Pretreatment With Intravenous Lipid Emulsion Reduces Mortality From Cocaine Toxicity in a Rat Model

Carreiro, Stephanie; Blum, Jared; Hack, Jason B.

doi:10.1016/j.annemergmed.2013.11.017

Cited by 15 publications

(8 citation statements)

References 30 publications

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“…These parallels, shared with bupivacaine toxicity and the commonality of reversal by ILE, suggest that ILE-based improvements in lipid metabolism during cocaine intoxication might underlie the cardiovascular recovery. Our results comport with prior clinical reports of the efficacy of ILE in combating cocaine cardiac toxicity, 12,13 and with previous animal models 14 that demonstrate that ILE can assist in recovery from toxicity. We have extended the results to cocaethylene, which is known to have significant detrimental effects on cardiovascular function, 36,37 and is found in a significant proportion of patients with cocaine-related visits to the ED.…”

Section: Discussionsupporting

confidence: 89%

“…Collectively, these data suggest that effects other than drug scavenging contribute to lipid emulsion-induced reversal of cocaine cardiotoxicity. This work provides evidence in support of others, 5,12–14 that lipid emulsion could provide an effective antidote to cocaine overdose. Future studies should focus on the development of more targeted therapeutics and optimal treatment of this potentially fatal overdose.…”

Section: Discussionsupporting

confidence: 88%

“…We used a large dose (15 mL/kg total) based on prior experience in animal models 14,54,55 and allometric scaling of human-to-rat doses. 56 Assuming a half-life of lipid (about 15 minutes), we expect a severely lipaemic plasma, but the lack of continuous infusion could mean that lipid is cleared.…”

Section: Limitationsmentioning

confidence: 99%

“…Case reports have identified the potential efficacy of intravenous (IV) lipid emulsion (ILE) as a treatment for cocaine overdose in humans 12,13 and in animal models 5,14 based on ILE’s ability to reverse local anesthetic toxicity 15 via a number of mechanisms, including partitioning of toxic drugs 16–20 and improved cardiac output. 20–22 We wanted to assess how these effects might combine to combat cocaine-induced cardiac depression.…”

Section: Introductionmentioning

confidence: 99%

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Cardiac Depression Induced by Cocaine or Cocaethylene Is Alleviated by Lipid Emulsion More Effectively Than by Sulfobutylether‐β‐cyclodextrin

Fettiplace

Pichurko

Ripper

et al. 2015

Academic Emergency Medicine

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Objectives Cocaine intoxication leads to over 500,000 emergency department visits annually in the USA and ethanol co-intoxication occurs in 34% of those cases. Cardiotoxicity is an ominous complication of cocaine and cocaethylene overdose for which no specific antidote exists. Because infusion of lipid emulsion (Intralipid) can treat lipophilic local anesthetic toxicity and cocaine is an amphipathic local anesthetic, the authors tested whether lipid emulsion could attenuate cocaine cardiotoxicity in vivo. The effects of lipid emulsion were compared with the metabolically inert sulfobutylether-β-cyclodextrin (Captisol) in an isolated heart model of cocaine and cocaethylene toxicity to determine if capture alone could exert similar benefit as lipid emulsion which exhibits multi-modal effects. The authors then tested if cocaine and cocaethylene, like bupivacaine, inhibit lipid-based metabolism in isolated cardiac mitochondria. Methods For whole animal experiments, Sprague-Dawley rats were anesthetized, instrumented, and pretreated with lipid emulsion followed by a continuous infusion of cocaine to assess time of onset of cocaine toxicity. For ex vivo experiments, rat hearts were placed onto a non-recirculating Langendorff system perfused with Krebs-Henseleit solution. Heart rate, left ventricle maximum developed pressure (LVdevP), left ventricle diastolic pressure (LVDP), maximum rate of contraction (+dP/dtmax), maximum rate of relaxation (−dP/dtmax), rate-pressure product (RPP = heart rate*LVdevP), and line pressure were monitored continuously during the experiment. A dose-response to cocaine (10, 30, 50, and 100 μM) and cocaethylene (10, 30, 50 μM) was generated in the absence or presence of either 0.25% lipid emulsion, or sulfobutyl-β-cyclodextrin. Substrate-specific rates of oxygen consumption were measured in interfibrillar cardiac mitochondria in the presence of cocaine, cocaethylene, ecgonine, and benzoylecgonine. Results Treatment with lipid emulsion delayed onset of hypotension (140 seconds vs. 279 seconds p = 0.008) and asystole (369 seconds vs. 607 seconds; p = 0.02) in whole animals. Cocaine and cocaethylene induced dose-dependent decreases in RPP, +dP/dtmax, and −dP/dtmaxabs (p < 0.0001) in Langendorff hearts; line pressure was increased by cocaine and cocaethylene infusion, but not altered by treatment. Lipid emulsion attenuated cocaine- and cocaethylene-induced cardiac depression. Sulfobutyl-β-cyclodetrin alone evoked a mild cardio-depressant effect (p < 0.0001) but attenuated further cocaine- and cocaethylene-induced decrements in cardiac contractility at high concentrations of drug (100 μM; p < 0.001). Finally, both cocaine and cocaethylene, but not ecgonine and benzoylecgonine, inhibited lipid-dependent mitochondrial respiration by blocking carnitine exchange (p < 0.05). Conclusions A commercially available lipid emulsion was able to delay progression of cocaine cardiac toxicity in vivo. Further, it improved acute cocaine- and cocaethylene-induced cardiac toxicity in rat isolated heart whil...

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 88%

Section: Limitationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cardiac Depression Induced by Cocaine or Cocaethylene Is Alleviated by Lipid Emulsion More Effectively Than by Sulfobutylether‐β‐cyclodextrin

Fettiplace

Pichurko

Ripper

et al. 2015

Academic Emergency Medicine

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“…Several experimental studies with cocaine and ILE using pre-treatment animal models [21,22] were excluded a priori due to the lack of generalizability to the clinical setting of human cocaine poisoning. The voting panel was in agreement on a neutral recommendation concerning the use of ILE in cardiac arrest and commented there was a paucity of data on the efficacy of ILE to reverse signs and symptoms of cocaine toxicity.…”

Section: Indicationsmentioning

confidence: 99%

Evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning

Gosselin

Hoffman

et al. 2016

Clinical Toxicology

131

104

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Background: Although intravenous lipid emulsion (ILE) was first used to treat life-threatening local anesthetic (LA) toxicity, its use has expanded to include both non-local anesthetic (non-LA) poisoning and less severe manifestations of toxicity. A collaborative workgroup appraised the literature and provides evidence-based recommendations for the use of ILE in poisoning. Methods: Following a systematic review of the literature, data were summarized in four publications: LA and non-LA poisoning efficacy, adverse effects, and analytical interferences. Twenty-two toxins or toxin categories and three clinical situations were selected for voting. Voting statements were proposed using a predetermined format. A two-round modified Delphi method was used to reach consensus on the voting statements. Disagreement was quantified using RAND/UCLA Appropriateness Method. Results: For the management of cardiac arrest, we recommend using ILE with bupivacaine toxicity, while our recommendations are neutral regarding its use for all other toxins. For the management of life-threatening toxicity, (1) as first line therapy, we suggest not to use ILE with toxicity from amitriptyline, non-lipid soluble beta receptor antagonists, bupropion, calcium channel blockers, cocaine, diphenhydramine, lamotrigine, malathion but are neutral for other toxins, (2) as part of treatment modalities, we suggest using ILE in bupivacaine toxicity if other therapies fail, but are neutral for other toxins, (3) if other therapies fail, we recommend ILE for bupivacaine toxicity and we suggest using ILE for toxicity due to other LAs, amitriptyline, and bupropion, but our recommendations are neutral for all other toxins. In the treatment of non-life-threatening toxicity, recommendations are variable according to the balance of expected risks and benefits for each toxin. For LA-toxicity we suggest the use of Intralipid V R 20% as it is the formulation the most often reported. There is no evidence to support a recommendation for the best formulation of ILE for non-LAs. The voting panel is neutral regarding ILE dosing and infusion duration due to insufficient data for non-LAs. All recommendations were based on very low quality of evidence. Conclusion: Clinical recommendations regarding the use of ILE in poisoning were only possible in a small number of scenarios and were based mainly on very low quality of evidence, balance of expected risks and benefits, adverse effects, laboratory interferences as well as related costs and resources. The workgroup emphasizes that dose-finding and controlled studies reflecting human poisoning scenarios are required to advance knowledge of limitations, indications, adverse effects, effectiveness, and best regimen for ILE treatment.

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Cardiac Conduction and Rate Disturbances

Gugelmann¹,

Benowitz²

2017

Critical Care Toxicology

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Pretreatment With Intravenous Lipid Emulsion Reduces Mortality From Cocaine Toxicity in a Rat Model

Cited by 15 publications

References 30 publications

Cardiac Depression Induced by Cocaine or Cocaethylene Is Alleviated by Lipid Emulsion More Effectively Than by Sulfobutylether‐β‐cyclodextrin

Cardiac Depression Induced by Cocaine or Cocaethylene Is Alleviated by Lipid Emulsion More Effectively Than by Sulfobutylether‐β‐cyclodextrin

Evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning

Cardiac Conduction and Rate Disturbances

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