Polypharmacy induced long QT and ventricular fibrillation in a child with leukemia

Öz

Dear Editor, Children receiving intensive chemotherapy frequently require multiple antimicrobial agents, which may increase the risk of drug-induced QT prolongation. Acquired long QT syndrome can predispose patients to life-threatening ventricular arrhythmias, including torsades de pointes and ventricular fibrillation (1). A 12-year-old girl with acute lymphoblastic leukemia (ALL, FAB L2) was treated according to the TRALL-2000 BFM protocol, including daunorubicin, vincristine, cyclophosphamide, cytarabine, 6-mercaptopurine, and dexamethasone. During chemotherapy, she developed febrile neutropenia unresponsive to empirical antibiotic therapy with sulperazone and amikacin, later escalated to teicoplanin and meropenem. Imaging studies revealed pulmonary and splenic lesions suggestive of invasive fungal infection. Antifungal therapy was initiated with amphotericin B but was switched to voriconazole due to an allergic reaction; caspofungin was subsequently added because of clinical deterioration. While receiving multiple potentially cardiotoxic and QT-prolonging agents, the patient developed ventricular fibrillation (VF) leading to cardiac arrest and was successfully resuscitated. Transthoracic echocardiography demonstrated dilated cardiomyopathy with a left ventricular ejection fraction of 25%. During treatment for heart failure, recurrent VF episodes necessitated transfer to the pediatric intensive care unit, where electrocardiography demonstrated a prolonged corrected QT interval (QTc) of 600 ms (Figure1). Blood cultures later grew Candida species. The patient was treated with antifungal therapy along with magnesium sulfate, amiodarone, metoprolol, and electrolyte replacement. During intensive care, QTc gradually normalized without further arrhythmias. Following completion of chemotherapy, the patient achieved remission. Over six years, QTc remained normal and cardiac function fully recovered. There was no family history or genetic evidence of congenital long QT syndrome or cardiomyopathy. Long QT syndrome (LQTS) is defined by QT interval prolongation on electrocardiography, with values ≥500 ms indicating a high risk of malignant arrhythmias such as torsades de pointes and ventricular fibrillation. Congenital forms result from mutations in cardiac ion channel genes, particularly potassium (KCNH2, KCNQ1) and sodium (SCN5A) channels, whereas acquired LQTS is more common and typically drug-induced (1). A wide range of medications have been implicated, including antiarrhythmics (particularly class IA and III agents), antibiotics (macrolides and fluoroquinolones), antifungal agents (e.g., triazoles such as voriconazole, fluconazole, itraconazole, and posaconazole), psychotropic drugs (e.g., haloperidol, thioridazine, sertindole), and gastrointestinal motility agents such as cisapride. Electrolyte abnormalities, including hypokalemia, hypocalcemia, and hypomagnesemia, which may occur with amphotericin B, further increase this risk. Drug-induced QT prolongation has been reported in approximately 0.7% of hospitalized patients, most often outside cardiology units (2). Several clinical factors predispose patients to acquired QT prolongation, including high drug doses, rapid administration, and the concomitant use of multiple QT-prolonging medications. Additional risk factors include diuretic use, bradycardia, renal or hepatic dysfunction, structural heart disease, and female sex (3). Information from drug labeling and pharmacovigilance databases is crucial for identifying QT-related risks and improving patient safety, particularly in patients receiving multiple QT-prolonging medications (4). In addition, antifungal agents may contribute not only to QT prolongation but also to myocardial dysfunction. Echinocandin-related cardiac toxicity has been suggested to involve mitochondrial injury and direct myocyte damage, particularly with high local exposure such as central line administration (5). This may partly explain the reversible cardiomyopathy observed in our patient. Careful ECG monitoring is therefore essential in patients receiving multiple medications, particularly those with severe underlying conditions. Our case highlights the risk of life-threatening arrhythmias associated with polypharmacy and underscores the importance of close cardiac monitoring during treatment.

Anahtar Kelimeler

• Drug-induced arrhythmia
• QT prolongation
• Polypharmacy
• Ventricular fibrillation
• Pediatric leukemia

Destekleyen Kurum

none

Etik Beyan

ETHICAL DECLARATIONS Conflict of Interest Statement: The authors have no conflicts of interest to declare. Financial Disclosure: The authors declared no financial support. Author Contributions: All of the authors declare that they have all participated in the design, execution, and analysis of the paper, and that they have approved the final version. Ethical approval was not required according to institutional policies. Verbal informed consent was obtained from the patient’s legal guardians for publication.

Pediatrik lösemi olgusunda polifarmasiye bağlı uzun QT ve ventriküler fibrilasyon

Öz

Acquired long QT and ventricular fibrillation during polypharmacy in childhood leukemia Dear Editor, Children receiving intensive chemotherapy frequently require multiple antimicrobial agents, which may increase the risk of drug-induced QT prolongation. Acquired long QT syndrome can predispose patients to life-threatening ventricular arrhythmias, including torsades de pointes and ventricular fibrillation (1). A 12-year-old girl with acute lymphoblastic leukemia (ALL, FAB L2) was treated according to the TRALL-2000 BFM protocol, including daunorubicin, vincristine, cyclophosphamide, cytarabine, 6-mercaptopurine, and dexamethasone. During chemotherapy, she developed febrile neutropenia unresponsive to empirical antibiotic therapy with sulperazone and amikacin, later escalated to teicoplanin and meropenem. Imaging studies revealed pulmonary and splenic lesions suggestive of invasive fungal infection. Antifungal therapy was initiated with amphotericin B but was switched to voriconazole due to an allergic reaction; caspofungin was subsequently added because of clinical deterioration. While receiving multiple potentially cardiotoxic and QT-prolonging agents, the patient developed ventricular fibrillation (VF) leading to cardiac arrest and was successfully resuscitated. Transthoracic echocardiography demonstrated dilated cardiomyopathy with a left ventricular ejection fraction of 25%. During treatment for heart failure, recurrent VF episodes necessitated transfer to the pediatric intensive care unit, where electrocardiography demonstrated a prolonged corrected QT interval (QTc) of 500 ms (Figure1). Blood cultures later grew Candida species. The patient was treated with antifungal therapy along with magnesium sulfate, amiodarone, metoprolol, and electrolyte replacement. During intensive care, QTc gradually normalized without further arrhythmias. Following completion of chemotherapy, the patient achieved remission. Over six years, QTc remained normal and cardiac function fully recovered. There was no family history or genetic evidence of congenital long QT syndrome or cardiomyopathy. Long QT syndrome (LQTS) is defined by QT interval prolongation on electrocardiography, with values ≥500 ms indicating a high risk of malignant arrhythmias such as torsades de pointes and ventricular fibrillation. Congenital forms result from mutations in cardiac ion channel genes, particularly potassium (KCNH2, KCNQ1) and sodium (SCN5A) channels, whereas acquired LQTS is more common and typically drug-induced (1). A wide range of medications have been implicated, including antiarrhythmics (particularly class IA and III agents), antibiotics (macrolides and fluoroquinolones), antifungal agents (e.g., triazoles such as voriconazole, fluconazole, itraconazole, and posaconazole), psychotropic drugs (e.g., haloperidol, thioridazine, sertindole), and gastrointestinal motility agents such as cisapride. Electrolyte abnormalities, including hypokalemia, hypocalcemia, and hypomagnesemia, which may occur with amphotericin B, further increase this risk. Drug-induced QT prolongation has been reported in approximately 0.7% of hospitalized patients, most often outside cardiology units (2). Several clinical factors predispose patients to acquired QT prolongation, including high drug doses, rapid administration, and the concomitant use of multiple QT-prolonging medications. Additional risk factors include diuretic use, bradycardia, renal or hepatic dysfunction, structural heart disease, and female sex (3). Information from drug labeling and pharmacovigilance databases is crucial for identifying QT-related risks and improving patient safety, particularly in patients receiving multiple QT-prolonging medications (4). In addition, antifungal agents may contribute not only to QT prolongation but also to myocardial dysfunction. Echinocandin-related cardiac toxicity has been suggested to involve mitochondrial injury and direct myocyte damage, particularly with high local exposure such as central line administration (5). This may partly explain the reversible cardiomyopathy observed in our patient. Careful ECG monitoring is therefore essential in patients receiving multiple medications, particularly those with severe underlying conditions. Our case highlights the risk of life-threatening arrhythmias associated with polypharmacy and underscores the importance of close cardiac monitoring during treatment.

Anahtar Kelimeler

• İLAÇ KAYNAKLI ARİTMİ
• KAZANILMIŞ UZUN QT
• POLİFARMASİ
• VENTRİKÜLER FİBRİLASYON
• PEDİATRİK LÖSEMİ

Kaynakça

1. 1. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: Document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10(12):1932–1963.
2. 2. Drew BJ, Ackerman MJ, Funk M, et al. Prevention of torsade de pointes in hospital settings: A scientific statement from the American Heart Association and the American College of Cardiology Foundation. Circulation. 2010;121:1047–1060.
3. 3. Yu H, Zhang L, Liu J, et al. Acquired long QT syndrome in hospitalized patients. Heart Rhythm. 2017;14:974–978.
4. 4. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350:1013–1022.
5. 5. Cleary JD, Stover KR. Antifungal-associated drug-induced cardiac disease. Clin Infect Dis. 2015;61(Suppl 6):S662–S668.