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.

Public Health Relevance

An effective treatment for lipophilic drug overdose would clearly benefit US Military Veterans. This proposal focuses on better understanding, optimizing and translating IFE to treatment of lipophilic drug overdoses with a focus on a acute cocaine intoxication a problem of specific relevance to the veteran population. The VA National Data Systems Inpatient Medical SAS dataset indicates that among the 618,902 inpatient admissions for fiscal year 2010, 1,764 veterans were admitted for cocaine overdose. ILE is a novel approach to treating cocaine toxicity that could save lives and prevent unnecessary morbidity. In addition, the geriatric population is at risk for mistakes involving prescription medication that can result in life- threatening overdose. This work will be directly translatable to treating a wide spectrum of other accidental drug overdoses.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Surgery (SURG)
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Jesse Brown VA Medical Center
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Fettiplace, Michael R; Kowal, Katarzyna; Ripper, Richard et al. (2016) Insulin Signaling in Bupivacaine-induced Cardiac Toxicity: Sensitization during Recovery and Potentiation by Lipid Emulsion. Anesthesiology 124:428-42
Fettiplace, Michael R; Lis, Kinga; Ripper, Richard et al. (2015) Multi-modal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro-emulsion. J Control Release 198:62-70
Fettiplace, Michael R; Pichurko, Adrian; Ripper, Richard et al. (2015) Cardiac depression induced by cocaine or cocaethylene is alleviated by lipid emulsion more effectively than by sulfobutylether-?-cyclodextrin. Acad Emerg Med 22:508-17
Fettiplace, Michael Robert; Ripper, Richard; Lis, Kinga et al. (2014) Intraosseous lipid emulsion: an effective alternative to IV delivery in emergency situations. Crit Care Med 42:e157-60
Fettiplace, Michael R; Akpa, Belinda S; Ripper, Richard et al. (2014) Resuscitation with lipid emulsion: dose-dependent recovery from cardiac pharmacotoxicity requires a cardiotonic effect. Anesthesiology 120:915-25
Merkel, Olivia M; Rubinstein, Israel; Kissel, Thomas (2014) siRNA delivery to the lung: what's new? Adv Drug Deliv Rev 75:112-28
Li, Jing; Fettiplace, Michael; Chen, Sy-Jou et al. (2014) Lipid emulsion rapidly restores contractility in stunned mouse cardiomyocytes: a comparison with therapeutic hypothermia. Crit Care Med 42:e734-40
Fettiplace, Michael R; Ripper, Richard; Lis, Kinga et al. (2013) Rapid cardiotonic effects of lipid emulsion infusion*. Crit Care Med 41:e156-62
Krishnamoorthy, Vijay; Hiller, David B; Ripper, Richard et al. (2012) Epinephrine induces rapid deterioration in pulmonary oxygen exchange in intact, anesthetized rats: a flow and pulmonary capillary pressure-dependent phenomenon. Anesthesiology 117:745-54