The Journal of Emergency Medicine, Vol. -, No. -, pp. 13, 2012 Copyright 2012 Elsevier Inc.

. Printed in the USA. All rights reserved 0736-4679/$ - see front matter

doi:10.1016/j.jemermed.2011.09.010

Selected Topics: Toxicology

LIPID RESCUE FOR TRICYCLIC ANTIDEPRESSANT CARDIOTOXICITY

Michael Stephen Blaber, MBCHB,* Jamal Nasir Khan, MRCP, Judith Anne Brebner, MRCP, and Rachel McColm, MRCP
*Department of Cardiology, Sandwell & West Birmingham Hospitals NHS Trust, Birmingham, UK, Department of Cardiology, University Hospital of North Staffordshire, Newcastle, Stoke-on-Trent, UK, Department of Respiratory Medicine, Sandwell & West Birmingham Hospitals NHS Trust, Birmingham, UK, and Department of Emergency Medicine, Hereford Hospitals NHS Trust, County Hospital, Hereford, UK Reprint Address: Jamal Nasir Khan, MRCP, Department of Cardiology, City General Hospital, University Hospital of North Staffordshire, Newcastle Road, Stoke-on-Trent ST4 7QP, UK

, AbstractBackground: Tricyclic antidepressant (TCA) toxicity results predominantly from myocardial sodiumchannel blockade. Subsequent ventricular dysrhythmias, myocardial depression, and hypotension cause cardiovascular collapse. Animal studies have demonstrated the effectiveness of intravenous lipid-emulsion in treating TCA cardiotoxicity. Case Report: We report a case of dothiepin (tricyclic antidepressant) overdose causing refractory cardiovascular collapse, which seemed to be successfully reversed with lipid-emulsion therapy (Intralipid; Fresenius, Cheshire, UK). Conclusions: Lipid emulsions are a potentially novel therapy for reversing cardiotoxicity seen in TCA overdose. Research is required into the role of lipid emulsion in the management of poisoning by oral lipophilic agents. 2012 Elsevier Inc. , Keywordstricyclic antidepressant; lipid emulsion; toxicity; overdose; dysrhythmia; cardiac arrest

from cardiovascular collapse resulting from myocardial sodium-channel blockade and subsequent ventricular dysrhythmias, myocardial depression, and hypotension. The mainstay of treatment is sodium bicarbonate, antidysrhythmics, and supportive therapy (1,2). Despite this, TCAs are substantial contributors to annual mortality from drug overdose, alongside opiates, analgesics, and benzodiazepines (3). CASE REPORT A 36-year-old woman was brought to the Emergency Department after ingestion of 30 75-mg tablets of the TCA dothiepin (2.25 g) 90 min earlier. Glasgow Coma Scale score was 4/15, blood pressure was 53/35 mm Hg, and pulse was 130 beats/min. Severe metabolic acidosis was demonstrated (pH 6.75). A 12-lead electrocardiogram (ECG) revealed a broad-complex tachycardia with prolonged corrected QT interval of 502 ms (Figure 1). Mechanical ventilation and uid resuscitation were commenced. Nasogastric activated-charcoal and several 50-mL boluses of intravenous 8.4% sodium bicarbonate were administered, serving to progressively correct the acidosis (Figure 2). Despite an improving pH, the patient suffered cardiac arrest; 200J debrillation was administered and cardiopulmonary resuscitation initiated, resulting in restoration

INTRODUCTION Introduced in the 1950s, tricyclic antidepressants (TCAs) were long the mainstay of antidepressant therapy. However, their potential for toxicity in overdose has seen them overtaken by safer alternatives such as selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (1). Toxicity results predominantly

RECEIVED: 6 January 2011; FINAL SUBMISSION RECEIVED: 10 May 2011; ACCEPTED: 27 September 2011
1

M. S. Blaber et al.

Figure 1. Twelve-lead electrocardiogram on arrival in the Emergency Department demonstrating a broad complex tachycardia (QRS 154 ms, QTc 502 ms, heart rate 130 beats/min).

of cardiac output after 11 min. The patient remained in the broad complex tachycardia with hemodynamic compromise. Intravenous amiodarone (300 mg) was commenced and transvenous overdrive-pacing attempted. However, these measures, alongside repeated 8.4% sodium bicarbonate boluses, were unsuccessful in regaining cardiovascular stability. Due to the lipid solubility of TCAs, intravenous lipidemulsion rescue was undertaken. As per guidelines on management of severe local-anesthetic cardiotoxicity, 100 mL (1.5 mL/kg/min) of 20% intravenous lipid-

emulsion (Intralipid, Fresenius, Cheshire, UK) was administered over 1 min (3). During administration, transient narrowing of the QRS duration was seen. Sinus rhythm was restored within minutes. Cardiac rhythm remained stable and the patient was transferred to Intensive Care on ventilatory and inotropic (dobutamine 2.5 mg/kg/ h) support, maintaining a blood pressure of 168/86 mm Hg. As per guidelines, a further 400-mL infusion of Intralipid (0.25 mL/kg/min) was given over 15 min (4). After 24 h, the patient was extubated and inotropic support withdrawn. Development of a ventilator-

Figure 2. Graph demonstrating the serial pH measurements in relation to the therapeutic interventions over time. ECG = electrocardiogram; ICU = Intensive Care Unit.

Lipid Rescue for Tricyclic Antidepressant Cardiotoxicity

associated pneumonia necessitated a 5-day Intensive Care admission. However, by day 7, the patient had completely recovered to the pre-morbid state, with neurological review nding no cognitive impairment, allowing discharge to independent living. The discharge 12-lead ECG revealed sinus rhythm with partial right bundle branch block with normal QRS and QTc durations. DISCUSSION Cardiotoxicity is the main mode of death in TCA poisoning. Hypotension and cardiovascular collapse predominantly result from ventricular dysrhythmias and reduced myocardial contractility secondary to sodium-channel blockade. Sodium-channel blockade prolongs the cardiac action-potential and refractory period, and delays atrioventricular-node conduction. This widens the QRS, QTc, and PR durations, respectively. Acidosis associated with toxicity potentiates myocardial irritation and dysrhythmogenesis (1,2). Management of TCA toxicity focuses on minimizing gastric absorption, alkalinisation with bicarbonate, and supportive therapy. However, recent animal studies have described the success of intravenous lipidemulsion in treating TCA poisoning due to the highly lipophilic nature of TCAs (4). A study investigating clomipramine-induced cardiotoxicity in rats showed lipid emulsion to be superior to sodium bicarbonate as a reversal agent. All rats receiving lipid-emulsion rescue survived (5). The use of lipid-emulsion is already well established in treating refractory cardiotoxicity in local anesthetic poisoning, also mediated by potent sodium channel blockade (511). The Association of Anesthetists of Great Britain and Ireland now recommend lipid emulsion for emergency management of local anesthetic poisoning (6). The lipid-sink theory postulates that introducing an expanded lipid compartment into the intravascular space draws lipophilic agents out of the aqueous plasma phase, reducing bioavailability (7,8). An alternative theory suggests that lipid-emulsion improves myocardial free fatty-acid availability, reversing the switch

from lipid to glucose metabolism seen in stunned myocardium. In addition, lipid emulsion may counteract the inhibition to oxidative phosphorylation in toxic myocardium (5). CONCLUSION Our case demonstrates that lipid emulsion is a potentially novel therapy for reversing cardiotoxicity seen in TCA overdose. Although this case does not provide conclusive or generalizable evidence, it does support the need for further, prospective research into the role of lipid emulsion in the management of poisoning by oral lipophilic agents such as tricyclic antidepressants.

REFERENCES
1. Kerr GW, McGufe AC, Wilkie S. Tricyclic antidepressant overdose: a review. Emerg Med J 2001;18:23641. 2. Thanacoody HKR, Thomas SHL. Tricyclic antidepressant poisoning: cardiovascular toxicity. Toxicol Rev 2005;24:20514. 3. Ofce for National Statistics. Deaths related to drug poisoning in England and Wales: Statistical Bulletin 2009 (August 24, 2010). Available at: http://www.statistics.gov.uk/pdfdir/dgdths0810.pdf. Accessed April 11, 2011. 4. Furlanut M, Benetello P. The pharmacokinetics of tricyclic antidepressant drugs in the elderly. Pharmacol Res 1990;22:1525. 5. Harvey M, Cave G. Intralipid outperforms sodium bicarbonate in a rabbit model of clomipramine toxicity. Ann Emerg Med 2006; 49:17885. 6. Association of Anaesthetists of Great Britain and Ireland. Guidelines for the management of severe local anaesthetic toxicity (March 2007). Available at: http://www.aagbi.org/publications/ guidelines/docs/latoxicity07.pdf. Accessed August 19, 2010. 7. Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology 1998;88:10715. 8. Weinberg G. Lipid rescue resuscitation from local anaesthetic cardiac toxicity. Toxicol Rev 2006;25:13945. 9. Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 2003;28:198202. 10. Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ, Eisenkraft JB. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anaesthesiology 2006;105:2178. 11. Picard J, Meek T. Lipid emulsion to treat overdose of local anaesthetic: the gift of the glob. Anaesthesia 2006;61:1079.