Mechanisms and translation of lipid resuscitation

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DESCRIPTION (provided by applicant): Work funded under the PI's previous VA Merit award has contributed directly to a novel and now widely accepted life-saving treatment for local anesthetic systemic toxicity (LAST). Intravenous lipid emulsion (ILE) resuscitation has also been used in many instances to rapidly reverse acute cardiac and neurological symptoms of toxicity caused by a wide range of lipophilic (fat soluble) medications. In many published case reports involving LAST or other overdoses, ILE was effective even after standard resuscitation measures had failed. ILE is now a principle element in treatment guidelines published by the American Society of Regional Anesthesia, the Anaesthetists of Great Britain and Ireland, the Resuscitation Council (UK) and was added to the most recent American Heart Association ACLS guidelines for treating LAST. Drug overdose is the second leading cause of accidental death in the United States contributing to 36,000 fatalities in 2007 placing it ahead of gunshot wounds and just behind motor vehicle accidents. Moreover, veterans are at particular risk given the prevalence of both illicit drug abuse and the difficulty for a geriatric population to adhere to instructions for such prescription drugs as long acting calcium channel blockers that can be potentially fatal in overdose. Notably, ILE has been used effectively in treating overdose of many common prescription medications (e.g. beta blockers, tricyclic antidepressants or calcium channel blockers) that can be highly resistant to standard resuscitation measures. Identifying the precise mechanism(s) underlying ILE holds the promise of improving its efficacy and providing an effective, generic antidotal treatment for a range of life-threatening toxic drug overdoses. However, the precise mechanisms of ILE are not well understood. The conventional explanation involves partitioning of the offending toxin into the newly created lipemic plasma phase, or 'lipid sink'. However, even this mechanism has not been tested rigorously in vivo. Moreover, we have observed that key aspects of ILE cannot be explained by the sink alone, indicating that other, less well-understood, mechanisms are also at play. We believe that ILE also directly benefits cardiovascular function and have confirmed in preliminary experiments that the infusion of lipid emulsion in the intact rat exerts positive effecs on cardiac contractility and aortic blood flow. We hypothesize that this results in part from direc, positive effects of fatty acid metabolism on cardiac function. Moreover, it is well-established tha tissue ischemia can cause intercellular endothelial gaps to expand, thereby allowing liposomes to migrate into the myocardial interstitium. Such passive targeting of lipid particles, essentially nano-medicine, will bypass the normal tissue barriers to diffusion of drug away from cells and diminish the response time to lipid signal effectors. We hypothesize that extravascular migration of lipid particles contributes to the overall efficacy of ILE in reversing cardiac drug toxicity. W propose studies to test the metabolic effects of ILE and transendothelial migration of lipid particles. Finally, we seek to improve the translation of ILE to cocaine-related toxicity and longer-lasting overdoses such as calcium channel blocker toxicity. Improved patient safety and outcomes from drug toxicity are the over-arching goals of this project.