Intralipid infusion ameliorates propranolol-induced hypotension in rabbits

Abstract

Objective: Recent case reports of successful amelioration of lipid-soluble drug toxidromes with Intralipid infusion have prompted interest in the scope of lipid emulsions as antidotal therapy. Propranolol is a highly lipid-soluble, nonselective beta-blocker with additional local-anaesthetic properties. We explored the hypothesis that propranolol toxicity may be similarly attenuated by Intralipid infusion in a rabbit model.Methods: Twenty sedated, invasively monitored, and mechanically ventilated New Zealand White rabbits underwent propranolol infusion at 4.2 mg/min to a target mean arterial pressure (MAP) of 60% baseline MAP. Animals subsequently received 6 ml/kg 20% Intralipid, or 6 ml/kg 0.9% saline solution over a 4-minute period. Pulse rate and MAP were recorded at 2.5-minute intervals to 15 minutes.Results: MAP was greatest in the Intralipid group (median 69 mmHg, interquartile range [IQR] 17.5 mmHg Intralipid vs. median 53 mmHg, IQR 12.75 mmHg saline; p ϭ 0.029) at 15 minutes. No difference was observed in first derivative of MAP, or pulse rate between groups.Conclusions: Propranolol-induced hypotension is ameliorated by Intralipid infusion in this intact rabbit model. The mechanism of action remains to be elucidated.

Intravenous Lipid Emulsion Does Not Augment Blood Pressure Recovery in A Rabbit Model of Metoprolol Toxicity

“…If such an effect were demonstrated, the inference of a metabolic effect for ILE could potentially extend application to alternate agents with similar cardiodepressant properties. The absence of observed effect in this study, when a near identical experiment purported Table 2 Metoprolol dosing and monitored haemodynamic parameters effect for ILE in toxicity from the highly lipophilic β-blocker propranolol [10], however, supports to the 'lipid sink' hypothesis over metabolic explanations as the major mechanism for any beneficial effect of ILE in β-blocker toxicity. Previous animal investigations support an effect for ILE in propranolol toxicity [8][9][10].…”

“…Sample size estimation was based on data from previous experiments in the programme [8,10] and sought a post-treatment effect of 1.6 standard deviation difference in MAP (corresponding to 25 mmHg in humans and deemed to be clinically significant). With power set at 80% and alpha level at 0.05, this equated ten animals in each group.…”

“…Specifically, our infusion of metoprolol to a defined blood pressure endpoint represents a model for rapidly progressive toxicity and includes no ongoing infusion as mimic for continuous intestinal absorption expected in enteric overdose. In this instance, initial drug redistribution following [10]. The decision to monitor post-toxicity for a relatively short period was based on our previous protocols of β-blocker toxicity.…”

“…There has furthermore been considerable laboratory and some clinical reporting of beneficial effect for ILE in toxicity from other lipophilic agents including calcium channel blockers [3,4], tricyclic antidepressants [5][6][7] and β-blockers [4,[8][9][10]. While the exact mechanism of action for ILE is at present uncertain, three main hypotheses have been forwarded to explain the effects of ILE as antidote.…”

“…In previous work, our group has demonstrated efficacy for ILE in reversing hypotension associated with infusion of the highly lipophilic β-blocker propranolol [10], but relative absence of effect in atenolol-induced hypotension in an inherently unstable rabbit model [20]. Given the methodologic limitations experienced with the later experiment, we determined to further evaluate ILE utilising another relatively hydrophilic β-blocker as toxin.…”