© 2005 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
CASE REPORT
Doxorubicin-induced second degree and complete atrioventricular block
Hacettepe University Oncology Institute, Medical Oncology Department, Hacettepe University Faculty of Medicine, Cardiology Department Sihhiye 06100 Ankara, Turkey
Manuscript submitted 30 August 2004. Accepted after revision 5 December 2004.
*Corresponding author. Tel.: C90 312 305 2937; fax: C90 312 309 2905. E-mail address: skilickap{at}yahoo.com (S. Kilickap).
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Abstract |
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Doxorubicin is one of the most effective chemotherapeutic agents used in the treatment of malignancies. Cardiotoxicity is the most important dose-limiting toxicity of doxorubicin. Although cardiomyopathy is the most well known side effect of doxorubicin, it usually occurs many years after the treatment and relates to cumulative doxorubicin dosage. Another form of doxorubicin cardiotoxicity is arrhythmia which may occur at any time and after any dosage. However, doxorubicin-induced arrhythmia is rarely a life-threatening side effect. In this report, we present a case in which there were doxorubicin-induced life-threatening arrhythmias.
Key Words: doxorubicin, cardiotoxicity, arrhythmia
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Introduction |
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Doxorubicin, an antitumor antibiotic, is a highly effective chemotherapeutic agent used in the treatment of solid tumors and hematological malignancies. The most important dose-limiting toxicity of doxorubicin is cardiotoxicity [3,
4]. Two major forms of cardiotoxicity can occur following the administration of doxorubicin. The most important one is delayed cardiomyopathy, which may develop many years after the cessation of therapy [1]. Cardiac decompensation may ensue due to doxorubicin-induced cardiomyopathy. The other form is acutely developed changes that can occur at any time and after any dosage. Doxorubicin-induced arrhythmias can vary from abnormal electrocardiographic changes including non-specific ST and T-wave changes to atrial and ventricular arrhythmias [1,5,7]. Acute cardiotoxicity usually presents in the form of arrhythmia, which is usually a minor problem and mostly transient. It is rarely life-threatening [7,13]. Here we present a case that developed the Mobitz type II block that eventually transformed into a complete atrioventricular block and ventricular asystole right after treatment with doxorubicin containing chemotherapy who had no prior cardiovascular symptoms and risk factors for a cardiovascular disease.
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Case report |
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A 36-year-old female was admitted to Hacettepe University Medical Oncology Department in September 2000 because of abdominal pain and a palpable mass in the right upper abdomen. The physical examination was unremarkable except for this mass. Computerized tomography (CT) of the abdomen revealed an intraabdominal mass measuring 65 × 50 × 40 mm near the pancreas. Laparotomy was performed and the intraabdominal mass, which was originating from the duodenum, was totally excised. Histopathological examination revealed a low-grade leiomyosarcoma. Fifteen months after her initial diagnosis, abdominal CT revealed multiple metastases in the liver. Histopathological examination of the liver biopsy disclosed metastatic leiomyosarcoma. Chemotherapy containing ifosfamide 4000 mg/m2 for 3 days, mesna 4000 mg/m2 for 3 days, and doxorubicin 60 mg/m2 for 1 day was planned for the patient who had no prior cardiovascular disease or symptoms. The patient developed a syncopal attack that lasted a few seconds after the administration of doxorubicin in the first cycle of chemotherapy. The blood pressure and other physical findings were normal. A 12-lead electrocardiogram and the plasma glucose level were also normal. During the second cycle of chemotherapy, 24-h electrocardiographic monitoring was performed. Another transient syncopal attack lasting a few seconds occurred during the second doxorubicin infusion. ECG monitoring revealed second degree possibly Mobitz type II atrioventricular block, and complete atrioventricular block lasting for 12 s (Figs. 1 and 2). The patient underwent permanent pacemaker implantation due to complete atrioventricular block, and because of disease progression the chemotherapy regimen was changed to cisplatin 80 mg/m2 for 1 day and etoposide 120 mg/m2 for 3 days.
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Discussion |
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Doxorubicin should be carefully used because of its cardiotoxic effects. The most important side effect of doxorubicin is dilated cardiomyopathy and is generally seen some few years after the completion of therapy [1,
2]. Doxorubicin-associated arrhythmia may be seen both in the early and the late stages of the management of the patient. Acute cardiotoxicity described as electrocardiographic abnormalities and arrhythmias occurs in 11–41% of patients treated during or after the administration of doxorubicin [3–7]. Although these are usually non-specific electrocardiographic repolarization abnormalities, there can be serious rhythm disturbances that are associated with mortality in rare instances. Previous studies designed in adult patients have suggested that anthracyclines could cause various electrocardiographic abnormalities including T-wave inversion, ST segment elevation or depression, decreased QRS voltage, prolonged QT interval and arrhythmias including AV block, and supraventricular and ventricular arrhythmias [2,8]. These are usually transient and have no long-term clinical significance. Although the cumulative dose of doxorubicin for cardiomyopathy has been expressed as 450 mg/m2, doxorubicin-associated arrhythmias in the early stage are thought to be dose-independent. The acute cardiac toxicities such as electrocardiographic abnormalities and arrhythmias after doxorubicin infusion are associated with the release of vasoactive substances [9,10]. Doxorubicin-associated arrhythmia can also occur many years after the completion of the therapy. This effect usually correlates with chronic impairment of left ventricular function. In a study performed using both 12-lead and 24-h ambulatory electrocardiography by Larsen et al., it was suggested that anthracycline-induced arrhythmias were transient and limited to the first month after therapy [11]. The authors stated that ventricular arrhythmias were seen in patients who received anthracyclines even at low doses such as 200 mg/m2 [11].
Some studies have reported that death might be due to doxorubicin infusion. O'Bryan and colleagues reported sudden death in four patients who had received doxorubicin [12]. Similarly, Wortman et al. [13] reported one patient who experienced cardiac arrest within 1 h of doxorubicin administration, and three other patients after the doxorubicin treatment. Although it was considered that these rhythm disturbances causing mortality could be related to anthracycline infusion, drug-induced allergy or hypotension might also play a role in these serious adverse effects. In another study, it was described that seven out of 30 patients who received doxorubicin showed severe ventricular ectopy after their first dose of the drug [8]. Couch et al. [14] reported sudden cardiac death one month after the completion of doxorubicin therapy. Ventricular fibrillation was documented in their case.
Herein, we report a case that recorded complete atrioventricular block and second degree possibly Mobitz type II block after doxorubicin administration. This patient had no previous heart disease and/or known arrhythmia or syncope history. Before the therapy, physical examination of the patient was normal. She experienced a syncopal attack lasting a few seconds after the first dose of doxorubicin infusion and she spontaneously improved. We were unable to find a cause that could explain the syncope such as an allergic reaction or hypotension. Because of the arrhythmogenic effect of doxorubicin and the syncopal attack occurring after the first dose of the drug, 24-h continuous ambulatory electrocardiographic monitoring was performed during the second dose. She again had a syncopal attack lasting 12 s after the completion of the infusion. Twenty-four-hour electrocardiography revealed rhythm disturbances including complete atrioventricular and second degree block. Because of the life-threatening arrhythmia resulting from doxorubicin infusion, the patient was judged to require permanent pacemaker implantation.
The cause of doxorubicin-induced electrocardiographic abnormalities and arrhythmias occurring in the early stage is unknown. Vasoactive substances released during or after doxorubicin infusion may be responsible for these effects. However, enhanced autonomic discharge resulting from adverse effects of doxorubicin such as nausea and vomiting may also play a role in its acute arrhythmogenicity. Hypotension and allergic reactions related to the drug could also cause arrhythmias. However, arrhythmias occurring many years after the completion of therapy are usually associated with dilated cardiomyopathy. Because of the doxorubicin-induced cardiomyopathy risk, patients receiving combined chemotherapy including doxorubicin should be regularly followed-up. In case of any life-threatening arrhythmias, appropriate therapy should be selected for these patients.
In summary, doxorubicin is a cardiotoxic agent that can cause rhythm disturbances during or after its infusion. We suggest that anthracyclines should be used with great caution even in patients with no preexisting cardiovascular risk factors and these cases must be monitored closely for arrhythmias.
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References |
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