We present a case of Torsade de Pointes secondary to multiple factors including patient susceptibility and iatrogenic influences. Contributing causes are presented, and the approach to treatment is discussed

Bernard Topi

Chaim Gitelis

Gabriel Bombino

Gerald Hollander

Jinu John

Joydeep Ghosh

Xixi Amley

Cardiology Research and Practice

PubMed

We present a case of Torsade de Pointes secondary to multiple factors including patient susceptibility and iatrogenic influences. Contributing causes are presented, and the approach to treatment is discussed.</jats:p

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SAGE-Hindawi Access to ResearchCardiology Research and PracticeVolume 2010, Article ID 524764, 4 pagesdoi:10.4061/2010/524764Case ReportTorsade de Pointes due to Methadone Use in a Patient withHIV and Hepatitis C CoinfectionJinu John,1 Xixi Amley,2 Gabriel Bombino,2 Chaim Gitelis,2 Bernard Topi,1Gerald Hollander,2 and Joydeep Ghosh21 Department of Internal Medicine, Maimonides Medical Center, 4802 Tenth Avenue, Brooklyn, NY 11219, USA2 Division of Cardiology, Maimonides Medical Center, 4802 Tenth Avenue, Brooklyn, NY 11219, USACorrespondence should be addressed to Jinu John, jjohn3@maimonidesmed.orgReceived 15 October 2010; Revised 2 December 2010; Accepted 9 December 2010Academic Editor: Brian OlshanskyCopyright © 2010 Jinu John et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We present a case of Torsade de Pointes secondary to multiple factors including patient susceptibility and iatrogenic influences.Contributing causes are presented, and the approach to treatment is discussed.1. Case ReportA 50-year-old male with a past history of HIV infection,acquired immune deficiency syndrome (AIDS), pneumocys-tis carinii pneumonia, hepatitis C, and hepatoma (postra-diofrequency ablation) presented to the emergency roomfor weakness and syncope which occurred in the bathroomwhile straining to defecate. He denied palpitation, chest pain,or shortness of breath prior to losing consciousness. Therewas no history of seizure disorder. The following day whilewalking to the hospital, he developed lightheadedness againwhich was associated with diaphoresis and had to hold ontoa pole for support for two minutes before feeling able tocontinue. There was a history of cocaine and IV heroin abuse(discontinued two years ago).Prehospital medications included lamivudine/zidovud-ine, atazanavir, trimethoprim/sulfamethoxazole, and meth-adone. He was on antiretroviral drugs for 10 years, and themethadone dosage was increased to 40mg/day two monthsprior to this presentation. On admission in the ER, hehad a regularly irregular pulse and a blood pressure of124/60. Physical examination was unremarkable except forecchymosis in the left periorbital region. Relevant lab reportsproduced the following results: MCV 131 FL, platelet count82,000/mm3, AST 176 IU/L, alkaline phosphatase 140 IU/L,ALT 104 IU/L, albumin 3.2 g/dL, and INR 1.3. Serum potas-sium, magnesium, corrected calcium, and cardiac enzymeswere within normal range. The patient’s chest X-ray wasunremarkable. EKG recorded 14 months prior to the ER pre-sentation showed sinus rhythm and QTc 455ms (Figure 1).The initial EKG on presentation showed ventricularbigeminy (Figure 2) with QTc 550ms. In the ER, he devel-oped two episodes of TdP (Figure 3) each resolving spon-taneously, although the patient became unconscious forapproximately two minutes during each episode. He wasgiven 2 g Magnesium IV and Amiodarone IV push 150mgtwice. The patient was transferred to cardiac ICU. HIVmedi-cations were switched to raltegravir, emtricitabine/tenofovir;methadone was discontinued. Three days later, he devel-oped sinus bradycardia at 38 beats per min (bpm) withQTc 571ms (Figure 4). To shorten his QTc and preventfurther episodes of TdP, the patient underwent a temporarypacemaker insertion and was paced at a rate of 100 bpm(Figure 5). After two days, his QTc slowly decreased andsinus bradycardia resolved. 23 days following the modifica-tion of the medications administered to the patient, the EKGstill exhibited prolonged QTc (Figure 6). As the patient wasconsidered at high risk to develop TdP, he underwent animplantable cardioverter defibrillator (ICD) placement. Heis currently being followed with no further episodes of TdP.2. DiscussionTdP belongs to a group of polymorphic ventricular tachy-cardia characterized by varying QRS amplitudes that appear2 Cardiology Research and PracticeI aVR V1V2V3V4V5V6aVLaVFIIIIIIIDevice: Speed: 25 mm/s Limb: 10 mm/mV F 60∼ 0.5–40 Hz W P?Chest: 10 mm/mV PH07T8Figure 1: Baseline EKG was acquired about 14 months prior to the syncope episodes. QTc 455ms.I aVR V1V2V3V4V5V6aVLaVFIIIIIIISpeed: 25 mm/s Limb: 10 mm/mV P?Device: 1249710 F 60∼ 0.5–100 Hz W bCLChest: 10 mm/mV PH100BFigure 2: Initial 12 lead EKG in emergency room showing ventricular bigeminy. QTc was 550ms.Figure 3: EKG tracing in emergency room showed short-long-short sequence of RR cycle followed by TdP. The patient had two episodes ofsyncope while he had TdP. The above two tracings are from one of the two episodes.to twist around an isoelectric line in the setting of long QTcas revealed in this patient’s baseline EKG. TdP is commonlypreceded by long-short R-R cycle which is followed bya late premature ventricular complex. Often, early afterdepolarization manifested as T-U waves in EKG precede TdP.In patients with prolonged QTc, the presence of pathologicalT-U waves (Figure 6) might be the only warning sign ofimminent TdP [1].Very often, the cause of TdP is multifactorial. The com-mon risk factors of TdP include (a) female gender, (b) heartdisease, (c) electrolyte abnormalities, (d) bradyarrhythmias,(e) stroke, and (f) a significant universe of drugs that leadto QT prolongation [2–4]. The upper limit of the durationof QTc is often considered to be 430ms for adult males and450ms for adult females, with a normal range of plus orminus 15 percent. QTc prolongation is defined as a QTcof more than 450ms for adult males and 470ms for adultfemales [5]. Studies have shown that QTc prolongation is anindependent predictor of cardiovascular mortality, especiallyfrom ventricular arrhythmias such as TdP [6].There is an increased prevalence of QTc prolongationin patients with active HIV infection. Sani and OkeahialamCardiology Research and Practice 3I aVR V1V2T waveU waveV3V4V5V6aVLaVFIIIIIIISpeed: 25 mm/s Limb: 10 mm/mV P?F 60∼ 0.5–100 Hz W bCLDevice: 1249582 Chest: 10 mm/mV PH100BFigure 4: Sinus bradycardia with heart rate of 38 beats per minute occurred three days after admission. QTc 571ms. Also noted arepathological T-U waves.I aVR V1V2V3V4V5V6aVLaVFIIIIIIISpeed: 25 mm/s Limb: 10 mm/mV P?F 60∼ 0.5–100 Hz W bCLDevice: 1249582 Chest: 10 mm/mV PH100BFigure 5: Intravenous temporary pace maker was inserted for sinus bradycardia with long QTc. To prevent TdP, pacing rate was set at100 beats per minute.I aVR V1V2V3V4V5V6aVLaVFIIIIIIISpeed: 25 mm/s Limb: 10 mm/mV P?F 60∼ 0.5–100 Hz W bCLDevice: 1249695 Chest: 10 mm/mV PH100BFigure 6: 23 days after admission, the EKG showed a QTc of 492ms prior to ICD placement. The pathological T-U waves are no longer seen.showed that prolonged QTc was present in 28% of suchpatients. In patients with AIDS, the prevalence increased to45% [7]. In patients with HIV and autonomic neuropathy,the prevalence of QTc prolongation is reported to be 65%[8]. The exact reason for such correlation between QTcprolongation and HIV infection is still a topic of debate.But chronic HIV infection itself and many drugs used totreat HIV and other opportunistic infections are plausibleexplanations. In contrast, Charbit et al. suggested that QTcprolongation is related to the duration of a patient’s HIVinfection rather than medications used during the treatmentof HIV or associated opportunistic infections [9]. Proteaseinhibitors (PIs) are a group of medications implicated inQTc prolongation because of the in vitro inhibition of4 Cardiology Research and Practicethe hERG (human ether-a-go-go-related gene) current [10].But Charbit et al. concluded that protease inhibitors are notindependently associated with QTc prolongation [9].Methadone is a very frequently used drug in the manage-ment of pain and heroin addiction. Methadone causes theblockade of hERG current and causes clinically significantQTc prolongation. Martell et al. found a 10.8ms increasein QTc within 2 months of starting methadone in a groupof heroin users [11]. The prevalence of methadone-inducedQTc prolongation ranges between 16% and 33%, and thiscan happen within a wide dose range of methadone (29–1690mg/day) [12]. Butmethadone doses less than 40mg/daydo not commonly cause QTC prolongation [13]. QTc pro-longation caused by methadone is dose dependant and oftenrecent dose escalation is associated with TdP. Methadoneis metabolized by CYP3A4, which is also induced by PIs.Patients, when started on PIs, might require escalation ofthe methadone dose for symptom control which can furtherprolong QTc. Methadone is also known to cause appearanceof pathological U waves in EKG which may be an indicatorof imminent TdP in some cases [14].Hepatitis C is indicated as an independent risk factorfor QTc prolongation. Nordin et al. investigated the impactof Hepatitis C and HIV coinfection on QTc prolongationand suggested that hepatitis C co-infection nearly doubledthe risk of QTc prolongation in HIV positive patients. Livercirrhosis, low albumin, and high AST predict QTc prolon-gation. These three factors tend to cluster with HepatitisC which explains the increased risk of QTc prolongationassociated with Hepatitis C infection [15].The above case shows how multiple contributing factorscan cumulatively cause TdP in patients who already are atrisk due to genetic predisposition. This patient had a longQTc to start with and also had HIV and Hepatitis C/liverdisease. He also was on antiretroviral medications for 10years. Methadone dose escalation might have prolonged theQTc further and caused appearance of T-U waves. In thissetting, a critically timed premature complex triggered oﬀTdP. As the patient hadmultiple risk factors and continued tohave an abnormal QTc despite changing medications, he wasconsidered to be at high risk for further development of TdP,and the decision of utilizing an ICD was made.This case also highlights the need for carefully mon-itoring susceptible patients treated with methadone forpotentially dangerous QT prolongation which can occureven after the patient has been on therapy for sometime. Patients should also be made aware of relevant druginteractions and the importance of reporting episodes ofdizziness or near syncope. Recent guidelines suggest gettinga baseline EKG before starting patients on methadone. Afterinitiation of therapy, EKG should be repeated to look for QTcprolongation within one month and then annually even ifpatients are asymptomatic. Discontinuation of methadoneshould be considered if QTc > 500ms [16].References[1] P. Kirchhof, M. R. Franz, A. Bardai, and A. M. Wilde, “GiantT-U waves precede torsades de pointes in long QT syndrome:a systematic electrocardiographic analysis in patients withacquired and congenital QT prolongation,” Journal of theAmerican College of Cardiology, vol. 54, no. 2, pp. 143–149,2009.[2] A. G. Kocheril, S. A. J. Bokhari, W. P. Batsford, and A. J.Sinusas, “Long QT(c) and torsades de pointes in humanimmunodeficiency virus disease,” Pacing and Clinical Electro-physiology, vol. 20, no. 11, pp. 2810–2816, 1997.[3] D. M. Roden, “Taking the “idio” out of “idiosyncratic”: pre-dicting torsades de pointes,” Pacing and Clinical Electrophysi-ology, vol. 21, no. 5, pp. 1029–1034, 1998.[4] Arizona Center for Education and Research on Therapeutics.University of Arizona College of Pharmacy. Resources forProfessionals, “Torsades List: Drugs With a Risk of Tor-sades de Pointes,” http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm.[5] I. Goldenberg, A. J. Moss, and W. Zareba, “QT interval: howto measure it and what is “normal”,” Journal of CardiovascularElectrophysiology, vol. 17, no. 3, pp. 333–336, 2006.[6] E. G. Schouten, J. M. Dekker, P. Meppelink, F. J. Kok, J.P. Vandenbroucke, and J. Pool, “QT interval prolongationpredicts cardiovascular mortality in an apparently healthypopulation,” Circulation, vol. 84, no. 4, pp. 1516–1523, 1991.[7] M. U. Sani and B. N. Okeahialam, “QTc interval prolongationin patients with HIV and AIDS,” Journal of the NationalMedical Association, vol. 97, no. 12, pp. 1657–1661, 2005.[8] A. Villa, V. Foresti, and F. Confalonieri, “Autonomic neuropa-thy and prolongation of QT interval in human immunodefi-ciency virus infection,” Clinical Autonomic Research, vol. 5, no.1, pp. 48–52, 1995.[9] B. Charbit, A. Rosier, D. Bollens et al., “Relationship betweenHIV protease inhibitors and QTc interval duration in HIV-infected patients: a cross-sectional study,” British Journal ofClinical Pharmacology, vol. 67, no. 1, pp. 76–82, 2009.[10] B. D. Anson, J. G. R. Weaver, M. J. Ackerman et al., “Blockadeof HERG channels by HIV protease inhibitors,” Lancet, vol.365, no. 9460, pp. 682–686, 2005.[11] B. A. Martell, J. H. Arnsten, M. J. Krantz, and M. N. Goure-vitch, “Impact of methadone treatment on cardiac repolar-ization and conduction in opioid users,” American Journal ofCardiology, vol. 95, no. 7, pp. 915–918, 2005.[12] D. W. Abramson, D. K. Quinn, and T. A. Stern, “Methadone-associated QTc prolongation: a case report and review of theliterature,” Primary Care Companion to the Journal of ClinicalPsychiatry, vol. 10, no. 6, pp. 470–476, 2008.[13] G. B. Ehret, C. Voide, M. Gex-Fabry et al., “Drug-induced longQT syndrome in injection drug users receiving methadone:high frequency in hospitalized patients and risk factors,”Archives of Internal Medicine, vol. 166, no. 12, pp. 1280–1287,2006.[14] P. Athanasos, A. L. Farquharson, P. Compton, P. Psaltis, andJ. Hay, “Electrocardiogram characteristics of methadone andbuprenorphine maintained subjects,” Journal of Addictive Dis-eases, vol. 27, no. 3, pp. 31–35, 2008.[15] C. Nordin, A. Kohli, S. Beca et al., “Importance of hepatitis Ccoinfection in the development of QT prolongation in HIV-infected patients,” Journal of Electrocardiology, vol. 39, no. 2,pp. 199–205, 2006.[16] M. J. Krantz, J. Martin, B. Stimmel, D. Mehta, and M. C. P.Haigney, “QTc interval screening in methadone treatment,”Annals of Internal Medicine, vol. 150, no. 6, pp. 387–395, 2009.Submit your manuscripts athttp://www.hindawi.comStem CellsInternationalHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014MEDIATORSINFLAMMATIONofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Behavioural NeurologyEndocrinologyInternational Journal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Disease MarkersHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014BioMed Research InternationalOncologyJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Oxidative Medicine and Cellular LongevityHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014PPAR ResearchThe Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Journal ofObesityJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014 Computational and  Mathematical Methods in MedicineOphthalmologyJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Diabetes ResearchJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Research and TreatmentAIDSHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Gastroenterology Research and PracticeHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Parkinson’s DiseaseEvidence-Based Complementary and Alternative MedicineVolume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

Torsade de Pointes due to Methadone Use in a Patient with HIV and Hepatitis C Coinfection

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Autonomic neuropathy and prolongation of QT interval in human immunodeﬁ-ciency virus infection,”

Electrocardiogram characteristics of methadone and buprenorphine maintained subjects,” J o u r n a lo fA d d i c t i v eD i s -eases,

for Education and Research on Therapeutics. University of Arizona College of Pharmacy. Resources for Professionals, “Torsades List: Drugs With a Risk of Torsades de

G.B.Ehret,C.Voide,M.Gex-Fabryetal.,“Drug-inducedlong QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors,”

Giant T-U waves precede torsades de pointes in long QT syndrome: a systematic electrocardiographic analysis in patients with acquired and congenital QT prolongation,”

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Long QT(c) and torsades de pointes in human immunodeﬁciency virus disease,” Pacing and Clinical Electrophysiology,

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o l d e n b e r g ,A .J .M o s s ,a n dW .Z a r e b a ,“ Q Ti n t e r v a l :h o w to measure it and what is “normal”,”

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Torsade de Pointes due to Methadone Use in a Patient with HIV and Hepatitis C Coinfection

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