TOXICOLOGY/ORIGINAL RESEARCH

Pretreatment With Intravenous Lipid Emulsion Reduces Mortality From Cocaine Toxicity in a Rat Model Stephanie Carreiro, MD; Jared Blum, MD; Jason B. Hack, MD

Study objective: We compare the effects of intravenous lipid emulsion and normal saline solution pretreatment on mortality and hemodynamic changes in a rat model of cocaine toxicity. We hypothesize that intravenous lipid emulsion will decrease mortality and hemodynamic changes caused by cocaine administration compared with saline solution. Methods: Twenty male Sprague-Dawley rats were sedated and randomized to receive intravenous lipid emulsion or normal saline solution, followed by a 10 mg/kg bolus of intravenous cocaine. Continuous monitoring included intraarterial blood pressure, pulse rate and ECG tracing. Endpoints included a sustained undetectable mean arterial pressure (MAP) or return to baseline MAP for 5 minutes. The log-rank test was used to compare mortality. A mixed-effect repeated-measures ANOVA was used to estimate the effects of group (intravenous lipid emulsion versus saline solution), time, and survival on change in MAP, pulse rate, or pulse pressure. Results: In the normal saline solution group, 7 of 10 animals died compared with 2 of 10 in the intravenous lipid emulsion group. The survival rate of 80% (95% confidence interval 55% to 100%) for the intravenous lipid emulsion rats and 30% (95% confidence interval 0.2% to 58%) for the normal saline solution group was statistically significant (P¼.045). Conclusion: Intravenous lipid emulsion pretreatment decreased cocaine-induced cardiovascular collapse and blunted hypotensive effects compared with normal saline solution in this rat model of acute lethal cocaine intoxication. Intravenous lipid emulsion should be investigated further as a potential adjunct in the treatment of severe cocaine toxicity. [Ann Emerg Med. 2013;-:1-6.] Please see page XX for the Editor’s Capsule Summary of this article. 0196-0644/$-see front matter Copyright © 2013 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2013.11.017

INTRODUCTION Background Intravenous lipid emulsion (Intralipid) was initially marketed as a nutritional component of total parenteral nutrition; however, during the last 2 decades it has been shown to have antidotal properties in local anesthetic toxicity.1 Case reports and animal studies have demonstrated improvement after intravenous lipid emulsion administration in cardiotoxicity and neurotoxicity from a variety of lipophilic agents, including local anesthetics,2-4 b-blockers,5 calcium channel blockers,6,7 antiarrhythmics,8 neuroleptics,9,10 selective serotonin reuptake inhibitors,10 tricyclic antidepressants,11 and phenyltriazines.12 According to these limited data, intravenous lipid emulsion has been proposed as an adjunctive therapy in multiple toxic exposures, and additional data are needed to better define its role in the toxic patient. Despite this increasing interest in intravenous lipid emulsion, researchers have yet to explore the potential benefit of the drug in the setting of intoxication with commonly used recreational drugs of abuse, including cocaine. The 2008 National Survey of Drug Use and Health estimated that approximately 1 in 4 emergency department visits for illicit Volume

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drug use involve cocaine,13 making it an especially pertinent toxic exposure for emergency physicians. Cocaine, a potent sympathomimetic and local anesthetic, carries a significant risk for morbidity and mortality. At lower cocaine doses, predominant effects include inhibition of catecholamine reuptake and stimulation of central sympathetic outflow. With increasing cocaine doses, local anesthetic effects of sodium- and potassium channel blockade become more prominent.14 Cardiovascular complications include myocardial ischemia or infarction, hypertensive crisis, arrhythmias, myocarditis, and aortic dissection.15,16 Patients are also at risk for cerebral infarction, hemorrhage, and seizures because of the same pathophysiologic factors.16 Current standard of care for cocaine intoxication is supportive care only with benzodiazepines and vasodilators because no antidote exists. Given that cocaine is both a local anesthetic and a lipophilic substance, it may be a candidate for intravenous lipid emulsion rescue. Jakkala-Saibaba et al17 described a 28-year-old man with refractory shock as a result of dysrhythmias and recurrent seizures in the setting of cocaine intoxication who rapidly stabilized after intravenous lipid emulsion infusion. Arora et al18 described a 26-year-old man with status epilepticus and cardiac Annals of Emergency Medicine 1

Carreiro, Blum & Hack

Intravenous Lipid Emulsion for Cocaine Toxicity

Editor’s Capsule Summary

What is already known on this topic Intravenous lipid emulsion is used for treatment of local anesthetic toxicity, but data are insufficient to determine its effectiveness for other drugs. Cocaine has local anesthetic effects. What question this study addressed The effect of intravenous lipid emulsion pretreatment and normal saline solution control on survival and hemodynamic parameters in a rodent model of acute severe cocaine toxicity. What this study adds to our knowledge Pretreatment with intravenous lipid emulsion decreased acute mortality and reduced cocaine’s effect on pulse rate and mean arterial pressure compared with saline solution. How this is relevant to clinical practice A clinical trial of intravenous lipid emulsion in acute severe cocaine intoxication may be reasonable. It should not alter current clinical practice until human data are available.

dysrhythmia with hypotension refractory to standard therapy who also improved after intravenous lipid emulsion infusion. To our knowledge, no formal studies have evaluated this effect. Goals of This Investigation The goal of the study was to explore the effect of intravenous lipid emulsion pretreatment on cocaine-induced toxicity in an animal model. The primary aim was to determine whether intravenous lipid emulsion alters cocaine-induced mortality. The secondary aim was to evaluate whether it alters the hemodynamic response to cocaine exposure. We hypothesized that rats pretreated with the emulsion before intravenous cocaine administration would demonstrate lower mortality and fewer hemodynamic changes than those controls pretreated with normal saline solution.

MATERIALS AND METHODS Study Design This was a randomized, unblinded, experimental animal model of cocaine toxicity. All study protocols were reviewed and approved by the Lifespan Institutional Animal Care and Use Committee before implementation. Animal care, handling, and euthanasia were all in accordance with National Institutes of Health guidelines for ethical animal research. Twenty male Sprague-Dawley rats were obtained from Harlan Laboratories (Indianapolis, IN), with femoral arterial and femoral 2 Annals of Emergency Medicine

venous catheters placed before arrival at our facility. Animals were housed in single cages for 2 to 5 days before the experiment and were given free access to food and water. Catheter patency assessment and locking with heparin/saline solution was performed 72 hours after arrival when applicable according to the vendor’s recommendations. Isoflurane was administered first by sedation chamber, then by nose cone, with a concentration of 5% for induction, and then 2% to 3% for maintenance for the duration of the study. The animals were spontaneously breathing and not paralyzed. Depth and adequacy of sedation were assessed periodically with the toe and tail pinch methods. On achievement of adequate sedation, subcutaneous 3-lead ECG leads were placed to calculate pulse rate by a continuous cardiac rhythm strip. An external chest motion sensing probe was used to continuously measure respiratory rate. Femoral arterial catheters were used to measure arterial blood pressure and medication administration. Data were collected electronically with an MP100 system from Biopac with AcqKnowledge software (version 3.9.1; Biopac, Goleta, CA). Animals were randomized into 2 equal groups (intravenous lipid emulsion or normal saline solution). Each was allowed 3 minutes to stabilize after all monitoring equipment was in place and catheters were accessed. A 15 mL/kg dose of intravenous lipid emulsion (20% intravenous lipid emulsion) (Baxter, Deerfield, IL) or normal saline solution was then administered during 7 minutes. This intravenous lipid emulsion dose was selected according to previous rat models of intravenous lipid emulsion resuscitation, which have successfully used doses ranging from 10 to 19 mL/kg.5-7 After an additional 2 minutes, a 10 mg/kg dose of cocaine was administered as a rapid intravenous bolus. The cocaine dose was based on reported median lethal dose (LD50), ranging from 10 to 14 mg/kg.19,20 The animals were observed and continuously monitored until they reached one of 2 predefined endpoints (an undetectable MAP [

Pretreatment with intravenous lipid emulsion reduces mortality from cocaine toxicity in a rat model.

We compare the effects of intravenous lipid emulsion and normal saline solution pretreatment on mortality and hemodynamic changes in a rat model of co...
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