReaction | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dehydration'. | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | ACETAMINOPHEN, ATORVASTATIN, BISOPROLOL, CELECOXIB, CITALOPRAM HYDROBROMIDE, CLOZAPINE, CYANOCOBALAMIN, FLURAZEPAM HYDROCHLORIDE, OXYBUTYNIN CHLORIDE, PANTOPRAZOLE, PROCYCLIDINE | DrugsGivenReaction | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug level increased'. | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | ACETAMINOPHEN, ATORVASTATIN, BISOPROLOL, CELECOXIB, CITALOPRAM HYDROBROMIDE, CLOZAPINE, CYANOCOBALAMIN, FLURAZEPAM HYDROCHLORIDE, OXYBUTYNIN CHLORIDE, PANTOPRAZOLE, PROCYCLIDINE | DrugsGivenReaction | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastroenteritis'. | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | ACETAMINOPHEN, ATORVASTATIN, BISOPROLOL, CELECOXIB, CITALOPRAM HYDROBROMIDE, CLOZAPINE, CYANOCOBALAMIN, FLURAZEPAM HYDROCHLORIDE, OXYBUTYNIN CHLORIDE, PANTOPRAZOLE, PROCYCLIDINE | DrugsGivenReaction | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal wall thickening'. | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | ACETAMINOPHEN, ATORVASTATIN, BISOPROLOL, CELECOXIB, CITALOPRAM HYDROBROMIDE, CLOZAPINE, CYANOCOBALAMIN, FLURAZEPAM HYDROCHLORIDE, OXYBUTYNIN CHLORIDE, PANTOPRAZOLE, PROCYCLIDINE | DrugsGivenReaction | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ileus'. | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | ACETAMINOPHEN, ATORVASTATIN, BISOPROLOL, CALCIUM\CHOLECALCIFEROL, CELECOXIB, CITALOPRAM HYDROBROMIDE, CLOZAPINE, CYANOCOBALAMIN, FLURAZEPAM HYDROCHLORIDE, OXYBUTYNIN CHLORIDE, PANTOPRAZOLE, PROCYCLIDINE | DrugsGivenReaction | CC BY | 33550992 | 18,921,014 | 2021-02-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lymphopenia'. | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | ACETAMINOPHEN, ATORVASTATIN, BISOPROLOL, CELECOXIB, CITALOPRAM HYDROBROMIDE, CLOZAPINE, CYANOCOBALAMIN, FLURAZEPAM HYDROCHLORIDE, OXYBUTYNIN CHLORIDE, PANTOPRAZOLE, PROCYCLIDINE | DrugsGivenReaction | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
What was the dosage of drug 'CALCIUM\CHOLECALCIFEROL'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | 500 MG?400 IU TWICE DAILY | DrugDosageText | CC BY | 33550992 | 18,921,014 | 2021-02-08 |
What was the dosage of drug 'CALCIUM\VITAMIN D'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | UNK, BID(500 MG?400 MG) | DrugDosageText | CC BY | 33550992 | 18,999,972 | 2021-02-08 |
What was the outcome of reaction 'Acute kidney injury'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
What was the outcome of reaction 'Anaemia'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
What was the outcome of reaction 'Colitis ischaemic'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
What was the outcome of reaction 'Colitis'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,921,014 | 2021-02-08 |
What was the outcome of reaction 'Condition aggravated'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
What was the outcome of reaction 'Confusional state'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
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Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
What was the outcome of reaction 'Dehydration'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
What was the outcome of reaction 'Drug level increased'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
What was the outcome of reaction 'Faecaloma'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovering | ReactionOutcome | CC BY | 33550992 | 18,963,448 | 2021-02-08 |
What was the outcome of reaction 'Gastroenteritis'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
What was the outcome of reaction 'Gastrointestinal wall thickening'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
What was the outcome of reaction 'Hypokalaemia'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
What was the outcome of reaction 'Hypotension'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,921,014 | 2021-02-08 |
What was the outcome of reaction 'Ileus'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,921,014 | 2021-02-08 |
What was the outcome of reaction 'Intestinal obstruction'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovering | ReactionOutcome | CC BY | 33550992 | 18,963,448 | 2021-02-08 |
What was the outcome of reaction 'Lethargy'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,963,448 | 2021-02-08 |
What was the outcome of reaction 'Lymphopenia'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
What was the outcome of reaction 'Mental status changes'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,921,014 | 2021-02-08 |
What was the outcome of reaction 'Neutropenia'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,921,014 | 2021-02-08 |
What was the outcome of reaction 'Sedation'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
What was the outcome of reaction 'Sepsis'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
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Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovering | ReactionOutcome | CC BY | 33550992 | 18,963,448 | 2021-02-08 |
What was the outcome of reaction 'Somnolence'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,921,014 | 2021-02-08 |
What was the outcome of reaction 'Toxicity to various agents'? | Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.
BACKGROUND
Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
METHODS
A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels.
CONCLUSIONS
This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.
Background
Clozapine is an atypical antipsychotic mainly used for the treatment of refractory schizophrenia. The standard daily dose of clozapine ranges from 300 to 600 mg/day, with a maximum daily dose of 900 mg [1].
Clozapine is metabolized in the liver by the cytochrome P450 (CYP) isoenzyme 1A2 into norclozapine, an active metabolite that could contribute to adverse events [2]. There is a wide interindividual variability in its metabolism, the most important factors being age, ethnicity, gender, genetic polymorphisms of CYP isoenzymes or neurotransmitter receptors, food and drink, smoking status, and drug interactions [2, 3]. It has been suggested that clozapine serum concentration monitoring may be useful in guiding therapy, optimizing therapeutic efficacy, and preventing adverse events [3].
A growing body of evidence suggests that clozapine serum concentrations may increase in patients with inflammation and/or infections, respiratory and urinary tract infections being the most frequently reported [4]. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection.
In the present report, we describe a patient who was on stable dose of clozapine for years and experienced clinically severe side effects with a decline in her general condition, associated with increased clozapine serum concentrations following sepsis.
Case presentation
A 64-year-old Caucasian woman living in a nursing home for people with psychiatric disorders was brought to the emergency department (ED) for drowsiness, general deterioration, and hypotension, with a systolic blood pressure (sBP) of around 75–80 mmHg (normally ranging around 115–120 mmHg) at her residence. The patient’s medical history included dyslipidemia, schizophrenia which was refractory and stabilized with high dose clozapine, anorexia and bulimia with associated laxative abuse, vitamin B12 deficiency, overactive bladder, and an intramedullary rod in the left shin bone associated with chronic pain since 2009. According to the nursing home, she had not abused any laxatives in the last 2 years or used any recreational drugs, alcohol, or tobacco. She had no known allergies and her caffeine consumption was limited to one to five times per month. Medications were dispensed in a pillbox at the nursing home and taken under supervision: clozapine 700 mg daily, citalopram 40 mg daily, flurazepam 30 mg daily at bedtime, procyclidine 5 mg twice daily, oxybutynin 5 mg daily at bedtime, bisoprolol 2.5 mg daily, pantoprazole 40 mg daily, atorvastatin 10 mg daily, celecoxib 200 mg daily, vitamin B12 1200 μg daily, calcium/vitamin D 500 mg–400 IU twice daily, and acetaminophen as needed. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The patient was admitted to the internal medicine ward.
One to two weeks prior to the ED visit, she suffered from abdominal pain with diarrhea, vomiting, loss of appetite with decreased intake, and she gradually developed sedation and confusion. No fever was reported, but temperature was not measured at the nursing home. The review of systems was otherwise unremarkable.
On arrival, the patient was lethargic with fluctuating confusion, sedation, loss of appetite, and abdominal pain. The diarrhea had resolved several days prior to admission. Acute constipation was suspected. The initial evaluation in the ED revealed an initial Glasgow score of 14, blood pressure of 90/59 mmHg, heart rate of 89 beats per minute (bpm), respiratory rate of 16 breaths per minute, and rectal temperature of 37.5 °C. Shortly after, a fever was recorded (38.4 °C orally). Physical examination was unremarkable and did not offer any substantial information. Laboratory tests revealed hypokalemia (3.2 mmol/L), elevated C-reactive protein (CRP) (320 mg/L), acute kidney injury (creatinine 115 µmol/L, baseline 85 µmol/L), anemia (hemoglobin 112 g/L), lymphopenia (0.5 × 109 cells/L), and neutropenia (1.5 × 109 cells/L) with a normal leukocyte count (4.6 × 109 cells/L). Peripheral blood smear showed Döhle bodies and toxic granulations. Six days earlier, the neutrophil count was 3.7 × 109 cells/L and hemoglobin concentration was 122 g/L. A chest radiograph was completed and appeared normal. A cerebral computed tomography (CT) scan without contrast was normal without any signs of acute intracranial process. The acute abdominal series (Fig. 1) showed light dilated loops with small air-fluid levels and diffuse stercoral retention with numerous feces formed at the rectal level without actual fecal impaction. She was successfully treated with an enema, and oxybutynin was discontinued. Developing intestinal paralytic ileus was suspected. Her blood pressure and renal function returned to normal following rehydration by intravenous (IV) fluids. Hypokalemia was corrected with potassium supplements. From this point forward, the patient’s blood pressure and heart rate remained stable during the hospital stay, at around 110–120/55–65 mmHg and 100–115 bpm, respectively. The first diagnostic hypothesis was sepsis from a gastrointestinal origin.Fig. 1 Acute abdominal series showing stools at the rectal level without any fecaloma but stercoral retention. Slight dilation of bowel loops with slight air-fluid levels
The next day (day 2) another febrile episode of 39.1 °C was recorded. The precise source of the infection was still unknown, but infectious colitis with possible bacterial translocation was suspected. The patient was still drowsy, had nausea, and her abdominal pain was still present. Toxicology screen was unremarkable. Concomitant drug intoxication by clozapine, citalopram, or flurazepam was considered. Blood samples were drawn to measure serum levels of clozapine/norclozapine, and CRP. The CRP level was 148 mg/L. Subsequently, piperacillin-tazobactam 3.375 g IV every 6 hours was empirically started. Clozapine, citalopram, and procyclidine doses were empirically decreased (400 mg daily, 20 mg daily, and 2.5 mg twice daily, respectively) and flurazepam was discontinued. An abdominal and pelvic CT scan revealed a thickened sigmoid colon without distension or signs of inflammation and presence of some of the small bowel loops being distended and interpreted by the radiologist as early signs of occlusion. A colonoscopy was performed 3 days later and was normal. Completed blood and stool cultures were negative.
On day 5, the results for clozapine and norclozapine serum concentrations (drawn on day 2) were available: 1315 ng/mL and 653 ng/mL, respectively. The high clozapine serum concentration, taken in the context of general deterioration, altered mental status, neutropenia, and ileus, confirmed the hypothesis of clozapine intoxication. The general condition of the patient had improved, including gastrointestinal transit, in the days following the reduction of clozapine, citalopram, and procyclidine doses, discontinuation of flurazepam, and antibiotic initiation. A total antibiotic course of 7 days was completed. Clozapine dose was raised to 500 mg daily as the patient’s condition improved. In order to maintain clozapine therapy despite the neutropenia and to avoid issues with the clozapine regulatory program, the patient received one subcutaneous dose of filgrastim 300 μg while the neutrophil and leukocyte counts were 1.6 × 109 cells/L and 2.5 × 109 cells/L, respectively.
On day 6, the CRP decreased (18 mg/L) and the neutrophil count increased to 21.5 × 109 cells/L. On day 7, clozapine dose was increased to 550 mg daily, citalopram dose was increased to 30 mg daily, and procyclidine was discontinued. At this point, the clozapine and norclozapine serum concentrations had decreased to 894 ng/mL and 443 ng/mL, respectively. At hospital discharge, on day 9, the clozapine and norclozapine serum concentrations were 859 ng/mL and 582 ng/mL respectively, while the neutrophil count was back to normal (5.2 × 109 cells/L). The patient was discharged with a clozapine dose of 600 mg daily.
Clozapine and norclozapine serum concentrations obtained 4 days after hospital discharge were 831 ng/mL and 582 ng/mL, respectively, and the neutrophil count was 3.6 × 109 cells/L. Two years later, the patient remained clinically stable on clozapine 600 mg daily with a clozapine and norclozapine serum concentrations of 828 ng/mL and 685 ng/mL, respectively.
Discussion and conclusions
This case highlights the importance of understanding clozapine metabolism. Clozapine is mainly metabolized by CYP1A2 (70%), and to a lesser extent by CYP2D6, 3A4, 2C9, and 2C19 [3, 4]. Modifying CYP1A2 activity has an important impact, as seen with tobacco smoking which induces metabolism resulting in reduced clozapine serum concentrations, and caffeine consumption which inhibits metabolism, resulting in increased clozapine serum concentrations [3]. Rises in concentrations can be the result of drug–drug interactions with strong CYP1A2 inhibitors, such as ciprofloxacin [3]. In the present case, the patient was a non-smoker, rarely consumed caffeine, and no drug interaction was identified. A clozapine overdose was unlikely as medication was dispensed in a pillbox and taken under supervision.
In our case, an acute infectious/inflammatory process was believed to have sparked clozapine intoxication, with dehydration and added constipation exacerbating clozapine toxicity by increasing its absorption (Fig. 2). Prior to hospitalization, the patient’s condition was stable with her pharmacotherapy and was well tolerated for years. She had regular complete blood count monitoring as part of the clozapine regulatory program, showing no signs of toxicity. She developed acute gastroenteritis/colitis, which was determined as the initiating factor to acute clozapine intoxication. She progressively developed adverse effects associated with clozapine: sedation, confusion, neutropenia, and ileus. Confusion and sedation lead to reduced fluid intake contributing to dehydration and general deterioration. Furthermore, extensive workup was conducted to rule out other causes of mental status change but was unremarkable. The psychiatrist’s evaluation did not show deterioration of her schizophrenia, nor did it highlight delirium.Fig. 2 Schematic proposed explanation for clozapine intoxication
Serum concentration of clozapine, taken shortly after her admission, confirmed intoxication with levels exceeding 1000 ng/mL. A serum concentration range of 350–400 ng/mL is a reasonable target for patients with schizophrenia, but great variation in symptomatic response and side effects is observed [3, 5]. Furthermore, some authors showed that in the absence of clinical improvement at these serum concentrations, clozapine should be further increased until intolerable side effects occur or a maximum dose of 900 mg/daily is reached [3]. A definite clozapine serum concentration associated with toxicity remains unclear. However, it is suggested that adverse effects are more likely to occur with serum levels above 600–1000 ng/mL [3].
The finding of diffuse stercoral retention was explained by the concomitant use of anticholinergic drugs in addition to clozapine intoxication. The temporal relationship, in addition to a normal colonoscopy, led us to favor the latter into explaining acute constipation with radiographic signs of ileus. Constipation and decreased gastrointestinal motility has been correlated with increased clozapine serum levels as it may reflect its antimuscarinic activity [6, 7]. Constipation likely contributed to exacerbation of intoxication by increasing drug absorption and decreasing fecal drug elimination.
In our case, there was very little clinical, radiological, or laboratory evidence of an infectious/inflammatory process, other than fever and elevated CRP levels. This can be explained by clozapine toxicity as it may prevent increase of white blood counts (notably neutrophil count) and development of fever [7]. Therefore, clinical hallmarks of infection may be subtle or even absent, with elevated CRP being the only clue [7]. As such, CRP levels should be measured in the context of clozapine intoxication. Furthermore, an elevated CRP in patients taking clozapine should prompt a thorough evaluation in finding the cause and aggressively seeking signs and symptoms of clozapine intoxication. The patient’s condition improved, and CRP level decreased with antibiotic therapy.
Resolution of overall toxicity occurred in a temporal relationship after decreasing clozapine dose, which correlated with decreased serum concentrations of clozapine and norclozapine. The application of the Naranjo Adverse Drug Reaction Probability Scale resulted in a score of 7, indicating that clozapine intoxication was probable (one point for previous conclusive reports of clozapine toxicity, two points because the adverse event appeared after the suspected drug was administered, two points because there were no known alternative causes, one point because the drug was detected in the serum in concentrations known to be toxic, and one point because the reaction became less severe after the dose was decreased).
The mechanism behind increased clozapine serum concentrations induced by an infectious/inflammatory process is not clearly understood. Inflammation affects metabolic pathways by altering the expression of CYP via inflammation-induced downregulation of CYP activity [8]. Infection or inflammation can decrease metabolic clearance of CYP substrates by 20–70% [9], notably reducing CYP1A2 expression by up to 90% [4]. The proposed mechanism is a direct loss of CYP450 gene transcription via cytokine-induced transcriptional depression resulting in downregulation of CYP activities and enzyme synthesis [10, 11]. The cytokines implicated in decreased expression of CYP1A2 are interleukin-6, tumor necrosis factor-α, and interleukin-1β [9–11]. Modification at the post-translational level is also implicated, with an increase in CYP degradation or a change in their enzymatic activity following cytokine release [8, 10].
A study investigated the correlation between pathological CRP levels and serum concentrations of clozapine, quetiapine, and risperidone [12]. Elevated CRP levels were associated with significantly elevated serum concentrations for clozapine (P < 0.01) and risperidone (P < 0.01), quetiapine having only a trend in increased serum concentrations (P = 0.05) [12]. The authors concluded that in patients with signs of infection/inflammation with increased CRP levels, therapeutic drug monitoring is recommended in order to minimize the risk of intoxication [12].
Clozapine toxicity secondary to inflammation/infection is variable from one patient to another. This can be attributed to alpha-1-glycoprotein (AGP), an acute phase protein to which 95% of clozapine is bound [4]. During infection/inflammation, AGP increases several-fold, thereby increasing the concentration of clozapine along with AGP leading to elevation of total drug level [4, 13]. However, the free drug level is not necessarily increased, explaining the absence of clinical toxicity in some patients [4, 13]. AGP increase might not be sufficient in all cases to prevent clozapine intoxication.
In the setting of an acute infectious/inflammatory process, the optimal clozapine dose reduction is unknown. It has been suggested that at least a 50% dose reduction may be required to avoid toxicity [14]. Clozapine serum concentration monitoring is used to confirm clinical intoxication by comparing it to a prior tolerated baseline serum level. However, in the scenario of evident signs and symptoms of clozapine toxicity, doses should be reduced empirically to ensure patient safety, even if clozapine serum levels are not available. As stated earlier, not all elevated serum levels will occur with clinical signs of toxicity. In these cases, maintaining the patient’s current dose with close monitoring for adverse effects and repeating clozapine serum levels after the acute infectious/inflammatory process resolves may be appropriate.
This case report highlights the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. This process is insidious, and it is therefore imperative that these patients be closely monitored for clozapine toxicity. It is essential that ileus and constipation be identified and treated quickly as they can be secondary to the initial intoxication process and contribute in perpetuating a vicious circle of intoxication by increasing drug absorption and decreasing fecal elimination of clozapine. CRP and clozapine serum levels are useful guiding tools for identifying and monitoring this phenomenon. Further research is warranted.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors' contributions
EB and MD conceptualized the work, organized the order of events in the patient’s hospitalization and interpreted the results. LW helped with the writing of the article. EB, LW and MD performed the review of the literature. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.
Funding
No funding was secured for this case report.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors have no competing interests to disclose. | Recovered | ReactionOutcome | CC BY | 33550992 | 18,965,627 | 2021-02-08 |
What was the outcome of reaction 'Drug ineffective'? | Pneumatosis Intestinalis in Lung Cancer Induced Twice by Different Drugs: Bevacizumab and Pemetrexed.
A 72-year-old man diagnosed with stage 4 lung adenocarcinoma developed asymptomatic pneumatosis intestinalis while undergoing treatment with first-line chemotherapy, which included carboplatin, paclitaxel, and bevacizumab (BEV). He was treated conservatively. The pneumatosis recurred while the patient was undergoing treatment with the third-line chemotherapy, which included pemetrexed (PEM). His condition resolved after 4 weeks of supportive therapy. To our knowledge, this is the first case in which pneumatosis intestinalis was induced twice by two drugs in a patient with lung cancer. BEV and PEM are often administered to patients with lung cancer; thus, it should be noted that pneumatosis intestinalis may occur as an adverse event in patients treated with these drugs.
Introduction
Pneumatosis intestinalis is an uncommon but significant illness in which gas is found in a linear or cystic form in the submucosa or subserosa of the bowel wall (1). It is caused by various factors, including pulmonary disease, gastrointestinal disease, and collagen disease. In recent years, the occurrence of pneumatosis intestinalis has been reported to be associated with drugs such as cytotoxic anticancer drugs and molecular targeted drugs. However, to our knowledge, no cases have been reported in which pneumatosis intestinalis developed twice in association with two different drugs. We herein report a case of pneumatosis intestinalis that was first caused by bevacizumab (BEV), which then relapsed during treatment with a cytotoxic chemotherapeutic agent: pemetrexed (PEM).
Case Report
A 72-year-old man visited our hospital to investigate the cause of left lateral chest pain. He had a 5-year history of hypertension and dyslipidemia and no history of allergic disease. He had smoked 20 cigarettes per day for 52 years. He was diagnosed with lung adenocarcinoma (cT3N0M1a, Stage 4) (2). No metastatic lesions in the intestinal tract were observed on positron emission tomography/computed tomography. Because the tumor was negative for epidermal growth factor receptor gene mutation and anaplastic lymphoma kinase fusion gene, he received three cycles of chemotherapy consisting of carboplatin (CBDCA, AUC 5), paclitaxel (PTX, 200 mg/m2), and BEV (15 mg/kg). When he was hospitalized to receive the fourth cycle of chemotherapy, abdominal CT revealed abdominal free air and pneumatosis intestinalis.
At the time of his admission, his vital signs were normal and no abdominal abnormalities were observed. His white blood cell count was normal (3,940 cells/μL) and his serum C-reactive protein was slightly increased (1.24 mg/dL). Chest radiography showed no evidence of free air. Abdominal CT showed intra-abdominal free air around the liver (Fig. 1A), and pneumatosis in the intestinal wall (Fig. 1B, C). Thus, because we observed no causative factors of pneumatosis intestinalis other than BEV, we diagnosed the patient with pneumatosis intestinalis due to BEV treatment. Intraportal venous gas was not observed. We did not perform a blood gas analysis and could not detect the presence or absence of acidosis. Since he had no symptoms, we discontinued the fourth chemotherapy cycle and treated the patient conservatively with observation.
Figure 1. Abdominal CT on admission after three cycles of carboplatin, paclitaxel, and bevacizumab revealed intra-abdominal free air (arrows) on the liver surface (A), and pneumatosis (arrowheads) in the intestinal wall (B, C).
Abdominal symptoms were not present during follow-up, and abdominal CT revealed that the intra-abdominal free air and pneumatosis had disappeared. CBDCA (AUC 5) and PTX (200 mg/m2) chemotherapy was initiated, with the patient receiving three cycles of the regimen. Follow-up chest CT revealed progressive disease. Treatment with PEM (500 mg/m2) was initiated as a third-line therapy. After two cycles of this regimen, intra-abdominal free air appeared on chest radiography. Abdominal CT revealed the recurrence of intra-abdominal gas and pneumatosis intestinalis (Fig. 2). Again, he did not have any other symptoms. Lower gastrointestinal endoscopy showed protruded lesions resembling a submucosal tumor in the center of the transverse colon, which was soft and movable. It was thought to be consistent with pneumatosis intestinalis (Fig. 3). The administration of PEM was stopped, and he was managed supportively. He remained asymptomatic and follow-up CT showed that the intra-abdominal free air and pneumatosis had nearly resolved. After that, he was treated with a tegafur-gimeracil-oteracil combination therapy (TS-1, one cycle of 120 mg/day and two cycles of 80 mg/day). However, the malignant lesions were exacerbated and he died of lung cancer 15 months after the diagnosis.
Figure 2. Abdominal CT under treatment with pemetrexed showed recurrence of intra-abdominal gas (arrows) around the liver (A) and pneumatosis intestinalis (arrowheads) (B).
Figure 3. Lower gastrointestinal endoscopy showed soft and movable protruded lesions resembling a submucosal tumor in the center of the transverse colon.
Discussion
Pneumatosis intestinalis is thought to be an infrequent but critical illness. It is reported to manifest as gas found in a linear or cystic form in the submucosa or subserosa of the bowel wall (1). Pneumatosis intestinalis is associated with various conditions, such as pulmonary disease (3,4), gastrointestinal disease (4), collagen disease (4-6), infectious disease (7,8), and iatrogenic disorder (9). Moreover, pneumatosis intestinalis is found in association with the use of certain drugs, including steroids (4,5,10,11) and α-glucosidase inhibitors (5,12).
Recently, several molecular targeted drugs have been reported to be associated with pneumatosis intestinalis, including gefitinib (13), sorafenib, and sunitinib (14). Asmis et al. reported the case of a patient with a low-grade neuroendocrine tumor originating from the pancreas, who presented pneumatosis intestinalis while receiving systematic chemotherapy plus BEV (15). Shinagare et al. reported that 24 cancer patients treated with molecular targeted therapy developed pneumatosis or intestinal perforation. Among these patients, 10 patients had pneumatosis intestinalis, and BEV (n=5) was the drug most commonly associated with pneumatosis in this study (16). Moreover, Lee et al. reported that BEV was administered to 6 of 84 patients in whom pneumatosis intestinalis was identified by CT (17).
Our patient had no relevant medical history and was not using any medications that might have caused pneumatosis intestinalis during his clinical course before chemotherapy. Pneumatosis intestinalis was found three months after the administration of BEV, and there were no findings that could be considered causative other than BEV. We considered that adverse events of BEV, such as gastrointestinal perforation, fistula formation, and wound healing (18), might be associated with pneumatosis intestinalis.
The second occurrence of pneumatosis intestinalis was revealed during chemotherapy with PEM. The patient received a definitive diagnosis following lower gastrointestinal endoscopy at that time. During the time between his first improvement and the recurrence of pneumatosis intestinalis, dexamethasone (1 mg per day; per oral) was administered to relieve the fever caused by lung cancer inflammation. However, dexamethasone continued to be administered until the end of his life, and pneumatosis intestinalis did not occur again after the improvement of the second occurrence. Moreover, he showed no onset of new disease or change in prescription medications except for the addition of dexamethasone. Consequently, we concluded that the second occurrence of pneumatosis intestinalis was associated with PEM.
Several reports have mentioned that cytotoxic chemotherapeutic agents, including etoposide (19), fluorouracil (20), methotrexate (5,11), irinotecan, and cisplatin (21) might cause pneumatosis intestinalis. Yamamoto et al. reported the case of a patient with lung cancer who was treated with PEM and erlotinib who subsequently developed pneumatosis intestinalis (22). However, to our knowledge, the case reported here is the only report of pneumatosis intestinalis due to PEM alone. Furthermore, to our knowledge, this is the first reported case of pneumatosis intestinalis that appeared twice at different times as a result of treatment with two different drugs.
Although the mechanism of pneumatosis intestinalis is unclear, multiple causes are likely to contribute to the pathogenesis of this disease. Some have suggested mechanical causes arising from gas entering the wall of the bowel, either from the luminal surface of a mucosal fissure due to increased pressure, increased peristalsis and mucosal breaks, or through the mesentery. Others have proposed that the origin may lay in gas-producing bacteria that invade the bowel wall, and that the resulting excessive hydrogen gas leads to pneumatosis intestinalis (23,24). Moreover, it is hypothesized that exposure to alkyl halides, such as chloral and trichloroethylene enhance hydrogen production and the formation of gas cysts (25).
BEV is a monoclonal antibody that specifically binds vascular endothelial growth factor. This inhibition leads to a reduction in the microvascular growth of tumor blood vessels and thus limits the blood supply to tumor tissues (18). PEM is an antimetabolite that inhibits at least three enzymes involved in the metabolism of folate, which is the mechanism of cytotoxicity of PEM. However, mucositis may occur as an adverse event in patients treated with PEM (26).
The precise mechanisms by which BEV and PEM cause pneumatosis intestinalis are not clear. In the present case, we hypothesize that the decrease in vasculature induced by BEV led to ischemia, causing mucosal breaks and increased pressure, leading to pneumatosis intestinalis. Furthermore, micro-intestinal hemorrhage and micro-intestinal perforation may have occurred. We should have considered the possibility of recurrence of intestinal emphysema after the administration of BEV. Previous reports have shown that the recurrence rate of intestinal emphysema is 30-40% (1). PEM may have caused pneumatosis intestinalis due to disorder of the intestinal mucosa. Pneumatosis intestinalis had been reported to be attributed to methotrexate (5,11), and the inhibition of folate metabolism might contribute to the development of pneumatosis intestinalis. Moreover, a combination of factors can lead to pneumatosis intestinalis (4,5,11), and in our case, a history of pneumatosis intestinalis due to BEV and steroid therapy may have accelerated the onset of pneumatosis intestinalis by PEM.
Possible treatments of pneumatosis intestinalis include emergency surgery, observation, and medical treatment of the underlying disease (27). Observation is recommended for asymptomatic cases or those with no critical findings. Treatment of underlying disease is necessary for patients with a significant past medical history (27). In the present case, the diagnosis was pneumatosis intestinalis due to BEV and PEM, so we discontinued both drugs. Additionally, the patient was asymptomatic at the onset of the disease, and a physical examination and CT showed only free abdominal air, without bowel perforation, obstruction, or necrosis. As a result, we treated him conservatively. However, because of the occurrence of pneumatosis intestinalis, we needed to discontinue the use of anticancer agents, such as BEV and PEM, which were expected to be effective for his lung cancer. This resulted in a narrowing of the treatment options for lung cancer, which may in turn have affected his prognosis.
There are many opportunities to use molecular targeted drugs, including BEV and cytotoxic anticancer drugs such as PEM. Although pneumatosis intestinalis is rare, it is important to consider pneumatosis intestinalis as a possible adverse event in patients treated with these drugs.
The authors state that they have no Conflict of Interest (COI). | Fatal | ReactionOutcome | CC BY-NC-ND | 33551401 | 19,803,430 | 2021-07-01 |
What was the outcome of reaction 'Pneumatosis intestinalis'? | Pneumatosis Intestinalis in Lung Cancer Induced Twice by Different Drugs: Bevacizumab and Pemetrexed.
A 72-year-old man diagnosed with stage 4 lung adenocarcinoma developed asymptomatic pneumatosis intestinalis while undergoing treatment with first-line chemotherapy, which included carboplatin, paclitaxel, and bevacizumab (BEV). He was treated conservatively. The pneumatosis recurred while the patient was undergoing treatment with the third-line chemotherapy, which included pemetrexed (PEM). His condition resolved after 4 weeks of supportive therapy. To our knowledge, this is the first case in which pneumatosis intestinalis was induced twice by two drugs in a patient with lung cancer. BEV and PEM are often administered to patients with lung cancer; thus, it should be noted that pneumatosis intestinalis may occur as an adverse event in patients treated with these drugs.
Introduction
Pneumatosis intestinalis is an uncommon but significant illness in which gas is found in a linear or cystic form in the submucosa or subserosa of the bowel wall (1). It is caused by various factors, including pulmonary disease, gastrointestinal disease, and collagen disease. In recent years, the occurrence of pneumatosis intestinalis has been reported to be associated with drugs such as cytotoxic anticancer drugs and molecular targeted drugs. However, to our knowledge, no cases have been reported in which pneumatosis intestinalis developed twice in association with two different drugs. We herein report a case of pneumatosis intestinalis that was first caused by bevacizumab (BEV), which then relapsed during treatment with a cytotoxic chemotherapeutic agent: pemetrexed (PEM).
Case Report
A 72-year-old man visited our hospital to investigate the cause of left lateral chest pain. He had a 5-year history of hypertension and dyslipidemia and no history of allergic disease. He had smoked 20 cigarettes per day for 52 years. He was diagnosed with lung adenocarcinoma (cT3N0M1a, Stage 4) (2). No metastatic lesions in the intestinal tract were observed on positron emission tomography/computed tomography. Because the tumor was negative for epidermal growth factor receptor gene mutation and anaplastic lymphoma kinase fusion gene, he received three cycles of chemotherapy consisting of carboplatin (CBDCA, AUC 5), paclitaxel (PTX, 200 mg/m2), and BEV (15 mg/kg). When he was hospitalized to receive the fourth cycle of chemotherapy, abdominal CT revealed abdominal free air and pneumatosis intestinalis.
At the time of his admission, his vital signs were normal and no abdominal abnormalities were observed. His white blood cell count was normal (3,940 cells/μL) and his serum C-reactive protein was slightly increased (1.24 mg/dL). Chest radiography showed no evidence of free air. Abdominal CT showed intra-abdominal free air around the liver (Fig. 1A), and pneumatosis in the intestinal wall (Fig. 1B, C). Thus, because we observed no causative factors of pneumatosis intestinalis other than BEV, we diagnosed the patient with pneumatosis intestinalis due to BEV treatment. Intraportal venous gas was not observed. We did not perform a blood gas analysis and could not detect the presence or absence of acidosis. Since he had no symptoms, we discontinued the fourth chemotherapy cycle and treated the patient conservatively with observation.
Figure 1. Abdominal CT on admission after three cycles of carboplatin, paclitaxel, and bevacizumab revealed intra-abdominal free air (arrows) on the liver surface (A), and pneumatosis (arrowheads) in the intestinal wall (B, C).
Abdominal symptoms were not present during follow-up, and abdominal CT revealed that the intra-abdominal free air and pneumatosis had disappeared. CBDCA (AUC 5) and PTX (200 mg/m2) chemotherapy was initiated, with the patient receiving three cycles of the regimen. Follow-up chest CT revealed progressive disease. Treatment with PEM (500 mg/m2) was initiated as a third-line therapy. After two cycles of this regimen, intra-abdominal free air appeared on chest radiography. Abdominal CT revealed the recurrence of intra-abdominal gas and pneumatosis intestinalis (Fig. 2). Again, he did not have any other symptoms. Lower gastrointestinal endoscopy showed protruded lesions resembling a submucosal tumor in the center of the transverse colon, which was soft and movable. It was thought to be consistent with pneumatosis intestinalis (Fig. 3). The administration of PEM was stopped, and he was managed supportively. He remained asymptomatic and follow-up CT showed that the intra-abdominal free air and pneumatosis had nearly resolved. After that, he was treated with a tegafur-gimeracil-oteracil combination therapy (TS-1, one cycle of 120 mg/day and two cycles of 80 mg/day). However, the malignant lesions were exacerbated and he died of lung cancer 15 months after the diagnosis.
Figure 2. Abdominal CT under treatment with pemetrexed showed recurrence of intra-abdominal gas (arrows) around the liver (A) and pneumatosis intestinalis (arrowheads) (B).
Figure 3. Lower gastrointestinal endoscopy showed soft and movable protruded lesions resembling a submucosal tumor in the center of the transverse colon.
Discussion
Pneumatosis intestinalis is thought to be an infrequent but critical illness. It is reported to manifest as gas found in a linear or cystic form in the submucosa or subserosa of the bowel wall (1). Pneumatosis intestinalis is associated with various conditions, such as pulmonary disease (3,4), gastrointestinal disease (4), collagen disease (4-6), infectious disease (7,8), and iatrogenic disorder (9). Moreover, pneumatosis intestinalis is found in association with the use of certain drugs, including steroids (4,5,10,11) and α-glucosidase inhibitors (5,12).
Recently, several molecular targeted drugs have been reported to be associated with pneumatosis intestinalis, including gefitinib (13), sorafenib, and sunitinib (14). Asmis et al. reported the case of a patient with a low-grade neuroendocrine tumor originating from the pancreas, who presented pneumatosis intestinalis while receiving systematic chemotherapy plus BEV (15). Shinagare et al. reported that 24 cancer patients treated with molecular targeted therapy developed pneumatosis or intestinal perforation. Among these patients, 10 patients had pneumatosis intestinalis, and BEV (n=5) was the drug most commonly associated with pneumatosis in this study (16). Moreover, Lee et al. reported that BEV was administered to 6 of 84 patients in whom pneumatosis intestinalis was identified by CT (17).
Our patient had no relevant medical history and was not using any medications that might have caused pneumatosis intestinalis during his clinical course before chemotherapy. Pneumatosis intestinalis was found three months after the administration of BEV, and there were no findings that could be considered causative other than BEV. We considered that adverse events of BEV, such as gastrointestinal perforation, fistula formation, and wound healing (18), might be associated with pneumatosis intestinalis.
The second occurrence of pneumatosis intestinalis was revealed during chemotherapy with PEM. The patient received a definitive diagnosis following lower gastrointestinal endoscopy at that time. During the time between his first improvement and the recurrence of pneumatosis intestinalis, dexamethasone (1 mg per day; per oral) was administered to relieve the fever caused by lung cancer inflammation. However, dexamethasone continued to be administered until the end of his life, and pneumatosis intestinalis did not occur again after the improvement of the second occurrence. Moreover, he showed no onset of new disease or change in prescription medications except for the addition of dexamethasone. Consequently, we concluded that the second occurrence of pneumatosis intestinalis was associated with PEM.
Several reports have mentioned that cytotoxic chemotherapeutic agents, including etoposide (19), fluorouracil (20), methotrexate (5,11), irinotecan, and cisplatin (21) might cause pneumatosis intestinalis. Yamamoto et al. reported the case of a patient with lung cancer who was treated with PEM and erlotinib who subsequently developed pneumatosis intestinalis (22). However, to our knowledge, the case reported here is the only report of pneumatosis intestinalis due to PEM alone. Furthermore, to our knowledge, this is the first reported case of pneumatosis intestinalis that appeared twice at different times as a result of treatment with two different drugs.
Although the mechanism of pneumatosis intestinalis is unclear, multiple causes are likely to contribute to the pathogenesis of this disease. Some have suggested mechanical causes arising from gas entering the wall of the bowel, either from the luminal surface of a mucosal fissure due to increased pressure, increased peristalsis and mucosal breaks, or through the mesentery. Others have proposed that the origin may lay in gas-producing bacteria that invade the bowel wall, and that the resulting excessive hydrogen gas leads to pneumatosis intestinalis (23,24). Moreover, it is hypothesized that exposure to alkyl halides, such as chloral and trichloroethylene enhance hydrogen production and the formation of gas cysts (25).
BEV is a monoclonal antibody that specifically binds vascular endothelial growth factor. This inhibition leads to a reduction in the microvascular growth of tumor blood vessels and thus limits the blood supply to tumor tissues (18). PEM is an antimetabolite that inhibits at least three enzymes involved in the metabolism of folate, which is the mechanism of cytotoxicity of PEM. However, mucositis may occur as an adverse event in patients treated with PEM (26).
The precise mechanisms by which BEV and PEM cause pneumatosis intestinalis are not clear. In the present case, we hypothesize that the decrease in vasculature induced by BEV led to ischemia, causing mucosal breaks and increased pressure, leading to pneumatosis intestinalis. Furthermore, micro-intestinal hemorrhage and micro-intestinal perforation may have occurred. We should have considered the possibility of recurrence of intestinal emphysema after the administration of BEV. Previous reports have shown that the recurrence rate of intestinal emphysema is 30-40% (1). PEM may have caused pneumatosis intestinalis due to disorder of the intestinal mucosa. Pneumatosis intestinalis had been reported to be attributed to methotrexate (5,11), and the inhibition of folate metabolism might contribute to the development of pneumatosis intestinalis. Moreover, a combination of factors can lead to pneumatosis intestinalis (4,5,11), and in our case, a history of pneumatosis intestinalis due to BEV and steroid therapy may have accelerated the onset of pneumatosis intestinalis by PEM.
Possible treatments of pneumatosis intestinalis include emergency surgery, observation, and medical treatment of the underlying disease (27). Observation is recommended for asymptomatic cases or those with no critical findings. Treatment of underlying disease is necessary for patients with a significant past medical history (27). In the present case, the diagnosis was pneumatosis intestinalis due to BEV and PEM, so we discontinued both drugs. Additionally, the patient was asymptomatic at the onset of the disease, and a physical examination and CT showed only free abdominal air, without bowel perforation, obstruction, or necrosis. As a result, we treated him conservatively. However, because of the occurrence of pneumatosis intestinalis, we needed to discontinue the use of anticancer agents, such as BEV and PEM, which were expected to be effective for his lung cancer. This resulted in a narrowing of the treatment options for lung cancer, which may in turn have affected his prognosis.
There are many opportunities to use molecular targeted drugs, including BEV and cytotoxic anticancer drugs such as PEM. Although pneumatosis intestinalis is rare, it is important to consider pneumatosis intestinalis as a possible adverse event in patients treated with these drugs.
The authors state that they have no Conflict of Interest (COI). | Recovered | ReactionOutcome | CC BY-NC-ND | 33551401 | 19,018,327 | 2021-07-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'International normalised ratio increased'. | Hemosuccus Pancreaticus Due to the Rupture of a Pseudoaneurysm That Developed in an Intraductal Papillary Mucinous Neoplasm.
A 76-year-old woman with branch duct intraductal papillary mucinous neoplasm (IPMN) was admitted with epigastric pain and vomiting. She had received warfarin due to a history of deep vein thrombosis. A blood test showed decreased serum hemoglobin and elevated serum amylase. Contrast-enhanced computed tomography revealed acute pancreatitis and formation of a pseudoaneurysm in the IPMN. We suspected rupture of a pseudoaneurysm and performed trans-catheter angiography. Angiography showed extravasation from the posterior superior pancreaticoduodenal artery, and coil embolization was performed. It is important to be alert for the formation of pseudoaneurysm in patients with cystic neoplasms.
Introduction
Hemosuccus pancreaticus (HP) is a rare disease involving bleeding from the papilla of Vater via the pancreatic duct (1). HP is associated with a high mortality rate of 25-40% (2-4); hemorrhagic shock is the most common cause of death (5). HP is mostly caused by acute or chronic pancreatitis, and aneurysms often occur in association with HP. There are a few reports of patients with pancreatic cystic neoplasms that developed HP; surgical treatment was usually performed for the control of HP in those cases.
We herein report a case of HP caused by intraductal papillary mucinous neoplasm (IPMN) with a pseudoaneurysm during anticoagulation drug treatment that was successfully treated with interventional radiography (IVR).
Case Report
The patient was a 76-year-old woman with branch duct IPMN (BD-IPMN) of the pancreatic head that had been followed up regularly with imaging studies twice a year for 8 years (Fig. 1). We also performed endoscopic ultrasonography, but no findings suggestive of malignancy in the IPMN were noted (Fig. 2). She had been treated with warfarin due to a history of deep vein thrombosis. The warfarin dose was 2.25 mg/day and had been optimally controlled for 13 years after she received bilateral total knee arthroplasty. She had no notable family history or drinking habit.
Figure 1. Contrast-enhanced computed tomography showed multiple cystic lesions suspected of being IPMN in the pancreas (arrows). IPMN: intraductal papillary mucinous neoplasm
Figure 2. Endoscopic ultrasonographic findings. Left: B mode, Right: contrast mode. Findings of wall thickening in the IPMN were noted, but there were no nodules on contrast EUS mode. IPMN: intraductal papillary mucinous neoplasm, EUS: endoscopic ultrasonography
Within seven days before the next follow-up, she was urgently admitted to our hospital with epigastric pain and vomiting. Her heart rate was 85/minute, systolic blood pressure was 145 mmHg, diastolic blood pressure was 85 mmHg, and body temperature was 37.0℃. Her abdomen was soft and flat. She had epigastric pain as well as pain in her back, but no tenderness or rebound was observed. A blood test showed a decreased serum hemoglobin level (12.2 to 10.9 g/dL), elevated serum amylase, and a slightly increased international ratio due to the administration of warfarin (Table 1). Contrast-enhanced (CE) computed tomography(CT) revealed acute pancreatitis and the formation of a pseudoaneurysm in the IPMN (Fig. 3). Based on the sudden onset of her symptoms and the blood test results, we suspected that rupture of a pseudoaneurysm. We performed trans-catheter angiography, which revealed extravasation from the posterior superior pancreaticoduodenal artery (PSPA) and performed coil embolization of the PSPA (Fig. 4). Melena was observed three times on the day after the procedure; however, this resolved naturally without the progression of anemia. Based on these findings, we diagnosed the patient with HP caused by the sudden rupture of a pseudoaneurysm.
Table 1. Laboratory Data on the Admission.
Hematologic test AST 27 U/L
White blood cells 11,820 /µL ALT 17 U/L
Red blood cells 3.57×106 /µL ALP 168 U/L
Hemoglobin 10.9 g/dL γ-GTP 13 U/L
Platelet count 23.9×104 /µL LDH 249 U/L
Coagulation Amylase 3,568 U/L
PT 33 % BUN 28.5 mg/dL
PT-INR 1.82 Creatinine 1.06 mg/dL
Fibrinogen 291 mg/dL Sodium 141 mmol/L
Chemistry Potassium 4.4 mmol/L
Total protein 6.1 g/dL Chloride 103 mmol/L
Albumin 4.1 g/dL CRP 0.68 mg/dL
Total bilirubin 0.67 mg/dL glucose 161 mg/dL
Direct bilirubin 0.15 mg/dL HbA1c 6.2 %
PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkali-phosphatase, γ-GTP: γ-glutamyl transpeptidase, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, CRP: C-reaction protein, HbA1c: hemoglobin A1c
Figure 3. Contrast-enhanced computed tomography revealed acute pancreatitis and the formation of a pseudoaneurysm in the head of the IPMN. A) Axial image. B) Coronal image. IPMN: intraductal papillary mucinous neoplasm
Figure 4. The angiography findings. A) Extravasation from the pseudoaneurysm at the PSPA (arrow). B) After coil embolization. The aneurysm disappeared (arrow), and the blood flow in the PSPA was blocked (arrowheads). PSPA: posterior superior pancreaticoduodenal artery
Her clinical course is shown in Fig. 5. She was discharged on the eighth day after the coil embolization. Follow-up CT revealed that the pseudoaneurysm had been completely treated and that the findings of acute pancreatitis were improved (Fig. 6). Although we recommended surgery (pancreaticoduodenectomy) for the prevention of recurrence of pancreatitis, she refused surgical treatment. Thus, she has been carefully followed up with imaging studies. There have been no events in the year of follow-up.
Figure 5. The clinical course from admission to discharge. IVR: interventional radiology, AMY: amylase, Hb: hemoglobin, BUN: blood urea nitrogen
Figure 6. Follow-up CT revealed that the pseudoaneurysm had been completely treated, and the findings of acute pancreatitis had improved.
Discussion
We herein report a rare case of HP caused by IPMN with a pseudoaneurysm during anticoagulation drug treatment. HP due to a pseudoaneurysm caused by a cystic neoplasm of the pancreas is rare. We successfully controlled the bleeding from a pseudoaneurysm using IVR.
According to a review of cases of HP, the main causes of HP are arterial aneurysm, inflammatory changes in the pancreas (acute and/or chronic), and pancreatic tumors (6,7). Ru Nan et al. summarized 114 HP cases (6), and the causes of HP were pancreatitis in 95 cases (82.6%), pancreatic tumor in 18 cases (16.5%), and congenital pancreatic malformation in 1 case (0.9%). The breakdowns of pancreatic tumors were cystadenoma in 8 cases (7.0%), IPMN in 5 cases (4.3%), endocrine tumors in 2 cases (1.7%), adenocarcinoma in 1 case (0.9%), and carcinoma in situ in 1 case (0.9%). Many studies have reported that the direct source of bleeding was a ruptured aneurysm; the most common site of causative aneurysms is the splenic artery (8-10). Aneurysms of the pancreatic and pancreaticoduodenal arteries are rare, accounting for only 2% of all splanchnic artery aneurysms (9), and peripancreatic aneurysms are among the most life-threatening of all splanchnic artery aneurysms (10).
In the diagnosis of HP, esophagogastroduodenoscopy (EGD) is a useful examination for confirming hemorrhaging from the main papilla. However, according to a report by Vimalraj et al. summarizing 31 HP cases, bleeding from the papilla was confirmed in about half of their 16 cases (51%). CE-CT (90%; 28/31) and angiography (88%; 23/26) depicted positive findings for HP (11). Thus, in some cases, bleeding from the papilla could not be detected, and these cases were diagnosed with HP based on other radiographic findings and the clinical course [of note, some cases were diagnosed by surgery (12)]. In the present case, HP was suspected because 1) anemia had progressed according to blood test findings, 2) there was extravasation from a pseudoaneurysm in the IPMN on CE-CT and IVR, 3) there was evidence of acute pancreatitis, and 4) melena appeared in the subsequent clinical course. We therefore diagnosed the patient with HP based on these radiographic findings and the clinical course.
The main treatments of HP are IVR and surgery. Once the patient is hemodynamically stable, IVR procedures are effective as an initial treatment in 67-100% of cases (13). If the source of bleeding is found on angiography, IVR procedures are the first choice for initial management, with immediate good results in 79-100% of cases and an overall success rate of 67% (14,15). For patients with hemodynamic instability, emergency operations are inevitable. Distal pancreatectomy is a surgical alternative to IVR procedures for a bleeding pancreatic pseudoaneurysm in the body or tail of the pancreas. However, when the pseudoaneurysm is located in the head of the pancreas, surgical resection is associated with increased mortality and morbidity, and IVR procedures have been proposed as the recommended treatment modality in such cases. In the present case, the patient's vital signs were stable, and the pseudoaneurysm was found in the IPMN at the head of the pancreas. The source of bleeding was found on angiography, and coil embolization was successfully performed. As a result, we were able to control the HP and avoid emergency surgery.
There have been eight reported cases of HP due to pancreatic cystic neoplasms in the relevant literature (16-23) (Table 2). Including our case, 5 cases (56%) were IPMN, and 2 cases each (22%) were mucinous cystic neoplasms and serous cystic neoplasms. The median age was 67 years old, and 4 of the patients (44%) were men. The median tumor size was 31 mm, and most of the tumors were ≥20 mm in diameter. Most of the tumors were located at the pancreatic body or tail. The causes of HP included bleeding from the tumor in 5 cases (56%) and rupture of an arterial pseudoaneurysm in 4 cases (44%). Two cases were treated with an antithrombotic drug. Most cases were treated with surgery, and two cases (including our case) were treated with an IVR procedure. The rupture of a splenic artery aneurysm was mostly seen as the cause of HP, and this is the first reported case with a ruptured PSPA pseudoaneurysm.
Table 2. Hemosuccus Pancreaticus with Pancreatic Cyst Neoplasms.
Reference
no. Age Sex Neoplasms Antithrombotic therapy Cause of HP Treatment
variation location size (mm)
16 57 F SCN tail 40 none rupture of SA aneurysm surgery
17 71 F MCN tail 25 none tumor bleeding surgery
18 58 M IPMN tail 36 n.d. rupture of SA aneurysm surgery
19 35 F SCN head/tail n.d. none tumor bleeding surgery
20 78 M IPMN tail n.d. antiplatelet (ticlopidine) tumor bleeding surgery
21 62 F MCN tail 30 none tumor bleeding surgery
22 67 M IPMN body n.d. none rupture of SA aneurysm IVR
23 79 M IPMN body 12 none tumor bleeding surgery
our case 76 F IPMN head 31 anticoagulation (warfarin) rupture of PSPA aneurysm IVR
HP: hemosuccus pancreaticus, SA: splenic artery, PSPA: posterior superior pancreaticoduodenal artery, SCN: serous cystic neoplasm, MCN: mucinous cystic neoplasm, IPMN: intraductal papillary mucinous neoplasm, IVR: interventional radiology, n.d.: no data, F: female, M: male
IPMN may reportedly cause HP due to rupture of the blood vessel wall in association with concomitant pancreatitis or hemorrhaging associated with tumor necrosis (20). In patients with IPMN, the blood vessel walls are exposed to viscous pancreatic juice. Such long-term exposure can cause the rupture of the elastic fibers in the vessel wall, forming an extravascular circulation space with the fibrous cap and thus creating a pseudoaneurysm (24). In this case, warfarin was controlled in the therapeutic range, and its involvement in the bleeding from the cyst is unclear. However, a case of HP in which a cystic neoplasm developed under antithrombotic therapy was previously reported (20), so further investigations concerning the relationship between antithrombotic therapy and HP should be conducted in the future.
Conclusions
We encountered a case of HP due to rupture of a pseudoaneurysm in a patient with IPMN. It is important to be alert for the formation of pseudoaneurysms when we follow patients with cystic neoplasms.
The authors state that they have no Conflict of Interest (COI). | WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 33551406 | 19,724,295 | 2021-07-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pancreatic haemorrhage'. | Hemosuccus Pancreaticus Due to the Rupture of a Pseudoaneurysm That Developed in an Intraductal Papillary Mucinous Neoplasm.
A 76-year-old woman with branch duct intraductal papillary mucinous neoplasm (IPMN) was admitted with epigastric pain and vomiting. She had received warfarin due to a history of deep vein thrombosis. A blood test showed decreased serum hemoglobin and elevated serum amylase. Contrast-enhanced computed tomography revealed acute pancreatitis and formation of a pseudoaneurysm in the IPMN. We suspected rupture of a pseudoaneurysm and performed trans-catheter angiography. Angiography showed extravasation from the posterior superior pancreaticoduodenal artery, and coil embolization was performed. It is important to be alert for the formation of pseudoaneurysm in patients with cystic neoplasms.
Introduction
Hemosuccus pancreaticus (HP) is a rare disease involving bleeding from the papilla of Vater via the pancreatic duct (1). HP is associated with a high mortality rate of 25-40% (2-4); hemorrhagic shock is the most common cause of death (5). HP is mostly caused by acute or chronic pancreatitis, and aneurysms often occur in association with HP. There are a few reports of patients with pancreatic cystic neoplasms that developed HP; surgical treatment was usually performed for the control of HP in those cases.
We herein report a case of HP caused by intraductal papillary mucinous neoplasm (IPMN) with a pseudoaneurysm during anticoagulation drug treatment that was successfully treated with interventional radiography (IVR).
Case Report
The patient was a 76-year-old woman with branch duct IPMN (BD-IPMN) of the pancreatic head that had been followed up regularly with imaging studies twice a year for 8 years (Fig. 1). We also performed endoscopic ultrasonography, but no findings suggestive of malignancy in the IPMN were noted (Fig. 2). She had been treated with warfarin due to a history of deep vein thrombosis. The warfarin dose was 2.25 mg/day and had been optimally controlled for 13 years after she received bilateral total knee arthroplasty. She had no notable family history or drinking habit.
Figure 1. Contrast-enhanced computed tomography showed multiple cystic lesions suspected of being IPMN in the pancreas (arrows). IPMN: intraductal papillary mucinous neoplasm
Figure 2. Endoscopic ultrasonographic findings. Left: B mode, Right: contrast mode. Findings of wall thickening in the IPMN were noted, but there were no nodules on contrast EUS mode. IPMN: intraductal papillary mucinous neoplasm, EUS: endoscopic ultrasonography
Within seven days before the next follow-up, she was urgently admitted to our hospital with epigastric pain and vomiting. Her heart rate was 85/minute, systolic blood pressure was 145 mmHg, diastolic blood pressure was 85 mmHg, and body temperature was 37.0℃. Her abdomen was soft and flat. She had epigastric pain as well as pain in her back, but no tenderness or rebound was observed. A blood test showed a decreased serum hemoglobin level (12.2 to 10.9 g/dL), elevated serum amylase, and a slightly increased international ratio due to the administration of warfarin (Table 1). Contrast-enhanced (CE) computed tomography(CT) revealed acute pancreatitis and the formation of a pseudoaneurysm in the IPMN (Fig. 3). Based on the sudden onset of her symptoms and the blood test results, we suspected that rupture of a pseudoaneurysm. We performed trans-catheter angiography, which revealed extravasation from the posterior superior pancreaticoduodenal artery (PSPA) and performed coil embolization of the PSPA (Fig. 4). Melena was observed three times on the day after the procedure; however, this resolved naturally without the progression of anemia. Based on these findings, we diagnosed the patient with HP caused by the sudden rupture of a pseudoaneurysm.
Table 1. Laboratory Data on the Admission.
Hematologic test AST 27 U/L
White blood cells 11,820 /µL ALT 17 U/L
Red blood cells 3.57×106 /µL ALP 168 U/L
Hemoglobin 10.9 g/dL γ-GTP 13 U/L
Platelet count 23.9×104 /µL LDH 249 U/L
Coagulation Amylase 3,568 U/L
PT 33 % BUN 28.5 mg/dL
PT-INR 1.82 Creatinine 1.06 mg/dL
Fibrinogen 291 mg/dL Sodium 141 mmol/L
Chemistry Potassium 4.4 mmol/L
Total protein 6.1 g/dL Chloride 103 mmol/L
Albumin 4.1 g/dL CRP 0.68 mg/dL
Total bilirubin 0.67 mg/dL glucose 161 mg/dL
Direct bilirubin 0.15 mg/dL HbA1c 6.2 %
PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkali-phosphatase, γ-GTP: γ-glutamyl transpeptidase, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, CRP: C-reaction protein, HbA1c: hemoglobin A1c
Figure 3. Contrast-enhanced computed tomography revealed acute pancreatitis and the formation of a pseudoaneurysm in the head of the IPMN. A) Axial image. B) Coronal image. IPMN: intraductal papillary mucinous neoplasm
Figure 4. The angiography findings. A) Extravasation from the pseudoaneurysm at the PSPA (arrow). B) After coil embolization. The aneurysm disappeared (arrow), and the blood flow in the PSPA was blocked (arrowheads). PSPA: posterior superior pancreaticoduodenal artery
Her clinical course is shown in Fig. 5. She was discharged on the eighth day after the coil embolization. Follow-up CT revealed that the pseudoaneurysm had been completely treated and that the findings of acute pancreatitis were improved (Fig. 6). Although we recommended surgery (pancreaticoduodenectomy) for the prevention of recurrence of pancreatitis, she refused surgical treatment. Thus, she has been carefully followed up with imaging studies. There have been no events in the year of follow-up.
Figure 5. The clinical course from admission to discharge. IVR: interventional radiology, AMY: amylase, Hb: hemoglobin, BUN: blood urea nitrogen
Figure 6. Follow-up CT revealed that the pseudoaneurysm had been completely treated, and the findings of acute pancreatitis had improved.
Discussion
We herein report a rare case of HP caused by IPMN with a pseudoaneurysm during anticoagulation drug treatment. HP due to a pseudoaneurysm caused by a cystic neoplasm of the pancreas is rare. We successfully controlled the bleeding from a pseudoaneurysm using IVR.
According to a review of cases of HP, the main causes of HP are arterial aneurysm, inflammatory changes in the pancreas (acute and/or chronic), and pancreatic tumors (6,7). Ru Nan et al. summarized 114 HP cases (6), and the causes of HP were pancreatitis in 95 cases (82.6%), pancreatic tumor in 18 cases (16.5%), and congenital pancreatic malformation in 1 case (0.9%). The breakdowns of pancreatic tumors were cystadenoma in 8 cases (7.0%), IPMN in 5 cases (4.3%), endocrine tumors in 2 cases (1.7%), adenocarcinoma in 1 case (0.9%), and carcinoma in situ in 1 case (0.9%). Many studies have reported that the direct source of bleeding was a ruptured aneurysm; the most common site of causative aneurysms is the splenic artery (8-10). Aneurysms of the pancreatic and pancreaticoduodenal arteries are rare, accounting for only 2% of all splanchnic artery aneurysms (9), and peripancreatic aneurysms are among the most life-threatening of all splanchnic artery aneurysms (10).
In the diagnosis of HP, esophagogastroduodenoscopy (EGD) is a useful examination for confirming hemorrhaging from the main papilla. However, according to a report by Vimalraj et al. summarizing 31 HP cases, bleeding from the papilla was confirmed in about half of their 16 cases (51%). CE-CT (90%; 28/31) and angiography (88%; 23/26) depicted positive findings for HP (11). Thus, in some cases, bleeding from the papilla could not be detected, and these cases were diagnosed with HP based on other radiographic findings and the clinical course [of note, some cases were diagnosed by surgery (12)]. In the present case, HP was suspected because 1) anemia had progressed according to blood test findings, 2) there was extravasation from a pseudoaneurysm in the IPMN on CE-CT and IVR, 3) there was evidence of acute pancreatitis, and 4) melena appeared in the subsequent clinical course. We therefore diagnosed the patient with HP based on these radiographic findings and the clinical course.
The main treatments of HP are IVR and surgery. Once the patient is hemodynamically stable, IVR procedures are effective as an initial treatment in 67-100% of cases (13). If the source of bleeding is found on angiography, IVR procedures are the first choice for initial management, with immediate good results in 79-100% of cases and an overall success rate of 67% (14,15). For patients with hemodynamic instability, emergency operations are inevitable. Distal pancreatectomy is a surgical alternative to IVR procedures for a bleeding pancreatic pseudoaneurysm in the body or tail of the pancreas. However, when the pseudoaneurysm is located in the head of the pancreas, surgical resection is associated with increased mortality and morbidity, and IVR procedures have been proposed as the recommended treatment modality in such cases. In the present case, the patient's vital signs were stable, and the pseudoaneurysm was found in the IPMN at the head of the pancreas. The source of bleeding was found on angiography, and coil embolization was successfully performed. As a result, we were able to control the HP and avoid emergency surgery.
There have been eight reported cases of HP due to pancreatic cystic neoplasms in the relevant literature (16-23) (Table 2). Including our case, 5 cases (56%) were IPMN, and 2 cases each (22%) were mucinous cystic neoplasms and serous cystic neoplasms. The median age was 67 years old, and 4 of the patients (44%) were men. The median tumor size was 31 mm, and most of the tumors were ≥20 mm in diameter. Most of the tumors were located at the pancreatic body or tail. The causes of HP included bleeding from the tumor in 5 cases (56%) and rupture of an arterial pseudoaneurysm in 4 cases (44%). Two cases were treated with an antithrombotic drug. Most cases were treated with surgery, and two cases (including our case) were treated with an IVR procedure. The rupture of a splenic artery aneurysm was mostly seen as the cause of HP, and this is the first reported case with a ruptured PSPA pseudoaneurysm.
Table 2. Hemosuccus Pancreaticus with Pancreatic Cyst Neoplasms.
Reference
no. Age Sex Neoplasms Antithrombotic therapy Cause of HP Treatment
variation location size (mm)
16 57 F SCN tail 40 none rupture of SA aneurysm surgery
17 71 F MCN tail 25 none tumor bleeding surgery
18 58 M IPMN tail 36 n.d. rupture of SA aneurysm surgery
19 35 F SCN head/tail n.d. none tumor bleeding surgery
20 78 M IPMN tail n.d. antiplatelet (ticlopidine) tumor bleeding surgery
21 62 F MCN tail 30 none tumor bleeding surgery
22 67 M IPMN body n.d. none rupture of SA aneurysm IVR
23 79 M IPMN body 12 none tumor bleeding surgery
our case 76 F IPMN head 31 anticoagulation (warfarin) rupture of PSPA aneurysm IVR
HP: hemosuccus pancreaticus, SA: splenic artery, PSPA: posterior superior pancreaticoduodenal artery, SCN: serous cystic neoplasm, MCN: mucinous cystic neoplasm, IPMN: intraductal papillary mucinous neoplasm, IVR: interventional radiology, n.d.: no data, F: female, M: male
IPMN may reportedly cause HP due to rupture of the blood vessel wall in association with concomitant pancreatitis or hemorrhaging associated with tumor necrosis (20). In patients with IPMN, the blood vessel walls are exposed to viscous pancreatic juice. Such long-term exposure can cause the rupture of the elastic fibers in the vessel wall, forming an extravascular circulation space with the fibrous cap and thus creating a pseudoaneurysm (24). In this case, warfarin was controlled in the therapeutic range, and its involvement in the bleeding from the cyst is unclear. However, a case of HP in which a cystic neoplasm developed under antithrombotic therapy was previously reported (20), so further investigations concerning the relationship between antithrombotic therapy and HP should be conducted in the future.
Conclusions
We encountered a case of HP due to rupture of a pseudoaneurysm in a patient with IPMN. It is important to be alert for the formation of pseudoaneurysms when we follow patients with cystic neoplasms.
The authors state that they have no Conflict of Interest (COI). | WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 33551406 | 19,724,295 | 2021-07-01 |
What was the outcome of reaction 'Pancreatic haemorrhage'? | Hemosuccus Pancreaticus Due to the Rupture of a Pseudoaneurysm That Developed in an Intraductal Papillary Mucinous Neoplasm.
A 76-year-old woman with branch duct intraductal papillary mucinous neoplasm (IPMN) was admitted with epigastric pain and vomiting. She had received warfarin due to a history of deep vein thrombosis. A blood test showed decreased serum hemoglobin and elevated serum amylase. Contrast-enhanced computed tomography revealed acute pancreatitis and formation of a pseudoaneurysm in the IPMN. We suspected rupture of a pseudoaneurysm and performed trans-catheter angiography. Angiography showed extravasation from the posterior superior pancreaticoduodenal artery, and coil embolization was performed. It is important to be alert for the formation of pseudoaneurysm in patients with cystic neoplasms.
Introduction
Hemosuccus pancreaticus (HP) is a rare disease involving bleeding from the papilla of Vater via the pancreatic duct (1). HP is associated with a high mortality rate of 25-40% (2-4); hemorrhagic shock is the most common cause of death (5). HP is mostly caused by acute or chronic pancreatitis, and aneurysms often occur in association with HP. There are a few reports of patients with pancreatic cystic neoplasms that developed HP; surgical treatment was usually performed for the control of HP in those cases.
We herein report a case of HP caused by intraductal papillary mucinous neoplasm (IPMN) with a pseudoaneurysm during anticoagulation drug treatment that was successfully treated with interventional radiography (IVR).
Case Report
The patient was a 76-year-old woman with branch duct IPMN (BD-IPMN) of the pancreatic head that had been followed up regularly with imaging studies twice a year for 8 years (Fig. 1). We also performed endoscopic ultrasonography, but no findings suggestive of malignancy in the IPMN were noted (Fig. 2). She had been treated with warfarin due to a history of deep vein thrombosis. The warfarin dose was 2.25 mg/day and had been optimally controlled for 13 years after she received bilateral total knee arthroplasty. She had no notable family history or drinking habit.
Figure 1. Contrast-enhanced computed tomography showed multiple cystic lesions suspected of being IPMN in the pancreas (arrows). IPMN: intraductal papillary mucinous neoplasm
Figure 2. Endoscopic ultrasonographic findings. Left: B mode, Right: contrast mode. Findings of wall thickening in the IPMN were noted, but there were no nodules on contrast EUS mode. IPMN: intraductal papillary mucinous neoplasm, EUS: endoscopic ultrasonography
Within seven days before the next follow-up, she was urgently admitted to our hospital with epigastric pain and vomiting. Her heart rate was 85/minute, systolic blood pressure was 145 mmHg, diastolic blood pressure was 85 mmHg, and body temperature was 37.0℃. Her abdomen was soft and flat. She had epigastric pain as well as pain in her back, but no tenderness or rebound was observed. A blood test showed a decreased serum hemoglobin level (12.2 to 10.9 g/dL), elevated serum amylase, and a slightly increased international ratio due to the administration of warfarin (Table 1). Contrast-enhanced (CE) computed tomography(CT) revealed acute pancreatitis and the formation of a pseudoaneurysm in the IPMN (Fig. 3). Based on the sudden onset of her symptoms and the blood test results, we suspected that rupture of a pseudoaneurysm. We performed trans-catheter angiography, which revealed extravasation from the posterior superior pancreaticoduodenal artery (PSPA) and performed coil embolization of the PSPA (Fig. 4). Melena was observed three times on the day after the procedure; however, this resolved naturally without the progression of anemia. Based on these findings, we diagnosed the patient with HP caused by the sudden rupture of a pseudoaneurysm.
Table 1. Laboratory Data on the Admission.
Hematologic test AST 27 U/L
White blood cells 11,820 /µL ALT 17 U/L
Red blood cells 3.57×106 /µL ALP 168 U/L
Hemoglobin 10.9 g/dL γ-GTP 13 U/L
Platelet count 23.9×104 /µL LDH 249 U/L
Coagulation Amylase 3,568 U/L
PT 33 % BUN 28.5 mg/dL
PT-INR 1.82 Creatinine 1.06 mg/dL
Fibrinogen 291 mg/dL Sodium 141 mmol/L
Chemistry Potassium 4.4 mmol/L
Total protein 6.1 g/dL Chloride 103 mmol/L
Albumin 4.1 g/dL CRP 0.68 mg/dL
Total bilirubin 0.67 mg/dL glucose 161 mg/dL
Direct bilirubin 0.15 mg/dL HbA1c 6.2 %
PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkali-phosphatase, γ-GTP: γ-glutamyl transpeptidase, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, CRP: C-reaction protein, HbA1c: hemoglobin A1c
Figure 3. Contrast-enhanced computed tomography revealed acute pancreatitis and the formation of a pseudoaneurysm in the head of the IPMN. A) Axial image. B) Coronal image. IPMN: intraductal papillary mucinous neoplasm
Figure 4. The angiography findings. A) Extravasation from the pseudoaneurysm at the PSPA (arrow). B) After coil embolization. The aneurysm disappeared (arrow), and the blood flow in the PSPA was blocked (arrowheads). PSPA: posterior superior pancreaticoduodenal artery
Her clinical course is shown in Fig. 5. She was discharged on the eighth day after the coil embolization. Follow-up CT revealed that the pseudoaneurysm had been completely treated and that the findings of acute pancreatitis were improved (Fig. 6). Although we recommended surgery (pancreaticoduodenectomy) for the prevention of recurrence of pancreatitis, she refused surgical treatment. Thus, she has been carefully followed up with imaging studies. There have been no events in the year of follow-up.
Figure 5. The clinical course from admission to discharge. IVR: interventional radiology, AMY: amylase, Hb: hemoglobin, BUN: blood urea nitrogen
Figure 6. Follow-up CT revealed that the pseudoaneurysm had been completely treated, and the findings of acute pancreatitis had improved.
Discussion
We herein report a rare case of HP caused by IPMN with a pseudoaneurysm during anticoagulation drug treatment. HP due to a pseudoaneurysm caused by a cystic neoplasm of the pancreas is rare. We successfully controlled the bleeding from a pseudoaneurysm using IVR.
According to a review of cases of HP, the main causes of HP are arterial aneurysm, inflammatory changes in the pancreas (acute and/or chronic), and pancreatic tumors (6,7). Ru Nan et al. summarized 114 HP cases (6), and the causes of HP were pancreatitis in 95 cases (82.6%), pancreatic tumor in 18 cases (16.5%), and congenital pancreatic malformation in 1 case (0.9%). The breakdowns of pancreatic tumors were cystadenoma in 8 cases (7.0%), IPMN in 5 cases (4.3%), endocrine tumors in 2 cases (1.7%), adenocarcinoma in 1 case (0.9%), and carcinoma in situ in 1 case (0.9%). Many studies have reported that the direct source of bleeding was a ruptured aneurysm; the most common site of causative aneurysms is the splenic artery (8-10). Aneurysms of the pancreatic and pancreaticoduodenal arteries are rare, accounting for only 2% of all splanchnic artery aneurysms (9), and peripancreatic aneurysms are among the most life-threatening of all splanchnic artery aneurysms (10).
In the diagnosis of HP, esophagogastroduodenoscopy (EGD) is a useful examination for confirming hemorrhaging from the main papilla. However, according to a report by Vimalraj et al. summarizing 31 HP cases, bleeding from the papilla was confirmed in about half of their 16 cases (51%). CE-CT (90%; 28/31) and angiography (88%; 23/26) depicted positive findings for HP (11). Thus, in some cases, bleeding from the papilla could not be detected, and these cases were diagnosed with HP based on other radiographic findings and the clinical course [of note, some cases were diagnosed by surgery (12)]. In the present case, HP was suspected because 1) anemia had progressed according to blood test findings, 2) there was extravasation from a pseudoaneurysm in the IPMN on CE-CT and IVR, 3) there was evidence of acute pancreatitis, and 4) melena appeared in the subsequent clinical course. We therefore diagnosed the patient with HP based on these radiographic findings and the clinical course.
The main treatments of HP are IVR and surgery. Once the patient is hemodynamically stable, IVR procedures are effective as an initial treatment in 67-100% of cases (13). If the source of bleeding is found on angiography, IVR procedures are the first choice for initial management, with immediate good results in 79-100% of cases and an overall success rate of 67% (14,15). For patients with hemodynamic instability, emergency operations are inevitable. Distal pancreatectomy is a surgical alternative to IVR procedures for a bleeding pancreatic pseudoaneurysm in the body or tail of the pancreas. However, when the pseudoaneurysm is located in the head of the pancreas, surgical resection is associated with increased mortality and morbidity, and IVR procedures have been proposed as the recommended treatment modality in such cases. In the present case, the patient's vital signs were stable, and the pseudoaneurysm was found in the IPMN at the head of the pancreas. The source of bleeding was found on angiography, and coil embolization was successfully performed. As a result, we were able to control the HP and avoid emergency surgery.
There have been eight reported cases of HP due to pancreatic cystic neoplasms in the relevant literature (16-23) (Table 2). Including our case, 5 cases (56%) were IPMN, and 2 cases each (22%) were mucinous cystic neoplasms and serous cystic neoplasms. The median age was 67 years old, and 4 of the patients (44%) were men. The median tumor size was 31 mm, and most of the tumors were ≥20 mm in diameter. Most of the tumors were located at the pancreatic body or tail. The causes of HP included bleeding from the tumor in 5 cases (56%) and rupture of an arterial pseudoaneurysm in 4 cases (44%). Two cases were treated with an antithrombotic drug. Most cases were treated with surgery, and two cases (including our case) were treated with an IVR procedure. The rupture of a splenic artery aneurysm was mostly seen as the cause of HP, and this is the first reported case with a ruptured PSPA pseudoaneurysm.
Table 2. Hemosuccus Pancreaticus with Pancreatic Cyst Neoplasms.
Reference
no. Age Sex Neoplasms Antithrombotic therapy Cause of HP Treatment
variation location size (mm)
16 57 F SCN tail 40 none rupture of SA aneurysm surgery
17 71 F MCN tail 25 none tumor bleeding surgery
18 58 M IPMN tail 36 n.d. rupture of SA aneurysm surgery
19 35 F SCN head/tail n.d. none tumor bleeding surgery
20 78 M IPMN tail n.d. antiplatelet (ticlopidine) tumor bleeding surgery
21 62 F MCN tail 30 none tumor bleeding surgery
22 67 M IPMN body n.d. none rupture of SA aneurysm IVR
23 79 M IPMN body 12 none tumor bleeding surgery
our case 76 F IPMN head 31 anticoagulation (warfarin) rupture of PSPA aneurysm IVR
HP: hemosuccus pancreaticus, SA: splenic artery, PSPA: posterior superior pancreaticoduodenal artery, SCN: serous cystic neoplasm, MCN: mucinous cystic neoplasm, IPMN: intraductal papillary mucinous neoplasm, IVR: interventional radiology, n.d.: no data, F: female, M: male
IPMN may reportedly cause HP due to rupture of the blood vessel wall in association with concomitant pancreatitis or hemorrhaging associated with tumor necrosis (20). In patients with IPMN, the blood vessel walls are exposed to viscous pancreatic juice. Such long-term exposure can cause the rupture of the elastic fibers in the vessel wall, forming an extravascular circulation space with the fibrous cap and thus creating a pseudoaneurysm (24). In this case, warfarin was controlled in the therapeutic range, and its involvement in the bleeding from the cyst is unclear. However, a case of HP in which a cystic neoplasm developed under antithrombotic therapy was previously reported (20), so further investigations concerning the relationship between antithrombotic therapy and HP should be conducted in the future.
Conclusions
We encountered a case of HP due to rupture of a pseudoaneurysm in a patient with IPMN. It is important to be alert for the formation of pseudoaneurysms when we follow patients with cystic neoplasms.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33551406 | 19,724,295 | 2021-07-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | DA-EPOCH-R therapy for high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements in a patient with renal dysfunction.
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit lymphoma, has been reported as refractory to R-CHOP therapy and requires more intensive regimens. However, intensive and safe regimens for patients with renal dysfunction are unknown. Herein, we report the successful use of DA-EPOCH-R therapy for double-hit lymphoma in a 64-year-old man with renal dysfunction. The patient had lymphoma-induced bilateral ureteral obstruction. Although renal dysfunction remained after removing the obstruction using R-CHOP therapy, we completed six cycles of DA-EPOCH-R therapy without any major adverse events. DA-EPOCH-R therapy may be a safe regimen for renal dysfunction patients.
INTRODUCTION
Diffuse large B-cell lymphoma (DLBCL) with MYC and BCL2 rearrangements is often reported to be refractory to R-CHOP therapy, with a poor prognosis.1-4 The 2016 revision of the World Health Organization classification of lymphoid neoplasms newly characterized high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,5 widely and commonly referred to as double-hit lymphoma (DHL) or triple-hit lymphoma (THL).
Although no standard initial treatment for DHL or THL has been established, it has been reported that if organ function is preserved, progression-free survival (PFS) is improved by selecting intensive regimens such as dose-adjusted (DA)-EPOCH-R therapy,6-8 R-HyperCVAD/MA therapy,9 or R-CODOX-M/IVAC therapy,10 rather than R-CHOP therapy.11-13 However, there are few known intensive regimens that can be safely administered to patients with DHL/THL who have moderate to severe renal dysfunction.
We report a case of double-hit lymphoma with renal dysfunction in a patient who underwent DA-EPOCH-R therapy according to the protocol, without initial dose reduction.
CASE REPORT
The patient was a 64-year-old Japanese man with no noteworthy medical or family history. He experienced malaise and abdominal distention three weeks before admission, and chest discomfort and orthopnea began five days before admission. The day before admission, he visited the emergency department, presenting with arm and leg edema and right pleural effusion seen on chest X-ray. Heart failure was suspected, and he was prescribed furosemide. The next day, he visited the internal department of the general hospital. Plain computed tomography (CT) revealed bilateral hydronephrosis and a retroperitoneal mass lesion. He was then transferred to the urology department of our hospital as an emergency case. Blood tests showed elevated soluble interleukin-2 receptor (sIL-2R) levels at 9334 IU/L, and he was referred to our department with suspicion of malignant lymphoma.
On admission, he was fully conscious, his temperature was 35.7°C, pulse was 53 beats per minute, blood pressure was 177/87 mmHg, and SpO2 was 98% on room air. He had no anemia in the foveal conjunctiva and no jaundice in the ocular conjunctiva. Respiratory and cardiac sounds were normal. The abdomen was flat and soft, and the liver and spleen were not palpable. Both lower limbs had pitting edema. Inguinal lymph nodes were 3-cm in size and elastic, hard, and smooth-textured on palpation bilaterally. No other superficial lymph nodes were palpated. There were no abnormal neurological findings. His Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 2. He had no systemic B symptoms (fever, night sweats, or weight loss).
Laboratory data on admission (Table 1) showed a markedly elevated creatinine (Cre) of 17.31 mg/dL, blood urea nitrogen (BUN) of 121 mg/dL, potassium (K) of 7.3 mEq/L, and inorganic phosphorus (IP) of 10.1 mg/dL. Lactate dehydrogenase (LDH) and sIL-2R were elevated to 666 IU/L and 9334 IU/mL, respectively. Plain CT (Figure 1) showed a 9 cm × 5 cm retroperitoneal mass causing bilateral hydronephrosis and partially kidney invasive lesion. It also showed pleural effusions and right cardiophrenic and bilateral inguinal lymphadenopathies. Bone marrow examination revealed no apparent tumor cell infiltration, and Giemsa banding showed a normal 46,XY karyotype. Cytopathologic examination of pleural fluid showed invasion of large abnormal lymphocytes.
Table 1 Laboratory data on admission
RBC 424×104 /μL TP 6.5 g/dL Ca 9.2 mg/dL
Hb 12.8 g/dL Alb 3.5 g/dL IP 10.1 mg/dL
Hct 37.0 % AST 14 IU/L CRP 3.17 mg/dL
MCV 87.3 fl ALT 14 IU/L sIL-2R 9334 IU/mL
MCH 30.2 pg LDH 666 IU/L Ferritin 417 ng/mL
MCHC 34.6 % ALP 187 IU/L IgG 467 mg/dL
WBC 9980 /μL γ-GTP 19 IU/L IgA 45 mg/dL
Neu 83.5 % T-Bil 0.4 mg/dL IgM 207 mg/dL
Lym 9.9 % BUN 121 mg/dL APTT 27.4 sec
Eos 5.3 % Cre 17.37 mg/dL (control) 26.7 sec
Bas 1.1 % Na 130 mEq/L PT% 98 %
Mon 0.2 % K 7.3 mEq/L PT-INR 1.01
Plt 45.7×104 /μL Cl 94 mEq/L
RBC: red blood cell, Hb: hemoglobin, Hct: hematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration, WBC: white blood cell, Neu: neutrophil, Lym: lymphocyte, Eos: eosinophil, Bas: basophil, Mon: monocyte, Plt: platelet, TP: total protein, Alb: albumin, AST: aspartate transaminase, ALT: alanine transaminase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, T-Bil: total bilirubin, BUN: blood urea nitrogen, Cre: creatinine, IP: inorganic phosphate, CRP: C-reactive protein, sIL-2R: soluble interleukin-2 receptor, APTT: activated partial thromboplastin time, PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio
Fig. 1 Systemic computed tomographic (CT) scan on admission (A, B, C, D) and after 6 cycles of DA-EPOCH-R therapy (E, F, G, H)
Systemic CT scan on admission shows a right cardiophrenic lymphadenopathy (arrow), pleural effusions (A), bilateral hydronephrosis (arrow) and renal infiltration (B), a 9 cm × 5 cm retroperitoneal mass (arrow) (C), and bilateral inguinal lymphadenopathies (arrow) (D). Each lesion shrank after 6 cycles of DA-EPOCH-R (E, F, G, H).
On the second day in hospital, inguinal lymph node biopsy was performed (Figure 2). Hematoxylin and eosin (H&E) staining showed a diffuse pattern of involvement with medium to large abnormal lymphocytes, and loss of the normal structure of lymphoid follicles. Immunostaining showed that the tumor was negative for CD3 and Bcl-6, and positive for CD10, CD20, CD79a, Ki67, c-Myc, and Bcl-2. The positive rate of Ki67, c-Myc and Bcl-2 was over 90% for each. Fluorescence in situ hybridization (FISH) showed split signals at 8q24 (MYC) and 18q21 (BCL2) (Figure 3). Based on these findings, we diagnosed high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements. Ann Arbor stage was IV A and International Prognostic Index was high-intermediate risk.
Fig. 2 Pathological images of inguinal lymph node biopsy
Hematoxylin and eosin (H&E) staining images show a diffuse pattern of involvement with medium to large abnormal lymphocytes, with loss of the normal structure of lymphoid follicles (A). Immunostaining images show that the tumor was negative for CD3 (B), negative for CD10 (C), positive for CD20 (D), positive for CD79a (E), positive for Ki67 (positive rate was over 90%) (F), positive for c-Myc (positive rate was over 90%) (G), positive for Bcl-2 (positive rate was over 90%) (H) and negative for Bcl-6 (I).
Fig. 3 Fluorescence in situ hybridization (FISH) of inguinal lymph node biopsy
Of 111 cells, 74 (66.7%) showed split signals at 8q24 (MYC) and duplication of 5’ MYC and 3’ MYC probe signals (A). Out of 104 cells, 68 (65.4%) showed split signals at 18q21 (BCL2) and duplication of 5’ BCL2 probe signals (B).
On the day of admission, right nephrostomy was performed for ureteral obstruction, but Cre improvement was poor, and the patient required emergency hemodialysis from the 4th hospital day. As diagnosis from the preliminary pathological report was diffuse large B-cell lymphoma (DLBCL), we started half-dose CHOP therapy (cyclophosphamide 375 mg/m2, day 1; doxorubicin 25 mg/m2, day 1; vincristine 0.7 mg/m2, day 1; prednisolone 60 mg/m2, days 1–5) on the 23rd hospital day. Rasburicase was administered to prevent tumor lysis syndrome. Urinary volume of 1000 mL/day was obtained on the 25th hospital day, but despite this and removal of the ureteral obstruction, Cre and 24-hour urine collection creatinine clearance (Ccr) improved only to 2.4 mg/dL and 37 mL/min, respectively, and right renal dysfunction remained (Figure 4). The patient was weaned off hemodialysis on the 30th hospital day. After the first cycle of half-dose CHOP therapy, the treatment response was stable disease (SD) with 47% tumor reduction (Figure 1). Cre remained approximately 2 mg/dL during treatment.
Fig. 4 Treatment and transition of serum lactate dehydrogenase (LDH), serum creatinine (Cre), and 24-hour urine collection creatinine clearance (Ccr)
Nephrostomy was performed for ureteral obstruction on the first hospital day. However, Cre did not improve, and we started hemodialysis. We performed half-dose CHOP therapy and the obstruction was removed immediately, although renal dysfunction remained (Cre 2.4 mg/dL, Ccr 37 mL/min). Owing to the confirmed diagnosis of the high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, we decided to use an intensive regimen and started full-dose DA-EPOCH-R therapy. Doses were reduced by 20% from the fourth cycle onward due to Common Terminology Criteria for Adverse Event (CTCAE) grade 4 neutropenia. Six cycles of DA-EPOCH-R therapy were completed without other adverse events greater than CTCAE grade 2. DA-EPOCH-R therapy did not exacerbate renal dysfunction. Cre and Ccr were stable at around 2-3 mg/dL and 30-40 mL/min, respectively, during the treatment.
Pathological examination and FISH revealed the diagnosis of high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements. Although Ccr was as low as 45 mL/min, we started DA-EPOCH-R therapy (rituximab 375 mg/m2, day 1; doxorubicin 10 mg/m2, days 2–5; vincristine 0.4 mg/m2, days 2–5; cyclophosphamide 750 mg/m2, day 6; prednisolone 60 mg/m2, days 2–6; administered every 21 days) without initial dose reduction on the 38th hospital day because more intensive treatment was considered necessary for DHL/THL. No worsening of renal function was observed during the treatment, and the patient completed the first cycle without any problems. The treatment response was partial response (PR) with 64% tumor reduction, and we decided to continue the DA-EPOCH-R therapy. On the third cycle, grade 4 neutropenia as categorized by the Common Terminology Criteria for Adverse Events (CTCAE) was observed, and we therefore reduced dosages from the fourth cycle onward by 20% in accordance with the protocol for DA-EPOCH-R therapy. The patient completed six cycles of DA-EPOCH-R without any new CTCAE grade 2 or higher adverse events. Ccr remained between 31 and 43 mL/min, with no further exacerbation. Plain CT after six cycles of DA-EPOCH-R therapy showed the response was PR with 65% tumor reduction, although contrast-enhanced CT was not possible due to renal dysfunction, and the accurate evaluation was difficult. There was no indication of tumor enlargement, and we therefore decided to monitor him as an outpatient and he was discharged on the 163rd hospital day. We scheduled positron emission tomography-computed tomography (PET-CT) after discharge. However, 22 days after discharge he presented diplopia. Head magnetic resonance imaging revealed swellings of the bilateral abducens nerves and the left optic nerve. Cytopathologic examination of lumbar puncture showed an invasion of large abnormal lymphocytes. He was readmitted, and we could not perform PET-CT.
DISCUSSION
We describe a case in which a DHL patient with moderate renal dysfunction (Cre 2 mg/dL, Ccr 30 mL/min) was treated with DA-EPOCH-R therapy according to the protocol without major adverse events, including worsening renal function.
Although a standard initial treatment for DHL/THL has not been established, it has been reported that intensive regimens such as DA-EPOCH-R therapy, R-HyperCVAD/MA therapy, and R-CODOX-M/IVAC therapy improve progression-free survival (PFS) rates more than R-CHOP therapy.11-13 A meta-analysis reported that DA-EPOCH-R had lower toxicity and superior PFS and overall survival (OS) than a combined R-HyperCVAD/MA and R-CODOX-M/IVAC treatment (median PFS 22.2 months and 18.9 months, respectively; median OS 31.4 months and 25.2 months, respectively).11 A phase 2 prospective study in DHL also showed a high efficacy of DA-EPOCH-R therapy.14
Although the efficacy of DA-EPOCH-R therapy as an initial treatment for DHL/THL has been established, in the prospective study mentioned above14 and in an initial report on DA-EPOCH-R therapy,6 patients with renal dysfunction with a Cre >1.5 mg/dL were excluded from the studies. Therefore, the safety of DA-EPOCH-R therapy in patients with renal dysfunction is currently unknown and presents a major question in daily clinical practice. There are few reports regarding DA-EPOCH-R in patients with moderate or severe renal dysfunction, and we could find only two such cases.15 One case of Burkitt lymphoma with acute kidney injury due to dehydration; this recovered to Cre of 1.73 mg/dL with hydration, and DA-EPOCH-R therapy was subsequently commenced. The second case of Burkitt lymphoma with ureteral obstruction due to the tumor. COP therapy (cyclophosphamide, vincristine, and methylprednisolone) was commenced as the initial treatment, and ureteral obstruction was removed. After improvement of Cre to 1.73 mg/dL, DA-EPOCH-R therapy was started. Both cases completed six cycles of DA-EPOCH-R therapy without exacerbation of renal dysfunction. Considering these reports, DA-EPOCH-R therapy is likely to be safe even in patients with moderate renal dysfunction. For this reason, we selected DA-EPOCH-R therapy instead of CHOP therapy in this case.
According to a report on dose recommendation for anticancer drugs for renal dysfunction,16 there is no need to adjust doses of rituximab, doxorubicin, vincristine, and cyclophosphamide if the Ccr is 45 mL/min, and a 75% dose of etoposide is recommended. In this case, etoposide was administered at 100% dose to prioritize efficacy over toxicity. If safety is more important, a 75% reduction in the dose of etoposide may be considered. We could safely administer the DA-EPOCH-R therapy both by preparing a system to resume dialysis at any time if renal dysfunction became exacerbated, and by monitoring the patient with frequent blood tests.
The patient in this case had a retroperitoneal mass and kidney invasion resulting in bilateral hydronephrosis and post-renal acute kidney injury. Cre on admission was 17.37 mg/dL, and it required temporary hemodialysis. Although half-dose CHOP therapy resolved the ureteral obstruction, Cre improved only to approximately 2 mg/dL, and renal dysfunction remained because of kidney lesion. We selected DA-EPOCH-R therapy considering the high risk of recurrence with R-CHOP therapy for DHL/THL, although there was concern regarding decreasing renal function due to high-intensive chemotherapy. We did not select R-CODOX-M/IVAC therapy because high-dose methotrexate therapy has been reported to worsen renal function in a high number of patients with renal dysfunction.17 We were able to complete six cycles of DA-EPOCH-R therapy according to the protocol and reach remission. Moreover, there was no worsening of renal dysfunction.
Recurrence of central nerve system (CNS) is known to have a high frequency in DLBCL with MYC translocation,2 for which CNS prophylaxis is recommended. The same is true for DHL, and a clinical trial showing the efficacy of R-EPOCH for DHL14 also included CNS prophylaxis with intrathecal methotrexate. In general, high-dose intravenous methotrexate and intrathecal methotrexate are widely used for CNS prophylaxis in NHL.18 While high-dose intravenous methotrexate has been reported to significantly reduce CNS recurrence,19,20 there is no evidence regarding whether intrathecal methotrexate alone significantly reduces or does not prevent CNS recurrence.21-23 In this case, intrathecal methotrexate could not be administered because the patient was in poor general condition on admission and could not be positioned for lumbar puncture. High-dose methotrexate therapy could not be administered due to renal dysfunction. Although there is no solid evidence that intrathecal methotrexate significantly suppresses CNS recurrence, the decision not to administer intrathecal methotrexate in this case is a major regret. Whether intrathecal methotrexate alone is useful for preventing CNS recurrence needs to be studied on a larger scale.
Our experience, combined with the conclusions of the two cases mentioned above, suggests that DA-EPOCH-R therapy may be safely administered even if Cre is below 2–3 mg/dL or Ccr is above 30–40 mL/min, although no definite reference values for Cre and Ccr can yet be set. There have been few reports of DA-EPOCH-R therapy administered to patients with renal dysfunction, and an appropriate treatment regimen for DHL/THL patients with renal dysfunction has not been established. We therefore recommend carrying out more case studies to continue the evaluation of the safety and efficacy of DA-EPOCH-R therapy for patients with renal dysfunction.
CONFLICT OF INTEREST
The authors declare no conflicts of interest. | CYCLOPHOSPHAMIDE, DOXORUBICIN, ETOPOSIDE, PREDNISOLONE, RITUXIMAB, VINCRISTINE | DrugsGivenReaction | CC BY-NC-SA | 33551436 | 19,067,711 | 2021-03-18 |
What was the dosage of drug 'CYCLOPHOSPHAMIDE'? | DA-EPOCH-R therapy for high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements in a patient with renal dysfunction.
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit lymphoma, has been reported as refractory to R-CHOP therapy and requires more intensive regimens. However, intensive and safe regimens for patients with renal dysfunction are unknown. Herein, we report the successful use of DA-EPOCH-R therapy for double-hit lymphoma in a 64-year-old man with renal dysfunction. The patient had lymphoma-induced bilateral ureteral obstruction. Although renal dysfunction remained after removing the obstruction using R-CHOP therapy, we completed six cycles of DA-EPOCH-R therapy without any major adverse events. DA-EPOCH-R therapy may be a safe regimen for renal dysfunction patients.
INTRODUCTION
Diffuse large B-cell lymphoma (DLBCL) with MYC and BCL2 rearrangements is often reported to be refractory to R-CHOP therapy, with a poor prognosis.1-4 The 2016 revision of the World Health Organization classification of lymphoid neoplasms newly characterized high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,5 widely and commonly referred to as double-hit lymphoma (DHL) or triple-hit lymphoma (THL).
Although no standard initial treatment for DHL or THL has been established, it has been reported that if organ function is preserved, progression-free survival (PFS) is improved by selecting intensive regimens such as dose-adjusted (DA)-EPOCH-R therapy,6-8 R-HyperCVAD/MA therapy,9 or R-CODOX-M/IVAC therapy,10 rather than R-CHOP therapy.11-13 However, there are few known intensive regimens that can be safely administered to patients with DHL/THL who have moderate to severe renal dysfunction.
We report a case of double-hit lymphoma with renal dysfunction in a patient who underwent DA-EPOCH-R therapy according to the protocol, without initial dose reduction.
CASE REPORT
The patient was a 64-year-old Japanese man with no noteworthy medical or family history. He experienced malaise and abdominal distention three weeks before admission, and chest discomfort and orthopnea began five days before admission. The day before admission, he visited the emergency department, presenting with arm and leg edema and right pleural effusion seen on chest X-ray. Heart failure was suspected, and he was prescribed furosemide. The next day, he visited the internal department of the general hospital. Plain computed tomography (CT) revealed bilateral hydronephrosis and a retroperitoneal mass lesion. He was then transferred to the urology department of our hospital as an emergency case. Blood tests showed elevated soluble interleukin-2 receptor (sIL-2R) levels at 9334 IU/L, and he was referred to our department with suspicion of malignant lymphoma.
On admission, he was fully conscious, his temperature was 35.7°C, pulse was 53 beats per minute, blood pressure was 177/87 mmHg, and SpO2 was 98% on room air. He had no anemia in the foveal conjunctiva and no jaundice in the ocular conjunctiva. Respiratory and cardiac sounds were normal. The abdomen was flat and soft, and the liver and spleen were not palpable. Both lower limbs had pitting edema. Inguinal lymph nodes were 3-cm in size and elastic, hard, and smooth-textured on palpation bilaterally. No other superficial lymph nodes were palpated. There were no abnormal neurological findings. His Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 2. He had no systemic B symptoms (fever, night sweats, or weight loss).
Laboratory data on admission (Table 1) showed a markedly elevated creatinine (Cre) of 17.31 mg/dL, blood urea nitrogen (BUN) of 121 mg/dL, potassium (K) of 7.3 mEq/L, and inorganic phosphorus (IP) of 10.1 mg/dL. Lactate dehydrogenase (LDH) and sIL-2R were elevated to 666 IU/L and 9334 IU/mL, respectively. Plain CT (Figure 1) showed a 9 cm × 5 cm retroperitoneal mass causing bilateral hydronephrosis and partially kidney invasive lesion. It also showed pleural effusions and right cardiophrenic and bilateral inguinal lymphadenopathies. Bone marrow examination revealed no apparent tumor cell infiltration, and Giemsa banding showed a normal 46,XY karyotype. Cytopathologic examination of pleural fluid showed invasion of large abnormal lymphocytes.
Table 1 Laboratory data on admission
RBC 424×104 /μL TP 6.5 g/dL Ca 9.2 mg/dL
Hb 12.8 g/dL Alb 3.5 g/dL IP 10.1 mg/dL
Hct 37.0 % AST 14 IU/L CRP 3.17 mg/dL
MCV 87.3 fl ALT 14 IU/L sIL-2R 9334 IU/mL
MCH 30.2 pg LDH 666 IU/L Ferritin 417 ng/mL
MCHC 34.6 % ALP 187 IU/L IgG 467 mg/dL
WBC 9980 /μL γ-GTP 19 IU/L IgA 45 mg/dL
Neu 83.5 % T-Bil 0.4 mg/dL IgM 207 mg/dL
Lym 9.9 % BUN 121 mg/dL APTT 27.4 sec
Eos 5.3 % Cre 17.37 mg/dL (control) 26.7 sec
Bas 1.1 % Na 130 mEq/L PT% 98 %
Mon 0.2 % K 7.3 mEq/L PT-INR 1.01
Plt 45.7×104 /μL Cl 94 mEq/L
RBC: red blood cell, Hb: hemoglobin, Hct: hematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration, WBC: white blood cell, Neu: neutrophil, Lym: lymphocyte, Eos: eosinophil, Bas: basophil, Mon: monocyte, Plt: platelet, TP: total protein, Alb: albumin, AST: aspartate transaminase, ALT: alanine transaminase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, T-Bil: total bilirubin, BUN: blood urea nitrogen, Cre: creatinine, IP: inorganic phosphate, CRP: C-reactive protein, sIL-2R: soluble interleukin-2 receptor, APTT: activated partial thromboplastin time, PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio
Fig. 1 Systemic computed tomographic (CT) scan on admission (A, B, C, D) and after 6 cycles of DA-EPOCH-R therapy (E, F, G, H)
Systemic CT scan on admission shows a right cardiophrenic lymphadenopathy (arrow), pleural effusions (A), bilateral hydronephrosis (arrow) and renal infiltration (B), a 9 cm × 5 cm retroperitoneal mass (arrow) (C), and bilateral inguinal lymphadenopathies (arrow) (D). Each lesion shrank after 6 cycles of DA-EPOCH-R (E, F, G, H).
On the second day in hospital, inguinal lymph node biopsy was performed (Figure 2). Hematoxylin and eosin (H&E) staining showed a diffuse pattern of involvement with medium to large abnormal lymphocytes, and loss of the normal structure of lymphoid follicles. Immunostaining showed that the tumor was negative for CD3 and Bcl-6, and positive for CD10, CD20, CD79a, Ki67, c-Myc, and Bcl-2. The positive rate of Ki67, c-Myc and Bcl-2 was over 90% for each. Fluorescence in situ hybridization (FISH) showed split signals at 8q24 (MYC) and 18q21 (BCL2) (Figure 3). Based on these findings, we diagnosed high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements. Ann Arbor stage was IV A and International Prognostic Index was high-intermediate risk.
Fig. 2 Pathological images of inguinal lymph node biopsy
Hematoxylin and eosin (H&E) staining images show a diffuse pattern of involvement with medium to large abnormal lymphocytes, with loss of the normal structure of lymphoid follicles (A). Immunostaining images show that the tumor was negative for CD3 (B), negative for CD10 (C), positive for CD20 (D), positive for CD79a (E), positive for Ki67 (positive rate was over 90%) (F), positive for c-Myc (positive rate was over 90%) (G), positive for Bcl-2 (positive rate was over 90%) (H) and negative for Bcl-6 (I).
Fig. 3 Fluorescence in situ hybridization (FISH) of inguinal lymph node biopsy
Of 111 cells, 74 (66.7%) showed split signals at 8q24 (MYC) and duplication of 5’ MYC and 3’ MYC probe signals (A). Out of 104 cells, 68 (65.4%) showed split signals at 18q21 (BCL2) and duplication of 5’ BCL2 probe signals (B).
On the day of admission, right nephrostomy was performed for ureteral obstruction, but Cre improvement was poor, and the patient required emergency hemodialysis from the 4th hospital day. As diagnosis from the preliminary pathological report was diffuse large B-cell lymphoma (DLBCL), we started half-dose CHOP therapy (cyclophosphamide 375 mg/m2, day 1; doxorubicin 25 mg/m2, day 1; vincristine 0.7 mg/m2, day 1; prednisolone 60 mg/m2, days 1–5) on the 23rd hospital day. Rasburicase was administered to prevent tumor lysis syndrome. Urinary volume of 1000 mL/day was obtained on the 25th hospital day, but despite this and removal of the ureteral obstruction, Cre and 24-hour urine collection creatinine clearance (Ccr) improved only to 2.4 mg/dL and 37 mL/min, respectively, and right renal dysfunction remained (Figure 4). The patient was weaned off hemodialysis on the 30th hospital day. After the first cycle of half-dose CHOP therapy, the treatment response was stable disease (SD) with 47% tumor reduction (Figure 1). Cre remained approximately 2 mg/dL during treatment.
Fig. 4 Treatment and transition of serum lactate dehydrogenase (LDH), serum creatinine (Cre), and 24-hour urine collection creatinine clearance (Ccr)
Nephrostomy was performed for ureteral obstruction on the first hospital day. However, Cre did not improve, and we started hemodialysis. We performed half-dose CHOP therapy and the obstruction was removed immediately, although renal dysfunction remained (Cre 2.4 mg/dL, Ccr 37 mL/min). Owing to the confirmed diagnosis of the high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, we decided to use an intensive regimen and started full-dose DA-EPOCH-R therapy. Doses were reduced by 20% from the fourth cycle onward due to Common Terminology Criteria for Adverse Event (CTCAE) grade 4 neutropenia. Six cycles of DA-EPOCH-R therapy were completed without other adverse events greater than CTCAE grade 2. DA-EPOCH-R therapy did not exacerbate renal dysfunction. Cre and Ccr were stable at around 2-3 mg/dL and 30-40 mL/min, respectively, during the treatment.
Pathological examination and FISH revealed the diagnosis of high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements. Although Ccr was as low as 45 mL/min, we started DA-EPOCH-R therapy (rituximab 375 mg/m2, day 1; doxorubicin 10 mg/m2, days 2–5; vincristine 0.4 mg/m2, days 2–5; cyclophosphamide 750 mg/m2, day 6; prednisolone 60 mg/m2, days 2–6; administered every 21 days) without initial dose reduction on the 38th hospital day because more intensive treatment was considered necessary for DHL/THL. No worsening of renal function was observed during the treatment, and the patient completed the first cycle without any problems. The treatment response was partial response (PR) with 64% tumor reduction, and we decided to continue the DA-EPOCH-R therapy. On the third cycle, grade 4 neutropenia as categorized by the Common Terminology Criteria for Adverse Events (CTCAE) was observed, and we therefore reduced dosages from the fourth cycle onward by 20% in accordance with the protocol for DA-EPOCH-R therapy. The patient completed six cycles of DA-EPOCH-R without any new CTCAE grade 2 or higher adverse events. Ccr remained between 31 and 43 mL/min, with no further exacerbation. Plain CT after six cycles of DA-EPOCH-R therapy showed the response was PR with 65% tumor reduction, although contrast-enhanced CT was not possible due to renal dysfunction, and the accurate evaluation was difficult. There was no indication of tumor enlargement, and we therefore decided to monitor him as an outpatient and he was discharged on the 163rd hospital day. We scheduled positron emission tomography-computed tomography (PET-CT) after discharge. However, 22 days after discharge he presented diplopia. Head magnetic resonance imaging revealed swellings of the bilateral abducens nerves and the left optic nerve. Cytopathologic examination of lumbar puncture showed an invasion of large abnormal lymphocytes. He was readmitted, and we could not perform PET-CT.
DISCUSSION
We describe a case in which a DHL patient with moderate renal dysfunction (Cre 2 mg/dL, Ccr 30 mL/min) was treated with DA-EPOCH-R therapy according to the protocol without major adverse events, including worsening renal function.
Although a standard initial treatment for DHL/THL has not been established, it has been reported that intensive regimens such as DA-EPOCH-R therapy, R-HyperCVAD/MA therapy, and R-CODOX-M/IVAC therapy improve progression-free survival (PFS) rates more than R-CHOP therapy.11-13 A meta-analysis reported that DA-EPOCH-R had lower toxicity and superior PFS and overall survival (OS) than a combined R-HyperCVAD/MA and R-CODOX-M/IVAC treatment (median PFS 22.2 months and 18.9 months, respectively; median OS 31.4 months and 25.2 months, respectively).11 A phase 2 prospective study in DHL also showed a high efficacy of DA-EPOCH-R therapy.14
Although the efficacy of DA-EPOCH-R therapy as an initial treatment for DHL/THL has been established, in the prospective study mentioned above14 and in an initial report on DA-EPOCH-R therapy,6 patients with renal dysfunction with a Cre >1.5 mg/dL were excluded from the studies. Therefore, the safety of DA-EPOCH-R therapy in patients with renal dysfunction is currently unknown and presents a major question in daily clinical practice. There are few reports regarding DA-EPOCH-R in patients with moderate or severe renal dysfunction, and we could find only two such cases.15 One case of Burkitt lymphoma with acute kidney injury due to dehydration; this recovered to Cre of 1.73 mg/dL with hydration, and DA-EPOCH-R therapy was subsequently commenced. The second case of Burkitt lymphoma with ureteral obstruction due to the tumor. COP therapy (cyclophosphamide, vincristine, and methylprednisolone) was commenced as the initial treatment, and ureteral obstruction was removed. After improvement of Cre to 1.73 mg/dL, DA-EPOCH-R therapy was started. Both cases completed six cycles of DA-EPOCH-R therapy without exacerbation of renal dysfunction. Considering these reports, DA-EPOCH-R therapy is likely to be safe even in patients with moderate renal dysfunction. For this reason, we selected DA-EPOCH-R therapy instead of CHOP therapy in this case.
According to a report on dose recommendation for anticancer drugs for renal dysfunction,16 there is no need to adjust doses of rituximab, doxorubicin, vincristine, and cyclophosphamide if the Ccr is 45 mL/min, and a 75% dose of etoposide is recommended. In this case, etoposide was administered at 100% dose to prioritize efficacy over toxicity. If safety is more important, a 75% reduction in the dose of etoposide may be considered. We could safely administer the DA-EPOCH-R therapy both by preparing a system to resume dialysis at any time if renal dysfunction became exacerbated, and by monitoring the patient with frequent blood tests.
The patient in this case had a retroperitoneal mass and kidney invasion resulting in bilateral hydronephrosis and post-renal acute kidney injury. Cre on admission was 17.37 mg/dL, and it required temporary hemodialysis. Although half-dose CHOP therapy resolved the ureteral obstruction, Cre improved only to approximately 2 mg/dL, and renal dysfunction remained because of kidney lesion. We selected DA-EPOCH-R therapy considering the high risk of recurrence with R-CHOP therapy for DHL/THL, although there was concern regarding decreasing renal function due to high-intensive chemotherapy. We did not select R-CODOX-M/IVAC therapy because high-dose methotrexate therapy has been reported to worsen renal function in a high number of patients with renal dysfunction.17 We were able to complete six cycles of DA-EPOCH-R therapy according to the protocol and reach remission. Moreover, there was no worsening of renal dysfunction.
Recurrence of central nerve system (CNS) is known to have a high frequency in DLBCL with MYC translocation,2 for which CNS prophylaxis is recommended. The same is true for DHL, and a clinical trial showing the efficacy of R-EPOCH for DHL14 also included CNS prophylaxis with intrathecal methotrexate. In general, high-dose intravenous methotrexate and intrathecal methotrexate are widely used for CNS prophylaxis in NHL.18 While high-dose intravenous methotrexate has been reported to significantly reduce CNS recurrence,19,20 there is no evidence regarding whether intrathecal methotrexate alone significantly reduces or does not prevent CNS recurrence.21-23 In this case, intrathecal methotrexate could not be administered because the patient was in poor general condition on admission and could not be positioned for lumbar puncture. High-dose methotrexate therapy could not be administered due to renal dysfunction. Although there is no solid evidence that intrathecal methotrexate significantly suppresses CNS recurrence, the decision not to administer intrathecal methotrexate in this case is a major regret. Whether intrathecal methotrexate alone is useful for preventing CNS recurrence needs to be studied on a larger scale.
Our experience, combined with the conclusions of the two cases mentioned above, suggests that DA-EPOCH-R therapy may be safely administered even if Cre is below 2–3 mg/dL or Ccr is above 30–40 mL/min, although no definite reference values for Cre and Ccr can yet be set. There have been few reports of DA-EPOCH-R therapy administered to patients with renal dysfunction, and an appropriate treatment regimen for DHL/THL patients with renal dysfunction has not been established. We therefore recommend carrying out more case studies to continue the evaluation of the safety and efficacy of DA-EPOCH-R therapy for patients with renal dysfunction.
CONFLICT OF INTEREST
The authors declare no conflicts of interest. | ON DAY 6; AS A PART OF DA?EPOCH?R REGIMEN ADMINISTERED EVERY 21 DAYS | DrugDosageText | CC BY-NC-SA | 33551436 | 19,067,711 | 2021-03-18 |
What was the dosage of drug 'DOXORUBICIN'? | DA-EPOCH-R therapy for high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements in a patient with renal dysfunction.
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit lymphoma, has been reported as refractory to R-CHOP therapy and requires more intensive regimens. However, intensive and safe regimens for patients with renal dysfunction are unknown. Herein, we report the successful use of DA-EPOCH-R therapy for double-hit lymphoma in a 64-year-old man with renal dysfunction. The patient had lymphoma-induced bilateral ureteral obstruction. Although renal dysfunction remained after removing the obstruction using R-CHOP therapy, we completed six cycles of DA-EPOCH-R therapy without any major adverse events. DA-EPOCH-R therapy may be a safe regimen for renal dysfunction patients.
INTRODUCTION
Diffuse large B-cell lymphoma (DLBCL) with MYC and BCL2 rearrangements is often reported to be refractory to R-CHOP therapy, with a poor prognosis.1-4 The 2016 revision of the World Health Organization classification of lymphoid neoplasms newly characterized high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,5 widely and commonly referred to as double-hit lymphoma (DHL) or triple-hit lymphoma (THL).
Although no standard initial treatment for DHL or THL has been established, it has been reported that if organ function is preserved, progression-free survival (PFS) is improved by selecting intensive regimens such as dose-adjusted (DA)-EPOCH-R therapy,6-8 R-HyperCVAD/MA therapy,9 or R-CODOX-M/IVAC therapy,10 rather than R-CHOP therapy.11-13 However, there are few known intensive regimens that can be safely administered to patients with DHL/THL who have moderate to severe renal dysfunction.
We report a case of double-hit lymphoma with renal dysfunction in a patient who underwent DA-EPOCH-R therapy according to the protocol, without initial dose reduction.
CASE REPORT
The patient was a 64-year-old Japanese man with no noteworthy medical or family history. He experienced malaise and abdominal distention three weeks before admission, and chest discomfort and orthopnea began five days before admission. The day before admission, he visited the emergency department, presenting with arm and leg edema and right pleural effusion seen on chest X-ray. Heart failure was suspected, and he was prescribed furosemide. The next day, he visited the internal department of the general hospital. Plain computed tomography (CT) revealed bilateral hydronephrosis and a retroperitoneal mass lesion. He was then transferred to the urology department of our hospital as an emergency case. Blood tests showed elevated soluble interleukin-2 receptor (sIL-2R) levels at 9334 IU/L, and he was referred to our department with suspicion of malignant lymphoma.
On admission, he was fully conscious, his temperature was 35.7°C, pulse was 53 beats per minute, blood pressure was 177/87 mmHg, and SpO2 was 98% on room air. He had no anemia in the foveal conjunctiva and no jaundice in the ocular conjunctiva. Respiratory and cardiac sounds were normal. The abdomen was flat and soft, and the liver and spleen were not palpable. Both lower limbs had pitting edema. Inguinal lymph nodes were 3-cm in size and elastic, hard, and smooth-textured on palpation bilaterally. No other superficial lymph nodes were palpated. There were no abnormal neurological findings. His Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 2. He had no systemic B symptoms (fever, night sweats, or weight loss).
Laboratory data on admission (Table 1) showed a markedly elevated creatinine (Cre) of 17.31 mg/dL, blood urea nitrogen (BUN) of 121 mg/dL, potassium (K) of 7.3 mEq/L, and inorganic phosphorus (IP) of 10.1 mg/dL. Lactate dehydrogenase (LDH) and sIL-2R were elevated to 666 IU/L and 9334 IU/mL, respectively. Plain CT (Figure 1) showed a 9 cm × 5 cm retroperitoneal mass causing bilateral hydronephrosis and partially kidney invasive lesion. It also showed pleural effusions and right cardiophrenic and bilateral inguinal lymphadenopathies. Bone marrow examination revealed no apparent tumor cell infiltration, and Giemsa banding showed a normal 46,XY karyotype. Cytopathologic examination of pleural fluid showed invasion of large abnormal lymphocytes.
Table 1 Laboratory data on admission
RBC 424×104 /μL TP 6.5 g/dL Ca 9.2 mg/dL
Hb 12.8 g/dL Alb 3.5 g/dL IP 10.1 mg/dL
Hct 37.0 % AST 14 IU/L CRP 3.17 mg/dL
MCV 87.3 fl ALT 14 IU/L sIL-2R 9334 IU/mL
MCH 30.2 pg LDH 666 IU/L Ferritin 417 ng/mL
MCHC 34.6 % ALP 187 IU/L IgG 467 mg/dL
WBC 9980 /μL γ-GTP 19 IU/L IgA 45 mg/dL
Neu 83.5 % T-Bil 0.4 mg/dL IgM 207 mg/dL
Lym 9.9 % BUN 121 mg/dL APTT 27.4 sec
Eos 5.3 % Cre 17.37 mg/dL (control) 26.7 sec
Bas 1.1 % Na 130 mEq/L PT% 98 %
Mon 0.2 % K 7.3 mEq/L PT-INR 1.01
Plt 45.7×104 /μL Cl 94 mEq/L
RBC: red blood cell, Hb: hemoglobin, Hct: hematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration, WBC: white blood cell, Neu: neutrophil, Lym: lymphocyte, Eos: eosinophil, Bas: basophil, Mon: monocyte, Plt: platelet, TP: total protein, Alb: albumin, AST: aspartate transaminase, ALT: alanine transaminase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, T-Bil: total bilirubin, BUN: blood urea nitrogen, Cre: creatinine, IP: inorganic phosphate, CRP: C-reactive protein, sIL-2R: soluble interleukin-2 receptor, APTT: activated partial thromboplastin time, PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio
Fig. 1 Systemic computed tomographic (CT) scan on admission (A, B, C, D) and after 6 cycles of DA-EPOCH-R therapy (E, F, G, H)
Systemic CT scan on admission shows a right cardiophrenic lymphadenopathy (arrow), pleural effusions (A), bilateral hydronephrosis (arrow) and renal infiltration (B), a 9 cm × 5 cm retroperitoneal mass (arrow) (C), and bilateral inguinal lymphadenopathies (arrow) (D). Each lesion shrank after 6 cycles of DA-EPOCH-R (E, F, G, H).
On the second day in hospital, inguinal lymph node biopsy was performed (Figure 2). Hematoxylin and eosin (H&E) staining showed a diffuse pattern of involvement with medium to large abnormal lymphocytes, and loss of the normal structure of lymphoid follicles. Immunostaining showed that the tumor was negative for CD3 and Bcl-6, and positive for CD10, CD20, CD79a, Ki67, c-Myc, and Bcl-2. The positive rate of Ki67, c-Myc and Bcl-2 was over 90% for each. Fluorescence in situ hybridization (FISH) showed split signals at 8q24 (MYC) and 18q21 (BCL2) (Figure 3). Based on these findings, we diagnosed high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements. Ann Arbor stage was IV A and International Prognostic Index was high-intermediate risk.
Fig. 2 Pathological images of inguinal lymph node biopsy
Hematoxylin and eosin (H&E) staining images show a diffuse pattern of involvement with medium to large abnormal lymphocytes, with loss of the normal structure of lymphoid follicles (A). Immunostaining images show that the tumor was negative for CD3 (B), negative for CD10 (C), positive for CD20 (D), positive for CD79a (E), positive for Ki67 (positive rate was over 90%) (F), positive for c-Myc (positive rate was over 90%) (G), positive for Bcl-2 (positive rate was over 90%) (H) and negative for Bcl-6 (I).
Fig. 3 Fluorescence in situ hybridization (FISH) of inguinal lymph node biopsy
Of 111 cells, 74 (66.7%) showed split signals at 8q24 (MYC) and duplication of 5’ MYC and 3’ MYC probe signals (A). Out of 104 cells, 68 (65.4%) showed split signals at 18q21 (BCL2) and duplication of 5’ BCL2 probe signals (B).
On the day of admission, right nephrostomy was performed for ureteral obstruction, but Cre improvement was poor, and the patient required emergency hemodialysis from the 4th hospital day. As diagnosis from the preliminary pathological report was diffuse large B-cell lymphoma (DLBCL), we started half-dose CHOP therapy (cyclophosphamide 375 mg/m2, day 1; doxorubicin 25 mg/m2, day 1; vincristine 0.7 mg/m2, day 1; prednisolone 60 mg/m2, days 1–5) on the 23rd hospital day. Rasburicase was administered to prevent tumor lysis syndrome. Urinary volume of 1000 mL/day was obtained on the 25th hospital day, but despite this and removal of the ureteral obstruction, Cre and 24-hour urine collection creatinine clearance (Ccr) improved only to 2.4 mg/dL and 37 mL/min, respectively, and right renal dysfunction remained (Figure 4). The patient was weaned off hemodialysis on the 30th hospital day. After the first cycle of half-dose CHOP therapy, the treatment response was stable disease (SD) with 47% tumor reduction (Figure 1). Cre remained approximately 2 mg/dL during treatment.
Fig. 4 Treatment and transition of serum lactate dehydrogenase (LDH), serum creatinine (Cre), and 24-hour urine collection creatinine clearance (Ccr)
Nephrostomy was performed for ureteral obstruction on the first hospital day. However, Cre did not improve, and we started hemodialysis. We performed half-dose CHOP therapy and the obstruction was removed immediately, although renal dysfunction remained (Cre 2.4 mg/dL, Ccr 37 mL/min). Owing to the confirmed diagnosis of the high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, we decided to use an intensive regimen and started full-dose DA-EPOCH-R therapy. Doses were reduced by 20% from the fourth cycle onward due to Common Terminology Criteria for Adverse Event (CTCAE) grade 4 neutropenia. Six cycles of DA-EPOCH-R therapy were completed without other adverse events greater than CTCAE grade 2. DA-EPOCH-R therapy did not exacerbate renal dysfunction. Cre and Ccr were stable at around 2-3 mg/dL and 30-40 mL/min, respectively, during the treatment.
Pathological examination and FISH revealed the diagnosis of high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements. Although Ccr was as low as 45 mL/min, we started DA-EPOCH-R therapy (rituximab 375 mg/m2, day 1; doxorubicin 10 mg/m2, days 2–5; vincristine 0.4 mg/m2, days 2–5; cyclophosphamide 750 mg/m2, day 6; prednisolone 60 mg/m2, days 2–6; administered every 21 days) without initial dose reduction on the 38th hospital day because more intensive treatment was considered necessary for DHL/THL. No worsening of renal function was observed during the treatment, and the patient completed the first cycle without any problems. The treatment response was partial response (PR) with 64% tumor reduction, and we decided to continue the DA-EPOCH-R therapy. On the third cycle, grade 4 neutropenia as categorized by the Common Terminology Criteria for Adverse Events (CTCAE) was observed, and we therefore reduced dosages from the fourth cycle onward by 20% in accordance with the protocol for DA-EPOCH-R therapy. The patient completed six cycles of DA-EPOCH-R without any new CTCAE grade 2 or higher adverse events. Ccr remained between 31 and 43 mL/min, with no further exacerbation. Plain CT after six cycles of DA-EPOCH-R therapy showed the response was PR with 65% tumor reduction, although contrast-enhanced CT was not possible due to renal dysfunction, and the accurate evaluation was difficult. There was no indication of tumor enlargement, and we therefore decided to monitor him as an outpatient and he was discharged on the 163rd hospital day. We scheduled positron emission tomography-computed tomography (PET-CT) after discharge. However, 22 days after discharge he presented diplopia. Head magnetic resonance imaging revealed swellings of the bilateral abducens nerves and the left optic nerve. Cytopathologic examination of lumbar puncture showed an invasion of large abnormal lymphocytes. He was readmitted, and we could not perform PET-CT.
DISCUSSION
We describe a case in which a DHL patient with moderate renal dysfunction (Cre 2 mg/dL, Ccr 30 mL/min) was treated with DA-EPOCH-R therapy according to the protocol without major adverse events, including worsening renal function.
Although a standard initial treatment for DHL/THL has not been established, it has been reported that intensive regimens such as DA-EPOCH-R therapy, R-HyperCVAD/MA therapy, and R-CODOX-M/IVAC therapy improve progression-free survival (PFS) rates more than R-CHOP therapy.11-13 A meta-analysis reported that DA-EPOCH-R had lower toxicity and superior PFS and overall survival (OS) than a combined R-HyperCVAD/MA and R-CODOX-M/IVAC treatment (median PFS 22.2 months and 18.9 months, respectively; median OS 31.4 months and 25.2 months, respectively).11 A phase 2 prospective study in DHL also showed a high efficacy of DA-EPOCH-R therapy.14
Although the efficacy of DA-EPOCH-R therapy as an initial treatment for DHL/THL has been established, in the prospective study mentioned above14 and in an initial report on DA-EPOCH-R therapy,6 patients with renal dysfunction with a Cre >1.5 mg/dL were excluded from the studies. Therefore, the safety of DA-EPOCH-R therapy in patients with renal dysfunction is currently unknown and presents a major question in daily clinical practice. There are few reports regarding DA-EPOCH-R in patients with moderate or severe renal dysfunction, and we could find only two such cases.15 One case of Burkitt lymphoma with acute kidney injury due to dehydration; this recovered to Cre of 1.73 mg/dL with hydration, and DA-EPOCH-R therapy was subsequently commenced. The second case of Burkitt lymphoma with ureteral obstruction due to the tumor. COP therapy (cyclophosphamide, vincristine, and methylprednisolone) was commenced as the initial treatment, and ureteral obstruction was removed. After improvement of Cre to 1.73 mg/dL, DA-EPOCH-R therapy was started. Both cases completed six cycles of DA-EPOCH-R therapy without exacerbation of renal dysfunction. Considering these reports, DA-EPOCH-R therapy is likely to be safe even in patients with moderate renal dysfunction. For this reason, we selected DA-EPOCH-R therapy instead of CHOP therapy in this case.
According to a report on dose recommendation for anticancer drugs for renal dysfunction,16 there is no need to adjust doses of rituximab, doxorubicin, vincristine, and cyclophosphamide if the Ccr is 45 mL/min, and a 75% dose of etoposide is recommended. In this case, etoposide was administered at 100% dose to prioritize efficacy over toxicity. If safety is more important, a 75% reduction in the dose of etoposide may be considered. We could safely administer the DA-EPOCH-R therapy both by preparing a system to resume dialysis at any time if renal dysfunction became exacerbated, and by monitoring the patient with frequent blood tests.
The patient in this case had a retroperitoneal mass and kidney invasion resulting in bilateral hydronephrosis and post-renal acute kidney injury. Cre on admission was 17.37 mg/dL, and it required temporary hemodialysis. Although half-dose CHOP therapy resolved the ureteral obstruction, Cre improved only to approximately 2 mg/dL, and renal dysfunction remained because of kidney lesion. We selected DA-EPOCH-R therapy considering the high risk of recurrence with R-CHOP therapy for DHL/THL, although there was concern regarding decreasing renal function due to high-intensive chemotherapy. We did not select R-CODOX-M/IVAC therapy because high-dose methotrexate therapy has been reported to worsen renal function in a high number of patients with renal dysfunction.17 We were able to complete six cycles of DA-EPOCH-R therapy according to the protocol and reach remission. Moreover, there was no worsening of renal dysfunction.
Recurrence of central nerve system (CNS) is known to have a high frequency in DLBCL with MYC translocation,2 for which CNS prophylaxis is recommended. The same is true for DHL, and a clinical trial showing the efficacy of R-EPOCH for DHL14 also included CNS prophylaxis with intrathecal methotrexate. In general, high-dose intravenous methotrexate and intrathecal methotrexate are widely used for CNS prophylaxis in NHL.18 While high-dose intravenous methotrexate has been reported to significantly reduce CNS recurrence,19,20 there is no evidence regarding whether intrathecal methotrexate alone significantly reduces or does not prevent CNS recurrence.21-23 In this case, intrathecal methotrexate could not be administered because the patient was in poor general condition on admission and could not be positioned for lumbar puncture. High-dose methotrexate therapy could not be administered due to renal dysfunction. Although there is no solid evidence that intrathecal methotrexate significantly suppresses CNS recurrence, the decision not to administer intrathecal methotrexate in this case is a major regret. Whether intrathecal methotrexate alone is useful for preventing CNS recurrence needs to be studied on a larger scale.
Our experience, combined with the conclusions of the two cases mentioned above, suggests that DA-EPOCH-R therapy may be safely administered even if Cre is below 2–3 mg/dL or Ccr is above 30–40 mL/min, although no definite reference values for Cre and Ccr can yet be set. There have been few reports of DA-EPOCH-R therapy administered to patients with renal dysfunction, and an appropriate treatment regimen for DHL/THL patients with renal dysfunction has not been established. We therefore recommend carrying out more case studies to continue the evaluation of the safety and efficacy of DA-EPOCH-R therapy for patients with renal dysfunction.
CONFLICT OF INTEREST
The authors declare no conflicts of interest. | ON DAYS 2?5; AS A PART OF DA?EPOCH?R REGIMEN ADMINISTERED EVERY 21 DAYS | DrugDosageText | CC BY-NC-SA | 33551436 | 19,067,711 | 2021-03-18 |
What was the dosage of drug 'ETOPOSIDE'? | DA-EPOCH-R therapy for high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements in a patient with renal dysfunction.
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit lymphoma, has been reported as refractory to R-CHOP therapy and requires more intensive regimens. However, intensive and safe regimens for patients with renal dysfunction are unknown. Herein, we report the successful use of DA-EPOCH-R therapy for double-hit lymphoma in a 64-year-old man with renal dysfunction. The patient had lymphoma-induced bilateral ureteral obstruction. Although renal dysfunction remained after removing the obstruction using R-CHOP therapy, we completed six cycles of DA-EPOCH-R therapy without any major adverse events. DA-EPOCH-R therapy may be a safe regimen for renal dysfunction patients.
INTRODUCTION
Diffuse large B-cell lymphoma (DLBCL) with MYC and BCL2 rearrangements is often reported to be refractory to R-CHOP therapy, with a poor prognosis.1-4 The 2016 revision of the World Health Organization classification of lymphoid neoplasms newly characterized high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,5 widely and commonly referred to as double-hit lymphoma (DHL) or triple-hit lymphoma (THL).
Although no standard initial treatment for DHL or THL has been established, it has been reported that if organ function is preserved, progression-free survival (PFS) is improved by selecting intensive regimens such as dose-adjusted (DA)-EPOCH-R therapy,6-8 R-HyperCVAD/MA therapy,9 or R-CODOX-M/IVAC therapy,10 rather than R-CHOP therapy.11-13 However, there are few known intensive regimens that can be safely administered to patients with DHL/THL who have moderate to severe renal dysfunction.
We report a case of double-hit lymphoma with renal dysfunction in a patient who underwent DA-EPOCH-R therapy according to the protocol, without initial dose reduction.
CASE REPORT
The patient was a 64-year-old Japanese man with no noteworthy medical or family history. He experienced malaise and abdominal distention three weeks before admission, and chest discomfort and orthopnea began five days before admission. The day before admission, he visited the emergency department, presenting with arm and leg edema and right pleural effusion seen on chest X-ray. Heart failure was suspected, and he was prescribed furosemide. The next day, he visited the internal department of the general hospital. Plain computed tomography (CT) revealed bilateral hydronephrosis and a retroperitoneal mass lesion. He was then transferred to the urology department of our hospital as an emergency case. Blood tests showed elevated soluble interleukin-2 receptor (sIL-2R) levels at 9334 IU/L, and he was referred to our department with suspicion of malignant lymphoma.
On admission, he was fully conscious, his temperature was 35.7°C, pulse was 53 beats per minute, blood pressure was 177/87 mmHg, and SpO2 was 98% on room air. He had no anemia in the foveal conjunctiva and no jaundice in the ocular conjunctiva. Respiratory and cardiac sounds were normal. The abdomen was flat and soft, and the liver and spleen were not palpable. Both lower limbs had pitting edema. Inguinal lymph nodes were 3-cm in size and elastic, hard, and smooth-textured on palpation bilaterally. No other superficial lymph nodes were palpated. There were no abnormal neurological findings. His Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 2. He had no systemic B symptoms (fever, night sweats, or weight loss).
Laboratory data on admission (Table 1) showed a markedly elevated creatinine (Cre) of 17.31 mg/dL, blood urea nitrogen (BUN) of 121 mg/dL, potassium (K) of 7.3 mEq/L, and inorganic phosphorus (IP) of 10.1 mg/dL. Lactate dehydrogenase (LDH) and sIL-2R were elevated to 666 IU/L and 9334 IU/mL, respectively. Plain CT (Figure 1) showed a 9 cm × 5 cm retroperitoneal mass causing bilateral hydronephrosis and partially kidney invasive lesion. It also showed pleural effusions and right cardiophrenic and bilateral inguinal lymphadenopathies. Bone marrow examination revealed no apparent tumor cell infiltration, and Giemsa banding showed a normal 46,XY karyotype. Cytopathologic examination of pleural fluid showed invasion of large abnormal lymphocytes.
Table 1 Laboratory data on admission
RBC 424×104 /μL TP 6.5 g/dL Ca 9.2 mg/dL
Hb 12.8 g/dL Alb 3.5 g/dL IP 10.1 mg/dL
Hct 37.0 % AST 14 IU/L CRP 3.17 mg/dL
MCV 87.3 fl ALT 14 IU/L sIL-2R 9334 IU/mL
MCH 30.2 pg LDH 666 IU/L Ferritin 417 ng/mL
MCHC 34.6 % ALP 187 IU/L IgG 467 mg/dL
WBC 9980 /μL γ-GTP 19 IU/L IgA 45 mg/dL
Neu 83.5 % T-Bil 0.4 mg/dL IgM 207 mg/dL
Lym 9.9 % BUN 121 mg/dL APTT 27.4 sec
Eos 5.3 % Cre 17.37 mg/dL (control) 26.7 sec
Bas 1.1 % Na 130 mEq/L PT% 98 %
Mon 0.2 % K 7.3 mEq/L PT-INR 1.01
Plt 45.7×104 /μL Cl 94 mEq/L
RBC: red blood cell, Hb: hemoglobin, Hct: hematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration, WBC: white blood cell, Neu: neutrophil, Lym: lymphocyte, Eos: eosinophil, Bas: basophil, Mon: monocyte, Plt: platelet, TP: total protein, Alb: albumin, AST: aspartate transaminase, ALT: alanine transaminase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, T-Bil: total bilirubin, BUN: blood urea nitrogen, Cre: creatinine, IP: inorganic phosphate, CRP: C-reactive protein, sIL-2R: soluble interleukin-2 receptor, APTT: activated partial thromboplastin time, PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio
Fig. 1 Systemic computed tomographic (CT) scan on admission (A, B, C, D) and after 6 cycles of DA-EPOCH-R therapy (E, F, G, H)
Systemic CT scan on admission shows a right cardiophrenic lymphadenopathy (arrow), pleural effusions (A), bilateral hydronephrosis (arrow) and renal infiltration (B), a 9 cm × 5 cm retroperitoneal mass (arrow) (C), and bilateral inguinal lymphadenopathies (arrow) (D). Each lesion shrank after 6 cycles of DA-EPOCH-R (E, F, G, H).
On the second day in hospital, inguinal lymph node biopsy was performed (Figure 2). Hematoxylin and eosin (H&E) staining showed a diffuse pattern of involvement with medium to large abnormal lymphocytes, and loss of the normal structure of lymphoid follicles. Immunostaining showed that the tumor was negative for CD3 and Bcl-6, and positive for CD10, CD20, CD79a, Ki67, c-Myc, and Bcl-2. The positive rate of Ki67, c-Myc and Bcl-2 was over 90% for each. Fluorescence in situ hybridization (FISH) showed split signals at 8q24 (MYC) and 18q21 (BCL2) (Figure 3). Based on these findings, we diagnosed high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements. Ann Arbor stage was IV A and International Prognostic Index was high-intermediate risk.
Fig. 2 Pathological images of inguinal lymph node biopsy
Hematoxylin and eosin (H&E) staining images show a diffuse pattern of involvement with medium to large abnormal lymphocytes, with loss of the normal structure of lymphoid follicles (A). Immunostaining images show that the tumor was negative for CD3 (B), negative for CD10 (C), positive for CD20 (D), positive for CD79a (E), positive for Ki67 (positive rate was over 90%) (F), positive for c-Myc (positive rate was over 90%) (G), positive for Bcl-2 (positive rate was over 90%) (H) and negative for Bcl-6 (I).
Fig. 3 Fluorescence in situ hybridization (FISH) of inguinal lymph node biopsy
Of 111 cells, 74 (66.7%) showed split signals at 8q24 (MYC) and duplication of 5’ MYC and 3’ MYC probe signals (A). Out of 104 cells, 68 (65.4%) showed split signals at 18q21 (BCL2) and duplication of 5’ BCL2 probe signals (B).
On the day of admission, right nephrostomy was performed for ureteral obstruction, but Cre improvement was poor, and the patient required emergency hemodialysis from the 4th hospital day. As diagnosis from the preliminary pathological report was diffuse large B-cell lymphoma (DLBCL), we started half-dose CHOP therapy (cyclophosphamide 375 mg/m2, day 1; doxorubicin 25 mg/m2, day 1; vincristine 0.7 mg/m2, day 1; prednisolone 60 mg/m2, days 1–5) on the 23rd hospital day. Rasburicase was administered to prevent tumor lysis syndrome. Urinary volume of 1000 mL/day was obtained on the 25th hospital day, but despite this and removal of the ureteral obstruction, Cre and 24-hour urine collection creatinine clearance (Ccr) improved only to 2.4 mg/dL and 37 mL/min, respectively, and right renal dysfunction remained (Figure 4). The patient was weaned off hemodialysis on the 30th hospital day. After the first cycle of half-dose CHOP therapy, the treatment response was stable disease (SD) with 47% tumor reduction (Figure 1). Cre remained approximately 2 mg/dL during treatment.
Fig. 4 Treatment and transition of serum lactate dehydrogenase (LDH), serum creatinine (Cre), and 24-hour urine collection creatinine clearance (Ccr)
Nephrostomy was performed for ureteral obstruction on the first hospital day. However, Cre did not improve, and we started hemodialysis. We performed half-dose CHOP therapy and the obstruction was removed immediately, although renal dysfunction remained (Cre 2.4 mg/dL, Ccr 37 mL/min). Owing to the confirmed diagnosis of the high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, we decided to use an intensive regimen and started full-dose DA-EPOCH-R therapy. Doses were reduced by 20% from the fourth cycle onward due to Common Terminology Criteria for Adverse Event (CTCAE) grade 4 neutropenia. Six cycles of DA-EPOCH-R therapy were completed without other adverse events greater than CTCAE grade 2. DA-EPOCH-R therapy did not exacerbate renal dysfunction. Cre and Ccr were stable at around 2-3 mg/dL and 30-40 mL/min, respectively, during the treatment.
Pathological examination and FISH revealed the diagnosis of high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements. Although Ccr was as low as 45 mL/min, we started DA-EPOCH-R therapy (rituximab 375 mg/m2, day 1; doxorubicin 10 mg/m2, days 2–5; vincristine 0.4 mg/m2, days 2–5; cyclophosphamide 750 mg/m2, day 6; prednisolone 60 mg/m2, days 2–6; administered every 21 days) without initial dose reduction on the 38th hospital day because more intensive treatment was considered necessary for DHL/THL. No worsening of renal function was observed during the treatment, and the patient completed the first cycle without any problems. The treatment response was partial response (PR) with 64% tumor reduction, and we decided to continue the DA-EPOCH-R therapy. On the third cycle, grade 4 neutropenia as categorized by the Common Terminology Criteria for Adverse Events (CTCAE) was observed, and we therefore reduced dosages from the fourth cycle onward by 20% in accordance with the protocol for DA-EPOCH-R therapy. The patient completed six cycles of DA-EPOCH-R without any new CTCAE grade 2 or higher adverse events. Ccr remained between 31 and 43 mL/min, with no further exacerbation. Plain CT after six cycles of DA-EPOCH-R therapy showed the response was PR with 65% tumor reduction, although contrast-enhanced CT was not possible due to renal dysfunction, and the accurate evaluation was difficult. There was no indication of tumor enlargement, and we therefore decided to monitor him as an outpatient and he was discharged on the 163rd hospital day. We scheduled positron emission tomography-computed tomography (PET-CT) after discharge. However, 22 days after discharge he presented diplopia. Head magnetic resonance imaging revealed swellings of the bilateral abducens nerves and the left optic nerve. Cytopathologic examination of lumbar puncture showed an invasion of large abnormal lymphocytes. He was readmitted, and we could not perform PET-CT.
DISCUSSION
We describe a case in which a DHL patient with moderate renal dysfunction (Cre 2 mg/dL, Ccr 30 mL/min) was treated with DA-EPOCH-R therapy according to the protocol without major adverse events, including worsening renal function.
Although a standard initial treatment for DHL/THL has not been established, it has been reported that intensive regimens such as DA-EPOCH-R therapy, R-HyperCVAD/MA therapy, and R-CODOX-M/IVAC therapy improve progression-free survival (PFS) rates more than R-CHOP therapy.11-13 A meta-analysis reported that DA-EPOCH-R had lower toxicity and superior PFS and overall survival (OS) than a combined R-HyperCVAD/MA and R-CODOX-M/IVAC treatment (median PFS 22.2 months and 18.9 months, respectively; median OS 31.4 months and 25.2 months, respectively).11 A phase 2 prospective study in DHL also showed a high efficacy of DA-EPOCH-R therapy.14
Although the efficacy of DA-EPOCH-R therapy as an initial treatment for DHL/THL has been established, in the prospective study mentioned above14 and in an initial report on DA-EPOCH-R therapy,6 patients with renal dysfunction with a Cre >1.5 mg/dL were excluded from the studies. Therefore, the safety of DA-EPOCH-R therapy in patients with renal dysfunction is currently unknown and presents a major question in daily clinical practice. There are few reports regarding DA-EPOCH-R in patients with moderate or severe renal dysfunction, and we could find only two such cases.15 One case of Burkitt lymphoma with acute kidney injury due to dehydration; this recovered to Cre of 1.73 mg/dL with hydration, and DA-EPOCH-R therapy was subsequently commenced. The second case of Burkitt lymphoma with ureteral obstruction due to the tumor. COP therapy (cyclophosphamide, vincristine, and methylprednisolone) was commenced as the initial treatment, and ureteral obstruction was removed. After improvement of Cre to 1.73 mg/dL, DA-EPOCH-R therapy was started. Both cases completed six cycles of DA-EPOCH-R therapy without exacerbation of renal dysfunction. Considering these reports, DA-EPOCH-R therapy is likely to be safe even in patients with moderate renal dysfunction. For this reason, we selected DA-EPOCH-R therapy instead of CHOP therapy in this case.
According to a report on dose recommendation for anticancer drugs for renal dysfunction,16 there is no need to adjust doses of rituximab, doxorubicin, vincristine, and cyclophosphamide if the Ccr is 45 mL/min, and a 75% dose of etoposide is recommended. In this case, etoposide was administered at 100% dose to prioritize efficacy over toxicity. If safety is more important, a 75% reduction in the dose of etoposide may be considered. We could safely administer the DA-EPOCH-R therapy both by preparing a system to resume dialysis at any time if renal dysfunction became exacerbated, and by monitoring the patient with frequent blood tests.
The patient in this case had a retroperitoneal mass and kidney invasion resulting in bilateral hydronephrosis and post-renal acute kidney injury. Cre on admission was 17.37 mg/dL, and it required temporary hemodialysis. Although half-dose CHOP therapy resolved the ureteral obstruction, Cre improved only to approximately 2 mg/dL, and renal dysfunction remained because of kidney lesion. We selected DA-EPOCH-R therapy considering the high risk of recurrence with R-CHOP therapy for DHL/THL, although there was concern regarding decreasing renal function due to high-intensive chemotherapy. We did not select R-CODOX-M/IVAC therapy because high-dose methotrexate therapy has been reported to worsen renal function in a high number of patients with renal dysfunction.17 We were able to complete six cycles of DA-EPOCH-R therapy according to the protocol and reach remission. Moreover, there was no worsening of renal dysfunction.
Recurrence of central nerve system (CNS) is known to have a high frequency in DLBCL with MYC translocation,2 for which CNS prophylaxis is recommended. The same is true for DHL, and a clinical trial showing the efficacy of R-EPOCH for DHL14 also included CNS prophylaxis with intrathecal methotrexate. In general, high-dose intravenous methotrexate and intrathecal methotrexate are widely used for CNS prophylaxis in NHL.18 While high-dose intravenous methotrexate has been reported to significantly reduce CNS recurrence,19,20 there is no evidence regarding whether intrathecal methotrexate alone significantly reduces or does not prevent CNS recurrence.21-23 In this case, intrathecal methotrexate could not be administered because the patient was in poor general condition on admission and could not be positioned for lumbar puncture. High-dose methotrexate therapy could not be administered due to renal dysfunction. Although there is no solid evidence that intrathecal methotrexate significantly suppresses CNS recurrence, the decision not to administer intrathecal methotrexate in this case is a major regret. Whether intrathecal methotrexate alone is useful for preventing CNS recurrence needs to be studied on a larger scale.
Our experience, combined with the conclusions of the two cases mentioned above, suggests that DA-EPOCH-R therapy may be safely administered even if Cre is below 2–3 mg/dL or Ccr is above 30–40 mL/min, although no definite reference values for Cre and Ccr can yet be set. There have been few reports of DA-EPOCH-R therapy administered to patients with renal dysfunction, and an appropriate treatment regimen for DHL/THL patients with renal dysfunction has not been established. We therefore recommend carrying out more case studies to continue the evaluation of the safety and efficacy of DA-EPOCH-R therapy for patients with renal dysfunction.
CONFLICT OF INTEREST
The authors declare no conflicts of interest. | AS A PART OF DA?EPOCH?R REGIMEN ADMINISTERED EVERY 21 DAYS | DrugDosageText | CC BY-NC-SA | 33551436 | 19,067,711 | 2021-03-18 |
What was the dosage of drug 'PREDNISOLONE'? | DA-EPOCH-R therapy for high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements in a patient with renal dysfunction.
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit lymphoma, has been reported as refractory to R-CHOP therapy and requires more intensive regimens. However, intensive and safe regimens for patients with renal dysfunction are unknown. Herein, we report the successful use of DA-EPOCH-R therapy for double-hit lymphoma in a 64-year-old man with renal dysfunction. The patient had lymphoma-induced bilateral ureteral obstruction. Although renal dysfunction remained after removing the obstruction using R-CHOP therapy, we completed six cycles of DA-EPOCH-R therapy without any major adverse events. DA-EPOCH-R therapy may be a safe regimen for renal dysfunction patients.
INTRODUCTION
Diffuse large B-cell lymphoma (DLBCL) with MYC and BCL2 rearrangements is often reported to be refractory to R-CHOP therapy, with a poor prognosis.1-4 The 2016 revision of the World Health Organization classification of lymphoid neoplasms newly characterized high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,5 widely and commonly referred to as double-hit lymphoma (DHL) or triple-hit lymphoma (THL).
Although no standard initial treatment for DHL or THL has been established, it has been reported that if organ function is preserved, progression-free survival (PFS) is improved by selecting intensive regimens such as dose-adjusted (DA)-EPOCH-R therapy,6-8 R-HyperCVAD/MA therapy,9 or R-CODOX-M/IVAC therapy,10 rather than R-CHOP therapy.11-13 However, there are few known intensive regimens that can be safely administered to patients with DHL/THL who have moderate to severe renal dysfunction.
We report a case of double-hit lymphoma with renal dysfunction in a patient who underwent DA-EPOCH-R therapy according to the protocol, without initial dose reduction.
CASE REPORT
The patient was a 64-year-old Japanese man with no noteworthy medical or family history. He experienced malaise and abdominal distention three weeks before admission, and chest discomfort and orthopnea began five days before admission. The day before admission, he visited the emergency department, presenting with arm and leg edema and right pleural effusion seen on chest X-ray. Heart failure was suspected, and he was prescribed furosemide. The next day, he visited the internal department of the general hospital. Plain computed tomography (CT) revealed bilateral hydronephrosis and a retroperitoneal mass lesion. He was then transferred to the urology department of our hospital as an emergency case. Blood tests showed elevated soluble interleukin-2 receptor (sIL-2R) levels at 9334 IU/L, and he was referred to our department with suspicion of malignant lymphoma.
On admission, he was fully conscious, his temperature was 35.7°C, pulse was 53 beats per minute, blood pressure was 177/87 mmHg, and SpO2 was 98% on room air. He had no anemia in the foveal conjunctiva and no jaundice in the ocular conjunctiva. Respiratory and cardiac sounds were normal. The abdomen was flat and soft, and the liver and spleen were not palpable. Both lower limbs had pitting edema. Inguinal lymph nodes were 3-cm in size and elastic, hard, and smooth-textured on palpation bilaterally. No other superficial lymph nodes were palpated. There were no abnormal neurological findings. His Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 2. He had no systemic B symptoms (fever, night sweats, or weight loss).
Laboratory data on admission (Table 1) showed a markedly elevated creatinine (Cre) of 17.31 mg/dL, blood urea nitrogen (BUN) of 121 mg/dL, potassium (K) of 7.3 mEq/L, and inorganic phosphorus (IP) of 10.1 mg/dL. Lactate dehydrogenase (LDH) and sIL-2R were elevated to 666 IU/L and 9334 IU/mL, respectively. Plain CT (Figure 1) showed a 9 cm × 5 cm retroperitoneal mass causing bilateral hydronephrosis and partially kidney invasive lesion. It also showed pleural effusions and right cardiophrenic and bilateral inguinal lymphadenopathies. Bone marrow examination revealed no apparent tumor cell infiltration, and Giemsa banding showed a normal 46,XY karyotype. Cytopathologic examination of pleural fluid showed invasion of large abnormal lymphocytes.
Table 1 Laboratory data on admission
RBC 424×104 /μL TP 6.5 g/dL Ca 9.2 mg/dL
Hb 12.8 g/dL Alb 3.5 g/dL IP 10.1 mg/dL
Hct 37.0 % AST 14 IU/L CRP 3.17 mg/dL
MCV 87.3 fl ALT 14 IU/L sIL-2R 9334 IU/mL
MCH 30.2 pg LDH 666 IU/L Ferritin 417 ng/mL
MCHC 34.6 % ALP 187 IU/L IgG 467 mg/dL
WBC 9980 /μL γ-GTP 19 IU/L IgA 45 mg/dL
Neu 83.5 % T-Bil 0.4 mg/dL IgM 207 mg/dL
Lym 9.9 % BUN 121 mg/dL APTT 27.4 sec
Eos 5.3 % Cre 17.37 mg/dL (control) 26.7 sec
Bas 1.1 % Na 130 mEq/L PT% 98 %
Mon 0.2 % K 7.3 mEq/L PT-INR 1.01
Plt 45.7×104 /μL Cl 94 mEq/L
RBC: red blood cell, Hb: hemoglobin, Hct: hematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration, WBC: white blood cell, Neu: neutrophil, Lym: lymphocyte, Eos: eosinophil, Bas: basophil, Mon: monocyte, Plt: platelet, TP: total protein, Alb: albumin, AST: aspartate transaminase, ALT: alanine transaminase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, T-Bil: total bilirubin, BUN: blood urea nitrogen, Cre: creatinine, IP: inorganic phosphate, CRP: C-reactive protein, sIL-2R: soluble interleukin-2 receptor, APTT: activated partial thromboplastin time, PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio
Fig. 1 Systemic computed tomographic (CT) scan on admission (A, B, C, D) and after 6 cycles of DA-EPOCH-R therapy (E, F, G, H)
Systemic CT scan on admission shows a right cardiophrenic lymphadenopathy (arrow), pleural effusions (A), bilateral hydronephrosis (arrow) and renal infiltration (B), a 9 cm × 5 cm retroperitoneal mass (arrow) (C), and bilateral inguinal lymphadenopathies (arrow) (D). Each lesion shrank after 6 cycles of DA-EPOCH-R (E, F, G, H).
On the second day in hospital, inguinal lymph node biopsy was performed (Figure 2). Hematoxylin and eosin (H&E) staining showed a diffuse pattern of involvement with medium to large abnormal lymphocytes, and loss of the normal structure of lymphoid follicles. Immunostaining showed that the tumor was negative for CD3 and Bcl-6, and positive for CD10, CD20, CD79a, Ki67, c-Myc, and Bcl-2. The positive rate of Ki67, c-Myc and Bcl-2 was over 90% for each. Fluorescence in situ hybridization (FISH) showed split signals at 8q24 (MYC) and 18q21 (BCL2) (Figure 3). Based on these findings, we diagnosed high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements. Ann Arbor stage was IV A and International Prognostic Index was high-intermediate risk.
Fig. 2 Pathological images of inguinal lymph node biopsy
Hematoxylin and eosin (H&E) staining images show a diffuse pattern of involvement with medium to large abnormal lymphocytes, with loss of the normal structure of lymphoid follicles (A). Immunostaining images show that the tumor was negative for CD3 (B), negative for CD10 (C), positive for CD20 (D), positive for CD79a (E), positive for Ki67 (positive rate was over 90%) (F), positive for c-Myc (positive rate was over 90%) (G), positive for Bcl-2 (positive rate was over 90%) (H) and negative for Bcl-6 (I).
Fig. 3 Fluorescence in situ hybridization (FISH) of inguinal lymph node biopsy
Of 111 cells, 74 (66.7%) showed split signals at 8q24 (MYC) and duplication of 5’ MYC and 3’ MYC probe signals (A). Out of 104 cells, 68 (65.4%) showed split signals at 18q21 (BCL2) and duplication of 5’ BCL2 probe signals (B).
On the day of admission, right nephrostomy was performed for ureteral obstruction, but Cre improvement was poor, and the patient required emergency hemodialysis from the 4th hospital day. As diagnosis from the preliminary pathological report was diffuse large B-cell lymphoma (DLBCL), we started half-dose CHOP therapy (cyclophosphamide 375 mg/m2, day 1; doxorubicin 25 mg/m2, day 1; vincristine 0.7 mg/m2, day 1; prednisolone 60 mg/m2, days 1–5) on the 23rd hospital day. Rasburicase was administered to prevent tumor lysis syndrome. Urinary volume of 1000 mL/day was obtained on the 25th hospital day, but despite this and removal of the ureteral obstruction, Cre and 24-hour urine collection creatinine clearance (Ccr) improved only to 2.4 mg/dL and 37 mL/min, respectively, and right renal dysfunction remained (Figure 4). The patient was weaned off hemodialysis on the 30th hospital day. After the first cycle of half-dose CHOP therapy, the treatment response was stable disease (SD) with 47% tumor reduction (Figure 1). Cre remained approximately 2 mg/dL during treatment.
Fig. 4 Treatment and transition of serum lactate dehydrogenase (LDH), serum creatinine (Cre), and 24-hour urine collection creatinine clearance (Ccr)
Nephrostomy was performed for ureteral obstruction on the first hospital day. However, Cre did not improve, and we started hemodialysis. We performed half-dose CHOP therapy and the obstruction was removed immediately, although renal dysfunction remained (Cre 2.4 mg/dL, Ccr 37 mL/min). Owing to the confirmed diagnosis of the high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, we decided to use an intensive regimen and started full-dose DA-EPOCH-R therapy. Doses were reduced by 20% from the fourth cycle onward due to Common Terminology Criteria for Adverse Event (CTCAE) grade 4 neutropenia. Six cycles of DA-EPOCH-R therapy were completed without other adverse events greater than CTCAE grade 2. DA-EPOCH-R therapy did not exacerbate renal dysfunction. Cre and Ccr were stable at around 2-3 mg/dL and 30-40 mL/min, respectively, during the treatment.
Pathological examination and FISH revealed the diagnosis of high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements. Although Ccr was as low as 45 mL/min, we started DA-EPOCH-R therapy (rituximab 375 mg/m2, day 1; doxorubicin 10 mg/m2, days 2–5; vincristine 0.4 mg/m2, days 2–5; cyclophosphamide 750 mg/m2, day 6; prednisolone 60 mg/m2, days 2–6; administered every 21 days) without initial dose reduction on the 38th hospital day because more intensive treatment was considered necessary for DHL/THL. No worsening of renal function was observed during the treatment, and the patient completed the first cycle without any problems. The treatment response was partial response (PR) with 64% tumor reduction, and we decided to continue the DA-EPOCH-R therapy. On the third cycle, grade 4 neutropenia as categorized by the Common Terminology Criteria for Adverse Events (CTCAE) was observed, and we therefore reduced dosages from the fourth cycle onward by 20% in accordance with the protocol for DA-EPOCH-R therapy. The patient completed six cycles of DA-EPOCH-R without any new CTCAE grade 2 or higher adverse events. Ccr remained between 31 and 43 mL/min, with no further exacerbation. Plain CT after six cycles of DA-EPOCH-R therapy showed the response was PR with 65% tumor reduction, although contrast-enhanced CT was not possible due to renal dysfunction, and the accurate evaluation was difficult. There was no indication of tumor enlargement, and we therefore decided to monitor him as an outpatient and he was discharged on the 163rd hospital day. We scheduled positron emission tomography-computed tomography (PET-CT) after discharge. However, 22 days after discharge he presented diplopia. Head magnetic resonance imaging revealed swellings of the bilateral abducens nerves and the left optic nerve. Cytopathologic examination of lumbar puncture showed an invasion of large abnormal lymphocytes. He was readmitted, and we could not perform PET-CT.
DISCUSSION
We describe a case in which a DHL patient with moderate renal dysfunction (Cre 2 mg/dL, Ccr 30 mL/min) was treated with DA-EPOCH-R therapy according to the protocol without major adverse events, including worsening renal function.
Although a standard initial treatment for DHL/THL has not been established, it has been reported that intensive regimens such as DA-EPOCH-R therapy, R-HyperCVAD/MA therapy, and R-CODOX-M/IVAC therapy improve progression-free survival (PFS) rates more than R-CHOP therapy.11-13 A meta-analysis reported that DA-EPOCH-R had lower toxicity and superior PFS and overall survival (OS) than a combined R-HyperCVAD/MA and R-CODOX-M/IVAC treatment (median PFS 22.2 months and 18.9 months, respectively; median OS 31.4 months and 25.2 months, respectively).11 A phase 2 prospective study in DHL also showed a high efficacy of DA-EPOCH-R therapy.14
Although the efficacy of DA-EPOCH-R therapy as an initial treatment for DHL/THL has been established, in the prospective study mentioned above14 and in an initial report on DA-EPOCH-R therapy,6 patients with renal dysfunction with a Cre >1.5 mg/dL were excluded from the studies. Therefore, the safety of DA-EPOCH-R therapy in patients with renal dysfunction is currently unknown and presents a major question in daily clinical practice. There are few reports regarding DA-EPOCH-R in patients with moderate or severe renal dysfunction, and we could find only two such cases.15 One case of Burkitt lymphoma with acute kidney injury due to dehydration; this recovered to Cre of 1.73 mg/dL with hydration, and DA-EPOCH-R therapy was subsequently commenced. The second case of Burkitt lymphoma with ureteral obstruction due to the tumor. COP therapy (cyclophosphamide, vincristine, and methylprednisolone) was commenced as the initial treatment, and ureteral obstruction was removed. After improvement of Cre to 1.73 mg/dL, DA-EPOCH-R therapy was started. Both cases completed six cycles of DA-EPOCH-R therapy without exacerbation of renal dysfunction. Considering these reports, DA-EPOCH-R therapy is likely to be safe even in patients with moderate renal dysfunction. For this reason, we selected DA-EPOCH-R therapy instead of CHOP therapy in this case.
According to a report on dose recommendation for anticancer drugs for renal dysfunction,16 there is no need to adjust doses of rituximab, doxorubicin, vincristine, and cyclophosphamide if the Ccr is 45 mL/min, and a 75% dose of etoposide is recommended. In this case, etoposide was administered at 100% dose to prioritize efficacy over toxicity. If safety is more important, a 75% reduction in the dose of etoposide may be considered. We could safely administer the DA-EPOCH-R therapy both by preparing a system to resume dialysis at any time if renal dysfunction became exacerbated, and by monitoring the patient with frequent blood tests.
The patient in this case had a retroperitoneal mass and kidney invasion resulting in bilateral hydronephrosis and post-renal acute kidney injury. Cre on admission was 17.37 mg/dL, and it required temporary hemodialysis. Although half-dose CHOP therapy resolved the ureteral obstruction, Cre improved only to approximately 2 mg/dL, and renal dysfunction remained because of kidney lesion. We selected DA-EPOCH-R therapy considering the high risk of recurrence with R-CHOP therapy for DHL/THL, although there was concern regarding decreasing renal function due to high-intensive chemotherapy. We did not select R-CODOX-M/IVAC therapy because high-dose methotrexate therapy has been reported to worsen renal function in a high number of patients with renal dysfunction.17 We were able to complete six cycles of DA-EPOCH-R therapy according to the protocol and reach remission. Moreover, there was no worsening of renal dysfunction.
Recurrence of central nerve system (CNS) is known to have a high frequency in DLBCL with MYC translocation,2 for which CNS prophylaxis is recommended. The same is true for DHL, and a clinical trial showing the efficacy of R-EPOCH for DHL14 also included CNS prophylaxis with intrathecal methotrexate. In general, high-dose intravenous methotrexate and intrathecal methotrexate are widely used for CNS prophylaxis in NHL.18 While high-dose intravenous methotrexate has been reported to significantly reduce CNS recurrence,19,20 there is no evidence regarding whether intrathecal methotrexate alone significantly reduces or does not prevent CNS recurrence.21-23 In this case, intrathecal methotrexate could not be administered because the patient was in poor general condition on admission and could not be positioned for lumbar puncture. High-dose methotrexate therapy could not be administered due to renal dysfunction. Although there is no solid evidence that intrathecal methotrexate significantly suppresses CNS recurrence, the decision not to administer intrathecal methotrexate in this case is a major regret. Whether intrathecal methotrexate alone is useful for preventing CNS recurrence needs to be studied on a larger scale.
Our experience, combined with the conclusions of the two cases mentioned above, suggests that DA-EPOCH-R therapy may be safely administered even if Cre is below 2–3 mg/dL or Ccr is above 30–40 mL/min, although no definite reference values for Cre and Ccr can yet be set. There have been few reports of DA-EPOCH-R therapy administered to patients with renal dysfunction, and an appropriate treatment regimen for DHL/THL patients with renal dysfunction has not been established. We therefore recommend carrying out more case studies to continue the evaluation of the safety and efficacy of DA-EPOCH-R therapy for patients with renal dysfunction.
CONFLICT OF INTEREST
The authors declare no conflicts of interest. | ON DAYS 2?6; AS A PART OF DA?EPOCH?R REGIMEN ADMINISTERED EVERY 21 DAYS | DrugDosageText | CC BY-NC-SA | 33551436 | 19,067,711 | 2021-03-18 |
What was the dosage of drug 'RITUXIMAB'? | DA-EPOCH-R therapy for high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements in a patient with renal dysfunction.
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit lymphoma, has been reported as refractory to R-CHOP therapy and requires more intensive regimens. However, intensive and safe regimens for patients with renal dysfunction are unknown. Herein, we report the successful use of DA-EPOCH-R therapy for double-hit lymphoma in a 64-year-old man with renal dysfunction. The patient had lymphoma-induced bilateral ureteral obstruction. Although renal dysfunction remained after removing the obstruction using R-CHOP therapy, we completed six cycles of DA-EPOCH-R therapy without any major adverse events. DA-EPOCH-R therapy may be a safe regimen for renal dysfunction patients.
INTRODUCTION
Diffuse large B-cell lymphoma (DLBCL) with MYC and BCL2 rearrangements is often reported to be refractory to R-CHOP therapy, with a poor prognosis.1-4 The 2016 revision of the World Health Organization classification of lymphoid neoplasms newly characterized high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,5 widely and commonly referred to as double-hit lymphoma (DHL) or triple-hit lymphoma (THL).
Although no standard initial treatment for DHL or THL has been established, it has been reported that if organ function is preserved, progression-free survival (PFS) is improved by selecting intensive regimens such as dose-adjusted (DA)-EPOCH-R therapy,6-8 R-HyperCVAD/MA therapy,9 or R-CODOX-M/IVAC therapy,10 rather than R-CHOP therapy.11-13 However, there are few known intensive regimens that can be safely administered to patients with DHL/THL who have moderate to severe renal dysfunction.
We report a case of double-hit lymphoma with renal dysfunction in a patient who underwent DA-EPOCH-R therapy according to the protocol, without initial dose reduction.
CASE REPORT
The patient was a 64-year-old Japanese man with no noteworthy medical or family history. He experienced malaise and abdominal distention three weeks before admission, and chest discomfort and orthopnea began five days before admission. The day before admission, he visited the emergency department, presenting with arm and leg edema and right pleural effusion seen on chest X-ray. Heart failure was suspected, and he was prescribed furosemide. The next day, he visited the internal department of the general hospital. Plain computed tomography (CT) revealed bilateral hydronephrosis and a retroperitoneal mass lesion. He was then transferred to the urology department of our hospital as an emergency case. Blood tests showed elevated soluble interleukin-2 receptor (sIL-2R) levels at 9334 IU/L, and he was referred to our department with suspicion of malignant lymphoma.
On admission, he was fully conscious, his temperature was 35.7°C, pulse was 53 beats per minute, blood pressure was 177/87 mmHg, and SpO2 was 98% on room air. He had no anemia in the foveal conjunctiva and no jaundice in the ocular conjunctiva. Respiratory and cardiac sounds were normal. The abdomen was flat and soft, and the liver and spleen were not palpable. Both lower limbs had pitting edema. Inguinal lymph nodes were 3-cm in size and elastic, hard, and smooth-textured on palpation bilaterally. No other superficial lymph nodes were palpated. There were no abnormal neurological findings. His Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 2. He had no systemic B symptoms (fever, night sweats, or weight loss).
Laboratory data on admission (Table 1) showed a markedly elevated creatinine (Cre) of 17.31 mg/dL, blood urea nitrogen (BUN) of 121 mg/dL, potassium (K) of 7.3 mEq/L, and inorganic phosphorus (IP) of 10.1 mg/dL. Lactate dehydrogenase (LDH) and sIL-2R were elevated to 666 IU/L and 9334 IU/mL, respectively. Plain CT (Figure 1) showed a 9 cm × 5 cm retroperitoneal mass causing bilateral hydronephrosis and partially kidney invasive lesion. It also showed pleural effusions and right cardiophrenic and bilateral inguinal lymphadenopathies. Bone marrow examination revealed no apparent tumor cell infiltration, and Giemsa banding showed a normal 46,XY karyotype. Cytopathologic examination of pleural fluid showed invasion of large abnormal lymphocytes.
Table 1 Laboratory data on admission
RBC 424×104 /μL TP 6.5 g/dL Ca 9.2 mg/dL
Hb 12.8 g/dL Alb 3.5 g/dL IP 10.1 mg/dL
Hct 37.0 % AST 14 IU/L CRP 3.17 mg/dL
MCV 87.3 fl ALT 14 IU/L sIL-2R 9334 IU/mL
MCH 30.2 pg LDH 666 IU/L Ferritin 417 ng/mL
MCHC 34.6 % ALP 187 IU/L IgG 467 mg/dL
WBC 9980 /μL γ-GTP 19 IU/L IgA 45 mg/dL
Neu 83.5 % T-Bil 0.4 mg/dL IgM 207 mg/dL
Lym 9.9 % BUN 121 mg/dL APTT 27.4 sec
Eos 5.3 % Cre 17.37 mg/dL (control) 26.7 sec
Bas 1.1 % Na 130 mEq/L PT% 98 %
Mon 0.2 % K 7.3 mEq/L PT-INR 1.01
Plt 45.7×104 /μL Cl 94 mEq/L
RBC: red blood cell, Hb: hemoglobin, Hct: hematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration, WBC: white blood cell, Neu: neutrophil, Lym: lymphocyte, Eos: eosinophil, Bas: basophil, Mon: monocyte, Plt: platelet, TP: total protein, Alb: albumin, AST: aspartate transaminase, ALT: alanine transaminase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, T-Bil: total bilirubin, BUN: blood urea nitrogen, Cre: creatinine, IP: inorganic phosphate, CRP: C-reactive protein, sIL-2R: soluble interleukin-2 receptor, APTT: activated partial thromboplastin time, PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio
Fig. 1 Systemic computed tomographic (CT) scan on admission (A, B, C, D) and after 6 cycles of DA-EPOCH-R therapy (E, F, G, H)
Systemic CT scan on admission shows a right cardiophrenic lymphadenopathy (arrow), pleural effusions (A), bilateral hydronephrosis (arrow) and renal infiltration (B), a 9 cm × 5 cm retroperitoneal mass (arrow) (C), and bilateral inguinal lymphadenopathies (arrow) (D). Each lesion shrank after 6 cycles of DA-EPOCH-R (E, F, G, H).
On the second day in hospital, inguinal lymph node biopsy was performed (Figure 2). Hematoxylin and eosin (H&E) staining showed a diffuse pattern of involvement with medium to large abnormal lymphocytes, and loss of the normal structure of lymphoid follicles. Immunostaining showed that the tumor was negative for CD3 and Bcl-6, and positive for CD10, CD20, CD79a, Ki67, c-Myc, and Bcl-2. The positive rate of Ki67, c-Myc and Bcl-2 was over 90% for each. Fluorescence in situ hybridization (FISH) showed split signals at 8q24 (MYC) and 18q21 (BCL2) (Figure 3). Based on these findings, we diagnosed high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements. Ann Arbor stage was IV A and International Prognostic Index was high-intermediate risk.
Fig. 2 Pathological images of inguinal lymph node biopsy
Hematoxylin and eosin (H&E) staining images show a diffuse pattern of involvement with medium to large abnormal lymphocytes, with loss of the normal structure of lymphoid follicles (A). Immunostaining images show that the tumor was negative for CD3 (B), negative for CD10 (C), positive for CD20 (D), positive for CD79a (E), positive for Ki67 (positive rate was over 90%) (F), positive for c-Myc (positive rate was over 90%) (G), positive for Bcl-2 (positive rate was over 90%) (H) and negative for Bcl-6 (I).
Fig. 3 Fluorescence in situ hybridization (FISH) of inguinal lymph node biopsy
Of 111 cells, 74 (66.7%) showed split signals at 8q24 (MYC) and duplication of 5’ MYC and 3’ MYC probe signals (A). Out of 104 cells, 68 (65.4%) showed split signals at 18q21 (BCL2) and duplication of 5’ BCL2 probe signals (B).
On the day of admission, right nephrostomy was performed for ureteral obstruction, but Cre improvement was poor, and the patient required emergency hemodialysis from the 4th hospital day. As diagnosis from the preliminary pathological report was diffuse large B-cell lymphoma (DLBCL), we started half-dose CHOP therapy (cyclophosphamide 375 mg/m2, day 1; doxorubicin 25 mg/m2, day 1; vincristine 0.7 mg/m2, day 1; prednisolone 60 mg/m2, days 1–5) on the 23rd hospital day. Rasburicase was administered to prevent tumor lysis syndrome. Urinary volume of 1000 mL/day was obtained on the 25th hospital day, but despite this and removal of the ureteral obstruction, Cre and 24-hour urine collection creatinine clearance (Ccr) improved only to 2.4 mg/dL and 37 mL/min, respectively, and right renal dysfunction remained (Figure 4). The patient was weaned off hemodialysis on the 30th hospital day. After the first cycle of half-dose CHOP therapy, the treatment response was stable disease (SD) with 47% tumor reduction (Figure 1). Cre remained approximately 2 mg/dL during treatment.
Fig. 4 Treatment and transition of serum lactate dehydrogenase (LDH), serum creatinine (Cre), and 24-hour urine collection creatinine clearance (Ccr)
Nephrostomy was performed for ureteral obstruction on the first hospital day. However, Cre did not improve, and we started hemodialysis. We performed half-dose CHOP therapy and the obstruction was removed immediately, although renal dysfunction remained (Cre 2.4 mg/dL, Ccr 37 mL/min). Owing to the confirmed diagnosis of the high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, we decided to use an intensive regimen and started full-dose DA-EPOCH-R therapy. Doses were reduced by 20% from the fourth cycle onward due to Common Terminology Criteria for Adverse Event (CTCAE) grade 4 neutropenia. Six cycles of DA-EPOCH-R therapy were completed without other adverse events greater than CTCAE grade 2. DA-EPOCH-R therapy did not exacerbate renal dysfunction. Cre and Ccr were stable at around 2-3 mg/dL and 30-40 mL/min, respectively, during the treatment.
Pathological examination and FISH revealed the diagnosis of high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements. Although Ccr was as low as 45 mL/min, we started DA-EPOCH-R therapy (rituximab 375 mg/m2, day 1; doxorubicin 10 mg/m2, days 2–5; vincristine 0.4 mg/m2, days 2–5; cyclophosphamide 750 mg/m2, day 6; prednisolone 60 mg/m2, days 2–6; administered every 21 days) without initial dose reduction on the 38th hospital day because more intensive treatment was considered necessary for DHL/THL. No worsening of renal function was observed during the treatment, and the patient completed the first cycle without any problems. The treatment response was partial response (PR) with 64% tumor reduction, and we decided to continue the DA-EPOCH-R therapy. On the third cycle, grade 4 neutropenia as categorized by the Common Terminology Criteria for Adverse Events (CTCAE) was observed, and we therefore reduced dosages from the fourth cycle onward by 20% in accordance with the protocol for DA-EPOCH-R therapy. The patient completed six cycles of DA-EPOCH-R without any new CTCAE grade 2 or higher adverse events. Ccr remained between 31 and 43 mL/min, with no further exacerbation. Plain CT after six cycles of DA-EPOCH-R therapy showed the response was PR with 65% tumor reduction, although contrast-enhanced CT was not possible due to renal dysfunction, and the accurate evaluation was difficult. There was no indication of tumor enlargement, and we therefore decided to monitor him as an outpatient and he was discharged on the 163rd hospital day. We scheduled positron emission tomography-computed tomography (PET-CT) after discharge. However, 22 days after discharge he presented diplopia. Head magnetic resonance imaging revealed swellings of the bilateral abducens nerves and the left optic nerve. Cytopathologic examination of lumbar puncture showed an invasion of large abnormal lymphocytes. He was readmitted, and we could not perform PET-CT.
DISCUSSION
We describe a case in which a DHL patient with moderate renal dysfunction (Cre 2 mg/dL, Ccr 30 mL/min) was treated with DA-EPOCH-R therapy according to the protocol without major adverse events, including worsening renal function.
Although a standard initial treatment for DHL/THL has not been established, it has been reported that intensive regimens such as DA-EPOCH-R therapy, R-HyperCVAD/MA therapy, and R-CODOX-M/IVAC therapy improve progression-free survival (PFS) rates more than R-CHOP therapy.11-13 A meta-analysis reported that DA-EPOCH-R had lower toxicity and superior PFS and overall survival (OS) than a combined R-HyperCVAD/MA and R-CODOX-M/IVAC treatment (median PFS 22.2 months and 18.9 months, respectively; median OS 31.4 months and 25.2 months, respectively).11 A phase 2 prospective study in DHL also showed a high efficacy of DA-EPOCH-R therapy.14
Although the efficacy of DA-EPOCH-R therapy as an initial treatment for DHL/THL has been established, in the prospective study mentioned above14 and in an initial report on DA-EPOCH-R therapy,6 patients with renal dysfunction with a Cre >1.5 mg/dL were excluded from the studies. Therefore, the safety of DA-EPOCH-R therapy in patients with renal dysfunction is currently unknown and presents a major question in daily clinical practice. There are few reports regarding DA-EPOCH-R in patients with moderate or severe renal dysfunction, and we could find only two such cases.15 One case of Burkitt lymphoma with acute kidney injury due to dehydration; this recovered to Cre of 1.73 mg/dL with hydration, and DA-EPOCH-R therapy was subsequently commenced. The second case of Burkitt lymphoma with ureteral obstruction due to the tumor. COP therapy (cyclophosphamide, vincristine, and methylprednisolone) was commenced as the initial treatment, and ureteral obstruction was removed. After improvement of Cre to 1.73 mg/dL, DA-EPOCH-R therapy was started. Both cases completed six cycles of DA-EPOCH-R therapy without exacerbation of renal dysfunction. Considering these reports, DA-EPOCH-R therapy is likely to be safe even in patients with moderate renal dysfunction. For this reason, we selected DA-EPOCH-R therapy instead of CHOP therapy in this case.
According to a report on dose recommendation for anticancer drugs for renal dysfunction,16 there is no need to adjust doses of rituximab, doxorubicin, vincristine, and cyclophosphamide if the Ccr is 45 mL/min, and a 75% dose of etoposide is recommended. In this case, etoposide was administered at 100% dose to prioritize efficacy over toxicity. If safety is more important, a 75% reduction in the dose of etoposide may be considered. We could safely administer the DA-EPOCH-R therapy both by preparing a system to resume dialysis at any time if renal dysfunction became exacerbated, and by monitoring the patient with frequent blood tests.
The patient in this case had a retroperitoneal mass and kidney invasion resulting in bilateral hydronephrosis and post-renal acute kidney injury. Cre on admission was 17.37 mg/dL, and it required temporary hemodialysis. Although half-dose CHOP therapy resolved the ureteral obstruction, Cre improved only to approximately 2 mg/dL, and renal dysfunction remained because of kidney lesion. We selected DA-EPOCH-R therapy considering the high risk of recurrence with R-CHOP therapy for DHL/THL, although there was concern regarding decreasing renal function due to high-intensive chemotherapy. We did not select R-CODOX-M/IVAC therapy because high-dose methotrexate therapy has been reported to worsen renal function in a high number of patients with renal dysfunction.17 We were able to complete six cycles of DA-EPOCH-R therapy according to the protocol and reach remission. Moreover, there was no worsening of renal dysfunction.
Recurrence of central nerve system (CNS) is known to have a high frequency in DLBCL with MYC translocation,2 for which CNS prophylaxis is recommended. The same is true for DHL, and a clinical trial showing the efficacy of R-EPOCH for DHL14 also included CNS prophylaxis with intrathecal methotrexate. In general, high-dose intravenous methotrexate and intrathecal methotrexate are widely used for CNS prophylaxis in NHL.18 While high-dose intravenous methotrexate has been reported to significantly reduce CNS recurrence,19,20 there is no evidence regarding whether intrathecal methotrexate alone significantly reduces or does not prevent CNS recurrence.21-23 In this case, intrathecal methotrexate could not be administered because the patient was in poor general condition on admission and could not be positioned for lumbar puncture. High-dose methotrexate therapy could not be administered due to renal dysfunction. Although there is no solid evidence that intrathecal methotrexate significantly suppresses CNS recurrence, the decision not to administer intrathecal methotrexate in this case is a major regret. Whether intrathecal methotrexate alone is useful for preventing CNS recurrence needs to be studied on a larger scale.
Our experience, combined with the conclusions of the two cases mentioned above, suggests that DA-EPOCH-R therapy may be safely administered even if Cre is below 2–3 mg/dL or Ccr is above 30–40 mL/min, although no definite reference values for Cre and Ccr can yet be set. There have been few reports of DA-EPOCH-R therapy administered to patients with renal dysfunction, and an appropriate treatment regimen for DHL/THL patients with renal dysfunction has not been established. We therefore recommend carrying out more case studies to continue the evaluation of the safety and efficacy of DA-EPOCH-R therapy for patients with renal dysfunction.
CONFLICT OF INTEREST
The authors declare no conflicts of interest. | ON DAY 1; AS A PART OF DA?EPOCH?R REGIMEN ADMINISTERED EVERY 21 DAYS | DrugDosageText | CC BY-NC-SA | 33551436 | 19,067,711 | 2021-03-18 |
What was the dosage of drug 'VINCRISTINE'? | DA-EPOCH-R therapy for high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements in a patient with renal dysfunction.
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit lymphoma, has been reported as refractory to R-CHOP therapy and requires more intensive regimens. However, intensive and safe regimens for patients with renal dysfunction are unknown. Herein, we report the successful use of DA-EPOCH-R therapy for double-hit lymphoma in a 64-year-old man with renal dysfunction. The patient had lymphoma-induced bilateral ureteral obstruction. Although renal dysfunction remained after removing the obstruction using R-CHOP therapy, we completed six cycles of DA-EPOCH-R therapy without any major adverse events. DA-EPOCH-R therapy may be a safe regimen for renal dysfunction patients.
INTRODUCTION
Diffuse large B-cell lymphoma (DLBCL) with MYC and BCL2 rearrangements is often reported to be refractory to R-CHOP therapy, with a poor prognosis.1-4 The 2016 revision of the World Health Organization classification of lymphoid neoplasms newly characterized high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,5 widely and commonly referred to as double-hit lymphoma (DHL) or triple-hit lymphoma (THL).
Although no standard initial treatment for DHL or THL has been established, it has been reported that if organ function is preserved, progression-free survival (PFS) is improved by selecting intensive regimens such as dose-adjusted (DA)-EPOCH-R therapy,6-8 R-HyperCVAD/MA therapy,9 or R-CODOX-M/IVAC therapy,10 rather than R-CHOP therapy.11-13 However, there are few known intensive regimens that can be safely administered to patients with DHL/THL who have moderate to severe renal dysfunction.
We report a case of double-hit lymphoma with renal dysfunction in a patient who underwent DA-EPOCH-R therapy according to the protocol, without initial dose reduction.
CASE REPORT
The patient was a 64-year-old Japanese man with no noteworthy medical or family history. He experienced malaise and abdominal distention three weeks before admission, and chest discomfort and orthopnea began five days before admission. The day before admission, he visited the emergency department, presenting with arm and leg edema and right pleural effusion seen on chest X-ray. Heart failure was suspected, and he was prescribed furosemide. The next day, he visited the internal department of the general hospital. Plain computed tomography (CT) revealed bilateral hydronephrosis and a retroperitoneal mass lesion. He was then transferred to the urology department of our hospital as an emergency case. Blood tests showed elevated soluble interleukin-2 receptor (sIL-2R) levels at 9334 IU/L, and he was referred to our department with suspicion of malignant lymphoma.
On admission, he was fully conscious, his temperature was 35.7°C, pulse was 53 beats per minute, blood pressure was 177/87 mmHg, and SpO2 was 98% on room air. He had no anemia in the foveal conjunctiva and no jaundice in the ocular conjunctiva. Respiratory and cardiac sounds were normal. The abdomen was flat and soft, and the liver and spleen were not palpable. Both lower limbs had pitting edema. Inguinal lymph nodes were 3-cm in size and elastic, hard, and smooth-textured on palpation bilaterally. No other superficial lymph nodes were palpated. There were no abnormal neurological findings. His Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 2. He had no systemic B symptoms (fever, night sweats, or weight loss).
Laboratory data on admission (Table 1) showed a markedly elevated creatinine (Cre) of 17.31 mg/dL, blood urea nitrogen (BUN) of 121 mg/dL, potassium (K) of 7.3 mEq/L, and inorganic phosphorus (IP) of 10.1 mg/dL. Lactate dehydrogenase (LDH) and sIL-2R were elevated to 666 IU/L and 9334 IU/mL, respectively. Plain CT (Figure 1) showed a 9 cm × 5 cm retroperitoneal mass causing bilateral hydronephrosis and partially kidney invasive lesion. It also showed pleural effusions and right cardiophrenic and bilateral inguinal lymphadenopathies. Bone marrow examination revealed no apparent tumor cell infiltration, and Giemsa banding showed a normal 46,XY karyotype. Cytopathologic examination of pleural fluid showed invasion of large abnormal lymphocytes.
Table 1 Laboratory data on admission
RBC 424×104 /μL TP 6.5 g/dL Ca 9.2 mg/dL
Hb 12.8 g/dL Alb 3.5 g/dL IP 10.1 mg/dL
Hct 37.0 % AST 14 IU/L CRP 3.17 mg/dL
MCV 87.3 fl ALT 14 IU/L sIL-2R 9334 IU/mL
MCH 30.2 pg LDH 666 IU/L Ferritin 417 ng/mL
MCHC 34.6 % ALP 187 IU/L IgG 467 mg/dL
WBC 9980 /μL γ-GTP 19 IU/L IgA 45 mg/dL
Neu 83.5 % T-Bil 0.4 mg/dL IgM 207 mg/dL
Lym 9.9 % BUN 121 mg/dL APTT 27.4 sec
Eos 5.3 % Cre 17.37 mg/dL (control) 26.7 sec
Bas 1.1 % Na 130 mEq/L PT% 98 %
Mon 0.2 % K 7.3 mEq/L PT-INR 1.01
Plt 45.7×104 /μL Cl 94 mEq/L
RBC: red blood cell, Hb: hemoglobin, Hct: hematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration, WBC: white blood cell, Neu: neutrophil, Lym: lymphocyte, Eos: eosinophil, Bas: basophil, Mon: monocyte, Plt: platelet, TP: total protein, Alb: albumin, AST: aspartate transaminase, ALT: alanine transaminase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: γ-glutamyl transpeptidase, T-Bil: total bilirubin, BUN: blood urea nitrogen, Cre: creatinine, IP: inorganic phosphate, CRP: C-reactive protein, sIL-2R: soluble interleukin-2 receptor, APTT: activated partial thromboplastin time, PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio
Fig. 1 Systemic computed tomographic (CT) scan on admission (A, B, C, D) and after 6 cycles of DA-EPOCH-R therapy (E, F, G, H)
Systemic CT scan on admission shows a right cardiophrenic lymphadenopathy (arrow), pleural effusions (A), bilateral hydronephrosis (arrow) and renal infiltration (B), a 9 cm × 5 cm retroperitoneal mass (arrow) (C), and bilateral inguinal lymphadenopathies (arrow) (D). Each lesion shrank after 6 cycles of DA-EPOCH-R (E, F, G, H).
On the second day in hospital, inguinal lymph node biopsy was performed (Figure 2). Hematoxylin and eosin (H&E) staining showed a diffuse pattern of involvement with medium to large abnormal lymphocytes, and loss of the normal structure of lymphoid follicles. Immunostaining showed that the tumor was negative for CD3 and Bcl-6, and positive for CD10, CD20, CD79a, Ki67, c-Myc, and Bcl-2. The positive rate of Ki67, c-Myc and Bcl-2 was over 90% for each. Fluorescence in situ hybridization (FISH) showed split signals at 8q24 (MYC) and 18q21 (BCL2) (Figure 3). Based on these findings, we diagnosed high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements. Ann Arbor stage was IV A and International Prognostic Index was high-intermediate risk.
Fig. 2 Pathological images of inguinal lymph node biopsy
Hematoxylin and eosin (H&E) staining images show a diffuse pattern of involvement with medium to large abnormal lymphocytes, with loss of the normal structure of lymphoid follicles (A). Immunostaining images show that the tumor was negative for CD3 (B), negative for CD10 (C), positive for CD20 (D), positive for CD79a (E), positive for Ki67 (positive rate was over 90%) (F), positive for c-Myc (positive rate was over 90%) (G), positive for Bcl-2 (positive rate was over 90%) (H) and negative for Bcl-6 (I).
Fig. 3 Fluorescence in situ hybridization (FISH) of inguinal lymph node biopsy
Of 111 cells, 74 (66.7%) showed split signals at 8q24 (MYC) and duplication of 5’ MYC and 3’ MYC probe signals (A). Out of 104 cells, 68 (65.4%) showed split signals at 18q21 (BCL2) and duplication of 5’ BCL2 probe signals (B).
On the day of admission, right nephrostomy was performed for ureteral obstruction, but Cre improvement was poor, and the patient required emergency hemodialysis from the 4th hospital day. As diagnosis from the preliminary pathological report was diffuse large B-cell lymphoma (DLBCL), we started half-dose CHOP therapy (cyclophosphamide 375 mg/m2, day 1; doxorubicin 25 mg/m2, day 1; vincristine 0.7 mg/m2, day 1; prednisolone 60 mg/m2, days 1–5) on the 23rd hospital day. Rasburicase was administered to prevent tumor lysis syndrome. Urinary volume of 1000 mL/day was obtained on the 25th hospital day, but despite this and removal of the ureteral obstruction, Cre and 24-hour urine collection creatinine clearance (Ccr) improved only to 2.4 mg/dL and 37 mL/min, respectively, and right renal dysfunction remained (Figure 4). The patient was weaned off hemodialysis on the 30th hospital day. After the first cycle of half-dose CHOP therapy, the treatment response was stable disease (SD) with 47% tumor reduction (Figure 1). Cre remained approximately 2 mg/dL during treatment.
Fig. 4 Treatment and transition of serum lactate dehydrogenase (LDH), serum creatinine (Cre), and 24-hour urine collection creatinine clearance (Ccr)
Nephrostomy was performed for ureteral obstruction on the first hospital day. However, Cre did not improve, and we started hemodialysis. We performed half-dose CHOP therapy and the obstruction was removed immediately, although renal dysfunction remained (Cre 2.4 mg/dL, Ccr 37 mL/min). Owing to the confirmed diagnosis of the high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, we decided to use an intensive regimen and started full-dose DA-EPOCH-R therapy. Doses were reduced by 20% from the fourth cycle onward due to Common Terminology Criteria for Adverse Event (CTCAE) grade 4 neutropenia. Six cycles of DA-EPOCH-R therapy were completed without other adverse events greater than CTCAE grade 2. DA-EPOCH-R therapy did not exacerbate renal dysfunction. Cre and Ccr were stable at around 2-3 mg/dL and 30-40 mL/min, respectively, during the treatment.
Pathological examination and FISH revealed the diagnosis of high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements. Although Ccr was as low as 45 mL/min, we started DA-EPOCH-R therapy (rituximab 375 mg/m2, day 1; doxorubicin 10 mg/m2, days 2–5; vincristine 0.4 mg/m2, days 2–5; cyclophosphamide 750 mg/m2, day 6; prednisolone 60 mg/m2, days 2–6; administered every 21 days) without initial dose reduction on the 38th hospital day because more intensive treatment was considered necessary for DHL/THL. No worsening of renal function was observed during the treatment, and the patient completed the first cycle without any problems. The treatment response was partial response (PR) with 64% tumor reduction, and we decided to continue the DA-EPOCH-R therapy. On the third cycle, grade 4 neutropenia as categorized by the Common Terminology Criteria for Adverse Events (CTCAE) was observed, and we therefore reduced dosages from the fourth cycle onward by 20% in accordance with the protocol for DA-EPOCH-R therapy. The patient completed six cycles of DA-EPOCH-R without any new CTCAE grade 2 or higher adverse events. Ccr remained between 31 and 43 mL/min, with no further exacerbation. Plain CT after six cycles of DA-EPOCH-R therapy showed the response was PR with 65% tumor reduction, although contrast-enhanced CT was not possible due to renal dysfunction, and the accurate evaluation was difficult. There was no indication of tumor enlargement, and we therefore decided to monitor him as an outpatient and he was discharged on the 163rd hospital day. We scheduled positron emission tomography-computed tomography (PET-CT) after discharge. However, 22 days after discharge he presented diplopia. Head magnetic resonance imaging revealed swellings of the bilateral abducens nerves and the left optic nerve. Cytopathologic examination of lumbar puncture showed an invasion of large abnormal lymphocytes. He was readmitted, and we could not perform PET-CT.
DISCUSSION
We describe a case in which a DHL patient with moderate renal dysfunction (Cre 2 mg/dL, Ccr 30 mL/min) was treated with DA-EPOCH-R therapy according to the protocol without major adverse events, including worsening renal function.
Although a standard initial treatment for DHL/THL has not been established, it has been reported that intensive regimens such as DA-EPOCH-R therapy, R-HyperCVAD/MA therapy, and R-CODOX-M/IVAC therapy improve progression-free survival (PFS) rates more than R-CHOP therapy.11-13 A meta-analysis reported that DA-EPOCH-R had lower toxicity and superior PFS and overall survival (OS) than a combined R-HyperCVAD/MA and R-CODOX-M/IVAC treatment (median PFS 22.2 months and 18.9 months, respectively; median OS 31.4 months and 25.2 months, respectively).11 A phase 2 prospective study in DHL also showed a high efficacy of DA-EPOCH-R therapy.14
Although the efficacy of DA-EPOCH-R therapy as an initial treatment for DHL/THL has been established, in the prospective study mentioned above14 and in an initial report on DA-EPOCH-R therapy,6 patients with renal dysfunction with a Cre >1.5 mg/dL were excluded from the studies. Therefore, the safety of DA-EPOCH-R therapy in patients with renal dysfunction is currently unknown and presents a major question in daily clinical practice. There are few reports regarding DA-EPOCH-R in patients with moderate or severe renal dysfunction, and we could find only two such cases.15 One case of Burkitt lymphoma with acute kidney injury due to dehydration; this recovered to Cre of 1.73 mg/dL with hydration, and DA-EPOCH-R therapy was subsequently commenced. The second case of Burkitt lymphoma with ureteral obstruction due to the tumor. COP therapy (cyclophosphamide, vincristine, and methylprednisolone) was commenced as the initial treatment, and ureteral obstruction was removed. After improvement of Cre to 1.73 mg/dL, DA-EPOCH-R therapy was started. Both cases completed six cycles of DA-EPOCH-R therapy without exacerbation of renal dysfunction. Considering these reports, DA-EPOCH-R therapy is likely to be safe even in patients with moderate renal dysfunction. For this reason, we selected DA-EPOCH-R therapy instead of CHOP therapy in this case.
According to a report on dose recommendation for anticancer drugs for renal dysfunction,16 there is no need to adjust doses of rituximab, doxorubicin, vincristine, and cyclophosphamide if the Ccr is 45 mL/min, and a 75% dose of etoposide is recommended. In this case, etoposide was administered at 100% dose to prioritize efficacy over toxicity. If safety is more important, a 75% reduction in the dose of etoposide may be considered. We could safely administer the DA-EPOCH-R therapy both by preparing a system to resume dialysis at any time if renal dysfunction became exacerbated, and by monitoring the patient with frequent blood tests.
The patient in this case had a retroperitoneal mass and kidney invasion resulting in bilateral hydronephrosis and post-renal acute kidney injury. Cre on admission was 17.37 mg/dL, and it required temporary hemodialysis. Although half-dose CHOP therapy resolved the ureteral obstruction, Cre improved only to approximately 2 mg/dL, and renal dysfunction remained because of kidney lesion. We selected DA-EPOCH-R therapy considering the high risk of recurrence with R-CHOP therapy for DHL/THL, although there was concern regarding decreasing renal function due to high-intensive chemotherapy. We did not select R-CODOX-M/IVAC therapy because high-dose methotrexate therapy has been reported to worsen renal function in a high number of patients with renal dysfunction.17 We were able to complete six cycles of DA-EPOCH-R therapy according to the protocol and reach remission. Moreover, there was no worsening of renal dysfunction.
Recurrence of central nerve system (CNS) is known to have a high frequency in DLBCL with MYC translocation,2 for which CNS prophylaxis is recommended. The same is true for DHL, and a clinical trial showing the efficacy of R-EPOCH for DHL14 also included CNS prophylaxis with intrathecal methotrexate. In general, high-dose intravenous methotrexate and intrathecal methotrexate are widely used for CNS prophylaxis in NHL.18 While high-dose intravenous methotrexate has been reported to significantly reduce CNS recurrence,19,20 there is no evidence regarding whether intrathecal methotrexate alone significantly reduces or does not prevent CNS recurrence.21-23 In this case, intrathecal methotrexate could not be administered because the patient was in poor general condition on admission and could not be positioned for lumbar puncture. High-dose methotrexate therapy could not be administered due to renal dysfunction. Although there is no solid evidence that intrathecal methotrexate significantly suppresses CNS recurrence, the decision not to administer intrathecal methotrexate in this case is a major regret. Whether intrathecal methotrexate alone is useful for preventing CNS recurrence needs to be studied on a larger scale.
Our experience, combined with the conclusions of the two cases mentioned above, suggests that DA-EPOCH-R therapy may be safely administered even if Cre is below 2–3 mg/dL or Ccr is above 30–40 mL/min, although no definite reference values for Cre and Ccr can yet be set. There have been few reports of DA-EPOCH-R therapy administered to patients with renal dysfunction, and an appropriate treatment regimen for DHL/THL patients with renal dysfunction has not been established. We therefore recommend carrying out more case studies to continue the evaluation of the safety and efficacy of DA-EPOCH-R therapy for patients with renal dysfunction.
CONFLICT OF INTEREST
The authors declare no conflicts of interest. | ON DAYS 2?5; AS A PART OF DA?EPOCH?R REGIMEN ADMINISTERED EVERY 21 DAYS | DrugDosageText | CC BY-NC-SA | 33551436 | 19,067,711 | 2021-03-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | MTX-HOPE is a low-dose salvage chemotherapy for aged patients with relapsed or refractory non-Hodgkin lymphoma.
As the aging society advances, the number of non-Hodgkin lymphoma (NHL) patients is increasing. Aged relapsed or refractory (r/r) NHL patients have limited treatment options. Therefore, a safe and effective regimen is urgently needed for these patients. Thus, we originally developed the MTX-HOPE (methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide) regimen for r/r NHL and validated the safety and efficacy of this regimen in a clinical setting. We analyzed the data of 42 r/r NHL patients who received MTX-HOPE in this single-center retrospective cohort study. The median age of the patients was 81 years. The overall response rate was 45.3%. The median overall survival (OS) was 7 months, the one-year OS was 43.7%, and the two-year OS was 40.8%. Grade ≥3 neutropenia and renal dysfunction were observed in 47.6% and 11.9% of patients, respectively, and treatment-related death were not observed. Appropriate supportive care enabled these patients to continue the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Multivariable analyses with the Cox proportional hazards model revealed that both OS and progression-free survival (PFS) were significantly influenced by high Ki-67 expression in pathology, with response to the MTX-HOPE regimen after three to five cycles as a time-dependent covariate. Our results suggest that MTX-HOPE therapy can be an option for non-aggressive r/r NHL patients. To validate MTX-HOPE therapy, further prospective investigation is needed.
INTRODUCTION
The aged population is increasing, particularly in advanced countries. As this population advances, the incidence of cancers, including malignant lymphoma, is rising.1-3 Because cancer can be considered an age-related disease, it is an urgent task to take measures for elderly patients with cancer in advanced countries.4 Because most vulnerable older adult patients cannot be enrolled in clinical trials, there are few data regarding the management of aged cancer patients, including those with lymphoma. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)/CHOP (CHOP) therapy is the gold standard regimen for elderly non-Hodgkin lymphoma (NHL) patients.5-8 However, even if complete response (CR) is reached with initial treatment, 20-50% of patients with diffuse large B cell lymphoma (DLBCL) experience relapse,9 and there are few therapeutic options, especially for aged patients with relapsed NHL.
Thus, it is unclear whether aged relapsed or refractory (r/r) NHL patients are suitable for certain therapeutic strategies. Aged patients with some comorbidities cannot receive sufficient intensity salvage chemotherapies in the clinic. We thus developed a combination salvage therapy for r/r NHL based on isobologram analysis data for these vulnerable patients.10-16 We selected methotrexate (MTX), hydrocortisone (HC), vincristine (VCR), sobuzoxane (MST-16), and etoposide (ETP) and named this regimen MTX-HOPE (Table 1).17 This regimen has the advantage of being performed on an outpatient basis. We previously reported the safety and efficacy of the MTX-HOPE regimen in a small number of NHL patients. In a previous study, the median age of the patients was 70 years, and the median overall survival (OS) was 11.1 months. In addition, another group recently reported the efficacy of the MTX-HOPE regimen, and the median OS and progression-free survival (PFS) were 10 months and 7 months, respectively.18 However, the characteristics of NHL patients who are more likely to respond to MTX-HOPE therapy are still unknown. We need to identify patients suitable for this regimen from the perspective of safety and effectiveness. Thus, we performed a single-center retrospective cohort study to validate the MTX-HOPE regimen.
Table 1 The protocol of MTX-HOPE
Agent Dose/day Route Days
Methotrexate (MTX) 20 mg po 1
Hydrocortisone (HC) 100 mg div (15min) 2
Vincristine (VCR) 1 mg div (15min) 2
Sobuzoxane (MST-16) 400 mg po 3, 4
Etoposide (ETP) 25 mg po 3, 4
Abbreviations: MTX-HOPE, methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide; po, per os; div, intravenous drip
MATERIALS AND METHODS
Study design and patients
This study was conducted as a single-center retrospective cohort study. A total of 42 patients who received MTX-HOPE therapy agreed to participate in this study, which was approved by the local Ethics Committee of Aizu Medical Center of Fukushima Medical University (FMU) and carried out in accordance with the relevant guidelines and regulations. Written informed consent was obtained from all subjects prior to enrollment. We obtained patient characteristics and laboratory data from the clinical records of all patients diagnosed with NHL, including DLBCL, mantle cell lymphoma (MCL), peripheral T cell lymphoma (PTCL), and others, from 2009 to 2020.
Treatment protocol
The MTX-HOPE regimen was repeated every 2-3 weeks and involved the administration of MTX (20 mg) orally on day 1, HC (100 mg) and VCR (1 mg) infusion on day 2, and MST-16 (400 mg) and ETP (25 mg) orally on days 3 and 4 (Table 1). Granulocyte colony-stimulating factor (G-CSF) was administered to patients who experienced neutropenia as supportive therapy.
Treatment response and toxicity criteria
Efficacy assessments were performed according to the international consensus on the revised response criteria for malignant lymphoma. According to these criteria, we defined therapy responses as follows: complete response (CR), unconfirmed CR (uCR), partial response (PR), stable disease (SD), and progressive disease (PD). Physical examination and laboratory tests were used to evaluate adverse reactions and toxicities. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, Version 4.0.
Statistical analysis
All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of the R commander designed to add statistical functions frequently used in biostatistics.19 The Kolmogorov-Smirnov test was used to analyze the normality of the distribution of parameters.20,21 All variables with a normal distribution are expressed as the mean ± standard deviation, and those with a log-normal distribution are expressed as the median with the interquartile range (IQR). OS was defined as the time from the start of MTX-HOPE therapy to death or the date of the last follow-up.22 PFS was defined as the time from the start of MTX-HOPE therapy to relapse, death, or the date of the last follow-up. The OS and PFS rates were estimated according to the Kaplan-Meier method and compared by the log-rank test.19,22 The hazard ratios (HRs) and their associated 95% confidence intervals (CIs) for potential prognostic factors were calculated using the Cox proportional hazards regression model. Variables with p < 0.10 in the univariate analysis were used as independent variables in the multivariate analysis.23 All statistical tests were two-sided, and a significance level of 0.05 was used.
RESULTS
Patient characteristics
The median age of the 42 patients who received MTX-HOPE therapy for r/r NHL in this study was 81 years (range, 57 to 90 years), and 35.7% were women (Table 2). In our study, seven patients (16.7%) who received the MTX-HOPE regimen were less than 70 years old. Six patients had a history of multiple pretreatment regimens, and the other patient had severe pulmonary disease and poor performance status (PS). These patients had no indication for intensive chemotherapy and agreed to receive the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Twenty-five patients were refractory to previous treatment, and 17 had relapsed disease. The proportion of patients with worse Eastern Cooperative Oncology Group (ECOG) PS scores (more than 2) was 59.5%, the proportion of patients with anemia (hemoglobin less than 10 g/dL) was 42.9%, and the proportion of patients with lactate dehydrogenase (LDH) levels greater than the upper limit of normal was 54.8%. At the time of diagnosis, the proportion of patients with intermediate- and high-risk International Prognostic Index (IPI) scores was 92.9%, and the proportion of patients with advanced stage (stage III and IV) disease was 85.6%. The lymphoma histology of the patients included 28 DLBCL, one follicular lymphoma (FL), one MCL, 11 T cell lymphoma, and one extranodal NK/T cell lymphoma. In addition, the proportion of patients with Ki-67 positivity greater than 50% by immunohistochemistry (IHC) was 36%. Furthermore, the MTX-HOPE regimen was given to patients as salvage therapy. We assessed the response to MTX-HOPE after three to five cycles by computed tomography (CT). The percentage of patients who achieved CR or unconfirmed CR was 19%, PR was 26.2%, SD was 31%, and PD was 23.8% at that time.
Table 2 Patient characteristics
Characteristics patients MTX-HOPE
Patients, n 42
Hospitalization during MTX-HOPE administration 9 (21)
At the start of treatment
Age, median [min, max] 81 [57, 90]
Women, n (%) 15 (36)
Performance status, n (%)
0-1 17 (41)
2-4 25 (60)
Status before MTX-HOPE treatment, n (%)
Relapsed 17 (41)
Refractory 25 (60)
Number of pretreatment regimens, n (%)
1 31(74)
2 3 (7.1)
≥3 8 (19)
Pretreatment regimen, n (%)
CHOP +/-R 28 (67)
DeVIC +/-R 5 (12)
GDP +/-R 3 (7.1)
Other 6 (14)
Previous treatment history of rituximab, n (%) 29 (69)
Histology, n (%)
B cell lymphoma 30 (71)
DLBCL 28 (67)
FL 1 (2.4)
MCL 1 (2.4)
T cell lymphoma 11 (26)
Extranodal NK/T cell lymphoma 1 (2.4)
Anemia (Hb <10), n (%) 18 (43)
CKD, n (%) 16 (38)
LDH high (≥upper normal limit; 240) 23 (55)
BMI (<20 kg/m2), n (%) 15 (36)
At diagnosis
IPI, n(%)
Low risk 3(7.1)
Intermediate risk 16 (38)
High risk 23 (55)
Stage, n(%)
I 4 (9.5)
II 2 (4.8)
III 9 (21)
IV 27 (64)
Bone marrow involvement, n (%) 12 (29)
Extranodal lesion, n (%) 33 (79)
B symptoms present, n (%) 12 (29)
Ki-67 high (≥50%), n(%) 15 (36)
DLBCL 12 (29)
MCL 1 (2.4)
T cell lymphoma 2 (4.8)
Response after 3 to 5 cycles, n (%)
Complete response (CR)/unconfirmed CR 8 (19)
Partial response (PR) 11 (26)
Stable disease (SD) 13 (31)
Progressive disease (PD) 10 (24)
Abbreviations: DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; CKD, chronic kidney disease
Safety of MTX-HOPE
The hematological and nonhematological toxicities of MTX-HOPE are shown in Table 3. Grade 3 and 4 neutropenia were observed in 47.6% of the patients, and febrile neutropenia was observed in 9.5%. Grade 3 and 4 anemia and thrombocytopenia were observed in 35.7% and 14.3% of the patients, respectively. Severe nonhematological toxicities, such as liver damage, renal dysfunction, nausea, vomiting, and infection, were infrequent in patients treated with MTX-HOPE therapy. Seventeen patients temporarily discontinued VCR due to grade 1 neuropathy in our study. However, most patients could continue VCR while administered vitamin B12 and pregabalin. The other drugs did not need to be reduced. Furthermore, there were no treatment-related deaths. However, there were six treatment discontinuation events: four pneumonia, one sepsis and one acute kidney injury (Table 3).
Table 3 Adverse effects of MTX-HOPE therapy
Hematological toxicity All Grades Grade ≥3
Neutropenia n, (%) 33 (79) 20 (48)
Febrile neutropenia n, (%) - 4 (9.5)
Anemia n, (%) 39 (93) 15 (36)
Thrombocytopenia n, (%) 30 (71) 6 (14)
Nonhematological toxicity
Liver damage 10 (24) 2 (4.8)
Renal dysfunction 24 (57) 5 (12)
Nausea 8 (19) 0 (0)
Vomiting 1 (2.4) 0 (0)
Infection 10 (24) 3 (7.1)
Neuropathy 17 (40) 0 (0)
Hematological supportive care
Red blood cell transfusion 13 (30.9)
Platelet transfusion 4 (9.5)
G-CSF 24 (57.1)
Treatment-related deaths 0 (0)
Treatment discontinuation events 6 (14)
Pneumonia 4 (9.5)
Sepsis 1 (2.4)
Acute kidney injury 1 (2.4)
Survival analysis
The median follow-up duration of the survivors was 213 days (range, 12-2763). The median OS was 7 months (range, 0-91) (Figure 1a), and the median PFS was 3.5 months (range, 0-91) (Figure 1b). Next, we performed univariate analysis to identify the independent factors for OS and PFS by univariate analyses (Table 4). OS was significantly influenced by Ki-67 positivity in pathology (≥50%) (P = 0.020) and PR to the MTX-HOPE regimen after three to five cycles (P = 0.002) (Figure 1c). PFS was also significantly influenced by Ki-67 positivity in pathology (≥50%) (P = 0.039) and PR to the MTX-HOPE regimen after three to five cycles (P < 0.001) (Figure 1d). IPI, lymphoma status (r/r), lymphoma histology (B cell lymphoma or T cell lymphoma), and other factors did not influence OS or PFS.
Fig. 1 Kaplan-Meier estimates. (a) Overall survival (OS) and (b) progression-free survival (PFS) of all patients who received MTX-HOPE therapy. (c) OS and (d) PFS stratified by the response to MTX-HOPE therapy after three to five cycles.
Table 4 Univariate analysis of overall survival and progression-free survival
Variable Overall survival Progression-free survival
Hazard ratio (95%CI) p-value Hazard ratio (95%CI) p-value
Age ≥ 75 1.11 (0.51-2.41) 0.79 1.23 (0.59-2.53) 0.58
Sex (female) 0.89 (0.42-1.92) 0.77 0.82 (0.40-1.65) 0.58
BMI ≥ 20 kg/m2 0.64 (0.29-1.43) 0.28 0.73 (0.35-1.54) 0.41
Hb > 10 0.61 (0.29-1.31) 0.20 0.97 (0.48-1.98) 0.94
eGFR > 60 0.75 (0.36-1.58) 0.45 0.75 (0.37-1.51) 0.42
Number of pretreatment regimens ≥ 2 1.37 (0.63-3.00) 0.43 1.44 (0.70-2.97) 0.32
IPI ≥ 3 0.69 (0.29-1.63) 0.39 1.02 (0.44-2.36) 0.96
Stage ≥ III 0.63 (0.26-1.56) 0.32 0.97 (0.40-2.35) 0.94
PS ≥ 2 1.22 (0.58-2.55) 0.61 1.22 (0.62-2.40) 0.57
Extra nodal lesion 1.30 (0.52-3.25) 0.57 1.54 (0.63-3.80) 0.34
LDH (>UNL) 1.65 (0.79-3.45) 0.18 1.36 (0.69-2.66) 0.38
Bone marrow involvement 0.74 (0.32-1.70) 0.48 0.90 (0.44-1.85) 0.78
B symptoms 0.89 (0.39-2.00) 0.77 0.89 (0.43-1.87) 0.77
Relapsed status 0.50 (0.23-1.09) 0.082 0.78 (0.38-1.58) 0.48
T-cell lymphoma histology 0.58 (0.25-1.37) 0.22 0.63 (0.29-1.35) 0.24
Ki-67 ≥50% 2.42 (1.15-5.09) 0.020* 2.10 (1.04-4.25) 0.039*
Response of PR after 3-5 cycles 0.30 (0.13-0.65) 0.002** 0.25 (0.12-0.53) < 0.001***
Abbreviations: UNL; upper normal limit, PR; partial response
*P < 0.05, **P < 0.01, ***P < 0.001
Furthermore, we performed multivariable analyses of OS and PFS with the Cox proportional hazards model to control confounding factors. Response to MTX-HOPE better than PR after three to five cycles was treated as a time-dependent covariate.23 Each analysis was evaluated by adding age (≥75), IPI (≥3), and lymphoma histology (B cell lymphoma or T cell lymphoma) to the independent factors (Table 5). The final models for OS and PFS included Ki-67 positivity (≥ 50%) (HR 2.42, 95% CI 1.15-5.09, P = 0.020 and HR 2.10, 95% CI 1.04-4.25, P = 0.039).
Table 5 Multivariate analysis of overall survival (OS) and progression-free survival (PFS) with the Cox proportional hazards model. Response to the MTX-HOPE regimen better than partial response after three to five cycles was treated as a time-dependent covariate.
Variable Hazard ratio (95% CI) p-value
Overall survival
Ki-67 (≥50%) 2.42 (1.15-5.09) 0.020*
Progression-free survival
Ki-67 (≥50%) 2.10 (1.04-4.25) 0.039*
Age (≥75), B cell lymphoma or T cell lymphoma, and International Prognostic Index (≥3) were also added to the OS and PFS analyses. The final models with significant differences are shown in the table.
DISCUSSION
In the present study, we analyzed the safety and efficacy of MTX-HOPE for aged r/r NHL patients who are vulnerable and were not eligible for autologous stem cell transplantation (ASCT) and conventional high-dose salvage chemotherapy. Our results showed that the MTX-HOPE regimen is effective and tolerable for these r/r NHL patients. High Ki-67 positivity was extracted as an independent factor of OS and PFS by multivariable analyses using response to MTX-HOPE treatment as a time-dependent covariate. In addition, most patients who receive MTX-HOPE can be treated without hospitalization.
Ki-67 is one of the cell cycle related protein and strongly associated with the lymphoma cell proliferation, leading to lymphoma progression. High Ki-67 positivity is also related to poor prognosis within the same lymphoma subtypes, such as DLBCL and FL.24-26 Our results suggest that MTX-HOPE is less effective for the highly Ki-67 positive lymphoma patients. Because there were a few patients other than DLBCL in our study, further study is needed to confirm these results.
In this study, the patients who received MTX-HOPE therapy were elderly individuals and had worse PS scores. Because these patients had some comorbidities, such as renal dysfunction and anemia, they could not receive other intensive salvage treatments. The overall response rate (ORR) of MTX-HOPE was 45.2%. The rate of treatment responsiveness above SD was 76.2%, and treatment response was observed in many cases. The median OS was 7 months, the 1-year OS was 43.7%, and the 2-year OS was 40.8%. Some patients achieved long-term survival. Moreover, MTX-HOPE therapy resulted in no treatment-related deaths and the acceptable rate of treatment discontinuation events. According to the SCHOLAR-1 study of relapsed DLBCL (the largest, patient-level pooled analysis), the median OS was 6.3 months, and the 2-year OS was 20%.27 Given our target frail population, these results indicate that MTX-HOPE therapy is tolerable and effective. Although there were several side effects of MTX-HOPE therapy worse than grade 3, these were temporary and recoverable. Appropriate supportive care, including blood transfusion and G-CSF, is generally important for elderly patients to continue chemotherapy.
Furthermore, most patients treated with MTX-HOPE were able to continue without hospitalization, leading to a great advantage in medical costs. Previous reports have shown that the medical costs of aggressive NHL are estimated at $5,871 per patient per month (PPPM) for the first two years of treatment,28 and those for elderly patients with r/r DLBCL are more than $97,000 per year.29 In addition, the costs of patients for febrile neutropenia (FN) are more expensive.30 In our study, the average medical cost of MTX-HOPE calculated by the medical claims data was ¥94,297/month. These data revealed that MTX-HOPE is a cost-effective regimen. Multivariable analysis with the Cox proportional hazards model revealed Ki-67 positivity in pathology and PR to the MTX-HOPE regimen as independent factors for OS and PFS. These results are useful for the indication of MTX-HOPE therapy.
There are some limitations in this study. First, although the response to MTX-HOPE was evaluated based on the International Workshop Response Criteria (IWRC), the evaluations were not conducted at fixed cycles. Therefore, there were differences in the response evaluation periods among MTX-HOPE patients. Last, this was a single-center, single-arm study. A prospective controlled trial with other salvage regimens may be needed to confirm the safety and effectiveness of MTX-HOPE therapy.
In conclusion, the MTX-HOPE regimen is safe and effective for r/r NHL patients. Pathologically high Ki-67 positivity was identified as an independent factor for MTX-HOPE treatment. The advantage of the MTX-HOPE regimen is that it contributes to maintaining quality of life (QOL) without hospitalization. Our results may help in considering the indications for MTX-HOPE. We concluded that MTX-HOPE is an attractive salvage regimen for aged patients or those with non-aggressive r/r NHL. To validate this regimen, further prospective studies are needed.
ACKNOWLEDGMENTS
We would like to express our special thanks to Dr. Yasuhiko Kano, who retired from the Tochigi Cancer Center (Utsunomiya, Japan). He developed the principle of MTX-HOPE therapy through a series of in vitro experiments with combination chemotherapy.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest (COIs). | ETOPOSIDE, HYDROCORTISONE SODIUM SUCCINATE, METHOTREXATE SODIUM, SOBUZOXANE, VINCRISTINE | DrugsGivenReaction | CC BY-NC-SA | 33551437 | 19,429,767 | 2021-03-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia'. | MTX-HOPE is a low-dose salvage chemotherapy for aged patients with relapsed or refractory non-Hodgkin lymphoma.
As the aging society advances, the number of non-Hodgkin lymphoma (NHL) patients is increasing. Aged relapsed or refractory (r/r) NHL patients have limited treatment options. Therefore, a safe and effective regimen is urgently needed for these patients. Thus, we originally developed the MTX-HOPE (methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide) regimen for r/r NHL and validated the safety and efficacy of this regimen in a clinical setting. We analyzed the data of 42 r/r NHL patients who received MTX-HOPE in this single-center retrospective cohort study. The median age of the patients was 81 years. The overall response rate was 45.3%. The median overall survival (OS) was 7 months, the one-year OS was 43.7%, and the two-year OS was 40.8%. Grade ≥3 neutropenia and renal dysfunction were observed in 47.6% and 11.9% of patients, respectively, and treatment-related death were not observed. Appropriate supportive care enabled these patients to continue the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Multivariable analyses with the Cox proportional hazards model revealed that both OS and progression-free survival (PFS) were significantly influenced by high Ki-67 expression in pathology, with response to the MTX-HOPE regimen after three to five cycles as a time-dependent covariate. Our results suggest that MTX-HOPE therapy can be an option for non-aggressive r/r NHL patients. To validate MTX-HOPE therapy, further prospective investigation is needed.
INTRODUCTION
The aged population is increasing, particularly in advanced countries. As this population advances, the incidence of cancers, including malignant lymphoma, is rising.1-3 Because cancer can be considered an age-related disease, it is an urgent task to take measures for elderly patients with cancer in advanced countries.4 Because most vulnerable older adult patients cannot be enrolled in clinical trials, there are few data regarding the management of aged cancer patients, including those with lymphoma. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)/CHOP (CHOP) therapy is the gold standard regimen for elderly non-Hodgkin lymphoma (NHL) patients.5-8 However, even if complete response (CR) is reached with initial treatment, 20-50% of patients with diffuse large B cell lymphoma (DLBCL) experience relapse,9 and there are few therapeutic options, especially for aged patients with relapsed NHL.
Thus, it is unclear whether aged relapsed or refractory (r/r) NHL patients are suitable for certain therapeutic strategies. Aged patients with some comorbidities cannot receive sufficient intensity salvage chemotherapies in the clinic. We thus developed a combination salvage therapy for r/r NHL based on isobologram analysis data for these vulnerable patients.10-16 We selected methotrexate (MTX), hydrocortisone (HC), vincristine (VCR), sobuzoxane (MST-16), and etoposide (ETP) and named this regimen MTX-HOPE (Table 1).17 This regimen has the advantage of being performed on an outpatient basis. We previously reported the safety and efficacy of the MTX-HOPE regimen in a small number of NHL patients. In a previous study, the median age of the patients was 70 years, and the median overall survival (OS) was 11.1 months. In addition, another group recently reported the efficacy of the MTX-HOPE regimen, and the median OS and progression-free survival (PFS) were 10 months and 7 months, respectively.18 However, the characteristics of NHL patients who are more likely to respond to MTX-HOPE therapy are still unknown. We need to identify patients suitable for this regimen from the perspective of safety and effectiveness. Thus, we performed a single-center retrospective cohort study to validate the MTX-HOPE regimen.
Table 1 The protocol of MTX-HOPE
Agent Dose/day Route Days
Methotrexate (MTX) 20 mg po 1
Hydrocortisone (HC) 100 mg div (15min) 2
Vincristine (VCR) 1 mg div (15min) 2
Sobuzoxane (MST-16) 400 mg po 3, 4
Etoposide (ETP) 25 mg po 3, 4
Abbreviations: MTX-HOPE, methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide; po, per os; div, intravenous drip
MATERIALS AND METHODS
Study design and patients
This study was conducted as a single-center retrospective cohort study. A total of 42 patients who received MTX-HOPE therapy agreed to participate in this study, which was approved by the local Ethics Committee of Aizu Medical Center of Fukushima Medical University (FMU) and carried out in accordance with the relevant guidelines and regulations. Written informed consent was obtained from all subjects prior to enrollment. We obtained patient characteristics and laboratory data from the clinical records of all patients diagnosed with NHL, including DLBCL, mantle cell lymphoma (MCL), peripheral T cell lymphoma (PTCL), and others, from 2009 to 2020.
Treatment protocol
The MTX-HOPE regimen was repeated every 2-3 weeks and involved the administration of MTX (20 mg) orally on day 1, HC (100 mg) and VCR (1 mg) infusion on day 2, and MST-16 (400 mg) and ETP (25 mg) orally on days 3 and 4 (Table 1). Granulocyte colony-stimulating factor (G-CSF) was administered to patients who experienced neutropenia as supportive therapy.
Treatment response and toxicity criteria
Efficacy assessments were performed according to the international consensus on the revised response criteria for malignant lymphoma. According to these criteria, we defined therapy responses as follows: complete response (CR), unconfirmed CR (uCR), partial response (PR), stable disease (SD), and progressive disease (PD). Physical examination and laboratory tests were used to evaluate adverse reactions and toxicities. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, Version 4.0.
Statistical analysis
All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of the R commander designed to add statistical functions frequently used in biostatistics.19 The Kolmogorov-Smirnov test was used to analyze the normality of the distribution of parameters.20,21 All variables with a normal distribution are expressed as the mean ± standard deviation, and those with a log-normal distribution are expressed as the median with the interquartile range (IQR). OS was defined as the time from the start of MTX-HOPE therapy to death or the date of the last follow-up.22 PFS was defined as the time from the start of MTX-HOPE therapy to relapse, death, or the date of the last follow-up. The OS and PFS rates were estimated according to the Kaplan-Meier method and compared by the log-rank test.19,22 The hazard ratios (HRs) and their associated 95% confidence intervals (CIs) for potential prognostic factors were calculated using the Cox proportional hazards regression model. Variables with p < 0.10 in the univariate analysis were used as independent variables in the multivariate analysis.23 All statistical tests were two-sided, and a significance level of 0.05 was used.
RESULTS
Patient characteristics
The median age of the 42 patients who received MTX-HOPE therapy for r/r NHL in this study was 81 years (range, 57 to 90 years), and 35.7% were women (Table 2). In our study, seven patients (16.7%) who received the MTX-HOPE regimen were less than 70 years old. Six patients had a history of multiple pretreatment regimens, and the other patient had severe pulmonary disease and poor performance status (PS). These patients had no indication for intensive chemotherapy and agreed to receive the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Twenty-five patients were refractory to previous treatment, and 17 had relapsed disease. The proportion of patients with worse Eastern Cooperative Oncology Group (ECOG) PS scores (more than 2) was 59.5%, the proportion of patients with anemia (hemoglobin less than 10 g/dL) was 42.9%, and the proportion of patients with lactate dehydrogenase (LDH) levels greater than the upper limit of normal was 54.8%. At the time of diagnosis, the proportion of patients with intermediate- and high-risk International Prognostic Index (IPI) scores was 92.9%, and the proportion of patients with advanced stage (stage III and IV) disease was 85.6%. The lymphoma histology of the patients included 28 DLBCL, one follicular lymphoma (FL), one MCL, 11 T cell lymphoma, and one extranodal NK/T cell lymphoma. In addition, the proportion of patients with Ki-67 positivity greater than 50% by immunohistochemistry (IHC) was 36%. Furthermore, the MTX-HOPE regimen was given to patients as salvage therapy. We assessed the response to MTX-HOPE after three to five cycles by computed tomography (CT). The percentage of patients who achieved CR or unconfirmed CR was 19%, PR was 26.2%, SD was 31%, and PD was 23.8% at that time.
Table 2 Patient characteristics
Characteristics patients MTX-HOPE
Patients, n 42
Hospitalization during MTX-HOPE administration 9 (21)
At the start of treatment
Age, median [min, max] 81 [57, 90]
Women, n (%) 15 (36)
Performance status, n (%)
0-1 17 (41)
2-4 25 (60)
Status before MTX-HOPE treatment, n (%)
Relapsed 17 (41)
Refractory 25 (60)
Number of pretreatment regimens, n (%)
1 31(74)
2 3 (7.1)
≥3 8 (19)
Pretreatment regimen, n (%)
CHOP +/-R 28 (67)
DeVIC +/-R 5 (12)
GDP +/-R 3 (7.1)
Other 6 (14)
Previous treatment history of rituximab, n (%) 29 (69)
Histology, n (%)
B cell lymphoma 30 (71)
DLBCL 28 (67)
FL 1 (2.4)
MCL 1 (2.4)
T cell lymphoma 11 (26)
Extranodal NK/T cell lymphoma 1 (2.4)
Anemia (Hb <10), n (%) 18 (43)
CKD, n (%) 16 (38)
LDH high (≥upper normal limit; 240) 23 (55)
BMI (<20 kg/m2), n (%) 15 (36)
At diagnosis
IPI, n(%)
Low risk 3(7.1)
Intermediate risk 16 (38)
High risk 23 (55)
Stage, n(%)
I 4 (9.5)
II 2 (4.8)
III 9 (21)
IV 27 (64)
Bone marrow involvement, n (%) 12 (29)
Extranodal lesion, n (%) 33 (79)
B symptoms present, n (%) 12 (29)
Ki-67 high (≥50%), n(%) 15 (36)
DLBCL 12 (29)
MCL 1 (2.4)
T cell lymphoma 2 (4.8)
Response after 3 to 5 cycles, n (%)
Complete response (CR)/unconfirmed CR 8 (19)
Partial response (PR) 11 (26)
Stable disease (SD) 13 (31)
Progressive disease (PD) 10 (24)
Abbreviations: DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; CKD, chronic kidney disease
Safety of MTX-HOPE
The hematological and nonhematological toxicities of MTX-HOPE are shown in Table 3. Grade 3 and 4 neutropenia were observed in 47.6% of the patients, and febrile neutropenia was observed in 9.5%. Grade 3 and 4 anemia and thrombocytopenia were observed in 35.7% and 14.3% of the patients, respectively. Severe nonhematological toxicities, such as liver damage, renal dysfunction, nausea, vomiting, and infection, were infrequent in patients treated with MTX-HOPE therapy. Seventeen patients temporarily discontinued VCR due to grade 1 neuropathy in our study. However, most patients could continue VCR while administered vitamin B12 and pregabalin. The other drugs did not need to be reduced. Furthermore, there were no treatment-related deaths. However, there were six treatment discontinuation events: four pneumonia, one sepsis and one acute kidney injury (Table 3).
Table 3 Adverse effects of MTX-HOPE therapy
Hematological toxicity All Grades Grade ≥3
Neutropenia n, (%) 33 (79) 20 (48)
Febrile neutropenia n, (%) - 4 (9.5)
Anemia n, (%) 39 (93) 15 (36)
Thrombocytopenia n, (%) 30 (71) 6 (14)
Nonhematological toxicity
Liver damage 10 (24) 2 (4.8)
Renal dysfunction 24 (57) 5 (12)
Nausea 8 (19) 0 (0)
Vomiting 1 (2.4) 0 (0)
Infection 10 (24) 3 (7.1)
Neuropathy 17 (40) 0 (0)
Hematological supportive care
Red blood cell transfusion 13 (30.9)
Platelet transfusion 4 (9.5)
G-CSF 24 (57.1)
Treatment-related deaths 0 (0)
Treatment discontinuation events 6 (14)
Pneumonia 4 (9.5)
Sepsis 1 (2.4)
Acute kidney injury 1 (2.4)
Survival analysis
The median follow-up duration of the survivors was 213 days (range, 12-2763). The median OS was 7 months (range, 0-91) (Figure 1a), and the median PFS was 3.5 months (range, 0-91) (Figure 1b). Next, we performed univariate analysis to identify the independent factors for OS and PFS by univariate analyses (Table 4). OS was significantly influenced by Ki-67 positivity in pathology (≥50%) (P = 0.020) and PR to the MTX-HOPE regimen after three to five cycles (P = 0.002) (Figure 1c). PFS was also significantly influenced by Ki-67 positivity in pathology (≥50%) (P = 0.039) and PR to the MTX-HOPE regimen after three to five cycles (P < 0.001) (Figure 1d). IPI, lymphoma status (r/r), lymphoma histology (B cell lymphoma or T cell lymphoma), and other factors did not influence OS or PFS.
Fig. 1 Kaplan-Meier estimates. (a) Overall survival (OS) and (b) progression-free survival (PFS) of all patients who received MTX-HOPE therapy. (c) OS and (d) PFS stratified by the response to MTX-HOPE therapy after three to five cycles.
Table 4 Univariate analysis of overall survival and progression-free survival
Variable Overall survival Progression-free survival
Hazard ratio (95%CI) p-value Hazard ratio (95%CI) p-value
Age ≥ 75 1.11 (0.51-2.41) 0.79 1.23 (0.59-2.53) 0.58
Sex (female) 0.89 (0.42-1.92) 0.77 0.82 (0.40-1.65) 0.58
BMI ≥ 20 kg/m2 0.64 (0.29-1.43) 0.28 0.73 (0.35-1.54) 0.41
Hb > 10 0.61 (0.29-1.31) 0.20 0.97 (0.48-1.98) 0.94
eGFR > 60 0.75 (0.36-1.58) 0.45 0.75 (0.37-1.51) 0.42
Number of pretreatment regimens ≥ 2 1.37 (0.63-3.00) 0.43 1.44 (0.70-2.97) 0.32
IPI ≥ 3 0.69 (0.29-1.63) 0.39 1.02 (0.44-2.36) 0.96
Stage ≥ III 0.63 (0.26-1.56) 0.32 0.97 (0.40-2.35) 0.94
PS ≥ 2 1.22 (0.58-2.55) 0.61 1.22 (0.62-2.40) 0.57
Extra nodal lesion 1.30 (0.52-3.25) 0.57 1.54 (0.63-3.80) 0.34
LDH (>UNL) 1.65 (0.79-3.45) 0.18 1.36 (0.69-2.66) 0.38
Bone marrow involvement 0.74 (0.32-1.70) 0.48 0.90 (0.44-1.85) 0.78
B symptoms 0.89 (0.39-2.00) 0.77 0.89 (0.43-1.87) 0.77
Relapsed status 0.50 (0.23-1.09) 0.082 0.78 (0.38-1.58) 0.48
T-cell lymphoma histology 0.58 (0.25-1.37) 0.22 0.63 (0.29-1.35) 0.24
Ki-67 ≥50% 2.42 (1.15-5.09) 0.020* 2.10 (1.04-4.25) 0.039*
Response of PR after 3-5 cycles 0.30 (0.13-0.65) 0.002** 0.25 (0.12-0.53) < 0.001***
Abbreviations: UNL; upper normal limit, PR; partial response
*P < 0.05, **P < 0.01, ***P < 0.001
Furthermore, we performed multivariable analyses of OS and PFS with the Cox proportional hazards model to control confounding factors. Response to MTX-HOPE better than PR after three to five cycles was treated as a time-dependent covariate.23 Each analysis was evaluated by adding age (≥75), IPI (≥3), and lymphoma histology (B cell lymphoma or T cell lymphoma) to the independent factors (Table 5). The final models for OS and PFS included Ki-67 positivity (≥ 50%) (HR 2.42, 95% CI 1.15-5.09, P = 0.020 and HR 2.10, 95% CI 1.04-4.25, P = 0.039).
Table 5 Multivariate analysis of overall survival (OS) and progression-free survival (PFS) with the Cox proportional hazards model. Response to the MTX-HOPE regimen better than partial response after three to five cycles was treated as a time-dependent covariate.
Variable Hazard ratio (95% CI) p-value
Overall survival
Ki-67 (≥50%) 2.42 (1.15-5.09) 0.020*
Progression-free survival
Ki-67 (≥50%) 2.10 (1.04-4.25) 0.039*
Age (≥75), B cell lymphoma or T cell lymphoma, and International Prognostic Index (≥3) were also added to the OS and PFS analyses. The final models with significant differences are shown in the table.
DISCUSSION
In the present study, we analyzed the safety and efficacy of MTX-HOPE for aged r/r NHL patients who are vulnerable and were not eligible for autologous stem cell transplantation (ASCT) and conventional high-dose salvage chemotherapy. Our results showed that the MTX-HOPE regimen is effective and tolerable for these r/r NHL patients. High Ki-67 positivity was extracted as an independent factor of OS and PFS by multivariable analyses using response to MTX-HOPE treatment as a time-dependent covariate. In addition, most patients who receive MTX-HOPE can be treated without hospitalization.
Ki-67 is one of the cell cycle related protein and strongly associated with the lymphoma cell proliferation, leading to lymphoma progression. High Ki-67 positivity is also related to poor prognosis within the same lymphoma subtypes, such as DLBCL and FL.24-26 Our results suggest that MTX-HOPE is less effective for the highly Ki-67 positive lymphoma patients. Because there were a few patients other than DLBCL in our study, further study is needed to confirm these results.
In this study, the patients who received MTX-HOPE therapy were elderly individuals and had worse PS scores. Because these patients had some comorbidities, such as renal dysfunction and anemia, they could not receive other intensive salvage treatments. The overall response rate (ORR) of MTX-HOPE was 45.2%. The rate of treatment responsiveness above SD was 76.2%, and treatment response was observed in many cases. The median OS was 7 months, the 1-year OS was 43.7%, and the 2-year OS was 40.8%. Some patients achieved long-term survival. Moreover, MTX-HOPE therapy resulted in no treatment-related deaths and the acceptable rate of treatment discontinuation events. According to the SCHOLAR-1 study of relapsed DLBCL (the largest, patient-level pooled analysis), the median OS was 6.3 months, and the 2-year OS was 20%.27 Given our target frail population, these results indicate that MTX-HOPE therapy is tolerable and effective. Although there were several side effects of MTX-HOPE therapy worse than grade 3, these were temporary and recoverable. Appropriate supportive care, including blood transfusion and G-CSF, is generally important for elderly patients to continue chemotherapy.
Furthermore, most patients treated with MTX-HOPE were able to continue without hospitalization, leading to a great advantage in medical costs. Previous reports have shown that the medical costs of aggressive NHL are estimated at $5,871 per patient per month (PPPM) for the first two years of treatment,28 and those for elderly patients with r/r DLBCL are more than $97,000 per year.29 In addition, the costs of patients for febrile neutropenia (FN) are more expensive.30 In our study, the average medical cost of MTX-HOPE calculated by the medical claims data was ¥94,297/month. These data revealed that MTX-HOPE is a cost-effective regimen. Multivariable analysis with the Cox proportional hazards model revealed Ki-67 positivity in pathology and PR to the MTX-HOPE regimen as independent factors for OS and PFS. These results are useful for the indication of MTX-HOPE therapy.
There are some limitations in this study. First, although the response to MTX-HOPE was evaluated based on the International Workshop Response Criteria (IWRC), the evaluations were not conducted at fixed cycles. Therefore, there were differences in the response evaluation periods among MTX-HOPE patients. Last, this was a single-center, single-arm study. A prospective controlled trial with other salvage regimens may be needed to confirm the safety and effectiveness of MTX-HOPE therapy.
In conclusion, the MTX-HOPE regimen is safe and effective for r/r NHL patients. Pathologically high Ki-67 positivity was identified as an independent factor for MTX-HOPE treatment. The advantage of the MTX-HOPE regimen is that it contributes to maintaining quality of life (QOL) without hospitalization. Our results may help in considering the indications for MTX-HOPE. We concluded that MTX-HOPE is an attractive salvage regimen for aged patients or those with non-aggressive r/r NHL. To validate this regimen, further prospective studies are needed.
ACKNOWLEDGMENTS
We would like to express our special thanks to Dr. Yasuhiko Kano, who retired from the Tochigi Cancer Center (Utsunomiya, Japan). He developed the principle of MTX-HOPE therapy through a series of in vitro experiments with combination chemotherapy.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest (COIs). | ETOPOSIDE, HYDROCORTISONE SODIUM SUCCINATE, METHOTREXATE SODIUM, SOBUZOXANE, VINCRISTINE | DrugsGivenReaction | CC BY-NC-SA | 33551437 | 19,429,768 | 2021-03-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sepsis'. | MTX-HOPE is a low-dose salvage chemotherapy for aged patients with relapsed or refractory non-Hodgkin lymphoma.
As the aging society advances, the number of non-Hodgkin lymphoma (NHL) patients is increasing. Aged relapsed or refractory (r/r) NHL patients have limited treatment options. Therefore, a safe and effective regimen is urgently needed for these patients. Thus, we originally developed the MTX-HOPE (methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide) regimen for r/r NHL and validated the safety and efficacy of this regimen in a clinical setting. We analyzed the data of 42 r/r NHL patients who received MTX-HOPE in this single-center retrospective cohort study. The median age of the patients was 81 years. The overall response rate was 45.3%. The median overall survival (OS) was 7 months, the one-year OS was 43.7%, and the two-year OS was 40.8%. Grade ≥3 neutropenia and renal dysfunction were observed in 47.6% and 11.9% of patients, respectively, and treatment-related death were not observed. Appropriate supportive care enabled these patients to continue the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Multivariable analyses with the Cox proportional hazards model revealed that both OS and progression-free survival (PFS) were significantly influenced by high Ki-67 expression in pathology, with response to the MTX-HOPE regimen after three to five cycles as a time-dependent covariate. Our results suggest that MTX-HOPE therapy can be an option for non-aggressive r/r NHL patients. To validate MTX-HOPE therapy, further prospective investigation is needed.
INTRODUCTION
The aged population is increasing, particularly in advanced countries. As this population advances, the incidence of cancers, including malignant lymphoma, is rising.1-3 Because cancer can be considered an age-related disease, it is an urgent task to take measures for elderly patients with cancer in advanced countries.4 Because most vulnerable older adult patients cannot be enrolled in clinical trials, there are few data regarding the management of aged cancer patients, including those with lymphoma. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)/CHOP (CHOP) therapy is the gold standard regimen for elderly non-Hodgkin lymphoma (NHL) patients.5-8 However, even if complete response (CR) is reached with initial treatment, 20-50% of patients with diffuse large B cell lymphoma (DLBCL) experience relapse,9 and there are few therapeutic options, especially for aged patients with relapsed NHL.
Thus, it is unclear whether aged relapsed or refractory (r/r) NHL patients are suitable for certain therapeutic strategies. Aged patients with some comorbidities cannot receive sufficient intensity salvage chemotherapies in the clinic. We thus developed a combination salvage therapy for r/r NHL based on isobologram analysis data for these vulnerable patients.10-16 We selected methotrexate (MTX), hydrocortisone (HC), vincristine (VCR), sobuzoxane (MST-16), and etoposide (ETP) and named this regimen MTX-HOPE (Table 1).17 This regimen has the advantage of being performed on an outpatient basis. We previously reported the safety and efficacy of the MTX-HOPE regimen in a small number of NHL patients. In a previous study, the median age of the patients was 70 years, and the median overall survival (OS) was 11.1 months. In addition, another group recently reported the efficacy of the MTX-HOPE regimen, and the median OS and progression-free survival (PFS) were 10 months and 7 months, respectively.18 However, the characteristics of NHL patients who are more likely to respond to MTX-HOPE therapy are still unknown. We need to identify patients suitable for this regimen from the perspective of safety and effectiveness. Thus, we performed a single-center retrospective cohort study to validate the MTX-HOPE regimen.
Table 1 The protocol of MTX-HOPE
Agent Dose/day Route Days
Methotrexate (MTX) 20 mg po 1
Hydrocortisone (HC) 100 mg div (15min) 2
Vincristine (VCR) 1 mg div (15min) 2
Sobuzoxane (MST-16) 400 mg po 3, 4
Etoposide (ETP) 25 mg po 3, 4
Abbreviations: MTX-HOPE, methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide; po, per os; div, intravenous drip
MATERIALS AND METHODS
Study design and patients
This study was conducted as a single-center retrospective cohort study. A total of 42 patients who received MTX-HOPE therapy agreed to participate in this study, which was approved by the local Ethics Committee of Aizu Medical Center of Fukushima Medical University (FMU) and carried out in accordance with the relevant guidelines and regulations. Written informed consent was obtained from all subjects prior to enrollment. We obtained patient characteristics and laboratory data from the clinical records of all patients diagnosed with NHL, including DLBCL, mantle cell lymphoma (MCL), peripheral T cell lymphoma (PTCL), and others, from 2009 to 2020.
Treatment protocol
The MTX-HOPE regimen was repeated every 2-3 weeks and involved the administration of MTX (20 mg) orally on day 1, HC (100 mg) and VCR (1 mg) infusion on day 2, and MST-16 (400 mg) and ETP (25 mg) orally on days 3 and 4 (Table 1). Granulocyte colony-stimulating factor (G-CSF) was administered to patients who experienced neutropenia as supportive therapy.
Treatment response and toxicity criteria
Efficacy assessments were performed according to the international consensus on the revised response criteria for malignant lymphoma. According to these criteria, we defined therapy responses as follows: complete response (CR), unconfirmed CR (uCR), partial response (PR), stable disease (SD), and progressive disease (PD). Physical examination and laboratory tests were used to evaluate adverse reactions and toxicities. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, Version 4.0.
Statistical analysis
All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of the R commander designed to add statistical functions frequently used in biostatistics.19 The Kolmogorov-Smirnov test was used to analyze the normality of the distribution of parameters.20,21 All variables with a normal distribution are expressed as the mean ± standard deviation, and those with a log-normal distribution are expressed as the median with the interquartile range (IQR). OS was defined as the time from the start of MTX-HOPE therapy to death or the date of the last follow-up.22 PFS was defined as the time from the start of MTX-HOPE therapy to relapse, death, or the date of the last follow-up. The OS and PFS rates were estimated according to the Kaplan-Meier method and compared by the log-rank test.19,22 The hazard ratios (HRs) and their associated 95% confidence intervals (CIs) for potential prognostic factors were calculated using the Cox proportional hazards regression model. Variables with p < 0.10 in the univariate analysis were used as independent variables in the multivariate analysis.23 All statistical tests were two-sided, and a significance level of 0.05 was used.
RESULTS
Patient characteristics
The median age of the 42 patients who received MTX-HOPE therapy for r/r NHL in this study was 81 years (range, 57 to 90 years), and 35.7% were women (Table 2). In our study, seven patients (16.7%) who received the MTX-HOPE regimen were less than 70 years old. Six patients had a history of multiple pretreatment regimens, and the other patient had severe pulmonary disease and poor performance status (PS). These patients had no indication for intensive chemotherapy and agreed to receive the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Twenty-five patients were refractory to previous treatment, and 17 had relapsed disease. The proportion of patients with worse Eastern Cooperative Oncology Group (ECOG) PS scores (more than 2) was 59.5%, the proportion of patients with anemia (hemoglobin less than 10 g/dL) was 42.9%, and the proportion of patients with lactate dehydrogenase (LDH) levels greater than the upper limit of normal was 54.8%. At the time of diagnosis, the proportion of patients with intermediate- and high-risk International Prognostic Index (IPI) scores was 92.9%, and the proportion of patients with advanced stage (stage III and IV) disease was 85.6%. The lymphoma histology of the patients included 28 DLBCL, one follicular lymphoma (FL), one MCL, 11 T cell lymphoma, and one extranodal NK/T cell lymphoma. In addition, the proportion of patients with Ki-67 positivity greater than 50% by immunohistochemistry (IHC) was 36%. Furthermore, the MTX-HOPE regimen was given to patients as salvage therapy. We assessed the response to MTX-HOPE after three to five cycles by computed tomography (CT). The percentage of patients who achieved CR or unconfirmed CR was 19%, PR was 26.2%, SD was 31%, and PD was 23.8% at that time.
Table 2 Patient characteristics
Characteristics patients MTX-HOPE
Patients, n 42
Hospitalization during MTX-HOPE administration 9 (21)
At the start of treatment
Age, median [min, max] 81 [57, 90]
Women, n (%) 15 (36)
Performance status, n (%)
0-1 17 (41)
2-4 25 (60)
Status before MTX-HOPE treatment, n (%)
Relapsed 17 (41)
Refractory 25 (60)
Number of pretreatment regimens, n (%)
1 31(74)
2 3 (7.1)
≥3 8 (19)
Pretreatment regimen, n (%)
CHOP +/-R 28 (67)
DeVIC +/-R 5 (12)
GDP +/-R 3 (7.1)
Other 6 (14)
Previous treatment history of rituximab, n (%) 29 (69)
Histology, n (%)
B cell lymphoma 30 (71)
DLBCL 28 (67)
FL 1 (2.4)
MCL 1 (2.4)
T cell lymphoma 11 (26)
Extranodal NK/T cell lymphoma 1 (2.4)
Anemia (Hb <10), n (%) 18 (43)
CKD, n (%) 16 (38)
LDH high (≥upper normal limit; 240) 23 (55)
BMI (<20 kg/m2), n (%) 15 (36)
At diagnosis
IPI, n(%)
Low risk 3(7.1)
Intermediate risk 16 (38)
High risk 23 (55)
Stage, n(%)
I 4 (9.5)
II 2 (4.8)
III 9 (21)
IV 27 (64)
Bone marrow involvement, n (%) 12 (29)
Extranodal lesion, n (%) 33 (79)
B symptoms present, n (%) 12 (29)
Ki-67 high (≥50%), n(%) 15 (36)
DLBCL 12 (29)
MCL 1 (2.4)
T cell lymphoma 2 (4.8)
Response after 3 to 5 cycles, n (%)
Complete response (CR)/unconfirmed CR 8 (19)
Partial response (PR) 11 (26)
Stable disease (SD) 13 (31)
Progressive disease (PD) 10 (24)
Abbreviations: DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; CKD, chronic kidney disease
Safety of MTX-HOPE
The hematological and nonhematological toxicities of MTX-HOPE are shown in Table 3. Grade 3 and 4 neutropenia were observed in 47.6% of the patients, and febrile neutropenia was observed in 9.5%. Grade 3 and 4 anemia and thrombocytopenia were observed in 35.7% and 14.3% of the patients, respectively. Severe nonhematological toxicities, such as liver damage, renal dysfunction, nausea, vomiting, and infection, were infrequent in patients treated with MTX-HOPE therapy. Seventeen patients temporarily discontinued VCR due to grade 1 neuropathy in our study. However, most patients could continue VCR while administered vitamin B12 and pregabalin. The other drugs did not need to be reduced. Furthermore, there were no treatment-related deaths. However, there were six treatment discontinuation events: four pneumonia, one sepsis and one acute kidney injury (Table 3).
Table 3 Adverse effects of MTX-HOPE therapy
Hematological toxicity All Grades Grade ≥3
Neutropenia n, (%) 33 (79) 20 (48)
Febrile neutropenia n, (%) - 4 (9.5)
Anemia n, (%) 39 (93) 15 (36)
Thrombocytopenia n, (%) 30 (71) 6 (14)
Nonhematological toxicity
Liver damage 10 (24) 2 (4.8)
Renal dysfunction 24 (57) 5 (12)
Nausea 8 (19) 0 (0)
Vomiting 1 (2.4) 0 (0)
Infection 10 (24) 3 (7.1)
Neuropathy 17 (40) 0 (0)
Hematological supportive care
Red blood cell transfusion 13 (30.9)
Platelet transfusion 4 (9.5)
G-CSF 24 (57.1)
Treatment-related deaths 0 (0)
Treatment discontinuation events 6 (14)
Pneumonia 4 (9.5)
Sepsis 1 (2.4)
Acute kidney injury 1 (2.4)
Survival analysis
The median follow-up duration of the survivors was 213 days (range, 12-2763). The median OS was 7 months (range, 0-91) (Figure 1a), and the median PFS was 3.5 months (range, 0-91) (Figure 1b). Next, we performed univariate analysis to identify the independent factors for OS and PFS by univariate analyses (Table 4). OS was significantly influenced by Ki-67 positivity in pathology (≥50%) (P = 0.020) and PR to the MTX-HOPE regimen after three to five cycles (P = 0.002) (Figure 1c). PFS was also significantly influenced by Ki-67 positivity in pathology (≥50%) (P = 0.039) and PR to the MTX-HOPE regimen after three to five cycles (P < 0.001) (Figure 1d). IPI, lymphoma status (r/r), lymphoma histology (B cell lymphoma or T cell lymphoma), and other factors did not influence OS or PFS.
Fig. 1 Kaplan-Meier estimates. (a) Overall survival (OS) and (b) progression-free survival (PFS) of all patients who received MTX-HOPE therapy. (c) OS and (d) PFS stratified by the response to MTX-HOPE therapy after three to five cycles.
Table 4 Univariate analysis of overall survival and progression-free survival
Variable Overall survival Progression-free survival
Hazard ratio (95%CI) p-value Hazard ratio (95%CI) p-value
Age ≥ 75 1.11 (0.51-2.41) 0.79 1.23 (0.59-2.53) 0.58
Sex (female) 0.89 (0.42-1.92) 0.77 0.82 (0.40-1.65) 0.58
BMI ≥ 20 kg/m2 0.64 (0.29-1.43) 0.28 0.73 (0.35-1.54) 0.41
Hb > 10 0.61 (0.29-1.31) 0.20 0.97 (0.48-1.98) 0.94
eGFR > 60 0.75 (0.36-1.58) 0.45 0.75 (0.37-1.51) 0.42
Number of pretreatment regimens ≥ 2 1.37 (0.63-3.00) 0.43 1.44 (0.70-2.97) 0.32
IPI ≥ 3 0.69 (0.29-1.63) 0.39 1.02 (0.44-2.36) 0.96
Stage ≥ III 0.63 (0.26-1.56) 0.32 0.97 (0.40-2.35) 0.94
PS ≥ 2 1.22 (0.58-2.55) 0.61 1.22 (0.62-2.40) 0.57
Extra nodal lesion 1.30 (0.52-3.25) 0.57 1.54 (0.63-3.80) 0.34
LDH (>UNL) 1.65 (0.79-3.45) 0.18 1.36 (0.69-2.66) 0.38
Bone marrow involvement 0.74 (0.32-1.70) 0.48 0.90 (0.44-1.85) 0.78
B symptoms 0.89 (0.39-2.00) 0.77 0.89 (0.43-1.87) 0.77
Relapsed status 0.50 (0.23-1.09) 0.082 0.78 (0.38-1.58) 0.48
T-cell lymphoma histology 0.58 (0.25-1.37) 0.22 0.63 (0.29-1.35) 0.24
Ki-67 ≥50% 2.42 (1.15-5.09) 0.020* 2.10 (1.04-4.25) 0.039*
Response of PR after 3-5 cycles 0.30 (0.13-0.65) 0.002** 0.25 (0.12-0.53) < 0.001***
Abbreviations: UNL; upper normal limit, PR; partial response
*P < 0.05, **P < 0.01, ***P < 0.001
Furthermore, we performed multivariable analyses of OS and PFS with the Cox proportional hazards model to control confounding factors. Response to MTX-HOPE better than PR after three to five cycles was treated as a time-dependent covariate.23 Each analysis was evaluated by adding age (≥75), IPI (≥3), and lymphoma histology (B cell lymphoma or T cell lymphoma) to the independent factors (Table 5). The final models for OS and PFS included Ki-67 positivity (≥ 50%) (HR 2.42, 95% CI 1.15-5.09, P = 0.020 and HR 2.10, 95% CI 1.04-4.25, P = 0.039).
Table 5 Multivariate analysis of overall survival (OS) and progression-free survival (PFS) with the Cox proportional hazards model. Response to the MTX-HOPE regimen better than partial response after three to five cycles was treated as a time-dependent covariate.
Variable Hazard ratio (95% CI) p-value
Overall survival
Ki-67 (≥50%) 2.42 (1.15-5.09) 0.020*
Progression-free survival
Ki-67 (≥50%) 2.10 (1.04-4.25) 0.039*
Age (≥75), B cell lymphoma or T cell lymphoma, and International Prognostic Index (≥3) were also added to the OS and PFS analyses. The final models with significant differences are shown in the table.
DISCUSSION
In the present study, we analyzed the safety and efficacy of MTX-HOPE for aged r/r NHL patients who are vulnerable and were not eligible for autologous stem cell transplantation (ASCT) and conventional high-dose salvage chemotherapy. Our results showed that the MTX-HOPE regimen is effective and tolerable for these r/r NHL patients. High Ki-67 positivity was extracted as an independent factor of OS and PFS by multivariable analyses using response to MTX-HOPE treatment as a time-dependent covariate. In addition, most patients who receive MTX-HOPE can be treated without hospitalization.
Ki-67 is one of the cell cycle related protein and strongly associated with the lymphoma cell proliferation, leading to lymphoma progression. High Ki-67 positivity is also related to poor prognosis within the same lymphoma subtypes, such as DLBCL and FL.24-26 Our results suggest that MTX-HOPE is less effective for the highly Ki-67 positive lymphoma patients. Because there were a few patients other than DLBCL in our study, further study is needed to confirm these results.
In this study, the patients who received MTX-HOPE therapy were elderly individuals and had worse PS scores. Because these patients had some comorbidities, such as renal dysfunction and anemia, they could not receive other intensive salvage treatments. The overall response rate (ORR) of MTX-HOPE was 45.2%. The rate of treatment responsiveness above SD was 76.2%, and treatment response was observed in many cases. The median OS was 7 months, the 1-year OS was 43.7%, and the 2-year OS was 40.8%. Some patients achieved long-term survival. Moreover, MTX-HOPE therapy resulted in no treatment-related deaths and the acceptable rate of treatment discontinuation events. According to the SCHOLAR-1 study of relapsed DLBCL (the largest, patient-level pooled analysis), the median OS was 6.3 months, and the 2-year OS was 20%.27 Given our target frail population, these results indicate that MTX-HOPE therapy is tolerable and effective. Although there were several side effects of MTX-HOPE therapy worse than grade 3, these were temporary and recoverable. Appropriate supportive care, including blood transfusion and G-CSF, is generally important for elderly patients to continue chemotherapy.
Furthermore, most patients treated with MTX-HOPE were able to continue without hospitalization, leading to a great advantage in medical costs. Previous reports have shown that the medical costs of aggressive NHL are estimated at $5,871 per patient per month (PPPM) for the first two years of treatment,28 and those for elderly patients with r/r DLBCL are more than $97,000 per year.29 In addition, the costs of patients for febrile neutropenia (FN) are more expensive.30 In our study, the average medical cost of MTX-HOPE calculated by the medical claims data was ¥94,297/month. These data revealed that MTX-HOPE is a cost-effective regimen. Multivariable analysis with the Cox proportional hazards model revealed Ki-67 positivity in pathology and PR to the MTX-HOPE regimen as independent factors for OS and PFS. These results are useful for the indication of MTX-HOPE therapy.
There are some limitations in this study. First, although the response to MTX-HOPE was evaluated based on the International Workshop Response Criteria (IWRC), the evaluations were not conducted at fixed cycles. Therefore, there were differences in the response evaluation periods among MTX-HOPE patients. Last, this was a single-center, single-arm study. A prospective controlled trial with other salvage regimens may be needed to confirm the safety and effectiveness of MTX-HOPE therapy.
In conclusion, the MTX-HOPE regimen is safe and effective for r/r NHL patients. Pathologically high Ki-67 positivity was identified as an independent factor for MTX-HOPE treatment. The advantage of the MTX-HOPE regimen is that it contributes to maintaining quality of life (QOL) without hospitalization. Our results may help in considering the indications for MTX-HOPE. We concluded that MTX-HOPE is an attractive salvage regimen for aged patients or those with non-aggressive r/r NHL. To validate this regimen, further prospective studies are needed.
ACKNOWLEDGMENTS
We would like to express our special thanks to Dr. Yasuhiko Kano, who retired from the Tochigi Cancer Center (Utsunomiya, Japan). He developed the principle of MTX-HOPE therapy through a series of in vitro experiments with combination chemotherapy.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest (COIs). | ETOPOSIDE, HYDROCORTISONE SODIUM SUCCINATE, METHOTREXATE SODIUM, SOBUZOXANE, VINCRISTINE | DrugsGivenReaction | CC BY-NC-SA | 33551437 | 19,442,198 | 2021-03-18 |
What was the administration route of drug 'ETOPOSIDE'? | MTX-HOPE is a low-dose salvage chemotherapy for aged patients with relapsed or refractory non-Hodgkin lymphoma.
As the aging society advances, the number of non-Hodgkin lymphoma (NHL) patients is increasing. Aged relapsed or refractory (r/r) NHL patients have limited treatment options. Therefore, a safe and effective regimen is urgently needed for these patients. Thus, we originally developed the MTX-HOPE (methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide) regimen for r/r NHL and validated the safety and efficacy of this regimen in a clinical setting. We analyzed the data of 42 r/r NHL patients who received MTX-HOPE in this single-center retrospective cohort study. The median age of the patients was 81 years. The overall response rate was 45.3%. The median overall survival (OS) was 7 months, the one-year OS was 43.7%, and the two-year OS was 40.8%. Grade ≥3 neutropenia and renal dysfunction were observed in 47.6% and 11.9% of patients, respectively, and treatment-related death were not observed. Appropriate supportive care enabled these patients to continue the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Multivariable analyses with the Cox proportional hazards model revealed that both OS and progression-free survival (PFS) were significantly influenced by high Ki-67 expression in pathology, with response to the MTX-HOPE regimen after three to five cycles as a time-dependent covariate. Our results suggest that MTX-HOPE therapy can be an option for non-aggressive r/r NHL patients. To validate MTX-HOPE therapy, further prospective investigation is needed.
INTRODUCTION
The aged population is increasing, particularly in advanced countries. As this population advances, the incidence of cancers, including malignant lymphoma, is rising.1-3 Because cancer can be considered an age-related disease, it is an urgent task to take measures for elderly patients with cancer in advanced countries.4 Because most vulnerable older adult patients cannot be enrolled in clinical trials, there are few data regarding the management of aged cancer patients, including those with lymphoma. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)/CHOP (CHOP) therapy is the gold standard regimen for elderly non-Hodgkin lymphoma (NHL) patients.5-8 However, even if complete response (CR) is reached with initial treatment, 20-50% of patients with diffuse large B cell lymphoma (DLBCL) experience relapse,9 and there are few therapeutic options, especially for aged patients with relapsed NHL.
Thus, it is unclear whether aged relapsed or refractory (r/r) NHL patients are suitable for certain therapeutic strategies. Aged patients with some comorbidities cannot receive sufficient intensity salvage chemotherapies in the clinic. We thus developed a combination salvage therapy for r/r NHL based on isobologram analysis data for these vulnerable patients.10-16 We selected methotrexate (MTX), hydrocortisone (HC), vincristine (VCR), sobuzoxane (MST-16), and etoposide (ETP) and named this regimen MTX-HOPE (Table 1).17 This regimen has the advantage of being performed on an outpatient basis. We previously reported the safety and efficacy of the MTX-HOPE regimen in a small number of NHL patients. In a previous study, the median age of the patients was 70 years, and the median overall survival (OS) was 11.1 months. In addition, another group recently reported the efficacy of the MTX-HOPE regimen, and the median OS and progression-free survival (PFS) were 10 months and 7 months, respectively.18 However, the characteristics of NHL patients who are more likely to respond to MTX-HOPE therapy are still unknown. We need to identify patients suitable for this regimen from the perspective of safety and effectiveness. Thus, we performed a single-center retrospective cohort study to validate the MTX-HOPE regimen.
Table 1 The protocol of MTX-HOPE
Agent Dose/day Route Days
Methotrexate (MTX) 20 mg po 1
Hydrocortisone (HC) 100 mg div (15min) 2
Vincristine (VCR) 1 mg div (15min) 2
Sobuzoxane (MST-16) 400 mg po 3, 4
Etoposide (ETP) 25 mg po 3, 4
Abbreviations: MTX-HOPE, methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide; po, per os; div, intravenous drip
MATERIALS AND METHODS
Study design and patients
This study was conducted as a single-center retrospective cohort study. A total of 42 patients who received MTX-HOPE therapy agreed to participate in this study, which was approved by the local Ethics Committee of Aizu Medical Center of Fukushima Medical University (FMU) and carried out in accordance with the relevant guidelines and regulations. Written informed consent was obtained from all subjects prior to enrollment. We obtained patient characteristics and laboratory data from the clinical records of all patients diagnosed with NHL, including DLBCL, mantle cell lymphoma (MCL), peripheral T cell lymphoma (PTCL), and others, from 2009 to 2020.
Treatment protocol
The MTX-HOPE regimen was repeated every 2-3 weeks and involved the administration of MTX (20 mg) orally on day 1, HC (100 mg) and VCR (1 mg) infusion on day 2, and MST-16 (400 mg) and ETP (25 mg) orally on days 3 and 4 (Table 1). Granulocyte colony-stimulating factor (G-CSF) was administered to patients who experienced neutropenia as supportive therapy.
Treatment response and toxicity criteria
Efficacy assessments were performed according to the international consensus on the revised response criteria for malignant lymphoma. According to these criteria, we defined therapy responses as follows: complete response (CR), unconfirmed CR (uCR), partial response (PR), stable disease (SD), and progressive disease (PD). Physical examination and laboratory tests were used to evaluate adverse reactions and toxicities. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, Version 4.0.
Statistical analysis
All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of the R commander designed to add statistical functions frequently used in biostatistics.19 The Kolmogorov-Smirnov test was used to analyze the normality of the distribution of parameters.20,21 All variables with a normal distribution are expressed as the mean ± standard deviation, and those with a log-normal distribution are expressed as the median with the interquartile range (IQR). OS was defined as the time from the start of MTX-HOPE therapy to death or the date of the last follow-up.22 PFS was defined as the time from the start of MTX-HOPE therapy to relapse, death, or the date of the last follow-up. The OS and PFS rates were estimated according to the Kaplan-Meier method and compared by the log-rank test.19,22 The hazard ratios (HRs) and their associated 95% confidence intervals (CIs) for potential prognostic factors were calculated using the Cox proportional hazards regression model. Variables with p < 0.10 in the univariate analysis were used as independent variables in the multivariate analysis.23 All statistical tests were two-sided, and a significance level of 0.05 was used.
RESULTS
Patient characteristics
The median age of the 42 patients who received MTX-HOPE therapy for r/r NHL in this study was 81 years (range, 57 to 90 years), and 35.7% were women (Table 2). In our study, seven patients (16.7%) who received the MTX-HOPE regimen were less than 70 years old. Six patients had a history of multiple pretreatment regimens, and the other patient had severe pulmonary disease and poor performance status (PS). These patients had no indication for intensive chemotherapy and agreed to receive the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Twenty-five patients were refractory to previous treatment, and 17 had relapsed disease. The proportion of patients with worse Eastern Cooperative Oncology Group (ECOG) PS scores (more than 2) was 59.5%, the proportion of patients with anemia (hemoglobin less than 10 g/dL) was 42.9%, and the proportion of patients with lactate dehydrogenase (LDH) levels greater than the upper limit of normal was 54.8%. At the time of diagnosis, the proportion of patients with intermediate- and high-risk International Prognostic Index (IPI) scores was 92.9%, and the proportion of patients with advanced stage (stage III and IV) disease was 85.6%. The lymphoma histology of the patients included 28 DLBCL, one follicular lymphoma (FL), one MCL, 11 T cell lymphoma, and one extranodal NK/T cell lymphoma. In addition, the proportion of patients with Ki-67 positivity greater than 50% by immunohistochemistry (IHC) was 36%. Furthermore, the MTX-HOPE regimen was given to patients as salvage therapy. We assessed the response to MTX-HOPE after three to five cycles by computed tomography (CT). The percentage of patients who achieved CR or unconfirmed CR was 19%, PR was 26.2%, SD was 31%, and PD was 23.8% at that time.
Table 2 Patient characteristics
Characteristics patients MTX-HOPE
Patients, n 42
Hospitalization during MTX-HOPE administration 9 (21)
At the start of treatment
Age, median [min, max] 81 [57, 90]
Women, n (%) 15 (36)
Performance status, n (%)
0-1 17 (41)
2-4 25 (60)
Status before MTX-HOPE treatment, n (%)
Relapsed 17 (41)
Refractory 25 (60)
Number of pretreatment regimens, n (%)
1 31(74)
2 3 (7.1)
≥3 8 (19)
Pretreatment regimen, n (%)
CHOP +/-R 28 (67)
DeVIC +/-R 5 (12)
GDP +/-R 3 (7.1)
Other 6 (14)
Previous treatment history of rituximab, n (%) 29 (69)
Histology, n (%)
B cell lymphoma 30 (71)
DLBCL 28 (67)
FL 1 (2.4)
MCL 1 (2.4)
T cell lymphoma 11 (26)
Extranodal NK/T cell lymphoma 1 (2.4)
Anemia (Hb <10), n (%) 18 (43)
CKD, n (%) 16 (38)
LDH high (≥upper normal limit; 240) 23 (55)
BMI (<20 kg/m2), n (%) 15 (36)
At diagnosis
IPI, n(%)
Low risk 3(7.1)
Intermediate risk 16 (38)
High risk 23 (55)
Stage, n(%)
I 4 (9.5)
II 2 (4.8)
III 9 (21)
IV 27 (64)
Bone marrow involvement, n (%) 12 (29)
Extranodal lesion, n (%) 33 (79)
B symptoms present, n (%) 12 (29)
Ki-67 high (≥50%), n(%) 15 (36)
DLBCL 12 (29)
MCL 1 (2.4)
T cell lymphoma 2 (4.8)
Response after 3 to 5 cycles, n (%)
Complete response (CR)/unconfirmed CR 8 (19)
Partial response (PR) 11 (26)
Stable disease (SD) 13 (31)
Progressive disease (PD) 10 (24)
Abbreviations: DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; CKD, chronic kidney disease
Safety of MTX-HOPE
The hematological and nonhematological toxicities of MTX-HOPE are shown in Table 3. Grade 3 and 4 neutropenia were observed in 47.6% of the patients, and febrile neutropenia was observed in 9.5%. Grade 3 and 4 anemia and thrombocytopenia were observed in 35.7% and 14.3% of the patients, respectively. Severe nonhematological toxicities, such as liver damage, renal dysfunction, nausea, vomiting, and infection, were infrequent in patients treated with MTX-HOPE therapy. Seventeen patients temporarily discontinued VCR due to grade 1 neuropathy in our study. However, most patients could continue VCR while administered vitamin B12 and pregabalin. The other drugs did not need to be reduced. Furthermore, there were no treatment-related deaths. However, there were six treatment discontinuation events: four pneumonia, one sepsis and one acute kidney injury (Table 3).
Table 3 Adverse effects of MTX-HOPE therapy
Hematological toxicity All Grades Grade ≥3
Neutropenia n, (%) 33 (79) 20 (48)
Febrile neutropenia n, (%) - 4 (9.5)
Anemia n, (%) 39 (93) 15 (36)
Thrombocytopenia n, (%) 30 (71) 6 (14)
Nonhematological toxicity
Liver damage 10 (24) 2 (4.8)
Renal dysfunction 24 (57) 5 (12)
Nausea 8 (19) 0 (0)
Vomiting 1 (2.4) 0 (0)
Infection 10 (24) 3 (7.1)
Neuropathy 17 (40) 0 (0)
Hematological supportive care
Red blood cell transfusion 13 (30.9)
Platelet transfusion 4 (9.5)
G-CSF 24 (57.1)
Treatment-related deaths 0 (0)
Treatment discontinuation events 6 (14)
Pneumonia 4 (9.5)
Sepsis 1 (2.4)
Acute kidney injury 1 (2.4)
Survival analysis
The median follow-up duration of the survivors was 213 days (range, 12-2763). The median OS was 7 months (range, 0-91) (Figure 1a), and the median PFS was 3.5 months (range, 0-91) (Figure 1b). Next, we performed univariate analysis to identify the independent factors for OS and PFS by univariate analyses (Table 4). OS was significantly influenced by Ki-67 positivity in pathology (≥50%) (P = 0.020) and PR to the MTX-HOPE regimen after three to five cycles (P = 0.002) (Figure 1c). PFS was also significantly influenced by Ki-67 positivity in pathology (≥50%) (P = 0.039) and PR to the MTX-HOPE regimen after three to five cycles (P < 0.001) (Figure 1d). IPI, lymphoma status (r/r), lymphoma histology (B cell lymphoma or T cell lymphoma), and other factors did not influence OS or PFS.
Fig. 1 Kaplan-Meier estimates. (a) Overall survival (OS) and (b) progression-free survival (PFS) of all patients who received MTX-HOPE therapy. (c) OS and (d) PFS stratified by the response to MTX-HOPE therapy after three to five cycles.
Table 4 Univariate analysis of overall survival and progression-free survival
Variable Overall survival Progression-free survival
Hazard ratio (95%CI) p-value Hazard ratio (95%CI) p-value
Age ≥ 75 1.11 (0.51-2.41) 0.79 1.23 (0.59-2.53) 0.58
Sex (female) 0.89 (0.42-1.92) 0.77 0.82 (0.40-1.65) 0.58
BMI ≥ 20 kg/m2 0.64 (0.29-1.43) 0.28 0.73 (0.35-1.54) 0.41
Hb > 10 0.61 (0.29-1.31) 0.20 0.97 (0.48-1.98) 0.94
eGFR > 60 0.75 (0.36-1.58) 0.45 0.75 (0.37-1.51) 0.42
Number of pretreatment regimens ≥ 2 1.37 (0.63-3.00) 0.43 1.44 (0.70-2.97) 0.32
IPI ≥ 3 0.69 (0.29-1.63) 0.39 1.02 (0.44-2.36) 0.96
Stage ≥ III 0.63 (0.26-1.56) 0.32 0.97 (0.40-2.35) 0.94
PS ≥ 2 1.22 (0.58-2.55) 0.61 1.22 (0.62-2.40) 0.57
Extra nodal lesion 1.30 (0.52-3.25) 0.57 1.54 (0.63-3.80) 0.34
LDH (>UNL) 1.65 (0.79-3.45) 0.18 1.36 (0.69-2.66) 0.38
Bone marrow involvement 0.74 (0.32-1.70) 0.48 0.90 (0.44-1.85) 0.78
B symptoms 0.89 (0.39-2.00) 0.77 0.89 (0.43-1.87) 0.77
Relapsed status 0.50 (0.23-1.09) 0.082 0.78 (0.38-1.58) 0.48
T-cell lymphoma histology 0.58 (0.25-1.37) 0.22 0.63 (0.29-1.35) 0.24
Ki-67 ≥50% 2.42 (1.15-5.09) 0.020* 2.10 (1.04-4.25) 0.039*
Response of PR after 3-5 cycles 0.30 (0.13-0.65) 0.002** 0.25 (0.12-0.53) < 0.001***
Abbreviations: UNL; upper normal limit, PR; partial response
*P < 0.05, **P < 0.01, ***P < 0.001
Furthermore, we performed multivariable analyses of OS and PFS with the Cox proportional hazards model to control confounding factors. Response to MTX-HOPE better than PR after three to five cycles was treated as a time-dependent covariate.23 Each analysis was evaluated by adding age (≥75), IPI (≥3), and lymphoma histology (B cell lymphoma or T cell lymphoma) to the independent factors (Table 5). The final models for OS and PFS included Ki-67 positivity (≥ 50%) (HR 2.42, 95% CI 1.15-5.09, P = 0.020 and HR 2.10, 95% CI 1.04-4.25, P = 0.039).
Table 5 Multivariate analysis of overall survival (OS) and progression-free survival (PFS) with the Cox proportional hazards model. Response to the MTX-HOPE regimen better than partial response after three to five cycles was treated as a time-dependent covariate.
Variable Hazard ratio (95% CI) p-value
Overall survival
Ki-67 (≥50%) 2.42 (1.15-5.09) 0.020*
Progression-free survival
Ki-67 (≥50%) 2.10 (1.04-4.25) 0.039*
Age (≥75), B cell lymphoma or T cell lymphoma, and International Prognostic Index (≥3) were also added to the OS and PFS analyses. The final models with significant differences are shown in the table.
DISCUSSION
In the present study, we analyzed the safety and efficacy of MTX-HOPE for aged r/r NHL patients who are vulnerable and were not eligible for autologous stem cell transplantation (ASCT) and conventional high-dose salvage chemotherapy. Our results showed that the MTX-HOPE regimen is effective and tolerable for these r/r NHL patients. High Ki-67 positivity was extracted as an independent factor of OS and PFS by multivariable analyses using response to MTX-HOPE treatment as a time-dependent covariate. In addition, most patients who receive MTX-HOPE can be treated without hospitalization.
Ki-67 is one of the cell cycle related protein and strongly associated with the lymphoma cell proliferation, leading to lymphoma progression. High Ki-67 positivity is also related to poor prognosis within the same lymphoma subtypes, such as DLBCL and FL.24-26 Our results suggest that MTX-HOPE is less effective for the highly Ki-67 positive lymphoma patients. Because there were a few patients other than DLBCL in our study, further study is needed to confirm these results.
In this study, the patients who received MTX-HOPE therapy were elderly individuals and had worse PS scores. Because these patients had some comorbidities, such as renal dysfunction and anemia, they could not receive other intensive salvage treatments. The overall response rate (ORR) of MTX-HOPE was 45.2%. The rate of treatment responsiveness above SD was 76.2%, and treatment response was observed in many cases. The median OS was 7 months, the 1-year OS was 43.7%, and the 2-year OS was 40.8%. Some patients achieved long-term survival. Moreover, MTX-HOPE therapy resulted in no treatment-related deaths and the acceptable rate of treatment discontinuation events. According to the SCHOLAR-1 study of relapsed DLBCL (the largest, patient-level pooled analysis), the median OS was 6.3 months, and the 2-year OS was 20%.27 Given our target frail population, these results indicate that MTX-HOPE therapy is tolerable and effective. Although there were several side effects of MTX-HOPE therapy worse than grade 3, these were temporary and recoverable. Appropriate supportive care, including blood transfusion and G-CSF, is generally important for elderly patients to continue chemotherapy.
Furthermore, most patients treated with MTX-HOPE were able to continue without hospitalization, leading to a great advantage in medical costs. Previous reports have shown that the medical costs of aggressive NHL are estimated at $5,871 per patient per month (PPPM) for the first two years of treatment,28 and those for elderly patients with r/r DLBCL are more than $97,000 per year.29 In addition, the costs of patients for febrile neutropenia (FN) are more expensive.30 In our study, the average medical cost of MTX-HOPE calculated by the medical claims data was ¥94,297/month. These data revealed that MTX-HOPE is a cost-effective regimen. Multivariable analysis with the Cox proportional hazards model revealed Ki-67 positivity in pathology and PR to the MTX-HOPE regimen as independent factors for OS and PFS. These results are useful for the indication of MTX-HOPE therapy.
There are some limitations in this study. First, although the response to MTX-HOPE was evaluated based on the International Workshop Response Criteria (IWRC), the evaluations were not conducted at fixed cycles. Therefore, there were differences in the response evaluation periods among MTX-HOPE patients. Last, this was a single-center, single-arm study. A prospective controlled trial with other salvage regimens may be needed to confirm the safety and effectiveness of MTX-HOPE therapy.
In conclusion, the MTX-HOPE regimen is safe and effective for r/r NHL patients. Pathologically high Ki-67 positivity was identified as an independent factor for MTX-HOPE treatment. The advantage of the MTX-HOPE regimen is that it contributes to maintaining quality of life (QOL) without hospitalization. Our results may help in considering the indications for MTX-HOPE. We concluded that MTX-HOPE is an attractive salvage regimen for aged patients or those with non-aggressive r/r NHL. To validate this regimen, further prospective studies are needed.
ACKNOWLEDGMENTS
We would like to express our special thanks to Dr. Yasuhiko Kano, who retired from the Tochigi Cancer Center (Utsunomiya, Japan). He developed the principle of MTX-HOPE therapy through a series of in vitro experiments with combination chemotherapy.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest (COIs). | Oral | DrugAdministrationRoute | CC BY-NC-SA | 33551437 | 19,429,767 | 2021-03-18 |
What was the administration route of drug 'HYDROCORTISONE SODIUM SUCCINATE'? | MTX-HOPE is a low-dose salvage chemotherapy for aged patients with relapsed or refractory non-Hodgkin lymphoma.
As the aging society advances, the number of non-Hodgkin lymphoma (NHL) patients is increasing. Aged relapsed or refractory (r/r) NHL patients have limited treatment options. Therefore, a safe and effective regimen is urgently needed for these patients. Thus, we originally developed the MTX-HOPE (methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide) regimen for r/r NHL and validated the safety and efficacy of this regimen in a clinical setting. We analyzed the data of 42 r/r NHL patients who received MTX-HOPE in this single-center retrospective cohort study. The median age of the patients was 81 years. The overall response rate was 45.3%. The median overall survival (OS) was 7 months, the one-year OS was 43.7%, and the two-year OS was 40.8%. Grade ≥3 neutropenia and renal dysfunction were observed in 47.6% and 11.9% of patients, respectively, and treatment-related death were not observed. Appropriate supportive care enabled these patients to continue the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Multivariable analyses with the Cox proportional hazards model revealed that both OS and progression-free survival (PFS) were significantly influenced by high Ki-67 expression in pathology, with response to the MTX-HOPE regimen after three to five cycles as a time-dependent covariate. Our results suggest that MTX-HOPE therapy can be an option for non-aggressive r/r NHL patients. To validate MTX-HOPE therapy, further prospective investigation is needed.
INTRODUCTION
The aged population is increasing, particularly in advanced countries. As this population advances, the incidence of cancers, including malignant lymphoma, is rising.1-3 Because cancer can be considered an age-related disease, it is an urgent task to take measures for elderly patients with cancer in advanced countries.4 Because most vulnerable older adult patients cannot be enrolled in clinical trials, there are few data regarding the management of aged cancer patients, including those with lymphoma. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)/CHOP (CHOP) therapy is the gold standard regimen for elderly non-Hodgkin lymphoma (NHL) patients.5-8 However, even if complete response (CR) is reached with initial treatment, 20-50% of patients with diffuse large B cell lymphoma (DLBCL) experience relapse,9 and there are few therapeutic options, especially for aged patients with relapsed NHL.
Thus, it is unclear whether aged relapsed or refractory (r/r) NHL patients are suitable for certain therapeutic strategies. Aged patients with some comorbidities cannot receive sufficient intensity salvage chemotherapies in the clinic. We thus developed a combination salvage therapy for r/r NHL based on isobologram analysis data for these vulnerable patients.10-16 We selected methotrexate (MTX), hydrocortisone (HC), vincristine (VCR), sobuzoxane (MST-16), and etoposide (ETP) and named this regimen MTX-HOPE (Table 1).17 This regimen has the advantage of being performed on an outpatient basis. We previously reported the safety and efficacy of the MTX-HOPE regimen in a small number of NHL patients. In a previous study, the median age of the patients was 70 years, and the median overall survival (OS) was 11.1 months. In addition, another group recently reported the efficacy of the MTX-HOPE regimen, and the median OS and progression-free survival (PFS) were 10 months and 7 months, respectively.18 However, the characteristics of NHL patients who are more likely to respond to MTX-HOPE therapy are still unknown. We need to identify patients suitable for this regimen from the perspective of safety and effectiveness. Thus, we performed a single-center retrospective cohort study to validate the MTX-HOPE regimen.
Table 1 The protocol of MTX-HOPE
Agent Dose/day Route Days
Methotrexate (MTX) 20 mg po 1
Hydrocortisone (HC) 100 mg div (15min) 2
Vincristine (VCR) 1 mg div (15min) 2
Sobuzoxane (MST-16) 400 mg po 3, 4
Etoposide (ETP) 25 mg po 3, 4
Abbreviations: MTX-HOPE, methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide; po, per os; div, intravenous drip
MATERIALS AND METHODS
Study design and patients
This study was conducted as a single-center retrospective cohort study. A total of 42 patients who received MTX-HOPE therapy agreed to participate in this study, which was approved by the local Ethics Committee of Aizu Medical Center of Fukushima Medical University (FMU) and carried out in accordance with the relevant guidelines and regulations. Written informed consent was obtained from all subjects prior to enrollment. We obtained patient characteristics and laboratory data from the clinical records of all patients diagnosed with NHL, including DLBCL, mantle cell lymphoma (MCL), peripheral T cell lymphoma (PTCL), and others, from 2009 to 2020.
Treatment protocol
The MTX-HOPE regimen was repeated every 2-3 weeks and involved the administration of MTX (20 mg) orally on day 1, HC (100 mg) and VCR (1 mg) infusion on day 2, and MST-16 (400 mg) and ETP (25 mg) orally on days 3 and 4 (Table 1). Granulocyte colony-stimulating factor (G-CSF) was administered to patients who experienced neutropenia as supportive therapy.
Treatment response and toxicity criteria
Efficacy assessments were performed according to the international consensus on the revised response criteria for malignant lymphoma. According to these criteria, we defined therapy responses as follows: complete response (CR), unconfirmed CR (uCR), partial response (PR), stable disease (SD), and progressive disease (PD). Physical examination and laboratory tests were used to evaluate adverse reactions and toxicities. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, Version 4.0.
Statistical analysis
All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of the R commander designed to add statistical functions frequently used in biostatistics.19 The Kolmogorov-Smirnov test was used to analyze the normality of the distribution of parameters.20,21 All variables with a normal distribution are expressed as the mean ± standard deviation, and those with a log-normal distribution are expressed as the median with the interquartile range (IQR). OS was defined as the time from the start of MTX-HOPE therapy to death or the date of the last follow-up.22 PFS was defined as the time from the start of MTX-HOPE therapy to relapse, death, or the date of the last follow-up. The OS and PFS rates were estimated according to the Kaplan-Meier method and compared by the log-rank test.19,22 The hazard ratios (HRs) and their associated 95% confidence intervals (CIs) for potential prognostic factors were calculated using the Cox proportional hazards regression model. Variables with p < 0.10 in the univariate analysis were used as independent variables in the multivariate analysis.23 All statistical tests were two-sided, and a significance level of 0.05 was used.
RESULTS
Patient characteristics
The median age of the 42 patients who received MTX-HOPE therapy for r/r NHL in this study was 81 years (range, 57 to 90 years), and 35.7% were women (Table 2). In our study, seven patients (16.7%) who received the MTX-HOPE regimen were less than 70 years old. Six patients had a history of multiple pretreatment regimens, and the other patient had severe pulmonary disease and poor performance status (PS). These patients had no indication for intensive chemotherapy and agreed to receive the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Twenty-five patients were refractory to previous treatment, and 17 had relapsed disease. The proportion of patients with worse Eastern Cooperative Oncology Group (ECOG) PS scores (more than 2) was 59.5%, the proportion of patients with anemia (hemoglobin less than 10 g/dL) was 42.9%, and the proportion of patients with lactate dehydrogenase (LDH) levels greater than the upper limit of normal was 54.8%. At the time of diagnosis, the proportion of patients with intermediate- and high-risk International Prognostic Index (IPI) scores was 92.9%, and the proportion of patients with advanced stage (stage III and IV) disease was 85.6%. The lymphoma histology of the patients included 28 DLBCL, one follicular lymphoma (FL), one MCL, 11 T cell lymphoma, and one extranodal NK/T cell lymphoma. In addition, the proportion of patients with Ki-67 positivity greater than 50% by immunohistochemistry (IHC) was 36%. Furthermore, the MTX-HOPE regimen was given to patients as salvage therapy. We assessed the response to MTX-HOPE after three to five cycles by computed tomography (CT). The percentage of patients who achieved CR or unconfirmed CR was 19%, PR was 26.2%, SD was 31%, and PD was 23.8% at that time.
Table 2 Patient characteristics
Characteristics patients MTX-HOPE
Patients, n 42
Hospitalization during MTX-HOPE administration 9 (21)
At the start of treatment
Age, median [min, max] 81 [57, 90]
Women, n (%) 15 (36)
Performance status, n (%)
0-1 17 (41)
2-4 25 (60)
Status before MTX-HOPE treatment, n (%)
Relapsed 17 (41)
Refractory 25 (60)
Number of pretreatment regimens, n (%)
1 31(74)
2 3 (7.1)
≥3 8 (19)
Pretreatment regimen, n (%)
CHOP +/-R 28 (67)
DeVIC +/-R 5 (12)
GDP +/-R 3 (7.1)
Other 6 (14)
Previous treatment history of rituximab, n (%) 29 (69)
Histology, n (%)
B cell lymphoma 30 (71)
DLBCL 28 (67)
FL 1 (2.4)
MCL 1 (2.4)
T cell lymphoma 11 (26)
Extranodal NK/T cell lymphoma 1 (2.4)
Anemia (Hb <10), n (%) 18 (43)
CKD, n (%) 16 (38)
LDH high (≥upper normal limit; 240) 23 (55)
BMI (<20 kg/m2), n (%) 15 (36)
At diagnosis
IPI, n(%)
Low risk 3(7.1)
Intermediate risk 16 (38)
High risk 23 (55)
Stage, n(%)
I 4 (9.5)
II 2 (4.8)
III 9 (21)
IV 27 (64)
Bone marrow involvement, n (%) 12 (29)
Extranodal lesion, n (%) 33 (79)
B symptoms present, n (%) 12 (29)
Ki-67 high (≥50%), n(%) 15 (36)
DLBCL 12 (29)
MCL 1 (2.4)
T cell lymphoma 2 (4.8)
Response after 3 to 5 cycles, n (%)
Complete response (CR)/unconfirmed CR 8 (19)
Partial response (PR) 11 (26)
Stable disease (SD) 13 (31)
Progressive disease (PD) 10 (24)
Abbreviations: DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; CKD, chronic kidney disease
Safety of MTX-HOPE
The hematological and nonhematological toxicities of MTX-HOPE are shown in Table 3. Grade 3 and 4 neutropenia were observed in 47.6% of the patients, and febrile neutropenia was observed in 9.5%. Grade 3 and 4 anemia and thrombocytopenia were observed in 35.7% and 14.3% of the patients, respectively. Severe nonhematological toxicities, such as liver damage, renal dysfunction, nausea, vomiting, and infection, were infrequent in patients treated with MTX-HOPE therapy. Seventeen patients temporarily discontinued VCR due to grade 1 neuropathy in our study. However, most patients could continue VCR while administered vitamin B12 and pregabalin. The other drugs did not need to be reduced. Furthermore, there were no treatment-related deaths. However, there were six treatment discontinuation events: four pneumonia, one sepsis and one acute kidney injury (Table 3).
Table 3 Adverse effects of MTX-HOPE therapy
Hematological toxicity All Grades Grade ≥3
Neutropenia n, (%) 33 (79) 20 (48)
Febrile neutropenia n, (%) - 4 (9.5)
Anemia n, (%) 39 (93) 15 (36)
Thrombocytopenia n, (%) 30 (71) 6 (14)
Nonhematological toxicity
Liver damage 10 (24) 2 (4.8)
Renal dysfunction 24 (57) 5 (12)
Nausea 8 (19) 0 (0)
Vomiting 1 (2.4) 0 (0)
Infection 10 (24) 3 (7.1)
Neuropathy 17 (40) 0 (0)
Hematological supportive care
Red blood cell transfusion 13 (30.9)
Platelet transfusion 4 (9.5)
G-CSF 24 (57.1)
Treatment-related deaths 0 (0)
Treatment discontinuation events 6 (14)
Pneumonia 4 (9.5)
Sepsis 1 (2.4)
Acute kidney injury 1 (2.4)
Survival analysis
The median follow-up duration of the survivors was 213 days (range, 12-2763). The median OS was 7 months (range, 0-91) (Figure 1a), and the median PFS was 3.5 months (range, 0-91) (Figure 1b). Next, we performed univariate analysis to identify the independent factors for OS and PFS by univariate analyses (Table 4). OS was significantly influenced by Ki-67 positivity in pathology (≥50%) (P = 0.020) and PR to the MTX-HOPE regimen after three to five cycles (P = 0.002) (Figure 1c). PFS was also significantly influenced by Ki-67 positivity in pathology (≥50%) (P = 0.039) and PR to the MTX-HOPE regimen after three to five cycles (P < 0.001) (Figure 1d). IPI, lymphoma status (r/r), lymphoma histology (B cell lymphoma or T cell lymphoma), and other factors did not influence OS or PFS.
Fig. 1 Kaplan-Meier estimates. (a) Overall survival (OS) and (b) progression-free survival (PFS) of all patients who received MTX-HOPE therapy. (c) OS and (d) PFS stratified by the response to MTX-HOPE therapy after three to five cycles.
Table 4 Univariate analysis of overall survival and progression-free survival
Variable Overall survival Progression-free survival
Hazard ratio (95%CI) p-value Hazard ratio (95%CI) p-value
Age ≥ 75 1.11 (0.51-2.41) 0.79 1.23 (0.59-2.53) 0.58
Sex (female) 0.89 (0.42-1.92) 0.77 0.82 (0.40-1.65) 0.58
BMI ≥ 20 kg/m2 0.64 (0.29-1.43) 0.28 0.73 (0.35-1.54) 0.41
Hb > 10 0.61 (0.29-1.31) 0.20 0.97 (0.48-1.98) 0.94
eGFR > 60 0.75 (0.36-1.58) 0.45 0.75 (0.37-1.51) 0.42
Number of pretreatment regimens ≥ 2 1.37 (0.63-3.00) 0.43 1.44 (0.70-2.97) 0.32
IPI ≥ 3 0.69 (0.29-1.63) 0.39 1.02 (0.44-2.36) 0.96
Stage ≥ III 0.63 (0.26-1.56) 0.32 0.97 (0.40-2.35) 0.94
PS ≥ 2 1.22 (0.58-2.55) 0.61 1.22 (0.62-2.40) 0.57
Extra nodal lesion 1.30 (0.52-3.25) 0.57 1.54 (0.63-3.80) 0.34
LDH (>UNL) 1.65 (0.79-3.45) 0.18 1.36 (0.69-2.66) 0.38
Bone marrow involvement 0.74 (0.32-1.70) 0.48 0.90 (0.44-1.85) 0.78
B symptoms 0.89 (0.39-2.00) 0.77 0.89 (0.43-1.87) 0.77
Relapsed status 0.50 (0.23-1.09) 0.082 0.78 (0.38-1.58) 0.48
T-cell lymphoma histology 0.58 (0.25-1.37) 0.22 0.63 (0.29-1.35) 0.24
Ki-67 ≥50% 2.42 (1.15-5.09) 0.020* 2.10 (1.04-4.25) 0.039*
Response of PR after 3-5 cycles 0.30 (0.13-0.65) 0.002** 0.25 (0.12-0.53) < 0.001***
Abbreviations: UNL; upper normal limit, PR; partial response
*P < 0.05, **P < 0.01, ***P < 0.001
Furthermore, we performed multivariable analyses of OS and PFS with the Cox proportional hazards model to control confounding factors. Response to MTX-HOPE better than PR after three to five cycles was treated as a time-dependent covariate.23 Each analysis was evaluated by adding age (≥75), IPI (≥3), and lymphoma histology (B cell lymphoma or T cell lymphoma) to the independent factors (Table 5). The final models for OS and PFS included Ki-67 positivity (≥ 50%) (HR 2.42, 95% CI 1.15-5.09, P = 0.020 and HR 2.10, 95% CI 1.04-4.25, P = 0.039).
Table 5 Multivariate analysis of overall survival (OS) and progression-free survival (PFS) with the Cox proportional hazards model. Response to the MTX-HOPE regimen better than partial response after three to five cycles was treated as a time-dependent covariate.
Variable Hazard ratio (95% CI) p-value
Overall survival
Ki-67 (≥50%) 2.42 (1.15-5.09) 0.020*
Progression-free survival
Ki-67 (≥50%) 2.10 (1.04-4.25) 0.039*
Age (≥75), B cell lymphoma or T cell lymphoma, and International Prognostic Index (≥3) were also added to the OS and PFS analyses. The final models with significant differences are shown in the table.
DISCUSSION
In the present study, we analyzed the safety and efficacy of MTX-HOPE for aged r/r NHL patients who are vulnerable and were not eligible for autologous stem cell transplantation (ASCT) and conventional high-dose salvage chemotherapy. Our results showed that the MTX-HOPE regimen is effective and tolerable for these r/r NHL patients. High Ki-67 positivity was extracted as an independent factor of OS and PFS by multivariable analyses using response to MTX-HOPE treatment as a time-dependent covariate. In addition, most patients who receive MTX-HOPE can be treated without hospitalization.
Ki-67 is one of the cell cycle related protein and strongly associated with the lymphoma cell proliferation, leading to lymphoma progression. High Ki-67 positivity is also related to poor prognosis within the same lymphoma subtypes, such as DLBCL and FL.24-26 Our results suggest that MTX-HOPE is less effective for the highly Ki-67 positive lymphoma patients. Because there were a few patients other than DLBCL in our study, further study is needed to confirm these results.
In this study, the patients who received MTX-HOPE therapy were elderly individuals and had worse PS scores. Because these patients had some comorbidities, such as renal dysfunction and anemia, they could not receive other intensive salvage treatments. The overall response rate (ORR) of MTX-HOPE was 45.2%. The rate of treatment responsiveness above SD was 76.2%, and treatment response was observed in many cases. The median OS was 7 months, the 1-year OS was 43.7%, and the 2-year OS was 40.8%. Some patients achieved long-term survival. Moreover, MTX-HOPE therapy resulted in no treatment-related deaths and the acceptable rate of treatment discontinuation events. According to the SCHOLAR-1 study of relapsed DLBCL (the largest, patient-level pooled analysis), the median OS was 6.3 months, and the 2-year OS was 20%.27 Given our target frail population, these results indicate that MTX-HOPE therapy is tolerable and effective. Although there were several side effects of MTX-HOPE therapy worse than grade 3, these were temporary and recoverable. Appropriate supportive care, including blood transfusion and G-CSF, is generally important for elderly patients to continue chemotherapy.
Furthermore, most patients treated with MTX-HOPE were able to continue without hospitalization, leading to a great advantage in medical costs. Previous reports have shown that the medical costs of aggressive NHL are estimated at $5,871 per patient per month (PPPM) for the first two years of treatment,28 and those for elderly patients with r/r DLBCL are more than $97,000 per year.29 In addition, the costs of patients for febrile neutropenia (FN) are more expensive.30 In our study, the average medical cost of MTX-HOPE calculated by the medical claims data was ¥94,297/month. These data revealed that MTX-HOPE is a cost-effective regimen. Multivariable analysis with the Cox proportional hazards model revealed Ki-67 positivity in pathology and PR to the MTX-HOPE regimen as independent factors for OS and PFS. These results are useful for the indication of MTX-HOPE therapy.
There are some limitations in this study. First, although the response to MTX-HOPE was evaluated based on the International Workshop Response Criteria (IWRC), the evaluations were not conducted at fixed cycles. Therefore, there were differences in the response evaluation periods among MTX-HOPE patients. Last, this was a single-center, single-arm study. A prospective controlled trial with other salvage regimens may be needed to confirm the safety and effectiveness of MTX-HOPE therapy.
In conclusion, the MTX-HOPE regimen is safe and effective for r/r NHL patients. Pathologically high Ki-67 positivity was identified as an independent factor for MTX-HOPE treatment. The advantage of the MTX-HOPE regimen is that it contributes to maintaining quality of life (QOL) without hospitalization. Our results may help in considering the indications for MTX-HOPE. We concluded that MTX-HOPE is an attractive salvage regimen for aged patients or those with non-aggressive r/r NHL. To validate this regimen, further prospective studies are needed.
ACKNOWLEDGMENTS
We would like to express our special thanks to Dr. Yasuhiko Kano, who retired from the Tochigi Cancer Center (Utsunomiya, Japan). He developed the principle of MTX-HOPE therapy through a series of in vitro experiments with combination chemotherapy.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest (COIs). | Intravenous drip | DrugAdministrationRoute | CC BY-NC-SA | 33551437 | 19,429,767 | 2021-03-18 |
What was the administration route of drug 'METHOTREXATE SODIUM'? | MTX-HOPE is a low-dose salvage chemotherapy for aged patients with relapsed or refractory non-Hodgkin lymphoma.
As the aging society advances, the number of non-Hodgkin lymphoma (NHL) patients is increasing. Aged relapsed or refractory (r/r) NHL patients have limited treatment options. Therefore, a safe and effective regimen is urgently needed for these patients. Thus, we originally developed the MTX-HOPE (methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide) regimen for r/r NHL and validated the safety and efficacy of this regimen in a clinical setting. We analyzed the data of 42 r/r NHL patients who received MTX-HOPE in this single-center retrospective cohort study. The median age of the patients was 81 years. The overall response rate was 45.3%. The median overall survival (OS) was 7 months, the one-year OS was 43.7%, and the two-year OS was 40.8%. Grade ≥3 neutropenia and renal dysfunction were observed in 47.6% and 11.9% of patients, respectively, and treatment-related death were not observed. Appropriate supportive care enabled these patients to continue the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Multivariable analyses with the Cox proportional hazards model revealed that both OS and progression-free survival (PFS) were significantly influenced by high Ki-67 expression in pathology, with response to the MTX-HOPE regimen after three to five cycles as a time-dependent covariate. Our results suggest that MTX-HOPE therapy can be an option for non-aggressive r/r NHL patients. To validate MTX-HOPE therapy, further prospective investigation is needed.
INTRODUCTION
The aged population is increasing, particularly in advanced countries. As this population advances, the incidence of cancers, including malignant lymphoma, is rising.1-3 Because cancer can be considered an age-related disease, it is an urgent task to take measures for elderly patients with cancer in advanced countries.4 Because most vulnerable older adult patients cannot be enrolled in clinical trials, there are few data regarding the management of aged cancer patients, including those with lymphoma. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)/CHOP (CHOP) therapy is the gold standard regimen for elderly non-Hodgkin lymphoma (NHL) patients.5-8 However, even if complete response (CR) is reached with initial treatment, 20-50% of patients with diffuse large B cell lymphoma (DLBCL) experience relapse,9 and there are few therapeutic options, especially for aged patients with relapsed NHL.
Thus, it is unclear whether aged relapsed or refractory (r/r) NHL patients are suitable for certain therapeutic strategies. Aged patients with some comorbidities cannot receive sufficient intensity salvage chemotherapies in the clinic. We thus developed a combination salvage therapy for r/r NHL based on isobologram analysis data for these vulnerable patients.10-16 We selected methotrexate (MTX), hydrocortisone (HC), vincristine (VCR), sobuzoxane (MST-16), and etoposide (ETP) and named this regimen MTX-HOPE (Table 1).17 This regimen has the advantage of being performed on an outpatient basis. We previously reported the safety and efficacy of the MTX-HOPE regimen in a small number of NHL patients. In a previous study, the median age of the patients was 70 years, and the median overall survival (OS) was 11.1 months. In addition, another group recently reported the efficacy of the MTX-HOPE regimen, and the median OS and progression-free survival (PFS) were 10 months and 7 months, respectively.18 However, the characteristics of NHL patients who are more likely to respond to MTX-HOPE therapy are still unknown. We need to identify patients suitable for this regimen from the perspective of safety and effectiveness. Thus, we performed a single-center retrospective cohort study to validate the MTX-HOPE regimen.
Table 1 The protocol of MTX-HOPE
Agent Dose/day Route Days
Methotrexate (MTX) 20 mg po 1
Hydrocortisone (HC) 100 mg div (15min) 2
Vincristine (VCR) 1 mg div (15min) 2
Sobuzoxane (MST-16) 400 mg po 3, 4
Etoposide (ETP) 25 mg po 3, 4
Abbreviations: MTX-HOPE, methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide; po, per os; div, intravenous drip
MATERIALS AND METHODS
Study design and patients
This study was conducted as a single-center retrospective cohort study. A total of 42 patients who received MTX-HOPE therapy agreed to participate in this study, which was approved by the local Ethics Committee of Aizu Medical Center of Fukushima Medical University (FMU) and carried out in accordance with the relevant guidelines and regulations. Written informed consent was obtained from all subjects prior to enrollment. We obtained patient characteristics and laboratory data from the clinical records of all patients diagnosed with NHL, including DLBCL, mantle cell lymphoma (MCL), peripheral T cell lymphoma (PTCL), and others, from 2009 to 2020.
Treatment protocol
The MTX-HOPE regimen was repeated every 2-3 weeks and involved the administration of MTX (20 mg) orally on day 1, HC (100 mg) and VCR (1 mg) infusion on day 2, and MST-16 (400 mg) and ETP (25 mg) orally on days 3 and 4 (Table 1). Granulocyte colony-stimulating factor (G-CSF) was administered to patients who experienced neutropenia as supportive therapy.
Treatment response and toxicity criteria
Efficacy assessments were performed according to the international consensus on the revised response criteria for malignant lymphoma. According to these criteria, we defined therapy responses as follows: complete response (CR), unconfirmed CR (uCR), partial response (PR), stable disease (SD), and progressive disease (PD). Physical examination and laboratory tests were used to evaluate adverse reactions and toxicities. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, Version 4.0.
Statistical analysis
All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of the R commander designed to add statistical functions frequently used in biostatistics.19 The Kolmogorov-Smirnov test was used to analyze the normality of the distribution of parameters.20,21 All variables with a normal distribution are expressed as the mean ± standard deviation, and those with a log-normal distribution are expressed as the median with the interquartile range (IQR). OS was defined as the time from the start of MTX-HOPE therapy to death or the date of the last follow-up.22 PFS was defined as the time from the start of MTX-HOPE therapy to relapse, death, or the date of the last follow-up. The OS and PFS rates were estimated according to the Kaplan-Meier method and compared by the log-rank test.19,22 The hazard ratios (HRs) and their associated 95% confidence intervals (CIs) for potential prognostic factors were calculated using the Cox proportional hazards regression model. Variables with p < 0.10 in the univariate analysis were used as independent variables in the multivariate analysis.23 All statistical tests were two-sided, and a significance level of 0.05 was used.
RESULTS
Patient characteristics
The median age of the 42 patients who received MTX-HOPE therapy for r/r NHL in this study was 81 years (range, 57 to 90 years), and 35.7% were women (Table 2). In our study, seven patients (16.7%) who received the MTX-HOPE regimen were less than 70 years old. Six patients had a history of multiple pretreatment regimens, and the other patient had severe pulmonary disease and poor performance status (PS). These patients had no indication for intensive chemotherapy and agreed to receive the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Twenty-five patients were refractory to previous treatment, and 17 had relapsed disease. The proportion of patients with worse Eastern Cooperative Oncology Group (ECOG) PS scores (more than 2) was 59.5%, the proportion of patients with anemia (hemoglobin less than 10 g/dL) was 42.9%, and the proportion of patients with lactate dehydrogenase (LDH) levels greater than the upper limit of normal was 54.8%. At the time of diagnosis, the proportion of patients with intermediate- and high-risk International Prognostic Index (IPI) scores was 92.9%, and the proportion of patients with advanced stage (stage III and IV) disease was 85.6%. The lymphoma histology of the patients included 28 DLBCL, one follicular lymphoma (FL), one MCL, 11 T cell lymphoma, and one extranodal NK/T cell lymphoma. In addition, the proportion of patients with Ki-67 positivity greater than 50% by immunohistochemistry (IHC) was 36%. Furthermore, the MTX-HOPE regimen was given to patients as salvage therapy. We assessed the response to MTX-HOPE after three to five cycles by computed tomography (CT). The percentage of patients who achieved CR or unconfirmed CR was 19%, PR was 26.2%, SD was 31%, and PD was 23.8% at that time.
Table 2 Patient characteristics
Characteristics patients MTX-HOPE
Patients, n 42
Hospitalization during MTX-HOPE administration 9 (21)
At the start of treatment
Age, median [min, max] 81 [57, 90]
Women, n (%) 15 (36)
Performance status, n (%)
0-1 17 (41)
2-4 25 (60)
Status before MTX-HOPE treatment, n (%)
Relapsed 17 (41)
Refractory 25 (60)
Number of pretreatment regimens, n (%)
1 31(74)
2 3 (7.1)
≥3 8 (19)
Pretreatment regimen, n (%)
CHOP +/-R 28 (67)
DeVIC +/-R 5 (12)
GDP +/-R 3 (7.1)
Other 6 (14)
Previous treatment history of rituximab, n (%) 29 (69)
Histology, n (%)
B cell lymphoma 30 (71)
DLBCL 28 (67)
FL 1 (2.4)
MCL 1 (2.4)
T cell lymphoma 11 (26)
Extranodal NK/T cell lymphoma 1 (2.4)
Anemia (Hb <10), n (%) 18 (43)
CKD, n (%) 16 (38)
LDH high (≥upper normal limit; 240) 23 (55)
BMI (<20 kg/m2), n (%) 15 (36)
At diagnosis
IPI, n(%)
Low risk 3(7.1)
Intermediate risk 16 (38)
High risk 23 (55)
Stage, n(%)
I 4 (9.5)
II 2 (4.8)
III 9 (21)
IV 27 (64)
Bone marrow involvement, n (%) 12 (29)
Extranodal lesion, n (%) 33 (79)
B symptoms present, n (%) 12 (29)
Ki-67 high (≥50%), n(%) 15 (36)
DLBCL 12 (29)
MCL 1 (2.4)
T cell lymphoma 2 (4.8)
Response after 3 to 5 cycles, n (%)
Complete response (CR)/unconfirmed CR 8 (19)
Partial response (PR) 11 (26)
Stable disease (SD) 13 (31)
Progressive disease (PD) 10 (24)
Abbreviations: DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; CKD, chronic kidney disease
Safety of MTX-HOPE
The hematological and nonhematological toxicities of MTX-HOPE are shown in Table 3. Grade 3 and 4 neutropenia were observed in 47.6% of the patients, and febrile neutropenia was observed in 9.5%. Grade 3 and 4 anemia and thrombocytopenia were observed in 35.7% and 14.3% of the patients, respectively. Severe nonhematological toxicities, such as liver damage, renal dysfunction, nausea, vomiting, and infection, were infrequent in patients treated with MTX-HOPE therapy. Seventeen patients temporarily discontinued VCR due to grade 1 neuropathy in our study. However, most patients could continue VCR while administered vitamin B12 and pregabalin. The other drugs did not need to be reduced. Furthermore, there were no treatment-related deaths. However, there were six treatment discontinuation events: four pneumonia, one sepsis and one acute kidney injury (Table 3).
Table 3 Adverse effects of MTX-HOPE therapy
Hematological toxicity All Grades Grade ≥3
Neutropenia n, (%) 33 (79) 20 (48)
Febrile neutropenia n, (%) - 4 (9.5)
Anemia n, (%) 39 (93) 15 (36)
Thrombocytopenia n, (%) 30 (71) 6 (14)
Nonhematological toxicity
Liver damage 10 (24) 2 (4.8)
Renal dysfunction 24 (57) 5 (12)
Nausea 8 (19) 0 (0)
Vomiting 1 (2.4) 0 (0)
Infection 10 (24) 3 (7.1)
Neuropathy 17 (40) 0 (0)
Hematological supportive care
Red blood cell transfusion 13 (30.9)
Platelet transfusion 4 (9.5)
G-CSF 24 (57.1)
Treatment-related deaths 0 (0)
Treatment discontinuation events 6 (14)
Pneumonia 4 (9.5)
Sepsis 1 (2.4)
Acute kidney injury 1 (2.4)
Survival analysis
The median follow-up duration of the survivors was 213 days (range, 12-2763). The median OS was 7 months (range, 0-91) (Figure 1a), and the median PFS was 3.5 months (range, 0-91) (Figure 1b). Next, we performed univariate analysis to identify the independent factors for OS and PFS by univariate analyses (Table 4). OS was significantly influenced by Ki-67 positivity in pathology (≥50%) (P = 0.020) and PR to the MTX-HOPE regimen after three to five cycles (P = 0.002) (Figure 1c). PFS was also significantly influenced by Ki-67 positivity in pathology (≥50%) (P = 0.039) and PR to the MTX-HOPE regimen after three to five cycles (P < 0.001) (Figure 1d). IPI, lymphoma status (r/r), lymphoma histology (B cell lymphoma or T cell lymphoma), and other factors did not influence OS or PFS.
Fig. 1 Kaplan-Meier estimates. (a) Overall survival (OS) and (b) progression-free survival (PFS) of all patients who received MTX-HOPE therapy. (c) OS and (d) PFS stratified by the response to MTX-HOPE therapy after three to five cycles.
Table 4 Univariate analysis of overall survival and progression-free survival
Variable Overall survival Progression-free survival
Hazard ratio (95%CI) p-value Hazard ratio (95%CI) p-value
Age ≥ 75 1.11 (0.51-2.41) 0.79 1.23 (0.59-2.53) 0.58
Sex (female) 0.89 (0.42-1.92) 0.77 0.82 (0.40-1.65) 0.58
BMI ≥ 20 kg/m2 0.64 (0.29-1.43) 0.28 0.73 (0.35-1.54) 0.41
Hb > 10 0.61 (0.29-1.31) 0.20 0.97 (0.48-1.98) 0.94
eGFR > 60 0.75 (0.36-1.58) 0.45 0.75 (0.37-1.51) 0.42
Number of pretreatment regimens ≥ 2 1.37 (0.63-3.00) 0.43 1.44 (0.70-2.97) 0.32
IPI ≥ 3 0.69 (0.29-1.63) 0.39 1.02 (0.44-2.36) 0.96
Stage ≥ III 0.63 (0.26-1.56) 0.32 0.97 (0.40-2.35) 0.94
PS ≥ 2 1.22 (0.58-2.55) 0.61 1.22 (0.62-2.40) 0.57
Extra nodal lesion 1.30 (0.52-3.25) 0.57 1.54 (0.63-3.80) 0.34
LDH (>UNL) 1.65 (0.79-3.45) 0.18 1.36 (0.69-2.66) 0.38
Bone marrow involvement 0.74 (0.32-1.70) 0.48 0.90 (0.44-1.85) 0.78
B symptoms 0.89 (0.39-2.00) 0.77 0.89 (0.43-1.87) 0.77
Relapsed status 0.50 (0.23-1.09) 0.082 0.78 (0.38-1.58) 0.48
T-cell lymphoma histology 0.58 (0.25-1.37) 0.22 0.63 (0.29-1.35) 0.24
Ki-67 ≥50% 2.42 (1.15-5.09) 0.020* 2.10 (1.04-4.25) 0.039*
Response of PR after 3-5 cycles 0.30 (0.13-0.65) 0.002** 0.25 (0.12-0.53) < 0.001***
Abbreviations: UNL; upper normal limit, PR; partial response
*P < 0.05, **P < 0.01, ***P < 0.001
Furthermore, we performed multivariable analyses of OS and PFS with the Cox proportional hazards model to control confounding factors. Response to MTX-HOPE better than PR after three to five cycles was treated as a time-dependent covariate.23 Each analysis was evaluated by adding age (≥75), IPI (≥3), and lymphoma histology (B cell lymphoma or T cell lymphoma) to the independent factors (Table 5). The final models for OS and PFS included Ki-67 positivity (≥ 50%) (HR 2.42, 95% CI 1.15-5.09, P = 0.020 and HR 2.10, 95% CI 1.04-4.25, P = 0.039).
Table 5 Multivariate analysis of overall survival (OS) and progression-free survival (PFS) with the Cox proportional hazards model. Response to the MTX-HOPE regimen better than partial response after three to five cycles was treated as a time-dependent covariate.
Variable Hazard ratio (95% CI) p-value
Overall survival
Ki-67 (≥50%) 2.42 (1.15-5.09) 0.020*
Progression-free survival
Ki-67 (≥50%) 2.10 (1.04-4.25) 0.039*
Age (≥75), B cell lymphoma or T cell lymphoma, and International Prognostic Index (≥3) were also added to the OS and PFS analyses. The final models with significant differences are shown in the table.
DISCUSSION
In the present study, we analyzed the safety and efficacy of MTX-HOPE for aged r/r NHL patients who are vulnerable and were not eligible for autologous stem cell transplantation (ASCT) and conventional high-dose salvage chemotherapy. Our results showed that the MTX-HOPE regimen is effective and tolerable for these r/r NHL patients. High Ki-67 positivity was extracted as an independent factor of OS and PFS by multivariable analyses using response to MTX-HOPE treatment as a time-dependent covariate. In addition, most patients who receive MTX-HOPE can be treated without hospitalization.
Ki-67 is one of the cell cycle related protein and strongly associated with the lymphoma cell proliferation, leading to lymphoma progression. High Ki-67 positivity is also related to poor prognosis within the same lymphoma subtypes, such as DLBCL and FL.24-26 Our results suggest that MTX-HOPE is less effective for the highly Ki-67 positive lymphoma patients. Because there were a few patients other than DLBCL in our study, further study is needed to confirm these results.
In this study, the patients who received MTX-HOPE therapy were elderly individuals and had worse PS scores. Because these patients had some comorbidities, such as renal dysfunction and anemia, they could not receive other intensive salvage treatments. The overall response rate (ORR) of MTX-HOPE was 45.2%. The rate of treatment responsiveness above SD was 76.2%, and treatment response was observed in many cases. The median OS was 7 months, the 1-year OS was 43.7%, and the 2-year OS was 40.8%. Some patients achieved long-term survival. Moreover, MTX-HOPE therapy resulted in no treatment-related deaths and the acceptable rate of treatment discontinuation events. According to the SCHOLAR-1 study of relapsed DLBCL (the largest, patient-level pooled analysis), the median OS was 6.3 months, and the 2-year OS was 20%.27 Given our target frail population, these results indicate that MTX-HOPE therapy is tolerable and effective. Although there were several side effects of MTX-HOPE therapy worse than grade 3, these were temporary and recoverable. Appropriate supportive care, including blood transfusion and G-CSF, is generally important for elderly patients to continue chemotherapy.
Furthermore, most patients treated with MTX-HOPE were able to continue without hospitalization, leading to a great advantage in medical costs. Previous reports have shown that the medical costs of aggressive NHL are estimated at $5,871 per patient per month (PPPM) for the first two years of treatment,28 and those for elderly patients with r/r DLBCL are more than $97,000 per year.29 In addition, the costs of patients for febrile neutropenia (FN) are more expensive.30 In our study, the average medical cost of MTX-HOPE calculated by the medical claims data was ¥94,297/month. These data revealed that MTX-HOPE is a cost-effective regimen. Multivariable analysis with the Cox proportional hazards model revealed Ki-67 positivity in pathology and PR to the MTX-HOPE regimen as independent factors for OS and PFS. These results are useful for the indication of MTX-HOPE therapy.
There are some limitations in this study. First, although the response to MTX-HOPE was evaluated based on the International Workshop Response Criteria (IWRC), the evaluations were not conducted at fixed cycles. Therefore, there were differences in the response evaluation periods among MTX-HOPE patients. Last, this was a single-center, single-arm study. A prospective controlled trial with other salvage regimens may be needed to confirm the safety and effectiveness of MTX-HOPE therapy.
In conclusion, the MTX-HOPE regimen is safe and effective for r/r NHL patients. Pathologically high Ki-67 positivity was identified as an independent factor for MTX-HOPE treatment. The advantage of the MTX-HOPE regimen is that it contributes to maintaining quality of life (QOL) without hospitalization. Our results may help in considering the indications for MTX-HOPE. We concluded that MTX-HOPE is an attractive salvage regimen for aged patients or those with non-aggressive r/r NHL. To validate this regimen, further prospective studies are needed.
ACKNOWLEDGMENTS
We would like to express our special thanks to Dr. Yasuhiko Kano, who retired from the Tochigi Cancer Center (Utsunomiya, Japan). He developed the principle of MTX-HOPE therapy through a series of in vitro experiments with combination chemotherapy.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest (COIs). | Oral | DrugAdministrationRoute | CC BY-NC-SA | 33551437 | 19,429,767 | 2021-03-18 |
What was the administration route of drug 'SOBUZOXANE'? | MTX-HOPE is a low-dose salvage chemotherapy for aged patients with relapsed or refractory non-Hodgkin lymphoma.
As the aging society advances, the number of non-Hodgkin lymphoma (NHL) patients is increasing. Aged relapsed or refractory (r/r) NHL patients have limited treatment options. Therefore, a safe and effective regimen is urgently needed for these patients. Thus, we originally developed the MTX-HOPE (methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide) regimen for r/r NHL and validated the safety and efficacy of this regimen in a clinical setting. We analyzed the data of 42 r/r NHL patients who received MTX-HOPE in this single-center retrospective cohort study. The median age of the patients was 81 years. The overall response rate was 45.3%. The median overall survival (OS) was 7 months, the one-year OS was 43.7%, and the two-year OS was 40.8%. Grade ≥3 neutropenia and renal dysfunction were observed in 47.6% and 11.9% of patients, respectively, and treatment-related death were not observed. Appropriate supportive care enabled these patients to continue the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Multivariable analyses with the Cox proportional hazards model revealed that both OS and progression-free survival (PFS) were significantly influenced by high Ki-67 expression in pathology, with response to the MTX-HOPE regimen after three to five cycles as a time-dependent covariate. Our results suggest that MTX-HOPE therapy can be an option for non-aggressive r/r NHL patients. To validate MTX-HOPE therapy, further prospective investigation is needed.
INTRODUCTION
The aged population is increasing, particularly in advanced countries. As this population advances, the incidence of cancers, including malignant lymphoma, is rising.1-3 Because cancer can be considered an age-related disease, it is an urgent task to take measures for elderly patients with cancer in advanced countries.4 Because most vulnerable older adult patients cannot be enrolled in clinical trials, there are few data regarding the management of aged cancer patients, including those with lymphoma. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)/CHOP (CHOP) therapy is the gold standard regimen for elderly non-Hodgkin lymphoma (NHL) patients.5-8 However, even if complete response (CR) is reached with initial treatment, 20-50% of patients with diffuse large B cell lymphoma (DLBCL) experience relapse,9 and there are few therapeutic options, especially for aged patients with relapsed NHL.
Thus, it is unclear whether aged relapsed or refractory (r/r) NHL patients are suitable for certain therapeutic strategies. Aged patients with some comorbidities cannot receive sufficient intensity salvage chemotherapies in the clinic. We thus developed a combination salvage therapy for r/r NHL based on isobologram analysis data for these vulnerable patients.10-16 We selected methotrexate (MTX), hydrocortisone (HC), vincristine (VCR), sobuzoxane (MST-16), and etoposide (ETP) and named this regimen MTX-HOPE (Table 1).17 This regimen has the advantage of being performed on an outpatient basis. We previously reported the safety and efficacy of the MTX-HOPE regimen in a small number of NHL patients. In a previous study, the median age of the patients was 70 years, and the median overall survival (OS) was 11.1 months. In addition, another group recently reported the efficacy of the MTX-HOPE regimen, and the median OS and progression-free survival (PFS) were 10 months and 7 months, respectively.18 However, the characteristics of NHL patients who are more likely to respond to MTX-HOPE therapy are still unknown. We need to identify patients suitable for this regimen from the perspective of safety and effectiveness. Thus, we performed a single-center retrospective cohort study to validate the MTX-HOPE regimen.
Table 1 The protocol of MTX-HOPE
Agent Dose/day Route Days
Methotrexate (MTX) 20 mg po 1
Hydrocortisone (HC) 100 mg div (15min) 2
Vincristine (VCR) 1 mg div (15min) 2
Sobuzoxane (MST-16) 400 mg po 3, 4
Etoposide (ETP) 25 mg po 3, 4
Abbreviations: MTX-HOPE, methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide; po, per os; div, intravenous drip
MATERIALS AND METHODS
Study design and patients
This study was conducted as a single-center retrospective cohort study. A total of 42 patients who received MTX-HOPE therapy agreed to participate in this study, which was approved by the local Ethics Committee of Aizu Medical Center of Fukushima Medical University (FMU) and carried out in accordance with the relevant guidelines and regulations. Written informed consent was obtained from all subjects prior to enrollment. We obtained patient characteristics and laboratory data from the clinical records of all patients diagnosed with NHL, including DLBCL, mantle cell lymphoma (MCL), peripheral T cell lymphoma (PTCL), and others, from 2009 to 2020.
Treatment protocol
The MTX-HOPE regimen was repeated every 2-3 weeks and involved the administration of MTX (20 mg) orally on day 1, HC (100 mg) and VCR (1 mg) infusion on day 2, and MST-16 (400 mg) and ETP (25 mg) orally on days 3 and 4 (Table 1). Granulocyte colony-stimulating factor (G-CSF) was administered to patients who experienced neutropenia as supportive therapy.
Treatment response and toxicity criteria
Efficacy assessments were performed according to the international consensus on the revised response criteria for malignant lymphoma. According to these criteria, we defined therapy responses as follows: complete response (CR), unconfirmed CR (uCR), partial response (PR), stable disease (SD), and progressive disease (PD). Physical examination and laboratory tests were used to evaluate adverse reactions and toxicities. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, Version 4.0.
Statistical analysis
All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of the R commander designed to add statistical functions frequently used in biostatistics.19 The Kolmogorov-Smirnov test was used to analyze the normality of the distribution of parameters.20,21 All variables with a normal distribution are expressed as the mean ± standard deviation, and those with a log-normal distribution are expressed as the median with the interquartile range (IQR). OS was defined as the time from the start of MTX-HOPE therapy to death or the date of the last follow-up.22 PFS was defined as the time from the start of MTX-HOPE therapy to relapse, death, or the date of the last follow-up. The OS and PFS rates were estimated according to the Kaplan-Meier method and compared by the log-rank test.19,22 The hazard ratios (HRs) and their associated 95% confidence intervals (CIs) for potential prognostic factors were calculated using the Cox proportional hazards regression model. Variables with p < 0.10 in the univariate analysis were used as independent variables in the multivariate analysis.23 All statistical tests were two-sided, and a significance level of 0.05 was used.
RESULTS
Patient characteristics
The median age of the 42 patients who received MTX-HOPE therapy for r/r NHL in this study was 81 years (range, 57 to 90 years), and 35.7% were women (Table 2). In our study, seven patients (16.7%) who received the MTX-HOPE regimen were less than 70 years old. Six patients had a history of multiple pretreatment regimens, and the other patient had severe pulmonary disease and poor performance status (PS). These patients had no indication for intensive chemotherapy and agreed to receive the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Twenty-five patients were refractory to previous treatment, and 17 had relapsed disease. The proportion of patients with worse Eastern Cooperative Oncology Group (ECOG) PS scores (more than 2) was 59.5%, the proportion of patients with anemia (hemoglobin less than 10 g/dL) was 42.9%, and the proportion of patients with lactate dehydrogenase (LDH) levels greater than the upper limit of normal was 54.8%. At the time of diagnosis, the proportion of patients with intermediate- and high-risk International Prognostic Index (IPI) scores was 92.9%, and the proportion of patients with advanced stage (stage III and IV) disease was 85.6%. The lymphoma histology of the patients included 28 DLBCL, one follicular lymphoma (FL), one MCL, 11 T cell lymphoma, and one extranodal NK/T cell lymphoma. In addition, the proportion of patients with Ki-67 positivity greater than 50% by immunohistochemistry (IHC) was 36%. Furthermore, the MTX-HOPE regimen was given to patients as salvage therapy. We assessed the response to MTX-HOPE after three to five cycles by computed tomography (CT). The percentage of patients who achieved CR or unconfirmed CR was 19%, PR was 26.2%, SD was 31%, and PD was 23.8% at that time.
Table 2 Patient characteristics
Characteristics patients MTX-HOPE
Patients, n 42
Hospitalization during MTX-HOPE administration 9 (21)
At the start of treatment
Age, median [min, max] 81 [57, 90]
Women, n (%) 15 (36)
Performance status, n (%)
0-1 17 (41)
2-4 25 (60)
Status before MTX-HOPE treatment, n (%)
Relapsed 17 (41)
Refractory 25 (60)
Number of pretreatment regimens, n (%)
1 31(74)
2 3 (7.1)
≥3 8 (19)
Pretreatment regimen, n (%)
CHOP +/-R 28 (67)
DeVIC +/-R 5 (12)
GDP +/-R 3 (7.1)
Other 6 (14)
Previous treatment history of rituximab, n (%) 29 (69)
Histology, n (%)
B cell lymphoma 30 (71)
DLBCL 28 (67)
FL 1 (2.4)
MCL 1 (2.4)
T cell lymphoma 11 (26)
Extranodal NK/T cell lymphoma 1 (2.4)
Anemia (Hb <10), n (%) 18 (43)
CKD, n (%) 16 (38)
LDH high (≥upper normal limit; 240) 23 (55)
BMI (<20 kg/m2), n (%) 15 (36)
At diagnosis
IPI, n(%)
Low risk 3(7.1)
Intermediate risk 16 (38)
High risk 23 (55)
Stage, n(%)
I 4 (9.5)
II 2 (4.8)
III 9 (21)
IV 27 (64)
Bone marrow involvement, n (%) 12 (29)
Extranodal lesion, n (%) 33 (79)
B symptoms present, n (%) 12 (29)
Ki-67 high (≥50%), n(%) 15 (36)
DLBCL 12 (29)
MCL 1 (2.4)
T cell lymphoma 2 (4.8)
Response after 3 to 5 cycles, n (%)
Complete response (CR)/unconfirmed CR 8 (19)
Partial response (PR) 11 (26)
Stable disease (SD) 13 (31)
Progressive disease (PD) 10 (24)
Abbreviations: DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; CKD, chronic kidney disease
Safety of MTX-HOPE
The hematological and nonhematological toxicities of MTX-HOPE are shown in Table 3. Grade 3 and 4 neutropenia were observed in 47.6% of the patients, and febrile neutropenia was observed in 9.5%. Grade 3 and 4 anemia and thrombocytopenia were observed in 35.7% and 14.3% of the patients, respectively. Severe nonhematological toxicities, such as liver damage, renal dysfunction, nausea, vomiting, and infection, were infrequent in patients treated with MTX-HOPE therapy. Seventeen patients temporarily discontinued VCR due to grade 1 neuropathy in our study. However, most patients could continue VCR while administered vitamin B12 and pregabalin. The other drugs did not need to be reduced. Furthermore, there were no treatment-related deaths. However, there were six treatment discontinuation events: four pneumonia, one sepsis and one acute kidney injury (Table 3).
Table 3 Adverse effects of MTX-HOPE therapy
Hematological toxicity All Grades Grade ≥3
Neutropenia n, (%) 33 (79) 20 (48)
Febrile neutropenia n, (%) - 4 (9.5)
Anemia n, (%) 39 (93) 15 (36)
Thrombocytopenia n, (%) 30 (71) 6 (14)
Nonhematological toxicity
Liver damage 10 (24) 2 (4.8)
Renal dysfunction 24 (57) 5 (12)
Nausea 8 (19) 0 (0)
Vomiting 1 (2.4) 0 (0)
Infection 10 (24) 3 (7.1)
Neuropathy 17 (40) 0 (0)
Hematological supportive care
Red blood cell transfusion 13 (30.9)
Platelet transfusion 4 (9.5)
G-CSF 24 (57.1)
Treatment-related deaths 0 (0)
Treatment discontinuation events 6 (14)
Pneumonia 4 (9.5)
Sepsis 1 (2.4)
Acute kidney injury 1 (2.4)
Survival analysis
The median follow-up duration of the survivors was 213 days (range, 12-2763). The median OS was 7 months (range, 0-91) (Figure 1a), and the median PFS was 3.5 months (range, 0-91) (Figure 1b). Next, we performed univariate analysis to identify the independent factors for OS and PFS by univariate analyses (Table 4). OS was significantly influenced by Ki-67 positivity in pathology (≥50%) (P = 0.020) and PR to the MTX-HOPE regimen after three to five cycles (P = 0.002) (Figure 1c). PFS was also significantly influenced by Ki-67 positivity in pathology (≥50%) (P = 0.039) and PR to the MTX-HOPE regimen after three to five cycles (P < 0.001) (Figure 1d). IPI, lymphoma status (r/r), lymphoma histology (B cell lymphoma or T cell lymphoma), and other factors did not influence OS or PFS.
Fig. 1 Kaplan-Meier estimates. (a) Overall survival (OS) and (b) progression-free survival (PFS) of all patients who received MTX-HOPE therapy. (c) OS and (d) PFS stratified by the response to MTX-HOPE therapy after three to five cycles.
Table 4 Univariate analysis of overall survival and progression-free survival
Variable Overall survival Progression-free survival
Hazard ratio (95%CI) p-value Hazard ratio (95%CI) p-value
Age ≥ 75 1.11 (0.51-2.41) 0.79 1.23 (0.59-2.53) 0.58
Sex (female) 0.89 (0.42-1.92) 0.77 0.82 (0.40-1.65) 0.58
BMI ≥ 20 kg/m2 0.64 (0.29-1.43) 0.28 0.73 (0.35-1.54) 0.41
Hb > 10 0.61 (0.29-1.31) 0.20 0.97 (0.48-1.98) 0.94
eGFR > 60 0.75 (0.36-1.58) 0.45 0.75 (0.37-1.51) 0.42
Number of pretreatment regimens ≥ 2 1.37 (0.63-3.00) 0.43 1.44 (0.70-2.97) 0.32
IPI ≥ 3 0.69 (0.29-1.63) 0.39 1.02 (0.44-2.36) 0.96
Stage ≥ III 0.63 (0.26-1.56) 0.32 0.97 (0.40-2.35) 0.94
PS ≥ 2 1.22 (0.58-2.55) 0.61 1.22 (0.62-2.40) 0.57
Extra nodal lesion 1.30 (0.52-3.25) 0.57 1.54 (0.63-3.80) 0.34
LDH (>UNL) 1.65 (0.79-3.45) 0.18 1.36 (0.69-2.66) 0.38
Bone marrow involvement 0.74 (0.32-1.70) 0.48 0.90 (0.44-1.85) 0.78
B symptoms 0.89 (0.39-2.00) 0.77 0.89 (0.43-1.87) 0.77
Relapsed status 0.50 (0.23-1.09) 0.082 0.78 (0.38-1.58) 0.48
T-cell lymphoma histology 0.58 (0.25-1.37) 0.22 0.63 (0.29-1.35) 0.24
Ki-67 ≥50% 2.42 (1.15-5.09) 0.020* 2.10 (1.04-4.25) 0.039*
Response of PR after 3-5 cycles 0.30 (0.13-0.65) 0.002** 0.25 (0.12-0.53) < 0.001***
Abbreviations: UNL; upper normal limit, PR; partial response
*P < 0.05, **P < 0.01, ***P < 0.001
Furthermore, we performed multivariable analyses of OS and PFS with the Cox proportional hazards model to control confounding factors. Response to MTX-HOPE better than PR after three to five cycles was treated as a time-dependent covariate.23 Each analysis was evaluated by adding age (≥75), IPI (≥3), and lymphoma histology (B cell lymphoma or T cell lymphoma) to the independent factors (Table 5). The final models for OS and PFS included Ki-67 positivity (≥ 50%) (HR 2.42, 95% CI 1.15-5.09, P = 0.020 and HR 2.10, 95% CI 1.04-4.25, P = 0.039).
Table 5 Multivariate analysis of overall survival (OS) and progression-free survival (PFS) with the Cox proportional hazards model. Response to the MTX-HOPE regimen better than partial response after three to five cycles was treated as a time-dependent covariate.
Variable Hazard ratio (95% CI) p-value
Overall survival
Ki-67 (≥50%) 2.42 (1.15-5.09) 0.020*
Progression-free survival
Ki-67 (≥50%) 2.10 (1.04-4.25) 0.039*
Age (≥75), B cell lymphoma or T cell lymphoma, and International Prognostic Index (≥3) were also added to the OS and PFS analyses. The final models with significant differences are shown in the table.
DISCUSSION
In the present study, we analyzed the safety and efficacy of MTX-HOPE for aged r/r NHL patients who are vulnerable and were not eligible for autologous stem cell transplantation (ASCT) and conventional high-dose salvage chemotherapy. Our results showed that the MTX-HOPE regimen is effective and tolerable for these r/r NHL patients. High Ki-67 positivity was extracted as an independent factor of OS and PFS by multivariable analyses using response to MTX-HOPE treatment as a time-dependent covariate. In addition, most patients who receive MTX-HOPE can be treated without hospitalization.
Ki-67 is one of the cell cycle related protein and strongly associated with the lymphoma cell proliferation, leading to lymphoma progression. High Ki-67 positivity is also related to poor prognosis within the same lymphoma subtypes, such as DLBCL and FL.24-26 Our results suggest that MTX-HOPE is less effective for the highly Ki-67 positive lymphoma patients. Because there were a few patients other than DLBCL in our study, further study is needed to confirm these results.
In this study, the patients who received MTX-HOPE therapy were elderly individuals and had worse PS scores. Because these patients had some comorbidities, such as renal dysfunction and anemia, they could not receive other intensive salvage treatments. The overall response rate (ORR) of MTX-HOPE was 45.2%. The rate of treatment responsiveness above SD was 76.2%, and treatment response was observed in many cases. The median OS was 7 months, the 1-year OS was 43.7%, and the 2-year OS was 40.8%. Some patients achieved long-term survival. Moreover, MTX-HOPE therapy resulted in no treatment-related deaths and the acceptable rate of treatment discontinuation events. According to the SCHOLAR-1 study of relapsed DLBCL (the largest, patient-level pooled analysis), the median OS was 6.3 months, and the 2-year OS was 20%.27 Given our target frail population, these results indicate that MTX-HOPE therapy is tolerable and effective. Although there were several side effects of MTX-HOPE therapy worse than grade 3, these were temporary and recoverable. Appropriate supportive care, including blood transfusion and G-CSF, is generally important for elderly patients to continue chemotherapy.
Furthermore, most patients treated with MTX-HOPE were able to continue without hospitalization, leading to a great advantage in medical costs. Previous reports have shown that the medical costs of aggressive NHL are estimated at $5,871 per patient per month (PPPM) for the first two years of treatment,28 and those for elderly patients with r/r DLBCL are more than $97,000 per year.29 In addition, the costs of patients for febrile neutropenia (FN) are more expensive.30 In our study, the average medical cost of MTX-HOPE calculated by the medical claims data was ¥94,297/month. These data revealed that MTX-HOPE is a cost-effective regimen. Multivariable analysis with the Cox proportional hazards model revealed Ki-67 positivity in pathology and PR to the MTX-HOPE regimen as independent factors for OS and PFS. These results are useful for the indication of MTX-HOPE therapy.
There are some limitations in this study. First, although the response to MTX-HOPE was evaluated based on the International Workshop Response Criteria (IWRC), the evaluations were not conducted at fixed cycles. Therefore, there were differences in the response evaluation periods among MTX-HOPE patients. Last, this was a single-center, single-arm study. A prospective controlled trial with other salvage regimens may be needed to confirm the safety and effectiveness of MTX-HOPE therapy.
In conclusion, the MTX-HOPE regimen is safe and effective for r/r NHL patients. Pathologically high Ki-67 positivity was identified as an independent factor for MTX-HOPE treatment. The advantage of the MTX-HOPE regimen is that it contributes to maintaining quality of life (QOL) without hospitalization. Our results may help in considering the indications for MTX-HOPE. We concluded that MTX-HOPE is an attractive salvage regimen for aged patients or those with non-aggressive r/r NHL. To validate this regimen, further prospective studies are needed.
ACKNOWLEDGMENTS
We would like to express our special thanks to Dr. Yasuhiko Kano, who retired from the Tochigi Cancer Center (Utsunomiya, Japan). He developed the principle of MTX-HOPE therapy through a series of in vitro experiments with combination chemotherapy.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest (COIs). | Oral | DrugAdministrationRoute | CC BY-NC-SA | 33551437 | 19,429,767 | 2021-03-18 |
What was the administration route of drug 'VINCRISTINE'? | MTX-HOPE is a low-dose salvage chemotherapy for aged patients with relapsed or refractory non-Hodgkin lymphoma.
As the aging society advances, the number of non-Hodgkin lymphoma (NHL) patients is increasing. Aged relapsed or refractory (r/r) NHL patients have limited treatment options. Therefore, a safe and effective regimen is urgently needed for these patients. Thus, we originally developed the MTX-HOPE (methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide) regimen for r/r NHL and validated the safety and efficacy of this regimen in a clinical setting. We analyzed the data of 42 r/r NHL patients who received MTX-HOPE in this single-center retrospective cohort study. The median age of the patients was 81 years. The overall response rate was 45.3%. The median overall survival (OS) was 7 months, the one-year OS was 43.7%, and the two-year OS was 40.8%. Grade ≥3 neutropenia and renal dysfunction were observed in 47.6% and 11.9% of patients, respectively, and treatment-related death were not observed. Appropriate supportive care enabled these patients to continue the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Multivariable analyses with the Cox proportional hazards model revealed that both OS and progression-free survival (PFS) were significantly influenced by high Ki-67 expression in pathology, with response to the MTX-HOPE regimen after three to five cycles as a time-dependent covariate. Our results suggest that MTX-HOPE therapy can be an option for non-aggressive r/r NHL patients. To validate MTX-HOPE therapy, further prospective investigation is needed.
INTRODUCTION
The aged population is increasing, particularly in advanced countries. As this population advances, the incidence of cancers, including malignant lymphoma, is rising.1-3 Because cancer can be considered an age-related disease, it is an urgent task to take measures for elderly patients with cancer in advanced countries.4 Because most vulnerable older adult patients cannot be enrolled in clinical trials, there are few data regarding the management of aged cancer patients, including those with lymphoma. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)/CHOP (CHOP) therapy is the gold standard regimen for elderly non-Hodgkin lymphoma (NHL) patients.5-8 However, even if complete response (CR) is reached with initial treatment, 20-50% of patients with diffuse large B cell lymphoma (DLBCL) experience relapse,9 and there are few therapeutic options, especially for aged patients with relapsed NHL.
Thus, it is unclear whether aged relapsed or refractory (r/r) NHL patients are suitable for certain therapeutic strategies. Aged patients with some comorbidities cannot receive sufficient intensity salvage chemotherapies in the clinic. We thus developed a combination salvage therapy for r/r NHL based on isobologram analysis data for these vulnerable patients.10-16 We selected methotrexate (MTX), hydrocortisone (HC), vincristine (VCR), sobuzoxane (MST-16), and etoposide (ETP) and named this regimen MTX-HOPE (Table 1).17 This regimen has the advantage of being performed on an outpatient basis. We previously reported the safety and efficacy of the MTX-HOPE regimen in a small number of NHL patients. In a previous study, the median age of the patients was 70 years, and the median overall survival (OS) was 11.1 months. In addition, another group recently reported the efficacy of the MTX-HOPE regimen, and the median OS and progression-free survival (PFS) were 10 months and 7 months, respectively.18 However, the characteristics of NHL patients who are more likely to respond to MTX-HOPE therapy are still unknown. We need to identify patients suitable for this regimen from the perspective of safety and effectiveness. Thus, we performed a single-center retrospective cohort study to validate the MTX-HOPE regimen.
Table 1 The protocol of MTX-HOPE
Agent Dose/day Route Days
Methotrexate (MTX) 20 mg po 1
Hydrocortisone (HC) 100 mg div (15min) 2
Vincristine (VCR) 1 mg div (15min) 2
Sobuzoxane (MST-16) 400 mg po 3, 4
Etoposide (ETP) 25 mg po 3, 4
Abbreviations: MTX-HOPE, methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide; po, per os; div, intravenous drip
MATERIALS AND METHODS
Study design and patients
This study was conducted as a single-center retrospective cohort study. A total of 42 patients who received MTX-HOPE therapy agreed to participate in this study, which was approved by the local Ethics Committee of Aizu Medical Center of Fukushima Medical University (FMU) and carried out in accordance with the relevant guidelines and regulations. Written informed consent was obtained from all subjects prior to enrollment. We obtained patient characteristics and laboratory data from the clinical records of all patients diagnosed with NHL, including DLBCL, mantle cell lymphoma (MCL), peripheral T cell lymphoma (PTCL), and others, from 2009 to 2020.
Treatment protocol
The MTX-HOPE regimen was repeated every 2-3 weeks and involved the administration of MTX (20 mg) orally on day 1, HC (100 mg) and VCR (1 mg) infusion on day 2, and MST-16 (400 mg) and ETP (25 mg) orally on days 3 and 4 (Table 1). Granulocyte colony-stimulating factor (G-CSF) was administered to patients who experienced neutropenia as supportive therapy.
Treatment response and toxicity criteria
Efficacy assessments were performed according to the international consensus on the revised response criteria for malignant lymphoma. According to these criteria, we defined therapy responses as follows: complete response (CR), unconfirmed CR (uCR), partial response (PR), stable disease (SD), and progressive disease (PD). Physical examination and laboratory tests were used to evaluate adverse reactions and toxicities. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, Version 4.0.
Statistical analysis
All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of the R commander designed to add statistical functions frequently used in biostatistics.19 The Kolmogorov-Smirnov test was used to analyze the normality of the distribution of parameters.20,21 All variables with a normal distribution are expressed as the mean ± standard deviation, and those with a log-normal distribution are expressed as the median with the interquartile range (IQR). OS was defined as the time from the start of MTX-HOPE therapy to death or the date of the last follow-up.22 PFS was defined as the time from the start of MTX-HOPE therapy to relapse, death, or the date of the last follow-up. The OS and PFS rates were estimated according to the Kaplan-Meier method and compared by the log-rank test.19,22 The hazard ratios (HRs) and their associated 95% confidence intervals (CIs) for potential prognostic factors were calculated using the Cox proportional hazards regression model. Variables with p < 0.10 in the univariate analysis were used as independent variables in the multivariate analysis.23 All statistical tests were two-sided, and a significance level of 0.05 was used.
RESULTS
Patient characteristics
The median age of the 42 patients who received MTX-HOPE therapy for r/r NHL in this study was 81 years (range, 57 to 90 years), and 35.7% were women (Table 2). In our study, seven patients (16.7%) who received the MTX-HOPE regimen were less than 70 years old. Six patients had a history of multiple pretreatment regimens, and the other patient had severe pulmonary disease and poor performance status (PS). These patients had no indication for intensive chemotherapy and agreed to receive the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Twenty-five patients were refractory to previous treatment, and 17 had relapsed disease. The proportion of patients with worse Eastern Cooperative Oncology Group (ECOG) PS scores (more than 2) was 59.5%, the proportion of patients with anemia (hemoglobin less than 10 g/dL) was 42.9%, and the proportion of patients with lactate dehydrogenase (LDH) levels greater than the upper limit of normal was 54.8%. At the time of diagnosis, the proportion of patients with intermediate- and high-risk International Prognostic Index (IPI) scores was 92.9%, and the proportion of patients with advanced stage (stage III and IV) disease was 85.6%. The lymphoma histology of the patients included 28 DLBCL, one follicular lymphoma (FL), one MCL, 11 T cell lymphoma, and one extranodal NK/T cell lymphoma. In addition, the proportion of patients with Ki-67 positivity greater than 50% by immunohistochemistry (IHC) was 36%. Furthermore, the MTX-HOPE regimen was given to patients as salvage therapy. We assessed the response to MTX-HOPE after three to five cycles by computed tomography (CT). The percentage of patients who achieved CR or unconfirmed CR was 19%, PR was 26.2%, SD was 31%, and PD was 23.8% at that time.
Table 2 Patient characteristics
Characteristics patients MTX-HOPE
Patients, n 42
Hospitalization during MTX-HOPE administration 9 (21)
At the start of treatment
Age, median [min, max] 81 [57, 90]
Women, n (%) 15 (36)
Performance status, n (%)
0-1 17 (41)
2-4 25 (60)
Status before MTX-HOPE treatment, n (%)
Relapsed 17 (41)
Refractory 25 (60)
Number of pretreatment regimens, n (%)
1 31(74)
2 3 (7.1)
≥3 8 (19)
Pretreatment regimen, n (%)
CHOP +/-R 28 (67)
DeVIC +/-R 5 (12)
GDP +/-R 3 (7.1)
Other 6 (14)
Previous treatment history of rituximab, n (%) 29 (69)
Histology, n (%)
B cell lymphoma 30 (71)
DLBCL 28 (67)
FL 1 (2.4)
MCL 1 (2.4)
T cell lymphoma 11 (26)
Extranodal NK/T cell lymphoma 1 (2.4)
Anemia (Hb <10), n (%) 18 (43)
CKD, n (%) 16 (38)
LDH high (≥upper normal limit; 240) 23 (55)
BMI (<20 kg/m2), n (%) 15 (36)
At diagnosis
IPI, n(%)
Low risk 3(7.1)
Intermediate risk 16 (38)
High risk 23 (55)
Stage, n(%)
I 4 (9.5)
II 2 (4.8)
III 9 (21)
IV 27 (64)
Bone marrow involvement, n (%) 12 (29)
Extranodal lesion, n (%) 33 (79)
B symptoms present, n (%) 12 (29)
Ki-67 high (≥50%), n(%) 15 (36)
DLBCL 12 (29)
MCL 1 (2.4)
T cell lymphoma 2 (4.8)
Response after 3 to 5 cycles, n (%)
Complete response (CR)/unconfirmed CR 8 (19)
Partial response (PR) 11 (26)
Stable disease (SD) 13 (31)
Progressive disease (PD) 10 (24)
Abbreviations: DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; CKD, chronic kidney disease
Safety of MTX-HOPE
The hematological and nonhematological toxicities of MTX-HOPE are shown in Table 3. Grade 3 and 4 neutropenia were observed in 47.6% of the patients, and febrile neutropenia was observed in 9.5%. Grade 3 and 4 anemia and thrombocytopenia were observed in 35.7% and 14.3% of the patients, respectively. Severe nonhematological toxicities, such as liver damage, renal dysfunction, nausea, vomiting, and infection, were infrequent in patients treated with MTX-HOPE therapy. Seventeen patients temporarily discontinued VCR due to grade 1 neuropathy in our study. However, most patients could continue VCR while administered vitamin B12 and pregabalin. The other drugs did not need to be reduced. Furthermore, there were no treatment-related deaths. However, there were six treatment discontinuation events: four pneumonia, one sepsis and one acute kidney injury (Table 3).
Table 3 Adverse effects of MTX-HOPE therapy
Hematological toxicity All Grades Grade ≥3
Neutropenia n, (%) 33 (79) 20 (48)
Febrile neutropenia n, (%) - 4 (9.5)
Anemia n, (%) 39 (93) 15 (36)
Thrombocytopenia n, (%) 30 (71) 6 (14)
Nonhematological toxicity
Liver damage 10 (24) 2 (4.8)
Renal dysfunction 24 (57) 5 (12)
Nausea 8 (19) 0 (0)
Vomiting 1 (2.4) 0 (0)
Infection 10 (24) 3 (7.1)
Neuropathy 17 (40) 0 (0)
Hematological supportive care
Red blood cell transfusion 13 (30.9)
Platelet transfusion 4 (9.5)
G-CSF 24 (57.1)
Treatment-related deaths 0 (0)
Treatment discontinuation events 6 (14)
Pneumonia 4 (9.5)
Sepsis 1 (2.4)
Acute kidney injury 1 (2.4)
Survival analysis
The median follow-up duration of the survivors was 213 days (range, 12-2763). The median OS was 7 months (range, 0-91) (Figure 1a), and the median PFS was 3.5 months (range, 0-91) (Figure 1b). Next, we performed univariate analysis to identify the independent factors for OS and PFS by univariate analyses (Table 4). OS was significantly influenced by Ki-67 positivity in pathology (≥50%) (P = 0.020) and PR to the MTX-HOPE regimen after three to five cycles (P = 0.002) (Figure 1c). PFS was also significantly influenced by Ki-67 positivity in pathology (≥50%) (P = 0.039) and PR to the MTX-HOPE regimen after three to five cycles (P < 0.001) (Figure 1d). IPI, lymphoma status (r/r), lymphoma histology (B cell lymphoma or T cell lymphoma), and other factors did not influence OS or PFS.
Fig. 1 Kaplan-Meier estimates. (a) Overall survival (OS) and (b) progression-free survival (PFS) of all patients who received MTX-HOPE therapy. (c) OS and (d) PFS stratified by the response to MTX-HOPE therapy after three to five cycles.
Table 4 Univariate analysis of overall survival and progression-free survival
Variable Overall survival Progression-free survival
Hazard ratio (95%CI) p-value Hazard ratio (95%CI) p-value
Age ≥ 75 1.11 (0.51-2.41) 0.79 1.23 (0.59-2.53) 0.58
Sex (female) 0.89 (0.42-1.92) 0.77 0.82 (0.40-1.65) 0.58
BMI ≥ 20 kg/m2 0.64 (0.29-1.43) 0.28 0.73 (0.35-1.54) 0.41
Hb > 10 0.61 (0.29-1.31) 0.20 0.97 (0.48-1.98) 0.94
eGFR > 60 0.75 (0.36-1.58) 0.45 0.75 (0.37-1.51) 0.42
Number of pretreatment regimens ≥ 2 1.37 (0.63-3.00) 0.43 1.44 (0.70-2.97) 0.32
IPI ≥ 3 0.69 (0.29-1.63) 0.39 1.02 (0.44-2.36) 0.96
Stage ≥ III 0.63 (0.26-1.56) 0.32 0.97 (0.40-2.35) 0.94
PS ≥ 2 1.22 (0.58-2.55) 0.61 1.22 (0.62-2.40) 0.57
Extra nodal lesion 1.30 (0.52-3.25) 0.57 1.54 (0.63-3.80) 0.34
LDH (>UNL) 1.65 (0.79-3.45) 0.18 1.36 (0.69-2.66) 0.38
Bone marrow involvement 0.74 (0.32-1.70) 0.48 0.90 (0.44-1.85) 0.78
B symptoms 0.89 (0.39-2.00) 0.77 0.89 (0.43-1.87) 0.77
Relapsed status 0.50 (0.23-1.09) 0.082 0.78 (0.38-1.58) 0.48
T-cell lymphoma histology 0.58 (0.25-1.37) 0.22 0.63 (0.29-1.35) 0.24
Ki-67 ≥50% 2.42 (1.15-5.09) 0.020* 2.10 (1.04-4.25) 0.039*
Response of PR after 3-5 cycles 0.30 (0.13-0.65) 0.002** 0.25 (0.12-0.53) < 0.001***
Abbreviations: UNL; upper normal limit, PR; partial response
*P < 0.05, **P < 0.01, ***P < 0.001
Furthermore, we performed multivariable analyses of OS and PFS with the Cox proportional hazards model to control confounding factors. Response to MTX-HOPE better than PR after three to five cycles was treated as a time-dependent covariate.23 Each analysis was evaluated by adding age (≥75), IPI (≥3), and lymphoma histology (B cell lymphoma or T cell lymphoma) to the independent factors (Table 5). The final models for OS and PFS included Ki-67 positivity (≥ 50%) (HR 2.42, 95% CI 1.15-5.09, P = 0.020 and HR 2.10, 95% CI 1.04-4.25, P = 0.039).
Table 5 Multivariate analysis of overall survival (OS) and progression-free survival (PFS) with the Cox proportional hazards model. Response to the MTX-HOPE regimen better than partial response after three to five cycles was treated as a time-dependent covariate.
Variable Hazard ratio (95% CI) p-value
Overall survival
Ki-67 (≥50%) 2.42 (1.15-5.09) 0.020*
Progression-free survival
Ki-67 (≥50%) 2.10 (1.04-4.25) 0.039*
Age (≥75), B cell lymphoma or T cell lymphoma, and International Prognostic Index (≥3) were also added to the OS and PFS analyses. The final models with significant differences are shown in the table.
DISCUSSION
In the present study, we analyzed the safety and efficacy of MTX-HOPE for aged r/r NHL patients who are vulnerable and were not eligible for autologous stem cell transplantation (ASCT) and conventional high-dose salvage chemotherapy. Our results showed that the MTX-HOPE regimen is effective and tolerable for these r/r NHL patients. High Ki-67 positivity was extracted as an independent factor of OS and PFS by multivariable analyses using response to MTX-HOPE treatment as a time-dependent covariate. In addition, most patients who receive MTX-HOPE can be treated without hospitalization.
Ki-67 is one of the cell cycle related protein and strongly associated with the lymphoma cell proliferation, leading to lymphoma progression. High Ki-67 positivity is also related to poor prognosis within the same lymphoma subtypes, such as DLBCL and FL.24-26 Our results suggest that MTX-HOPE is less effective for the highly Ki-67 positive lymphoma patients. Because there were a few patients other than DLBCL in our study, further study is needed to confirm these results.
In this study, the patients who received MTX-HOPE therapy were elderly individuals and had worse PS scores. Because these patients had some comorbidities, such as renal dysfunction and anemia, they could not receive other intensive salvage treatments. The overall response rate (ORR) of MTX-HOPE was 45.2%. The rate of treatment responsiveness above SD was 76.2%, and treatment response was observed in many cases. The median OS was 7 months, the 1-year OS was 43.7%, and the 2-year OS was 40.8%. Some patients achieved long-term survival. Moreover, MTX-HOPE therapy resulted in no treatment-related deaths and the acceptable rate of treatment discontinuation events. According to the SCHOLAR-1 study of relapsed DLBCL (the largest, patient-level pooled analysis), the median OS was 6.3 months, and the 2-year OS was 20%.27 Given our target frail population, these results indicate that MTX-HOPE therapy is tolerable and effective. Although there were several side effects of MTX-HOPE therapy worse than grade 3, these were temporary and recoverable. Appropriate supportive care, including blood transfusion and G-CSF, is generally important for elderly patients to continue chemotherapy.
Furthermore, most patients treated with MTX-HOPE were able to continue without hospitalization, leading to a great advantage in medical costs. Previous reports have shown that the medical costs of aggressive NHL are estimated at $5,871 per patient per month (PPPM) for the first two years of treatment,28 and those for elderly patients with r/r DLBCL are more than $97,000 per year.29 In addition, the costs of patients for febrile neutropenia (FN) are more expensive.30 In our study, the average medical cost of MTX-HOPE calculated by the medical claims data was ¥94,297/month. These data revealed that MTX-HOPE is a cost-effective regimen. Multivariable analysis with the Cox proportional hazards model revealed Ki-67 positivity in pathology and PR to the MTX-HOPE regimen as independent factors for OS and PFS. These results are useful for the indication of MTX-HOPE therapy.
There are some limitations in this study. First, although the response to MTX-HOPE was evaluated based on the International Workshop Response Criteria (IWRC), the evaluations were not conducted at fixed cycles. Therefore, there were differences in the response evaluation periods among MTX-HOPE patients. Last, this was a single-center, single-arm study. A prospective controlled trial with other salvage regimens may be needed to confirm the safety and effectiveness of MTX-HOPE therapy.
In conclusion, the MTX-HOPE regimen is safe and effective for r/r NHL patients. Pathologically high Ki-67 positivity was identified as an independent factor for MTX-HOPE treatment. The advantage of the MTX-HOPE regimen is that it contributes to maintaining quality of life (QOL) without hospitalization. Our results may help in considering the indications for MTX-HOPE. We concluded that MTX-HOPE is an attractive salvage regimen for aged patients or those with non-aggressive r/r NHL. To validate this regimen, further prospective studies are needed.
ACKNOWLEDGMENTS
We would like to express our special thanks to Dr. Yasuhiko Kano, who retired from the Tochigi Cancer Center (Utsunomiya, Japan). He developed the principle of MTX-HOPE therapy through a series of in vitro experiments with combination chemotherapy.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest (COIs). | Intravenous drip | DrugAdministrationRoute | CC BY-NC-SA | 33551437 | 19,429,767 | 2021-03-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaemia'. | Ruptured idiopathic hepatic artery pseudoaneurysm causing portal vein thrombosis with portal hypertension and variceal bleeding.
Portal vein thrombosis (PVT) is an important cause of noncirrhotic portal hypertension. Noncancerous extrinsic compression of portal vein to drive PVT formation is rare, but important to identify. A 64-year-old female with idiopathic hepatic artery pseudoaneurysm (HAPA) rupture 7 months prior presented with acute-onset hematemesis and melena and was found to have prehepatic portal hypertensive variceal bleeding. Her HAPA-related retroperitoneal hematoma had resulted in portal vein compression, thrombosis, and cavernous transformation despite prompt stent graft placement across the ruptured HAPA, and required definitive treatment by transjugular intrahepatic portosystemic shunt creation with portal vein reconstruction utilizing a trans-splenic access. This case highlights the importance of interval abdominal imaging and hypercoagulability screening for noncirrhotic patients at-risk for PVT, which identified the patient as a heterozygous carrier of Factor V Leiden.
Introduction
The prehepatic occlusion of the portal vein by thrombus is an important cause of portal hypertension (PHTN) [1]. Portal vein thrombosis (PVT) occurs in diverse clinical contexts that drive thrombus formation by potentially enabling multiple elements of Virchow's triad (stasis, endothelial injury, and hypercoagulability) [2]. Not surprisingly, local factors acting in the vicinity of portal vein including inflammation, infection, malignancy, and iatrogenic injury are frequently identified, as well systemic factors such as inherited or acquired hypercoagulability.
Hepatic artery pseudoaneurysm (HAPA), which lacks a complete 3-layer arterial wall, tends to rupture or fistulize rather than cause mass effect on neighboring structures [3,4]. HAPA most commonly occurs in the right or common hepatic artery and often has an identifiable prior injurious event such as abdominal trauma, iatrogenic hepatobiliary procedure, or local inflammation [3]. We describe a case of ruptured idiopathic common HAPA with unique sequelae of PVT, cavernous transformation, and PHTN-related variceal bleeding.
Case report
A 64-year-old Caucasian female with no past medical history presented to an outside institution with new-onset, nonbilious, nonbloody vomiting and severe epigastric abdominal pain. There was no history of alcohol use, liver disease, trauma, hepatobiliary procedures, pancreatitis, or hypercoagulable state. Computed tomography (CT) scan of her abdomen showed a ruptured common HAPA causing a large retroperitoneal hematoma (Fig. 1). She underwent emergent hepatic artery stent graft placement (6 mm × 5 cm covered Viabahn, Gore Medical, Flagstaff, AZ) and was discharged on aspirin and clopidogrel with resolution of her symptoms.Fig. 1 Initial presentation. Slices of contrast-enhanced CT in arterial (A-B) and delayed (C) phase showing ruptured common HAPA (arrowhead, A-C) prior to stent grafting. Ruptured HAPA measuring 4.0 cm × 2.4 cm × 2.3 cm (A-B) impinged on portal venous structures in the porta hepatis (C).
Fig 1
Seven months later, she represented with an episode of sudden-onset hematemesis. She reported several months of mild diffuse abdominal pain and distension, as well as 3 recent episodes of self-limited melena. Her blood pressure was 162/97 mm Hg and heart rate was 83 beats/min. Physical exam was significant for soft, slightly distended abdomen without any organomegaly. Labs showed a hemoglobin of 6.7 g/dL (reference range 12-16), platelets 342 k/mm3 (reference range 150-450), international normalized ratio 1.06 (reference range 1-2), normal leukocyte differential, and normal liver chemistries. CT abdomen and pelvis with contrast showed a resolving hematoma related to the ruptured HAPA, however with interval development of cavernous transformation of the portal vein. The liver appeared normal in size and echotexture, but there was trace ascites (Fig. 2). She was transferred to our institution for further management.Fig. 2 Second presentation at 7 months. Two slices of contrast-enhanced CT in venous phase showing previously ruptured common HAPA with stent graft (thick arrow, A-B) causing portal cavernous transformation (arrowhead, A-B). Superior mesenteric and splenic veins merging to form the stenotic native portal vein (thin arrow) giving rise to collaterals.
Fig 2
Upon arrival, she was hemodynamically stable. Aspirin and clopidogrel were held. Esophagogastroduodenoscopy identified large bleeding esophageal varices with red wale signs, which were banded. She developed hematochezia and a hemoglobin drop to 6.3 g/dL despite receiving 4 units of packed red blood cells over the next 3 days. Repeat endoscopy showed small esophageal varices and portal hypertensive gastropathy, but no active bleeding. She continued to have PHTN-related hematochezia requiring serial blood transfusions. During the course of her stay, she developed abdominal distension and ascites requiring paracentesis. Ascitic fluid analysis was consistent with spontaneous bacterial peritonitis (ascitic fluid: 800 WBC, 60% neutrophils), which was treated with ceftriaxone and intravenous albumin.
Interventional radiology was consulted and she underwent a transjugular intrahepatic portosystemic shunt (TIPS) creation with portal vein reconstruction utilizing trans-splenic access (Fig. 3). A 6-Fr sheath was inserted into the splenic vein via trans-splenic approach. A 0.035 inch (0.89 mm) Glide Advantage wire (Terumo Medical Corporation, Somerset, NJ) and 5-Fr Berenstein catheter were used to navigate through the native, now-stenotic main portal vein channel. A 10 mm snare was positioned in the mid-right intrahepatic portal vein. Via a 10-Fr sheath access in the right internal jugular vein, the snare was targeted and a Rosch-Uchida needle (Cook Medical, Bloomington, IN) was used to cross from the middle hepatic vein into the right portal vein. A 10 mm × 8 cm + 2 cm Viatorr (Gore Medical) was deployed and postdilated to 10 mm. Prolonged balloon angioplasty to 10 mm was also performed along the unstented, stenotic portion of the native portal vein. After TIPS, the mean portosystemic gradient decreased from 13 to 4 mm Hg. Her hematochezia and ascites resolved and she was discharged.Fig. 3 Second presentation at 7 months. Trans-splenic venogram during TIPS showing superior mesenteric and splenic veins merging to form the prestenotic portal vein (thin long arrow) with collaterals typical of cavernous transformation (arrowheads). The stenotic thread-like native main portal vein channel (short arrow), adjacent to common HAPA with stent graft (thick long arrow), was successfully recanalized as the TIPS was created from middle hepatic vein to right portal vein.
Fig 3
At 1-month follow-up, she was asymptomatic, and her TIPS was patent both by color Doppler ultrasound and a conventional venogram (Fig. 4). Subsequently at 3-month clinic follow-up, color Doppler ultrasound continued to show patent TIPS. Screening for hypercoagulability revealed Factor V Leiden (FVL) heterozygosity, but was negative for elevated homocysteine, antiphospholipid antibodies, and prothrombin G20210A.Fig. 4 Follow-up after second presentation. Conventional venogram 1-month post-TIPS showing brisk flow through TIPS without filling defect or anomaly. Nearby common HAPA with stent graft (thick long arrow).
Fig 4
Discussion
We present a patient with noncirrhotic, prehepatic PHTN-related variceal bleeding due to idiopathic ruptured HAPA and resultant portal vein compression and thrombosis. This was a unique clinical course for HAPA, which has a high risk for progression, fistulization, or rupture, and often presents as right upper quadrant pain, gastrointestinal bleeding, or hemoperitoneum [4].
Her clinical course with the development of PVT likely resulted from an interplay of HAPA-related extrinsic compression slowing portal flow combined with her inherited FVL hypercoagulability. Inherited or acquired hypercoagulability is frequently identified in patients with PVT: one study noted 26 of 36 noncirrhotic PVT patients had an identifiable hypercoagulable state [5]. FVL is the most common inherited hypercoagulability in those of European descent with 5% frequency. Interestingly, studies of both noncirrhotics and cirrhotics have noted no statistically different FVL frequency in PVT patients vs controls, with a trend toward increased FVL in one study [5], [6], [7], [8]. This is in sharp contrast to statistically higher prothrombin G20210A frequency in PVT, which suggests that FVL alone may not play as potent of a role in stimulating PVT development.
Noncirrhotic PVT is rare compared to cirrhosis-related PVT [9]. Not surprisingly, there is a lack of guidelines for PVT screening in at-risk noncirrhotic patients in contrast to cirrhotic patients, where guidelines exist for ultrasound screening due to higher risk for hepatocellular carcinoma during which PVT may be found [10]. The key benefit to identifying PVT early is the possibility of early anticoagulation initiation with low molecular weight heparin or vitamin K antagonists, which can help dissolve clots and halt thrombus extension [9,11]. Though rare, PVT expanding proximally into superior mesenteric vein can cause life-threatening intestinal infarction.
In our patient, HAPA rupture resulted in significant extrinsic compression of the portal vein at the porta hepatis. Given the slow-resolving and persistent nature of this hematoma's mass effect on the portal vein, we posit that our patient could have benefited from regular PVT screening, hypercoagulability testing, and consideration of pre-emptive TIPS before she developed refractory PHTN-related bleeding. This raises an important management consideration, because hematoma is not limited to rare pseudoaneursymal ruptures and can arise after trauma, biopsy, or surgery. Of note, our patient did undergo CT abdominal imaging to follow-up HAPA stent graft placement 1 month after her procedure, but did not have any subsequent follow-up due to the COVID-19 pandemic.
The development of complete PVT with cavernous transformation has historically posed technical challenges for performing TIPS to treat refractory PHTN-related bleeding [12]. Various strategies to facilitate locating and navigating through the intrahepatic portal vein have included ultrasound guidance and percutaneous transhepatic access [13]. The strategy we chose, portal vein reconstruction with trans-splenic access, has emerged as a very safe and effective strategy for treating complete PVT with cavernous transformation in both cirrhotics [14,15] and noncirrhotics [16].
Patients with PVT without other comorbidities including ours have a good prognosis [17]. This report highlights PVT and PHTN development despite timely HAPA stenting and resolving extrinsic compression, which underscores the need for follow-up, hypercoagulability screening, and definitive intervention in this unique patient population.
Authors’ contributions
K. Ni provided care from endoscopic service and wrote the manuscript. C. Jansson-Knodell provided care from endoscopic service, helped interpret clinical findings, and revised the manuscript. M.E. Krosin and P.M. Haste performed TIPS creation with portal vein reconstruction, interpreted radiological findings, and revised the manuscript. I. Obaitan and L.E. Nephew led the care from hepatology service, helped interpret clinical findings, and revised the manuscript. S.V. Sagi performed endoscopic interventions, helped interpret clinical findings, and revised the manuscript.
Patient consent
Informed patient consent was obtained for publishing this case report.
Funding: KN was supported by a NRSA from NIH/NHLBI, USA (1F30HL136169-03). No other financial support.
Competing Interests: Authors have no conflicts or competing interests to declare. | ASPIRIN, CLOPIDOGREL BISULFATE | DrugsGivenReaction | CC BY-NC-ND | 33552333 | 19,270,194 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ascites'. | Ruptured idiopathic hepatic artery pseudoaneurysm causing portal vein thrombosis with portal hypertension and variceal bleeding.
Portal vein thrombosis (PVT) is an important cause of noncirrhotic portal hypertension. Noncancerous extrinsic compression of portal vein to drive PVT formation is rare, but important to identify. A 64-year-old female with idiopathic hepatic artery pseudoaneurysm (HAPA) rupture 7 months prior presented with acute-onset hematemesis and melena and was found to have prehepatic portal hypertensive variceal bleeding. Her HAPA-related retroperitoneal hematoma had resulted in portal vein compression, thrombosis, and cavernous transformation despite prompt stent graft placement across the ruptured HAPA, and required definitive treatment by transjugular intrahepatic portosystemic shunt creation with portal vein reconstruction utilizing a trans-splenic access. This case highlights the importance of interval abdominal imaging and hypercoagulability screening for noncirrhotic patients at-risk for PVT, which identified the patient as a heterozygous carrier of Factor V Leiden.
Introduction
The prehepatic occlusion of the portal vein by thrombus is an important cause of portal hypertension (PHTN) [1]. Portal vein thrombosis (PVT) occurs in diverse clinical contexts that drive thrombus formation by potentially enabling multiple elements of Virchow's triad (stasis, endothelial injury, and hypercoagulability) [2]. Not surprisingly, local factors acting in the vicinity of portal vein including inflammation, infection, malignancy, and iatrogenic injury are frequently identified, as well systemic factors such as inherited or acquired hypercoagulability.
Hepatic artery pseudoaneurysm (HAPA), which lacks a complete 3-layer arterial wall, tends to rupture or fistulize rather than cause mass effect on neighboring structures [3,4]. HAPA most commonly occurs in the right or common hepatic artery and often has an identifiable prior injurious event such as abdominal trauma, iatrogenic hepatobiliary procedure, or local inflammation [3]. We describe a case of ruptured idiopathic common HAPA with unique sequelae of PVT, cavernous transformation, and PHTN-related variceal bleeding.
Case report
A 64-year-old Caucasian female with no past medical history presented to an outside institution with new-onset, nonbilious, nonbloody vomiting and severe epigastric abdominal pain. There was no history of alcohol use, liver disease, trauma, hepatobiliary procedures, pancreatitis, or hypercoagulable state. Computed tomography (CT) scan of her abdomen showed a ruptured common HAPA causing a large retroperitoneal hematoma (Fig. 1). She underwent emergent hepatic artery stent graft placement (6 mm × 5 cm covered Viabahn, Gore Medical, Flagstaff, AZ) and was discharged on aspirin and clopidogrel with resolution of her symptoms.Fig. 1 Initial presentation. Slices of contrast-enhanced CT in arterial (A-B) and delayed (C) phase showing ruptured common HAPA (arrowhead, A-C) prior to stent grafting. Ruptured HAPA measuring 4.0 cm × 2.4 cm × 2.3 cm (A-B) impinged on portal venous structures in the porta hepatis (C).
Fig 1
Seven months later, she represented with an episode of sudden-onset hematemesis. She reported several months of mild diffuse abdominal pain and distension, as well as 3 recent episodes of self-limited melena. Her blood pressure was 162/97 mm Hg and heart rate was 83 beats/min. Physical exam was significant for soft, slightly distended abdomen without any organomegaly. Labs showed a hemoglobin of 6.7 g/dL (reference range 12-16), platelets 342 k/mm3 (reference range 150-450), international normalized ratio 1.06 (reference range 1-2), normal leukocyte differential, and normal liver chemistries. CT abdomen and pelvis with contrast showed a resolving hematoma related to the ruptured HAPA, however with interval development of cavernous transformation of the portal vein. The liver appeared normal in size and echotexture, but there was trace ascites (Fig. 2). She was transferred to our institution for further management.Fig. 2 Second presentation at 7 months. Two slices of contrast-enhanced CT in venous phase showing previously ruptured common HAPA with stent graft (thick arrow, A-B) causing portal cavernous transformation (arrowhead, A-B). Superior mesenteric and splenic veins merging to form the stenotic native portal vein (thin arrow) giving rise to collaterals.
Fig 2
Upon arrival, she was hemodynamically stable. Aspirin and clopidogrel were held. Esophagogastroduodenoscopy identified large bleeding esophageal varices with red wale signs, which were banded. She developed hematochezia and a hemoglobin drop to 6.3 g/dL despite receiving 4 units of packed red blood cells over the next 3 days. Repeat endoscopy showed small esophageal varices and portal hypertensive gastropathy, but no active bleeding. She continued to have PHTN-related hematochezia requiring serial blood transfusions. During the course of her stay, she developed abdominal distension and ascites requiring paracentesis. Ascitic fluid analysis was consistent with spontaneous bacterial peritonitis (ascitic fluid: 800 WBC, 60% neutrophils), which was treated with ceftriaxone and intravenous albumin.
Interventional radiology was consulted and she underwent a transjugular intrahepatic portosystemic shunt (TIPS) creation with portal vein reconstruction utilizing trans-splenic access (Fig. 3). A 6-Fr sheath was inserted into the splenic vein via trans-splenic approach. A 0.035 inch (0.89 mm) Glide Advantage wire (Terumo Medical Corporation, Somerset, NJ) and 5-Fr Berenstein catheter were used to navigate through the native, now-stenotic main portal vein channel. A 10 mm snare was positioned in the mid-right intrahepatic portal vein. Via a 10-Fr sheath access in the right internal jugular vein, the snare was targeted and a Rosch-Uchida needle (Cook Medical, Bloomington, IN) was used to cross from the middle hepatic vein into the right portal vein. A 10 mm × 8 cm + 2 cm Viatorr (Gore Medical) was deployed and postdilated to 10 mm. Prolonged balloon angioplasty to 10 mm was also performed along the unstented, stenotic portion of the native portal vein. After TIPS, the mean portosystemic gradient decreased from 13 to 4 mm Hg. Her hematochezia and ascites resolved and she was discharged.Fig. 3 Second presentation at 7 months. Trans-splenic venogram during TIPS showing superior mesenteric and splenic veins merging to form the prestenotic portal vein (thin long arrow) with collaterals typical of cavernous transformation (arrowheads). The stenotic thread-like native main portal vein channel (short arrow), adjacent to common HAPA with stent graft (thick long arrow), was successfully recanalized as the TIPS was created from middle hepatic vein to right portal vein.
Fig 3
At 1-month follow-up, she was asymptomatic, and her TIPS was patent both by color Doppler ultrasound and a conventional venogram (Fig. 4). Subsequently at 3-month clinic follow-up, color Doppler ultrasound continued to show patent TIPS. Screening for hypercoagulability revealed Factor V Leiden (FVL) heterozygosity, but was negative for elevated homocysteine, antiphospholipid antibodies, and prothrombin G20210A.Fig. 4 Follow-up after second presentation. Conventional venogram 1-month post-TIPS showing brisk flow through TIPS without filling defect or anomaly. Nearby common HAPA with stent graft (thick long arrow).
Fig 4
Discussion
We present a patient with noncirrhotic, prehepatic PHTN-related variceal bleeding due to idiopathic ruptured HAPA and resultant portal vein compression and thrombosis. This was a unique clinical course for HAPA, which has a high risk for progression, fistulization, or rupture, and often presents as right upper quadrant pain, gastrointestinal bleeding, or hemoperitoneum [4].
Her clinical course with the development of PVT likely resulted from an interplay of HAPA-related extrinsic compression slowing portal flow combined with her inherited FVL hypercoagulability. Inherited or acquired hypercoagulability is frequently identified in patients with PVT: one study noted 26 of 36 noncirrhotic PVT patients had an identifiable hypercoagulable state [5]. FVL is the most common inherited hypercoagulability in those of European descent with 5% frequency. Interestingly, studies of both noncirrhotics and cirrhotics have noted no statistically different FVL frequency in PVT patients vs controls, with a trend toward increased FVL in one study [5], [6], [7], [8]. This is in sharp contrast to statistically higher prothrombin G20210A frequency in PVT, which suggests that FVL alone may not play as potent of a role in stimulating PVT development.
Noncirrhotic PVT is rare compared to cirrhosis-related PVT [9]. Not surprisingly, there is a lack of guidelines for PVT screening in at-risk noncirrhotic patients in contrast to cirrhotic patients, where guidelines exist for ultrasound screening due to higher risk for hepatocellular carcinoma during which PVT may be found [10]. The key benefit to identifying PVT early is the possibility of early anticoagulation initiation with low molecular weight heparin or vitamin K antagonists, which can help dissolve clots and halt thrombus extension [9,11]. Though rare, PVT expanding proximally into superior mesenteric vein can cause life-threatening intestinal infarction.
In our patient, HAPA rupture resulted in significant extrinsic compression of the portal vein at the porta hepatis. Given the slow-resolving and persistent nature of this hematoma's mass effect on the portal vein, we posit that our patient could have benefited from regular PVT screening, hypercoagulability testing, and consideration of pre-emptive TIPS before she developed refractory PHTN-related bleeding. This raises an important management consideration, because hematoma is not limited to rare pseudoaneursymal ruptures and can arise after trauma, biopsy, or surgery. Of note, our patient did undergo CT abdominal imaging to follow-up HAPA stent graft placement 1 month after her procedure, but did not have any subsequent follow-up due to the COVID-19 pandemic.
The development of complete PVT with cavernous transformation has historically posed technical challenges for performing TIPS to treat refractory PHTN-related bleeding [12]. Various strategies to facilitate locating and navigating through the intrahepatic portal vein have included ultrasound guidance and percutaneous transhepatic access [13]. The strategy we chose, portal vein reconstruction with trans-splenic access, has emerged as a very safe and effective strategy for treating complete PVT with cavernous transformation in both cirrhotics [14,15] and noncirrhotics [16].
Patients with PVT without other comorbidities including ours have a good prognosis [17]. This report highlights PVT and PHTN development despite timely HAPA stenting and resolving extrinsic compression, which underscores the need for follow-up, hypercoagulability screening, and definitive intervention in this unique patient population.
Authors’ contributions
K. Ni provided care from endoscopic service and wrote the manuscript. C. Jansson-Knodell provided care from endoscopic service, helped interpret clinical findings, and revised the manuscript. M.E. Krosin and P.M. Haste performed TIPS creation with portal vein reconstruction, interpreted radiological findings, and revised the manuscript. I. Obaitan and L.E. Nephew led the care from hepatology service, helped interpret clinical findings, and revised the manuscript. S.V. Sagi performed endoscopic interventions, helped interpret clinical findings, and revised the manuscript.
Patient consent
Informed patient consent was obtained for publishing this case report.
Funding: KN was supported by a NRSA from NIH/NHLBI, USA (1F30HL136169-03). No other financial support.
Competing Interests: Authors have no conflicts or competing interests to declare. | ASPIRIN, CLOPIDOGREL BISULFATE | DrugsGivenReaction | CC BY-NC-ND | 33552333 | 19,270,194 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haematochezia'. | Ruptured idiopathic hepatic artery pseudoaneurysm causing portal vein thrombosis with portal hypertension and variceal bleeding.
Portal vein thrombosis (PVT) is an important cause of noncirrhotic portal hypertension. Noncancerous extrinsic compression of portal vein to drive PVT formation is rare, but important to identify. A 64-year-old female with idiopathic hepatic artery pseudoaneurysm (HAPA) rupture 7 months prior presented with acute-onset hematemesis and melena and was found to have prehepatic portal hypertensive variceal bleeding. Her HAPA-related retroperitoneal hematoma had resulted in portal vein compression, thrombosis, and cavernous transformation despite prompt stent graft placement across the ruptured HAPA, and required definitive treatment by transjugular intrahepatic portosystemic shunt creation with portal vein reconstruction utilizing a trans-splenic access. This case highlights the importance of interval abdominal imaging and hypercoagulability screening for noncirrhotic patients at-risk for PVT, which identified the patient as a heterozygous carrier of Factor V Leiden.
Introduction
The prehepatic occlusion of the portal vein by thrombus is an important cause of portal hypertension (PHTN) [1]. Portal vein thrombosis (PVT) occurs in diverse clinical contexts that drive thrombus formation by potentially enabling multiple elements of Virchow's triad (stasis, endothelial injury, and hypercoagulability) [2]. Not surprisingly, local factors acting in the vicinity of portal vein including inflammation, infection, malignancy, and iatrogenic injury are frequently identified, as well systemic factors such as inherited or acquired hypercoagulability.
Hepatic artery pseudoaneurysm (HAPA), which lacks a complete 3-layer arterial wall, tends to rupture or fistulize rather than cause mass effect on neighboring structures [3,4]. HAPA most commonly occurs in the right or common hepatic artery and often has an identifiable prior injurious event such as abdominal trauma, iatrogenic hepatobiliary procedure, or local inflammation [3]. We describe a case of ruptured idiopathic common HAPA with unique sequelae of PVT, cavernous transformation, and PHTN-related variceal bleeding.
Case report
A 64-year-old Caucasian female with no past medical history presented to an outside institution with new-onset, nonbilious, nonbloody vomiting and severe epigastric abdominal pain. There was no history of alcohol use, liver disease, trauma, hepatobiliary procedures, pancreatitis, or hypercoagulable state. Computed tomography (CT) scan of her abdomen showed a ruptured common HAPA causing a large retroperitoneal hematoma (Fig. 1). She underwent emergent hepatic artery stent graft placement (6 mm × 5 cm covered Viabahn, Gore Medical, Flagstaff, AZ) and was discharged on aspirin and clopidogrel with resolution of her symptoms.Fig. 1 Initial presentation. Slices of contrast-enhanced CT in arterial (A-B) and delayed (C) phase showing ruptured common HAPA (arrowhead, A-C) prior to stent grafting. Ruptured HAPA measuring 4.0 cm × 2.4 cm × 2.3 cm (A-B) impinged on portal venous structures in the porta hepatis (C).
Fig 1
Seven months later, she represented with an episode of sudden-onset hematemesis. She reported several months of mild diffuse abdominal pain and distension, as well as 3 recent episodes of self-limited melena. Her blood pressure was 162/97 mm Hg and heart rate was 83 beats/min. Physical exam was significant for soft, slightly distended abdomen without any organomegaly. Labs showed a hemoglobin of 6.7 g/dL (reference range 12-16), platelets 342 k/mm3 (reference range 150-450), international normalized ratio 1.06 (reference range 1-2), normal leukocyte differential, and normal liver chemistries. CT abdomen and pelvis with contrast showed a resolving hematoma related to the ruptured HAPA, however with interval development of cavernous transformation of the portal vein. The liver appeared normal in size and echotexture, but there was trace ascites (Fig. 2). She was transferred to our institution for further management.Fig. 2 Second presentation at 7 months. Two slices of contrast-enhanced CT in venous phase showing previously ruptured common HAPA with stent graft (thick arrow, A-B) causing portal cavernous transformation (arrowhead, A-B). Superior mesenteric and splenic veins merging to form the stenotic native portal vein (thin arrow) giving rise to collaterals.
Fig 2
Upon arrival, she was hemodynamically stable. Aspirin and clopidogrel were held. Esophagogastroduodenoscopy identified large bleeding esophageal varices with red wale signs, which were banded. She developed hematochezia and a hemoglobin drop to 6.3 g/dL despite receiving 4 units of packed red blood cells over the next 3 days. Repeat endoscopy showed small esophageal varices and portal hypertensive gastropathy, but no active bleeding. She continued to have PHTN-related hematochezia requiring serial blood transfusions. During the course of her stay, she developed abdominal distension and ascites requiring paracentesis. Ascitic fluid analysis was consistent with spontaneous bacterial peritonitis (ascitic fluid: 800 WBC, 60% neutrophils), which was treated with ceftriaxone and intravenous albumin.
Interventional radiology was consulted and she underwent a transjugular intrahepatic portosystemic shunt (TIPS) creation with portal vein reconstruction utilizing trans-splenic access (Fig. 3). A 6-Fr sheath was inserted into the splenic vein via trans-splenic approach. A 0.035 inch (0.89 mm) Glide Advantage wire (Terumo Medical Corporation, Somerset, NJ) and 5-Fr Berenstein catheter were used to navigate through the native, now-stenotic main portal vein channel. A 10 mm snare was positioned in the mid-right intrahepatic portal vein. Via a 10-Fr sheath access in the right internal jugular vein, the snare was targeted and a Rosch-Uchida needle (Cook Medical, Bloomington, IN) was used to cross from the middle hepatic vein into the right portal vein. A 10 mm × 8 cm + 2 cm Viatorr (Gore Medical) was deployed and postdilated to 10 mm. Prolonged balloon angioplasty to 10 mm was also performed along the unstented, stenotic portion of the native portal vein. After TIPS, the mean portosystemic gradient decreased from 13 to 4 mm Hg. Her hematochezia and ascites resolved and she was discharged.Fig. 3 Second presentation at 7 months. Trans-splenic venogram during TIPS showing superior mesenteric and splenic veins merging to form the prestenotic portal vein (thin long arrow) with collaterals typical of cavernous transformation (arrowheads). The stenotic thread-like native main portal vein channel (short arrow), adjacent to common HAPA with stent graft (thick long arrow), was successfully recanalized as the TIPS was created from middle hepatic vein to right portal vein.
Fig 3
At 1-month follow-up, she was asymptomatic, and her TIPS was patent both by color Doppler ultrasound and a conventional venogram (Fig. 4). Subsequently at 3-month clinic follow-up, color Doppler ultrasound continued to show patent TIPS. Screening for hypercoagulability revealed Factor V Leiden (FVL) heterozygosity, but was negative for elevated homocysteine, antiphospholipid antibodies, and prothrombin G20210A.Fig. 4 Follow-up after second presentation. Conventional venogram 1-month post-TIPS showing brisk flow through TIPS without filling defect or anomaly. Nearby common HAPA with stent graft (thick long arrow).
Fig 4
Discussion
We present a patient with noncirrhotic, prehepatic PHTN-related variceal bleeding due to idiopathic ruptured HAPA and resultant portal vein compression and thrombosis. This was a unique clinical course for HAPA, which has a high risk for progression, fistulization, or rupture, and often presents as right upper quadrant pain, gastrointestinal bleeding, or hemoperitoneum [4].
Her clinical course with the development of PVT likely resulted from an interplay of HAPA-related extrinsic compression slowing portal flow combined with her inherited FVL hypercoagulability. Inherited or acquired hypercoagulability is frequently identified in patients with PVT: one study noted 26 of 36 noncirrhotic PVT patients had an identifiable hypercoagulable state [5]. FVL is the most common inherited hypercoagulability in those of European descent with 5% frequency. Interestingly, studies of both noncirrhotics and cirrhotics have noted no statistically different FVL frequency in PVT patients vs controls, with a trend toward increased FVL in one study [5], [6], [7], [8]. This is in sharp contrast to statistically higher prothrombin G20210A frequency in PVT, which suggests that FVL alone may not play as potent of a role in stimulating PVT development.
Noncirrhotic PVT is rare compared to cirrhosis-related PVT [9]. Not surprisingly, there is a lack of guidelines for PVT screening in at-risk noncirrhotic patients in contrast to cirrhotic patients, where guidelines exist for ultrasound screening due to higher risk for hepatocellular carcinoma during which PVT may be found [10]. The key benefit to identifying PVT early is the possibility of early anticoagulation initiation with low molecular weight heparin or vitamin K antagonists, which can help dissolve clots and halt thrombus extension [9,11]. Though rare, PVT expanding proximally into superior mesenteric vein can cause life-threatening intestinal infarction.
In our patient, HAPA rupture resulted in significant extrinsic compression of the portal vein at the porta hepatis. Given the slow-resolving and persistent nature of this hematoma's mass effect on the portal vein, we posit that our patient could have benefited from regular PVT screening, hypercoagulability testing, and consideration of pre-emptive TIPS before she developed refractory PHTN-related bleeding. This raises an important management consideration, because hematoma is not limited to rare pseudoaneursymal ruptures and can arise after trauma, biopsy, or surgery. Of note, our patient did undergo CT abdominal imaging to follow-up HAPA stent graft placement 1 month after her procedure, but did not have any subsequent follow-up due to the COVID-19 pandemic.
The development of complete PVT with cavernous transformation has historically posed technical challenges for performing TIPS to treat refractory PHTN-related bleeding [12]. Various strategies to facilitate locating and navigating through the intrahepatic portal vein have included ultrasound guidance and percutaneous transhepatic access [13]. The strategy we chose, portal vein reconstruction with trans-splenic access, has emerged as a very safe and effective strategy for treating complete PVT with cavernous transformation in both cirrhotics [14,15] and noncirrhotics [16].
Patients with PVT without other comorbidities including ours have a good prognosis [17]. This report highlights PVT and PHTN development despite timely HAPA stenting and resolving extrinsic compression, which underscores the need for follow-up, hypercoagulability screening, and definitive intervention in this unique patient population.
Authors’ contributions
K. Ni provided care from endoscopic service and wrote the manuscript. C. Jansson-Knodell provided care from endoscopic service, helped interpret clinical findings, and revised the manuscript. M.E. Krosin and P.M. Haste performed TIPS creation with portal vein reconstruction, interpreted radiological findings, and revised the manuscript. I. Obaitan and L.E. Nephew led the care from hepatology service, helped interpret clinical findings, and revised the manuscript. S.V. Sagi performed endoscopic interventions, helped interpret clinical findings, and revised the manuscript.
Patient consent
Informed patient consent was obtained for publishing this case report.
Funding: KN was supported by a NRSA from NIH/NHLBI, USA (1F30HL136169-03). No other financial support.
Competing Interests: Authors have no conflicts or competing interests to declare. | ASPIRIN, CLOPIDOGREL BISULFATE | DrugsGivenReaction | CC BY-NC-ND | 33552333 | 19,270,194 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Labelled drug-drug interaction medication error'. | Ruptured idiopathic hepatic artery pseudoaneurysm causing portal vein thrombosis with portal hypertension and variceal bleeding.
Portal vein thrombosis (PVT) is an important cause of noncirrhotic portal hypertension. Noncancerous extrinsic compression of portal vein to drive PVT formation is rare, but important to identify. A 64-year-old female with idiopathic hepatic artery pseudoaneurysm (HAPA) rupture 7 months prior presented with acute-onset hematemesis and melena and was found to have prehepatic portal hypertensive variceal bleeding. Her HAPA-related retroperitoneal hematoma had resulted in portal vein compression, thrombosis, and cavernous transformation despite prompt stent graft placement across the ruptured HAPA, and required definitive treatment by transjugular intrahepatic portosystemic shunt creation with portal vein reconstruction utilizing a trans-splenic access. This case highlights the importance of interval abdominal imaging and hypercoagulability screening for noncirrhotic patients at-risk for PVT, which identified the patient as a heterozygous carrier of Factor V Leiden.
Introduction
The prehepatic occlusion of the portal vein by thrombus is an important cause of portal hypertension (PHTN) [1]. Portal vein thrombosis (PVT) occurs in diverse clinical contexts that drive thrombus formation by potentially enabling multiple elements of Virchow's triad (stasis, endothelial injury, and hypercoagulability) [2]. Not surprisingly, local factors acting in the vicinity of portal vein including inflammation, infection, malignancy, and iatrogenic injury are frequently identified, as well systemic factors such as inherited or acquired hypercoagulability.
Hepatic artery pseudoaneurysm (HAPA), which lacks a complete 3-layer arterial wall, tends to rupture or fistulize rather than cause mass effect on neighboring structures [3,4]. HAPA most commonly occurs in the right or common hepatic artery and often has an identifiable prior injurious event such as abdominal trauma, iatrogenic hepatobiliary procedure, or local inflammation [3]. We describe a case of ruptured idiopathic common HAPA with unique sequelae of PVT, cavernous transformation, and PHTN-related variceal bleeding.
Case report
A 64-year-old Caucasian female with no past medical history presented to an outside institution with new-onset, nonbilious, nonbloody vomiting and severe epigastric abdominal pain. There was no history of alcohol use, liver disease, trauma, hepatobiliary procedures, pancreatitis, or hypercoagulable state. Computed tomography (CT) scan of her abdomen showed a ruptured common HAPA causing a large retroperitoneal hematoma (Fig. 1). She underwent emergent hepatic artery stent graft placement (6 mm × 5 cm covered Viabahn, Gore Medical, Flagstaff, AZ) and was discharged on aspirin and clopidogrel with resolution of her symptoms.Fig. 1 Initial presentation. Slices of contrast-enhanced CT in arterial (A-B) and delayed (C) phase showing ruptured common HAPA (arrowhead, A-C) prior to stent grafting. Ruptured HAPA measuring 4.0 cm × 2.4 cm × 2.3 cm (A-B) impinged on portal venous structures in the porta hepatis (C).
Fig 1
Seven months later, she represented with an episode of sudden-onset hematemesis. She reported several months of mild diffuse abdominal pain and distension, as well as 3 recent episodes of self-limited melena. Her blood pressure was 162/97 mm Hg and heart rate was 83 beats/min. Physical exam was significant for soft, slightly distended abdomen without any organomegaly. Labs showed a hemoglobin of 6.7 g/dL (reference range 12-16), platelets 342 k/mm3 (reference range 150-450), international normalized ratio 1.06 (reference range 1-2), normal leukocyte differential, and normal liver chemistries. CT abdomen and pelvis with contrast showed a resolving hematoma related to the ruptured HAPA, however with interval development of cavernous transformation of the portal vein. The liver appeared normal in size and echotexture, but there was trace ascites (Fig. 2). She was transferred to our institution for further management.Fig. 2 Second presentation at 7 months. Two slices of contrast-enhanced CT in venous phase showing previously ruptured common HAPA with stent graft (thick arrow, A-B) causing portal cavernous transformation (arrowhead, A-B). Superior mesenteric and splenic veins merging to form the stenotic native portal vein (thin arrow) giving rise to collaterals.
Fig 2
Upon arrival, she was hemodynamically stable. Aspirin and clopidogrel were held. Esophagogastroduodenoscopy identified large bleeding esophageal varices with red wale signs, which were banded. She developed hematochezia and a hemoglobin drop to 6.3 g/dL despite receiving 4 units of packed red blood cells over the next 3 days. Repeat endoscopy showed small esophageal varices and portal hypertensive gastropathy, but no active bleeding. She continued to have PHTN-related hematochezia requiring serial blood transfusions. During the course of her stay, she developed abdominal distension and ascites requiring paracentesis. Ascitic fluid analysis was consistent with spontaneous bacterial peritonitis (ascitic fluid: 800 WBC, 60% neutrophils), which was treated with ceftriaxone and intravenous albumin.
Interventional radiology was consulted and she underwent a transjugular intrahepatic portosystemic shunt (TIPS) creation with portal vein reconstruction utilizing trans-splenic access (Fig. 3). A 6-Fr sheath was inserted into the splenic vein via trans-splenic approach. A 0.035 inch (0.89 mm) Glide Advantage wire (Terumo Medical Corporation, Somerset, NJ) and 5-Fr Berenstein catheter were used to navigate through the native, now-stenotic main portal vein channel. A 10 mm snare was positioned in the mid-right intrahepatic portal vein. Via a 10-Fr sheath access in the right internal jugular vein, the snare was targeted and a Rosch-Uchida needle (Cook Medical, Bloomington, IN) was used to cross from the middle hepatic vein into the right portal vein. A 10 mm × 8 cm + 2 cm Viatorr (Gore Medical) was deployed and postdilated to 10 mm. Prolonged balloon angioplasty to 10 mm was also performed along the unstented, stenotic portion of the native portal vein. After TIPS, the mean portosystemic gradient decreased from 13 to 4 mm Hg. Her hematochezia and ascites resolved and she was discharged.Fig. 3 Second presentation at 7 months. Trans-splenic venogram during TIPS showing superior mesenteric and splenic veins merging to form the prestenotic portal vein (thin long arrow) with collaterals typical of cavernous transformation (arrowheads). The stenotic thread-like native main portal vein channel (short arrow), adjacent to common HAPA with stent graft (thick long arrow), was successfully recanalized as the TIPS was created from middle hepatic vein to right portal vein.
Fig 3
At 1-month follow-up, she was asymptomatic, and her TIPS was patent both by color Doppler ultrasound and a conventional venogram (Fig. 4). Subsequently at 3-month clinic follow-up, color Doppler ultrasound continued to show patent TIPS. Screening for hypercoagulability revealed Factor V Leiden (FVL) heterozygosity, but was negative for elevated homocysteine, antiphospholipid antibodies, and prothrombin G20210A.Fig. 4 Follow-up after second presentation. Conventional venogram 1-month post-TIPS showing brisk flow through TIPS without filling defect or anomaly. Nearby common HAPA with stent graft (thick long arrow).
Fig 4
Discussion
We present a patient with noncirrhotic, prehepatic PHTN-related variceal bleeding due to idiopathic ruptured HAPA and resultant portal vein compression and thrombosis. This was a unique clinical course for HAPA, which has a high risk for progression, fistulization, or rupture, and often presents as right upper quadrant pain, gastrointestinal bleeding, or hemoperitoneum [4].
Her clinical course with the development of PVT likely resulted from an interplay of HAPA-related extrinsic compression slowing portal flow combined with her inherited FVL hypercoagulability. Inherited or acquired hypercoagulability is frequently identified in patients with PVT: one study noted 26 of 36 noncirrhotic PVT patients had an identifiable hypercoagulable state [5]. FVL is the most common inherited hypercoagulability in those of European descent with 5% frequency. Interestingly, studies of both noncirrhotics and cirrhotics have noted no statistically different FVL frequency in PVT patients vs controls, with a trend toward increased FVL in one study [5], [6], [7], [8]. This is in sharp contrast to statistically higher prothrombin G20210A frequency in PVT, which suggests that FVL alone may not play as potent of a role in stimulating PVT development.
Noncirrhotic PVT is rare compared to cirrhosis-related PVT [9]. Not surprisingly, there is a lack of guidelines for PVT screening in at-risk noncirrhotic patients in contrast to cirrhotic patients, where guidelines exist for ultrasound screening due to higher risk for hepatocellular carcinoma during which PVT may be found [10]. The key benefit to identifying PVT early is the possibility of early anticoagulation initiation with low molecular weight heparin or vitamin K antagonists, which can help dissolve clots and halt thrombus extension [9,11]. Though rare, PVT expanding proximally into superior mesenteric vein can cause life-threatening intestinal infarction.
In our patient, HAPA rupture resulted in significant extrinsic compression of the portal vein at the porta hepatis. Given the slow-resolving and persistent nature of this hematoma's mass effect on the portal vein, we posit that our patient could have benefited from regular PVT screening, hypercoagulability testing, and consideration of pre-emptive TIPS before she developed refractory PHTN-related bleeding. This raises an important management consideration, because hematoma is not limited to rare pseudoaneursymal ruptures and can arise after trauma, biopsy, or surgery. Of note, our patient did undergo CT abdominal imaging to follow-up HAPA stent graft placement 1 month after her procedure, but did not have any subsequent follow-up due to the COVID-19 pandemic.
The development of complete PVT with cavernous transformation has historically posed technical challenges for performing TIPS to treat refractory PHTN-related bleeding [12]. Various strategies to facilitate locating and navigating through the intrahepatic portal vein have included ultrasound guidance and percutaneous transhepatic access [13]. The strategy we chose, portal vein reconstruction with trans-splenic access, has emerged as a very safe and effective strategy for treating complete PVT with cavernous transformation in both cirrhotics [14,15] and noncirrhotics [16].
Patients with PVT without other comorbidities including ours have a good prognosis [17]. This report highlights PVT and PHTN development despite timely HAPA stenting and resolving extrinsic compression, which underscores the need for follow-up, hypercoagulability screening, and definitive intervention in this unique patient population.
Authors’ contributions
K. Ni provided care from endoscopic service and wrote the manuscript. C. Jansson-Knodell provided care from endoscopic service, helped interpret clinical findings, and revised the manuscript. M.E. Krosin and P.M. Haste performed TIPS creation with portal vein reconstruction, interpreted radiological findings, and revised the manuscript. I. Obaitan and L.E. Nephew led the care from hepatology service, helped interpret clinical findings, and revised the manuscript. S.V. Sagi performed endoscopic interventions, helped interpret clinical findings, and revised the manuscript.
Patient consent
Informed patient consent was obtained for publishing this case report.
Funding: KN was supported by a NRSA from NIH/NHLBI, USA (1F30HL136169-03). No other financial support.
Competing Interests: Authors have no conflicts or competing interests to declare. | ASPIRIN, CLOPIDOGREL BISULFATE | DrugsGivenReaction | CC BY-NC-ND | 33552333 | 19,270,194 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Oesophageal varices haemorrhage'. | Ruptured idiopathic hepatic artery pseudoaneurysm causing portal vein thrombosis with portal hypertension and variceal bleeding.
Portal vein thrombosis (PVT) is an important cause of noncirrhotic portal hypertension. Noncancerous extrinsic compression of portal vein to drive PVT formation is rare, but important to identify. A 64-year-old female with idiopathic hepatic artery pseudoaneurysm (HAPA) rupture 7 months prior presented with acute-onset hematemesis and melena and was found to have prehepatic portal hypertensive variceal bleeding. Her HAPA-related retroperitoneal hematoma had resulted in portal vein compression, thrombosis, and cavernous transformation despite prompt stent graft placement across the ruptured HAPA, and required definitive treatment by transjugular intrahepatic portosystemic shunt creation with portal vein reconstruction utilizing a trans-splenic access. This case highlights the importance of interval abdominal imaging and hypercoagulability screening for noncirrhotic patients at-risk for PVT, which identified the patient as a heterozygous carrier of Factor V Leiden.
Introduction
The prehepatic occlusion of the portal vein by thrombus is an important cause of portal hypertension (PHTN) [1]. Portal vein thrombosis (PVT) occurs in diverse clinical contexts that drive thrombus formation by potentially enabling multiple elements of Virchow's triad (stasis, endothelial injury, and hypercoagulability) [2]. Not surprisingly, local factors acting in the vicinity of portal vein including inflammation, infection, malignancy, and iatrogenic injury are frequently identified, as well systemic factors such as inherited or acquired hypercoagulability.
Hepatic artery pseudoaneurysm (HAPA), which lacks a complete 3-layer arterial wall, tends to rupture or fistulize rather than cause mass effect on neighboring structures [3,4]. HAPA most commonly occurs in the right or common hepatic artery and often has an identifiable prior injurious event such as abdominal trauma, iatrogenic hepatobiliary procedure, or local inflammation [3]. We describe a case of ruptured idiopathic common HAPA with unique sequelae of PVT, cavernous transformation, and PHTN-related variceal bleeding.
Case report
A 64-year-old Caucasian female with no past medical history presented to an outside institution with new-onset, nonbilious, nonbloody vomiting and severe epigastric abdominal pain. There was no history of alcohol use, liver disease, trauma, hepatobiliary procedures, pancreatitis, or hypercoagulable state. Computed tomography (CT) scan of her abdomen showed a ruptured common HAPA causing a large retroperitoneal hematoma (Fig. 1). She underwent emergent hepatic artery stent graft placement (6 mm × 5 cm covered Viabahn, Gore Medical, Flagstaff, AZ) and was discharged on aspirin and clopidogrel with resolution of her symptoms.Fig. 1 Initial presentation. Slices of contrast-enhanced CT in arterial (A-B) and delayed (C) phase showing ruptured common HAPA (arrowhead, A-C) prior to stent grafting. Ruptured HAPA measuring 4.0 cm × 2.4 cm × 2.3 cm (A-B) impinged on portal venous structures in the porta hepatis (C).
Fig 1
Seven months later, she represented with an episode of sudden-onset hematemesis. She reported several months of mild diffuse abdominal pain and distension, as well as 3 recent episodes of self-limited melena. Her blood pressure was 162/97 mm Hg and heart rate was 83 beats/min. Physical exam was significant for soft, slightly distended abdomen without any organomegaly. Labs showed a hemoglobin of 6.7 g/dL (reference range 12-16), platelets 342 k/mm3 (reference range 150-450), international normalized ratio 1.06 (reference range 1-2), normal leukocyte differential, and normal liver chemistries. CT abdomen and pelvis with contrast showed a resolving hematoma related to the ruptured HAPA, however with interval development of cavernous transformation of the portal vein. The liver appeared normal in size and echotexture, but there was trace ascites (Fig. 2). She was transferred to our institution for further management.Fig. 2 Second presentation at 7 months. Two slices of contrast-enhanced CT in venous phase showing previously ruptured common HAPA with stent graft (thick arrow, A-B) causing portal cavernous transformation (arrowhead, A-B). Superior mesenteric and splenic veins merging to form the stenotic native portal vein (thin arrow) giving rise to collaterals.
Fig 2
Upon arrival, she was hemodynamically stable. Aspirin and clopidogrel were held. Esophagogastroduodenoscopy identified large bleeding esophageal varices with red wale signs, which were banded. She developed hematochezia and a hemoglobin drop to 6.3 g/dL despite receiving 4 units of packed red blood cells over the next 3 days. Repeat endoscopy showed small esophageal varices and portal hypertensive gastropathy, but no active bleeding. She continued to have PHTN-related hematochezia requiring serial blood transfusions. During the course of her stay, she developed abdominal distension and ascites requiring paracentesis. Ascitic fluid analysis was consistent with spontaneous bacterial peritonitis (ascitic fluid: 800 WBC, 60% neutrophils), which was treated with ceftriaxone and intravenous albumin.
Interventional radiology was consulted and she underwent a transjugular intrahepatic portosystemic shunt (TIPS) creation with portal vein reconstruction utilizing trans-splenic access (Fig. 3). A 6-Fr sheath was inserted into the splenic vein via trans-splenic approach. A 0.035 inch (0.89 mm) Glide Advantage wire (Terumo Medical Corporation, Somerset, NJ) and 5-Fr Berenstein catheter were used to navigate through the native, now-stenotic main portal vein channel. A 10 mm snare was positioned in the mid-right intrahepatic portal vein. Via a 10-Fr sheath access in the right internal jugular vein, the snare was targeted and a Rosch-Uchida needle (Cook Medical, Bloomington, IN) was used to cross from the middle hepatic vein into the right portal vein. A 10 mm × 8 cm + 2 cm Viatorr (Gore Medical) was deployed and postdilated to 10 mm. Prolonged balloon angioplasty to 10 mm was also performed along the unstented, stenotic portion of the native portal vein. After TIPS, the mean portosystemic gradient decreased from 13 to 4 mm Hg. Her hematochezia and ascites resolved and she was discharged.Fig. 3 Second presentation at 7 months. Trans-splenic venogram during TIPS showing superior mesenteric and splenic veins merging to form the prestenotic portal vein (thin long arrow) with collaterals typical of cavernous transformation (arrowheads). The stenotic thread-like native main portal vein channel (short arrow), adjacent to common HAPA with stent graft (thick long arrow), was successfully recanalized as the TIPS was created from middle hepatic vein to right portal vein.
Fig 3
At 1-month follow-up, she was asymptomatic, and her TIPS was patent both by color Doppler ultrasound and a conventional venogram (Fig. 4). Subsequently at 3-month clinic follow-up, color Doppler ultrasound continued to show patent TIPS. Screening for hypercoagulability revealed Factor V Leiden (FVL) heterozygosity, but was negative for elevated homocysteine, antiphospholipid antibodies, and prothrombin G20210A.Fig. 4 Follow-up after second presentation. Conventional venogram 1-month post-TIPS showing brisk flow through TIPS without filling defect or anomaly. Nearby common HAPA with stent graft (thick long arrow).
Fig 4
Discussion
We present a patient with noncirrhotic, prehepatic PHTN-related variceal bleeding due to idiopathic ruptured HAPA and resultant portal vein compression and thrombosis. This was a unique clinical course for HAPA, which has a high risk for progression, fistulization, or rupture, and often presents as right upper quadrant pain, gastrointestinal bleeding, or hemoperitoneum [4].
Her clinical course with the development of PVT likely resulted from an interplay of HAPA-related extrinsic compression slowing portal flow combined with her inherited FVL hypercoagulability. Inherited or acquired hypercoagulability is frequently identified in patients with PVT: one study noted 26 of 36 noncirrhotic PVT patients had an identifiable hypercoagulable state [5]. FVL is the most common inherited hypercoagulability in those of European descent with 5% frequency. Interestingly, studies of both noncirrhotics and cirrhotics have noted no statistically different FVL frequency in PVT patients vs controls, with a trend toward increased FVL in one study [5], [6], [7], [8]. This is in sharp contrast to statistically higher prothrombin G20210A frequency in PVT, which suggests that FVL alone may not play as potent of a role in stimulating PVT development.
Noncirrhotic PVT is rare compared to cirrhosis-related PVT [9]. Not surprisingly, there is a lack of guidelines for PVT screening in at-risk noncirrhotic patients in contrast to cirrhotic patients, where guidelines exist for ultrasound screening due to higher risk for hepatocellular carcinoma during which PVT may be found [10]. The key benefit to identifying PVT early is the possibility of early anticoagulation initiation with low molecular weight heparin or vitamin K antagonists, which can help dissolve clots and halt thrombus extension [9,11]. Though rare, PVT expanding proximally into superior mesenteric vein can cause life-threatening intestinal infarction.
In our patient, HAPA rupture resulted in significant extrinsic compression of the portal vein at the porta hepatis. Given the slow-resolving and persistent nature of this hematoma's mass effect on the portal vein, we posit that our patient could have benefited from regular PVT screening, hypercoagulability testing, and consideration of pre-emptive TIPS before she developed refractory PHTN-related bleeding. This raises an important management consideration, because hematoma is not limited to rare pseudoaneursymal ruptures and can arise after trauma, biopsy, or surgery. Of note, our patient did undergo CT abdominal imaging to follow-up HAPA stent graft placement 1 month after her procedure, but did not have any subsequent follow-up due to the COVID-19 pandemic.
The development of complete PVT with cavernous transformation has historically posed technical challenges for performing TIPS to treat refractory PHTN-related bleeding [12]. Various strategies to facilitate locating and navigating through the intrahepatic portal vein have included ultrasound guidance and percutaneous transhepatic access [13]. The strategy we chose, portal vein reconstruction with trans-splenic access, has emerged as a very safe and effective strategy for treating complete PVT with cavernous transformation in both cirrhotics [14,15] and noncirrhotics [16].
Patients with PVT without other comorbidities including ours have a good prognosis [17]. This report highlights PVT and PHTN development despite timely HAPA stenting and resolving extrinsic compression, which underscores the need for follow-up, hypercoagulability screening, and definitive intervention in this unique patient population.
Authors’ contributions
K. Ni provided care from endoscopic service and wrote the manuscript. C. Jansson-Knodell provided care from endoscopic service, helped interpret clinical findings, and revised the manuscript. M.E. Krosin and P.M. Haste performed TIPS creation with portal vein reconstruction, interpreted radiological findings, and revised the manuscript. I. Obaitan and L.E. Nephew led the care from hepatology service, helped interpret clinical findings, and revised the manuscript. S.V. Sagi performed endoscopic interventions, helped interpret clinical findings, and revised the manuscript.
Patient consent
Informed patient consent was obtained for publishing this case report.
Funding: KN was supported by a NRSA from NIH/NHLBI, USA (1F30HL136169-03). No other financial support.
Competing Interests: Authors have no conflicts or competing interests to declare. | ASPIRIN, CLOPIDOGREL BISULFATE | DrugsGivenReaction | CC BY-NC-ND | 33552333 | 19,270,194 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Peritonitis bacterial'. | Ruptured idiopathic hepatic artery pseudoaneurysm causing portal vein thrombosis with portal hypertension and variceal bleeding.
Portal vein thrombosis (PVT) is an important cause of noncirrhotic portal hypertension. Noncancerous extrinsic compression of portal vein to drive PVT formation is rare, but important to identify. A 64-year-old female with idiopathic hepatic artery pseudoaneurysm (HAPA) rupture 7 months prior presented with acute-onset hematemesis and melena and was found to have prehepatic portal hypertensive variceal bleeding. Her HAPA-related retroperitoneal hematoma had resulted in portal vein compression, thrombosis, and cavernous transformation despite prompt stent graft placement across the ruptured HAPA, and required definitive treatment by transjugular intrahepatic portosystemic shunt creation with portal vein reconstruction utilizing a trans-splenic access. This case highlights the importance of interval abdominal imaging and hypercoagulability screening for noncirrhotic patients at-risk for PVT, which identified the patient as a heterozygous carrier of Factor V Leiden.
Introduction
The prehepatic occlusion of the portal vein by thrombus is an important cause of portal hypertension (PHTN) [1]. Portal vein thrombosis (PVT) occurs in diverse clinical contexts that drive thrombus formation by potentially enabling multiple elements of Virchow's triad (stasis, endothelial injury, and hypercoagulability) [2]. Not surprisingly, local factors acting in the vicinity of portal vein including inflammation, infection, malignancy, and iatrogenic injury are frequently identified, as well systemic factors such as inherited or acquired hypercoagulability.
Hepatic artery pseudoaneurysm (HAPA), which lacks a complete 3-layer arterial wall, tends to rupture or fistulize rather than cause mass effect on neighboring structures [3,4]. HAPA most commonly occurs in the right or common hepatic artery and often has an identifiable prior injurious event such as abdominal trauma, iatrogenic hepatobiliary procedure, or local inflammation [3]. We describe a case of ruptured idiopathic common HAPA with unique sequelae of PVT, cavernous transformation, and PHTN-related variceal bleeding.
Case report
A 64-year-old Caucasian female with no past medical history presented to an outside institution with new-onset, nonbilious, nonbloody vomiting and severe epigastric abdominal pain. There was no history of alcohol use, liver disease, trauma, hepatobiliary procedures, pancreatitis, or hypercoagulable state. Computed tomography (CT) scan of her abdomen showed a ruptured common HAPA causing a large retroperitoneal hematoma (Fig. 1). She underwent emergent hepatic artery stent graft placement (6 mm × 5 cm covered Viabahn, Gore Medical, Flagstaff, AZ) and was discharged on aspirin and clopidogrel with resolution of her symptoms.Fig. 1 Initial presentation. Slices of contrast-enhanced CT in arterial (A-B) and delayed (C) phase showing ruptured common HAPA (arrowhead, A-C) prior to stent grafting. Ruptured HAPA measuring 4.0 cm × 2.4 cm × 2.3 cm (A-B) impinged on portal venous structures in the porta hepatis (C).
Fig 1
Seven months later, she represented with an episode of sudden-onset hematemesis. She reported several months of mild diffuse abdominal pain and distension, as well as 3 recent episodes of self-limited melena. Her blood pressure was 162/97 mm Hg and heart rate was 83 beats/min. Physical exam was significant for soft, slightly distended abdomen without any organomegaly. Labs showed a hemoglobin of 6.7 g/dL (reference range 12-16), platelets 342 k/mm3 (reference range 150-450), international normalized ratio 1.06 (reference range 1-2), normal leukocyte differential, and normal liver chemistries. CT abdomen and pelvis with contrast showed a resolving hematoma related to the ruptured HAPA, however with interval development of cavernous transformation of the portal vein. The liver appeared normal in size and echotexture, but there was trace ascites (Fig. 2). She was transferred to our institution for further management.Fig. 2 Second presentation at 7 months. Two slices of contrast-enhanced CT in venous phase showing previously ruptured common HAPA with stent graft (thick arrow, A-B) causing portal cavernous transformation (arrowhead, A-B). Superior mesenteric and splenic veins merging to form the stenotic native portal vein (thin arrow) giving rise to collaterals.
Fig 2
Upon arrival, she was hemodynamically stable. Aspirin and clopidogrel were held. Esophagogastroduodenoscopy identified large bleeding esophageal varices with red wale signs, which were banded. She developed hematochezia and a hemoglobin drop to 6.3 g/dL despite receiving 4 units of packed red blood cells over the next 3 days. Repeat endoscopy showed small esophageal varices and portal hypertensive gastropathy, but no active bleeding. She continued to have PHTN-related hematochezia requiring serial blood transfusions. During the course of her stay, she developed abdominal distension and ascites requiring paracentesis. Ascitic fluid analysis was consistent with spontaneous bacterial peritonitis (ascitic fluid: 800 WBC, 60% neutrophils), which was treated with ceftriaxone and intravenous albumin.
Interventional radiology was consulted and she underwent a transjugular intrahepatic portosystemic shunt (TIPS) creation with portal vein reconstruction utilizing trans-splenic access (Fig. 3). A 6-Fr sheath was inserted into the splenic vein via trans-splenic approach. A 0.035 inch (0.89 mm) Glide Advantage wire (Terumo Medical Corporation, Somerset, NJ) and 5-Fr Berenstein catheter were used to navigate through the native, now-stenotic main portal vein channel. A 10 mm snare was positioned in the mid-right intrahepatic portal vein. Via a 10-Fr sheath access in the right internal jugular vein, the snare was targeted and a Rosch-Uchida needle (Cook Medical, Bloomington, IN) was used to cross from the middle hepatic vein into the right portal vein. A 10 mm × 8 cm + 2 cm Viatorr (Gore Medical) was deployed and postdilated to 10 mm. Prolonged balloon angioplasty to 10 mm was also performed along the unstented, stenotic portion of the native portal vein. After TIPS, the mean portosystemic gradient decreased from 13 to 4 mm Hg. Her hematochezia and ascites resolved and she was discharged.Fig. 3 Second presentation at 7 months. Trans-splenic venogram during TIPS showing superior mesenteric and splenic veins merging to form the prestenotic portal vein (thin long arrow) with collaterals typical of cavernous transformation (arrowheads). The stenotic thread-like native main portal vein channel (short arrow), adjacent to common HAPA with stent graft (thick long arrow), was successfully recanalized as the TIPS was created from middle hepatic vein to right portal vein.
Fig 3
At 1-month follow-up, she was asymptomatic, and her TIPS was patent both by color Doppler ultrasound and a conventional venogram (Fig. 4). Subsequently at 3-month clinic follow-up, color Doppler ultrasound continued to show patent TIPS. Screening for hypercoagulability revealed Factor V Leiden (FVL) heterozygosity, but was negative for elevated homocysteine, antiphospholipid antibodies, and prothrombin G20210A.Fig. 4 Follow-up after second presentation. Conventional venogram 1-month post-TIPS showing brisk flow through TIPS without filling defect or anomaly. Nearby common HAPA with stent graft (thick long arrow).
Fig 4
Discussion
We present a patient with noncirrhotic, prehepatic PHTN-related variceal bleeding due to idiopathic ruptured HAPA and resultant portal vein compression and thrombosis. This was a unique clinical course for HAPA, which has a high risk for progression, fistulization, or rupture, and often presents as right upper quadrant pain, gastrointestinal bleeding, or hemoperitoneum [4].
Her clinical course with the development of PVT likely resulted from an interplay of HAPA-related extrinsic compression slowing portal flow combined with her inherited FVL hypercoagulability. Inherited or acquired hypercoagulability is frequently identified in patients with PVT: one study noted 26 of 36 noncirrhotic PVT patients had an identifiable hypercoagulable state [5]. FVL is the most common inherited hypercoagulability in those of European descent with 5% frequency. Interestingly, studies of both noncirrhotics and cirrhotics have noted no statistically different FVL frequency in PVT patients vs controls, with a trend toward increased FVL in one study [5], [6], [7], [8]. This is in sharp contrast to statistically higher prothrombin G20210A frequency in PVT, which suggests that FVL alone may not play as potent of a role in stimulating PVT development.
Noncirrhotic PVT is rare compared to cirrhosis-related PVT [9]. Not surprisingly, there is a lack of guidelines for PVT screening in at-risk noncirrhotic patients in contrast to cirrhotic patients, where guidelines exist for ultrasound screening due to higher risk for hepatocellular carcinoma during which PVT may be found [10]. The key benefit to identifying PVT early is the possibility of early anticoagulation initiation with low molecular weight heparin or vitamin K antagonists, which can help dissolve clots and halt thrombus extension [9,11]. Though rare, PVT expanding proximally into superior mesenteric vein can cause life-threatening intestinal infarction.
In our patient, HAPA rupture resulted in significant extrinsic compression of the portal vein at the porta hepatis. Given the slow-resolving and persistent nature of this hematoma's mass effect on the portal vein, we posit that our patient could have benefited from regular PVT screening, hypercoagulability testing, and consideration of pre-emptive TIPS before she developed refractory PHTN-related bleeding. This raises an important management consideration, because hematoma is not limited to rare pseudoaneursymal ruptures and can arise after trauma, biopsy, or surgery. Of note, our patient did undergo CT abdominal imaging to follow-up HAPA stent graft placement 1 month after her procedure, but did not have any subsequent follow-up due to the COVID-19 pandemic.
The development of complete PVT with cavernous transformation has historically posed technical challenges for performing TIPS to treat refractory PHTN-related bleeding [12]. Various strategies to facilitate locating and navigating through the intrahepatic portal vein have included ultrasound guidance and percutaneous transhepatic access [13]. The strategy we chose, portal vein reconstruction with trans-splenic access, has emerged as a very safe and effective strategy for treating complete PVT with cavernous transformation in both cirrhotics [14,15] and noncirrhotics [16].
Patients with PVT without other comorbidities including ours have a good prognosis [17]. This report highlights PVT and PHTN development despite timely HAPA stenting and resolving extrinsic compression, which underscores the need for follow-up, hypercoagulability screening, and definitive intervention in this unique patient population.
Authors’ contributions
K. Ni provided care from endoscopic service and wrote the manuscript. C. Jansson-Knodell provided care from endoscopic service, helped interpret clinical findings, and revised the manuscript. M.E. Krosin and P.M. Haste performed TIPS creation with portal vein reconstruction, interpreted radiological findings, and revised the manuscript. I. Obaitan and L.E. Nephew led the care from hepatology service, helped interpret clinical findings, and revised the manuscript. S.V. Sagi performed endoscopic interventions, helped interpret clinical findings, and revised the manuscript.
Patient consent
Informed patient consent was obtained for publishing this case report.
Funding: KN was supported by a NRSA from NIH/NHLBI, USA (1F30HL136169-03). No other financial support.
Competing Interests: Authors have no conflicts or competing interests to declare. | ASPIRIN, CLOPIDOGREL BISULFATE | DrugsGivenReaction | CC BY-NC-ND | 33552333 | 19,270,194 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Retroperitoneal haematoma'. | Ruptured idiopathic hepatic artery pseudoaneurysm causing portal vein thrombosis with portal hypertension and variceal bleeding.
Portal vein thrombosis (PVT) is an important cause of noncirrhotic portal hypertension. Noncancerous extrinsic compression of portal vein to drive PVT formation is rare, but important to identify. A 64-year-old female with idiopathic hepatic artery pseudoaneurysm (HAPA) rupture 7 months prior presented with acute-onset hematemesis and melena and was found to have prehepatic portal hypertensive variceal bleeding. Her HAPA-related retroperitoneal hematoma had resulted in portal vein compression, thrombosis, and cavernous transformation despite prompt stent graft placement across the ruptured HAPA, and required definitive treatment by transjugular intrahepatic portosystemic shunt creation with portal vein reconstruction utilizing a trans-splenic access. This case highlights the importance of interval abdominal imaging and hypercoagulability screening for noncirrhotic patients at-risk for PVT, which identified the patient as a heterozygous carrier of Factor V Leiden.
Introduction
The prehepatic occlusion of the portal vein by thrombus is an important cause of portal hypertension (PHTN) [1]. Portal vein thrombosis (PVT) occurs in diverse clinical contexts that drive thrombus formation by potentially enabling multiple elements of Virchow's triad (stasis, endothelial injury, and hypercoagulability) [2]. Not surprisingly, local factors acting in the vicinity of portal vein including inflammation, infection, malignancy, and iatrogenic injury are frequently identified, as well systemic factors such as inherited or acquired hypercoagulability.
Hepatic artery pseudoaneurysm (HAPA), which lacks a complete 3-layer arterial wall, tends to rupture or fistulize rather than cause mass effect on neighboring structures [3,4]. HAPA most commonly occurs in the right or common hepatic artery and often has an identifiable prior injurious event such as abdominal trauma, iatrogenic hepatobiliary procedure, or local inflammation [3]. We describe a case of ruptured idiopathic common HAPA with unique sequelae of PVT, cavernous transformation, and PHTN-related variceal bleeding.
Case report
A 64-year-old Caucasian female with no past medical history presented to an outside institution with new-onset, nonbilious, nonbloody vomiting and severe epigastric abdominal pain. There was no history of alcohol use, liver disease, trauma, hepatobiliary procedures, pancreatitis, or hypercoagulable state. Computed tomography (CT) scan of her abdomen showed a ruptured common HAPA causing a large retroperitoneal hematoma (Fig. 1). She underwent emergent hepatic artery stent graft placement (6 mm × 5 cm covered Viabahn, Gore Medical, Flagstaff, AZ) and was discharged on aspirin and clopidogrel with resolution of her symptoms.Fig. 1 Initial presentation. Slices of contrast-enhanced CT in arterial (A-B) and delayed (C) phase showing ruptured common HAPA (arrowhead, A-C) prior to stent grafting. Ruptured HAPA measuring 4.0 cm × 2.4 cm × 2.3 cm (A-B) impinged on portal venous structures in the porta hepatis (C).
Fig 1
Seven months later, she represented with an episode of sudden-onset hematemesis. She reported several months of mild diffuse abdominal pain and distension, as well as 3 recent episodes of self-limited melena. Her blood pressure was 162/97 mm Hg and heart rate was 83 beats/min. Physical exam was significant for soft, slightly distended abdomen without any organomegaly. Labs showed a hemoglobin of 6.7 g/dL (reference range 12-16), platelets 342 k/mm3 (reference range 150-450), international normalized ratio 1.06 (reference range 1-2), normal leukocyte differential, and normal liver chemistries. CT abdomen and pelvis with contrast showed a resolving hematoma related to the ruptured HAPA, however with interval development of cavernous transformation of the portal vein. The liver appeared normal in size and echotexture, but there was trace ascites (Fig. 2). She was transferred to our institution for further management.Fig. 2 Second presentation at 7 months. Two slices of contrast-enhanced CT in venous phase showing previously ruptured common HAPA with stent graft (thick arrow, A-B) causing portal cavernous transformation (arrowhead, A-B). Superior mesenteric and splenic veins merging to form the stenotic native portal vein (thin arrow) giving rise to collaterals.
Fig 2
Upon arrival, she was hemodynamically stable. Aspirin and clopidogrel were held. Esophagogastroduodenoscopy identified large bleeding esophageal varices with red wale signs, which were banded. She developed hematochezia and a hemoglobin drop to 6.3 g/dL despite receiving 4 units of packed red blood cells over the next 3 days. Repeat endoscopy showed small esophageal varices and portal hypertensive gastropathy, but no active bleeding. She continued to have PHTN-related hematochezia requiring serial blood transfusions. During the course of her stay, she developed abdominal distension and ascites requiring paracentesis. Ascitic fluid analysis was consistent with spontaneous bacterial peritonitis (ascitic fluid: 800 WBC, 60% neutrophils), which was treated with ceftriaxone and intravenous albumin.
Interventional radiology was consulted and she underwent a transjugular intrahepatic portosystemic shunt (TIPS) creation with portal vein reconstruction utilizing trans-splenic access (Fig. 3). A 6-Fr sheath was inserted into the splenic vein via trans-splenic approach. A 0.035 inch (0.89 mm) Glide Advantage wire (Terumo Medical Corporation, Somerset, NJ) and 5-Fr Berenstein catheter were used to navigate through the native, now-stenotic main portal vein channel. A 10 mm snare was positioned in the mid-right intrahepatic portal vein. Via a 10-Fr sheath access in the right internal jugular vein, the snare was targeted and a Rosch-Uchida needle (Cook Medical, Bloomington, IN) was used to cross from the middle hepatic vein into the right portal vein. A 10 mm × 8 cm + 2 cm Viatorr (Gore Medical) was deployed and postdilated to 10 mm. Prolonged balloon angioplasty to 10 mm was also performed along the unstented, stenotic portion of the native portal vein. After TIPS, the mean portosystemic gradient decreased from 13 to 4 mm Hg. Her hematochezia and ascites resolved and she was discharged.Fig. 3 Second presentation at 7 months. Trans-splenic venogram during TIPS showing superior mesenteric and splenic veins merging to form the prestenotic portal vein (thin long arrow) with collaterals typical of cavernous transformation (arrowheads). The stenotic thread-like native main portal vein channel (short arrow), adjacent to common HAPA with stent graft (thick long arrow), was successfully recanalized as the TIPS was created from middle hepatic vein to right portal vein.
Fig 3
At 1-month follow-up, she was asymptomatic, and her TIPS was patent both by color Doppler ultrasound and a conventional venogram (Fig. 4). Subsequently at 3-month clinic follow-up, color Doppler ultrasound continued to show patent TIPS. Screening for hypercoagulability revealed Factor V Leiden (FVL) heterozygosity, but was negative for elevated homocysteine, antiphospholipid antibodies, and prothrombin G20210A.Fig. 4 Follow-up after second presentation. Conventional venogram 1-month post-TIPS showing brisk flow through TIPS without filling defect or anomaly. Nearby common HAPA with stent graft (thick long arrow).
Fig 4
Discussion
We present a patient with noncirrhotic, prehepatic PHTN-related variceal bleeding due to idiopathic ruptured HAPA and resultant portal vein compression and thrombosis. This was a unique clinical course for HAPA, which has a high risk for progression, fistulization, or rupture, and often presents as right upper quadrant pain, gastrointestinal bleeding, or hemoperitoneum [4].
Her clinical course with the development of PVT likely resulted from an interplay of HAPA-related extrinsic compression slowing portal flow combined with her inherited FVL hypercoagulability. Inherited or acquired hypercoagulability is frequently identified in patients with PVT: one study noted 26 of 36 noncirrhotic PVT patients had an identifiable hypercoagulable state [5]. FVL is the most common inherited hypercoagulability in those of European descent with 5% frequency. Interestingly, studies of both noncirrhotics and cirrhotics have noted no statistically different FVL frequency in PVT patients vs controls, with a trend toward increased FVL in one study [5], [6], [7], [8]. This is in sharp contrast to statistically higher prothrombin G20210A frequency in PVT, which suggests that FVL alone may not play as potent of a role in stimulating PVT development.
Noncirrhotic PVT is rare compared to cirrhosis-related PVT [9]. Not surprisingly, there is a lack of guidelines for PVT screening in at-risk noncirrhotic patients in contrast to cirrhotic patients, where guidelines exist for ultrasound screening due to higher risk for hepatocellular carcinoma during which PVT may be found [10]. The key benefit to identifying PVT early is the possibility of early anticoagulation initiation with low molecular weight heparin or vitamin K antagonists, which can help dissolve clots and halt thrombus extension [9,11]. Though rare, PVT expanding proximally into superior mesenteric vein can cause life-threatening intestinal infarction.
In our patient, HAPA rupture resulted in significant extrinsic compression of the portal vein at the porta hepatis. Given the slow-resolving and persistent nature of this hematoma's mass effect on the portal vein, we posit that our patient could have benefited from regular PVT screening, hypercoagulability testing, and consideration of pre-emptive TIPS before she developed refractory PHTN-related bleeding. This raises an important management consideration, because hematoma is not limited to rare pseudoaneursymal ruptures and can arise after trauma, biopsy, or surgery. Of note, our patient did undergo CT abdominal imaging to follow-up HAPA stent graft placement 1 month after her procedure, but did not have any subsequent follow-up due to the COVID-19 pandemic.
The development of complete PVT with cavernous transformation has historically posed technical challenges for performing TIPS to treat refractory PHTN-related bleeding [12]. Various strategies to facilitate locating and navigating through the intrahepatic portal vein have included ultrasound guidance and percutaneous transhepatic access [13]. The strategy we chose, portal vein reconstruction with trans-splenic access, has emerged as a very safe and effective strategy for treating complete PVT with cavernous transformation in both cirrhotics [14,15] and noncirrhotics [16].
Patients with PVT without other comorbidities including ours have a good prognosis [17]. This report highlights PVT and PHTN development despite timely HAPA stenting and resolving extrinsic compression, which underscores the need for follow-up, hypercoagulability screening, and definitive intervention in this unique patient population.
Authors’ contributions
K. Ni provided care from endoscopic service and wrote the manuscript. C. Jansson-Knodell provided care from endoscopic service, helped interpret clinical findings, and revised the manuscript. M.E. Krosin and P.M. Haste performed TIPS creation with portal vein reconstruction, interpreted radiological findings, and revised the manuscript. I. Obaitan and L.E. Nephew led the care from hepatology service, helped interpret clinical findings, and revised the manuscript. S.V. Sagi performed endoscopic interventions, helped interpret clinical findings, and revised the manuscript.
Patient consent
Informed patient consent was obtained for publishing this case report.
Funding: KN was supported by a NRSA from NIH/NHLBI, USA (1F30HL136169-03). No other financial support.
Competing Interests: Authors have no conflicts or competing interests to declare. | ASPIRIN, CLOPIDOGREL BISULFATE | DrugsGivenReaction | CC BY-NC-ND | 33552333 | 19,270,194 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug intolerance'. | Primary undifferentiated pleomorphic cardiac sarcoma presenting as right heart failure.
Right-sided heart failure is a common sequela of left heart failure and seldom presents as a primary disorder. The differential diagnosis of right heart failure includes a cardiac tumor. Cardiac malignancies are rare tumors with an overall poor prognosis. We evaluated a 69-year-old man who presented with a 3-week history of progressive lower extremity swelling, ascites, and scrotal swelling. Laboratory studies were significant only for mildly elevated liver function tests. CT scan of the abdomen and pelvis showed ascites, hepatic swelling, and a bland clot in the inferior vena cava extending from the level of the kidneys to the right atrium. A large mass originating from the right atrium was identified, and biopsy confirmed an undifferentiated pleomorphic cardiac sarcoma. Given the extensive tumor and clot burden, he was not an operative candidate. He developed portal hypertension with esophageal varices and expired due to variceal bleeding.
Background
Right-sided heart failure usually does not occur in isolation. Most often it presents as a manifestation of either left-sided heart failure or pulmonary pathology such as obstructive sleep apnea or pulmonary embolism. The potential for accumulation of significant amounts of fluid below the diaphragm may result in dramatic presentations of ascites, marked scrotal swelling, and lower extremity edema. Hepatic congestion from right heart failure leads to the complications of portal hypertension including esophageal varices and clotting disorders.
While the majority of right heart failure is caused by left heart failure, valvular disorders, and portal hypertension, it is incumbent on the medical team to ensure that other, less common conditions do not exist. Since the potential causes of right heart failure are extensive, primary right atrial malignancy is seldom considered. The current case was illustrative of the importance of a thorough differential diagnosis.
Case presentation
A 69-year-old male with a past medical history of diabetes mellitus type 2 presented to the emergency department with a 2-week history of progressively worsening bilateral lower extremity swelling and abdominal distention associated with mild weight loss and dyspnea on exertion. There was no previous history of cardiac, hepatic, or renal disease, and no history of hepatitis or alcohol abuse. He had recently been on a trip out of the country when his symptoms progressed to the point where he was no longer able to walk. He was evaluated at a local medical facility where he was started on several diuretics. Once his swelling receded, he returned back to the USA to be further evaluated. On initial clinical examination, he was found to be hypertensive (170/101) and tachycardic (104 beats per minute) with normal respirations and an oxygen saturation of 97% on room air. Physical examination was notable for bitemporal wasting, jugular venous distention, a tense distended abdomen, and 3+ pitting edema up to his bilateral hips.
Upon admission, a complete blood count was normal, and electrolytes were significant only for mildly decreased sodium at 131 millimoles (mmol) per liter. Creatinine clearance was normal and hemoglobin A1c was elevated at 7.3% (normal <5.7%). Alanine aminotransferase (ALT) was elevated at 174 International Units/liter (IU/L) (normal <55 IU/L), aspartate aminotransferase (AST) was high at 134 IU/L (normal 5-34 IU/L), and alkaline phosphatase was abnormal at 207 IU/L (normal 38-126 IU/L). Albumin was low at 3.2 grams/deciliter (g/dL) (normal 3.5-5.0 g/dL). Troponin I was negative. Prothrombin time (PT) was elevated at 20.9 seconds (normal ≤ 14.6 seconds) and International Normalized Ratio (INR) was 1.9 (normal 0.8-1.2). Hepatitis serologies were negative for hepatitis A, B, and C. HIV and tuberculosis testing were negative.
A computed tomographic (CT) study of the abdomen and pelvis revealed moderate ascites, liver congestion, and renal congestion. Bland thrombus was noted in the inferior vena cava (IVC) extending to the level of the renal veins. Evaluating more cephalad, the CT study showed bland thrombus filling the right atrium extending through the length of the superior vena cava (SVC), with the posterior aspect of the heart nearly encased by an irregular curvilinear mass. The mass was seen to extend along the left ventricular wall, along the posterior interventricular septum, and into the right atrium. This mass appeared to involve the medial diaphragmatic crus as well as adjacent mediastinal lymph nodes. The enhancing heterogeneous mass along the border of the left heart measured 7.0 × 3.0 cm (Fig. 1). Two 5-mm pulmonary nodules were noted to be suspicious for malignancy. A transthoracic echocardiogram showed a large, calcified, circular mass in the right atrium with an associated thickened pericardium (Fig. 2).Fig. 1 Abdomen/pelvis CT coronal reformat demonstrating thrombus extending from the right atrium (long red arrow) inferiorly to the level of the infra-renal inferior vena cava (short red arrow). Dense accumulation of intravenous contrast within the right atrium.
Fig 1Fig. 2 Abdomen/pelvis CT with contrast showing right atrial sarcoma extending into inferior vena cava (red arrow).
Fig. 2
Subsequently, a CT-guided core biopsy was performed. Microscopic histopathology revealed the presence of medium-sized hypochromatic spindled nuclei without prominent nucleoli and moderate eosinophilic cytoplasm with indistinct cell borders and immunostaining positive for vimentin, supporting the diagnosis of an undifferentiated pleomorphic sarcoma (Fig. 3).Fig. 3 Abdomen/pelvis CT coronal MIPS reformat demonstrating thrombus at the origin of the left renal vein (red arrow), contiguous with the IVC thrombosis.
Fig. 3
The patient arrived with a working diagnosis of congestive heart failure of uncertain etiology, presumed to be a sign of ischemia. However, given his negative cardiac history, unremarkable electrocardiogram and negative troponin I, imaging of the abdomen was ordered to determine the source and quantity of ascites. CT of the abdomen/pelvis showed moderate ascites, bilateral pleural effusions, and extensive clot formation in the IVC. The superior planes imaged included the heart, showing the massive extent of the clot throughout the length of the vena cava from the heart to the kidneys. Further inspection of the images revealed that mass as described as well as possible metastatic lesions in the lungs. A cardiac tumor, likely malignant, was diagnosed.
Transthoracic echocardiogram confirmed the presence of a right atrial mass of undetermined potential along with a constrictive epicardial mass as described. Percutaneous biopsy of the mass confirmed the core biopsy's aforementioned pathology.
Initial management included gentle diuresis and intravenous anticoagulation. Given the extensive nature of the clot, he was not deemed a candidate for thrombectomy. Thoracentesis and paracentesis combined with diuresis brought significant relief of symptoms. The patient developed esophageal varices along with portal hypertensive gastropathy, requiring several banding procedures for bleeding. The clot did extend into the renal veins, leading to acute kidney injury.
Discussions were held between hematology, oncology, hepatology, and cardiothoracic surgery. Given the extensive nature of both the tumor and the clot, he was not felt to be an operative candidate. The patient was not amenable initially to palliative care, hoping for a cure.
Due to his extensive mass and clot burden, he was unable to be offered an interventional procedure including resection and transitioned to compassionate use of pembrolizumab. He was readmitted 1.5 months later for hematemesis, melena, and anasarca along with have portal hypertension complications including bleeding 3+ esophageal varices requiring band ligation x4 and portal hypertensive gastropathy. Repeat TTE and CT showed the right atrial mass now extending external to the right heart chambers with a moderate pericardial effusion. He was medically stabilized with IV diuresis, paracentesis, and thoracentesis, and discharged with the plan to follow-up with GI for repeat upper endoscopy in 4-6 weeks. He was readmitted less than a month later for a hypervolemic exacerbation. Since the patient was unable to tolerate further immunotherapy, the multidisciplinary team and patient decided to focus on symptom management and strengthening at home. He expired 4 months after initial presentation during his fourth admission due to an esophageal variceal hemorrhage. A postmortem autopsy was not performed.
Discussion
Rapid onset of right-sided ventricular failure prompts the search for common cardiac etiologies including left-sided heart failure, mitral valve dysfunction, pulmonary hypertension, pulmonary emboli, myocarditis, pericardial fibrosis, or tricuspid valve dysfunction due to endocarditis or rheumatic myocarditis [1,2]. Despite a past medical history that was negative for the above conditions, this patient developed right-sided heart failure with rapid progression of expected stigmata including lower extremity edema, ascites, scrotal edema, liver engorgement, and portal hypertension with esophageal varices. While his initial presentation involved signs and symptoms below the diaphragm, further evaluation revealed that the source of his disease was a right atrial malignancy.
Primary cardiac malignancies are uncommon. Cardiac tumors have been noted in between 0.001% and 0.3% in autopsy series [3], [4], [5]. About 75% of cardiac tumors are benign [6]. Of all cardiac malignancies, about 75% are sarcomas [7,8]. Patients tend to be middle-age (unlike the current case) and present with advanced disease [9,10]. Undifferentiated pleomorphic sarcomas are a rare subtype of cardiac sarcomas, representing one-third of all primary cardiac sarcomas [4,11]. While cardiac malignancies may affect any structure from the endothelium to the pericardium [12], most undifferentiated pleomorphic sarcomas develop in the left atrium.
Because of the distensibility of the atria, atrial tumors can become quite extensive and bulky before producing symptoms. The onset of symptoms is often insidious, and diagnostic imaging including transthoracic echocardiogram and computed tomography demonstrate an intracardiac mass that is typically located in the left atrium in 81% of undifferentiated pleomorphic sarcomas [12]. The current patient presented with a tumor that essentially filled the right atrium, and arguably the majority of his symptoms were related more to the subsequent development of an extensive bland clot extending from the heart to the kidneys. Diagnosis using ultrasound, contrast CT, and/or MRI is followed by biopsy confirmation [13,14].
Cardiac sarcomas are typically aggressive tumors [4,15]. Complete surgical resection combined with adjuvant chemotherapy and/or radiation is recommended for resectable disease, although there is a high risk of rapid recurrence [16,17]. While it is often technically difficult, R0 resection has shown significantly better outcomes than R1 resection. Therapeutic success is often challenging and unfeasible due to the highly aggressive and invasive nature of the sarcoma, with positive surgical margins being an independent predictor for poor survival [18,19]. More recent surgical approaches have included autotransplantation wherein the heart is removed, the lesion is excised, the heart is reconstructed, then reimplanted [7,20]. Cardiac transplantation is an emerging option in select patients.
Unfortunately due to the lack of prevalence of the disease and therapeutic data, evidence-based recommendations on choice or timing of chemotherapy and radiation are challenging [21]. In a series by Abu Salah, adding neoadjuvant chemotherapy to radical surgery was found to improve outcomes in right heart sarcomas, with overall survival increasing from 9.5 to 20 months [22]. Overall prognosis for undifferentiated pleomorphic sarcomas remains very poor with a median survival of less than 1 year [11,19,23,24]. Immunotherapy and tyrosine kinase angiogenesis inhibitors have shown some benefit [25] while a phase 2 trial of the programmed cell death 1 inhibitor pembrolizumab showed limited efficacy [26] in the treatment of cardiac sarcomas (Fig. 4, Fig. 5).Fig. 4 TTE showing a large, calcified, circular mass in the right atrium (red arrow) with an associated thickened pericardium.
Fig. 4Fig. 5 High magnification microscopic histopathology with H&E staining revealed the presence of medium-sized hypochromatic spindled nuclei without prominent nucleoli and moderate eosinophilic cytoplasm with indistinct cell borders.
Fig. 5
Patient consent
Please check that all articles state that patient consent has been obtained. Please raise a query to the author if no such statement is present. | PEMBROLIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33552334 | 19,303,620 | 2021-04 |
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