Lipid Emulsion as Antidote: An Exposition of Experimental Animal Models

Abstract

Objective: The primary goal of this thesis was to explore the utility of intravenous lipid emulsion formulations in amelioration of a variety of non local-anaesthetic drug induced toxic states, and thereby inform clinicians contemplating incorporation of lipid emulsions as therapy in human poisonings. A secondary goal was to elucidate the fundamental beneficial mechanism(s) of action of lipid emulsion as antidote. An additional goal was to explore the effect of intravenous lipid emulsion in non toxin-induced cardiovascular collapse. Methods: This thesis consists of a collection of pre-clinical studies evaluating the hemodynamic, and to a lesser extent central nervous system effects of intravenous lipid emulsion when administered in a variety of animal models of intoxication with non local-anaesthetic drugs. Results: Infusion of lipid emulsion accelerated reversal of thiopental induced respiratory depression in rats. Pre-treatment with lipid emulsion conferred a trend toward greater survival, and lesser bradycardia and ECG QRS prolongation, in rats undergoing propranolol infusion. Infusion of lipid emulsion increased survival times and LD50 in rats undergoing verapamil infusion. Infusion of intravenous lipid emulsion resulted in hemodymanic improvement in propranolol induced hypotension in rabbits, but not in atenolol or metoprolol induced hypotension. Infusion of lipid emulsion resulted in accelerated recovery in blood pressure, and more rapid reduction in ECG QRS duration, in clomipramine toxic rabbits when compared with sodium bicarbonate. Lipid emulsion proved more effective than sodium bicarbonate in resuscitation from profound clomipramine induced hypotension in rabbits. Hemodynamic recovery following infusion of intravenous lipid emulsion was shown to correlate with elevated serum clomipramine concentration consistent with sequestration of drug to an expanded intravascular lipid phase. Peritoneal dialysis with lipid emulsion resulted in increased clomipramine extraction. iii Pre-treatment with intravenous lipid emulsion failed to alter rates of return of spontaneous circulation in rabbits resuscitated from asphyxia cardiac arrest. Administration of intravenous lipid emulsion concurrent with advanced cardiac life support resuscitative measures resulted in lesser return of spontaneous circulation in rabbits suffering asphyxia induced pulseless electrical activity. Conclusions: Intravenous lipid emulsion is effective in amelioration of adverse central nervous system and hemodynamic sequelae attributable to overdose of highly lipophillic pharmaceutical agents in the described animal models. These findings are consistent with the hypothesis of sequestration of toxin from pharmacologic sites of action to an expanded plasma lipid phase. Application of intravenous lipid emulsion in non-toxin induced hypoxic cardiac arrest impairs resuscitation.