Resuscitation 80 (2009) 591–593
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Case reports
Intravenous fat emulsion therapy for intentional sustained-release verapamil overdose夽 Amy C. Young a,b,∗ , Larissa I. Velez c , Kurt C. Kleinschmidt d a Department of Surgery, Division of Emergency Medicine University of Texas Southwestern Medical Center, Emergency Medicine, 5323 Harry Hines Blvd, Dallas, TX 75390-8579, United States b North Texas Poison Center, 5201 Harry Hines Blvd, Dallas, TX 75235, United States c Emergency Medicine Education UT Southwestern Medical Center, Emergency Medicine, 5323 Harry Hines Blvd, Dallas, TX 75390-8579, United States d Department of Surgery, Division of Emergency Medicine, Section of Medical Toxicology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8579, United States
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Article history: Received 30 October 2008 Received in revised form 27 January 2009 Accepted 30 January 2009 Keywords: Intralipid fat emulsion Lipids Calcium channel blockers Verapamil Lipophilic Resuscitation
a b s t r a c t We report the first case of sustained-release verapamil toxicity treated with Intralipid fat emulsion (IFE). Toxicity was confirmed by elevated serial serum verapamil and metabolite, norverapamil, levels. Most previously reported cases of IFE therapy involve local anaesthetic toxicity and cardiac arrest. Our patient was in shock despite standard therapy. No adverse events were noted and the patient fully recovered. © 2009 Elsevier Ireland Ltd. All rights reserved.
Introduction Verapamil is a lipophilic drug associated with cardiovascular decompensation in overdose. The optimal therapy for overdose remains unclear.1 Intravenous fat emulsion (IFE) is composed of triglycerides and a phospholipid emulsifier. It provides calories and essential fatty acids within total parenteral nutrition (TPN).1 Another novel use of IFE is as an antidote. In case reports and animal models, IFEs attenuated the cardiotoxic effects of some lipophilic drugs. We present the first case where IFE was used to manage a patient who overdosed on sustained-release verapamil. This was verified by serial serum verapamil levels. Case A 32-year-old male was transferred from another hospital after overdosing on sustained-release verapamil 13.44 g, levothyrox-
夽 A Spanish translated version of the summary of this article appears as Appendix in the online version at doi:10.1016/j.resuscitation.2009.01.023. ∗ Corresponding author at: Department of Surgery, Division of Emergency Medicine University of Texas Southwestern Medical Center, Emergency Medicine, 5323 Harry Hines Blvd, Dallas, TX 75390-8579, United States. Tel.: +1 518 488 4038. E-mail address: acyoung
[email protected] (A.C. Young). 0300-9572/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.resuscitation.2009.01.023
ine 1.125 mg, bupropion 4.8 g, zolpidem CR 200 mg, quetiapine (unknown amount or strength), clonazepam 22 mg and benazepril (32 tablets, unknown strength). The patient was found at 10:00 on day 1, poorly responsive with incoherent speech. His trachea was intubated at 11:58 followed by orogastric lavage and charcoal. When the poison centre was contacted at 14:48; the patient had received 6 L of normal saline and had a blood pressure of 69/26 mmHg, heart rate of 55/min, a temperature of 36 ◦ C, and an oxygen saturation of 100% on 100% inspired oxygen. The poison centre recommended the patient received a further 3 L of normal saline, a noradrenaline (norepinephrine) infusion, an intravenous calcium gluconate bolus, and an intravenous glucagon bolus plus infusion. Upon arrival to our hospital at 17:23; he had a blood pressure of 96/42 mmHg, a heart rate of 77/min, and an oxygen saturation of 90% (ventilated with positive end expiratory pressure of 5 cm H2 O, 100% inspired oxygen at rate of 14/min). The physical exam showed sluggishly reactive, dilated pupils at 8 mm; bibasilar crackles on lung auscultation; decreased bowel sounds; normal heart sounds; distal pulses bilaterally; and cool, dry skin. Initial investigations included CO2 14 mmol/L, creatinine 2.5 mg/dL (221 mol/L), and lactate 5.4 mmol/L. The arterial blood gas at 18:14 showed pH 7.09, pCO2 51 mmHg (6.8 kPa), pO2 of 89 mmHg (11.9 kPa). Salicylate, paracetamol (acetaminophen), and ethanol serum concentrations were negative. His chest radiograph
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Figure 1. Junctional bradycardia 14 h after ingestion.
showed diffuse bilateral infiltrates. The electrocardiogram showed a junctional bradycardia (Figure 1). We gave 100 mL of Intralipid® 20% over 20 min at 17:40 plus an infusion at 0.5 mL/kg/h until 17:00 the next day. By 18:40, the noradrenaline infusion rate was halved. The glucagon infusion was stopped at 19:30. The systolic blood pressure remained 120–140 mmHg except for briefly decreasing to 99 mmHg when the noradrenaline infusion was stopped at 03:00 on day 2. The patient’s trachea was extubated on day 2. He informed us that he had taken his overdose at 22:00 the day before his admission. He was discharged on hospital day 5 without any neurological deficits. The serum levels of verapamil and norverapamil 20 h after ingestion were 0.99 and 1.11 mol/L, respectively. At 36 h after ingestion, the respective levels were 0.62 and 0.91 mol/L (Mayo Medical Laboratories, therapeutic ranges for both 0.11–0.45 mol/L). Discussion Verapamil is a lipophilic phenylalkylamine calcium channel antagonist that is more toxic than dihydropyridine antagonists. Seventeen United States deaths were attributed to verapamil in 2006.2 The suggested antidotal mechanism of IFEs is that they sequester lipophilic toxins in a newly created intravascular lipid channel. This lipid channel decreases the distribution of lipophilic agents into the tissues and may result in the redistribution of the toxic drug from the tissues back into the lipid channel.1,3 In calcium channel antagonist toxicity, the pancreatic calcium channels are blocked; inhibiting insulin secretion; decreasing intracellular energy. IFEs increase beta-ketoacids and nitric oxide; stimulating insulin secretion.4 Long-chain fatty acids may also directly activate calcium channels; attenuating toxicity. Additional cytosolic calcium may benefit the non-ischaemic, drug-depressed myocardium.5,6 Several case reports exist of 20% IFEs used for overdoses. One patient arrested after a regional local anaesthetic injection of bupivacaine and mepivacaine. The patient was unresponsive to 20 min of cardiopulmonary resuscitation (CPR), defibrillation, adrenaline (epinephrine), atropine, amiodarone, and vasopressin. Immediately after a bolus of 100 mL of IFE, the patient had a full recovery.7 Another patient arrested after a ropivacaine local anaesthetic
block. After 10 min of unsuccessful CPR and adrenaline, 200 mL IFE was given by intravenous bolus and continuous infusion. Circulation immediately returned and the patient recovered without complications.8 A pregnant woman became unresponsive after a bupivacaine epidural but maintained a BP of 150/110 mmHg. She received 100 mL IFE bolus plus another 400 mL as an infusion. She immediately regained full consciousness and the baby was born with a normal Apgar score at 10 min.9 Another case of bupivacaine toxicity had severe hypotension and QRS widening. IFE 100 mL was given over 5 min with immediate narrowing of the QRS complex, improvement in blood pressure, and recovery without complications.10 In a case of bupropion and lamotrigine toxicity, the patient had periods of CPR lasting 20 and 52 min. The last period of CPR ended when a 100-mL bolus of IFE was given with return of circulation within 1 min.3 The patient sustained mild neurologic sequelae. The safety of using bolus-dosed IFEs is not established. Complications with IFEs are related to their extended use as a part of TPN, particularly in neonates.11 High triglycerides may alter immunity, lung function, and haemodynamics in patients with acute respiratory distress syndrome (ARDS). Although it remains controversial, ARDS patients may get transient changes in oxygenation and pulmonary vascular tone during IFE administration. In early case series involving patients with respiratory failure and/or sepsis, IFEs caused lower blood oxygen content, increased shunting, and pulmonary vasoconstriction. More recent studies are conflicting.3,11,12 The IFE doses in animal models are higher than those in the human case reports; using 4 mL/kg over 10 min and up to 16 mL/kg.13,14 All human cases except one child case used a 100 mL bolus; few also used infusions.12,15 When used as TPN, the maximum recommended infusion rate is 0.11 g of fat/kg/h.11 While the 100 mL IFE bolus is faster than this recommended infusion speed, the recommended TPN rate is based on weeks of continuous infusion. Our infusion rate of 0.5 mL/kg/h is similar to the maximum rate recommended for TPN. Conclusion Most previous case reports of IFE use involved local anesthetics toxicity associated with cardiac arrest. Our patient had verapamil-induced refractory shock that stabilized rapidly after IFE administration.
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Conflict of interest Amy C. Young and Larissa I. Velez have no conflicts of interest. Kurt C. Kleinschmidt has the following conflicts of interest: Speakers Bureau with Bristor Myers Squibb/Sanofi Aventis and The Medicines Company. Research funded by the Medicines Company. References 1. Bania TC, Chu J, Perez E, Su M, Hahn IH. Hemodynamic effects of intravenous fat emulsion in an animal model of severe verapamil toxicity resuscitated with atropine, calcium, and saline. Acad Emerg Med 2007:105–11. 2. Bronstein AC, Spyker DA, Cantilena Jr LR, Green J, Rumack BH, Heard SE. 2006 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS). Clin Toxicol (Phila) 2007;45:815–917. 3. Sirianni AJ, Osterhoudt KC, Calello DP, et al. Use of lipid emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine. Ann Emerg Med 2008:412–5. 4. Tebbutt S, Harvey M, Nicholson T, Cave G. Intralipid prolongs survival in a rat model of verapamil toxicity. Acad Emerg Med 2006;13:134–9. 5. Gueret G, Pennec JP, Arvieux CC. Hemodynamic effects of intralipid after verapamil intoxication may be due to a direct effect of fatty acids on myocardial calcium channels. Acad Emerg Med 2007;14:761.
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6. Turner-Lawrence DE, Kerns WI. Intravenous fat emulsion: a potential novel antidote. J Med Toxicol 2008;4:109–14. 7. 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. Anesthesiology 2006;105:217–8. 8. Litz RJ, Popp M, Stehr SN, et al. Successful resuscitation of a patient with ropivacaine-induced asystole after axillary plexus block using lipid infusion. Anaesthesia 2006:800–1. 9. Spence GA. Lipid reversal of central nervous system symptoms of bupivacaine toxicity. Anesthesiology 2007;107:516–7. 10. Foxall G, McCahon R, Lamb J, Hardman JG, Bedforth NM. Levobupivacaineinduced seizures and cardiovascular collapse treated with intralipid® . Anaesthesia 2007;62:516–8. 11. Intralipid 20%, Baxter Healthcare Corporation, Deerfield, IL (2000) [package insert]. 12. Weinberg G. Lipid rescue resuscitation from local anaesthetic cardiac toxicity. Toxicol Rev 2006;25:139–45. 13. Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 2003;28:198–202. 14. Harvey M, Cave G. Intralipid outperforms sodium bicarbonate in a rabbit model of clomipramine toxicity. Ann Emerg Med 2007:178–85. 15. Weinberg G, Hertz P, Newman J. Lipid, not propofol, treats bupivicaine overdose (letter). Anesth Analg 2004;99:1875.
