Determining the Optimal Dose of Intravenous Fat Emulsion for the Treatment of Severe Verapamil Toxicity in a Rodent Model

Abstract

Objectives: Recent animal studies have shown that intravenous fat emulsion (IFE) increases survival and hemodynamics in severe verapamil toxicity. However, the optimal dose of IFE is unknown. The primary objective was to determine the optimal dose of IFE based on survival in severe verapamil toxicity. Secondary objectives were to determine the effects on hemodynamic and metabolic parameters. The hypothesis was that there is a dose-dependent effect of IFE on survival until a maximum dose is reached.Methods: This was a controlled dose-escalation study. Thirty male rats were anesthetized, ventilated, and instrumented to record mean arterial pressure (MAP) and heart rate (HR). Verapamil toxicity was achieved by a constant infusion of 15 mg ⁄ kg ⁄ hr. After 5 minutes, a bolus of 20% IFE was given. Animals were divided into six groups based on differing doses of IFE. Arterial base excess (ABE) was measured every 30 minutes. Data were analyzed with analysis of variance. Results:The mean survival time for each dose of IFE was 0 mL ⁄ kg = 34 minutes, 6.2 mL ⁄ kg = 58 minutes, 12.4 mL ⁄ kg = 63 minutes, 18.6 mL ⁄ kg = 143.8 minutes, 24.8 mL ⁄ kg = 125.6 minutes, and 37.6 mL ⁄ kg = 130 minutes. Post hoc testing determined that the 18.6 mL ⁄ kg dose resulted in the greatest survival when compared to other doses. It increased survival 107.2 minutes (p = 0.004), 91.2 minutes (p = 0.001), and 80.8 minutes (p = 0.023) when compared to the lower doses of 0, 6.2, and 12.4 mL ⁄ kg, respectively. There was no added benefit to survival for doses greater than 18.6 mL ⁄ kg. The secondary outcomes of HR, MAP, and ABE showed the most benefit with 24.8 mL ⁄ kg of IFE at both 30 and 60 minutes. Conclusions:The greatest benefit to survival occurs with 18.6 mL ⁄ kg IFE, while the greatest benefit to HR, MAP, and BE occurs at 24.8 mL ⁄ kg IFE. The optimal dose for the treatment of severe verapamil toxicity in this murine model was 18.6 mL ⁄ kg.

In Vitro Studies Indicate Intravenous Lipid Emulsion Acts as Lipid Sink in Verapamil Poisoning

“…Although there are no therapies that consistently reverse cardiovascular collapse caused by CCB poisoning, both high-dose insulin/euglycemia (HIE) therapy [2][3][4] and intravenous lipid emulsion (ILE) [5][6][7] have been shown to improve hemodynamics and survival following intravenous administration of verapamil in animals. On the other hand, while several case reports indicate amelioration of CCB-induced cardiotoxicity by the administration of ILE [8][9][10][11], others report no benefit [12].…”

Intravenous Lipid Emulsion Alters the Hemodynamic Response to Epinephrine in a Rat Model

“…After a 3-min stabilization period, each animal received either an ILE (20 % intravenous lipid emulsion, Baxter, Deerfield, IL, USA) 15 cm 3 /kg bolus over seven minutes or NS 15 cm 3 /kg bolus over 7 min. This ILE dose was selected based on previous rat models of ILE resuscitation which have successfully used doses ranging from 10 to 19 cm 3 /kg [4,6,7]. Two minutes after completion of the infusion and once MAP/HR returned to baseline, a bolus dose of intravenous epinephrine (15 μm/kg) was administered.…”

“…Following this trend of expanding utility, ILE has been shown to be efficacious in the emergency treatment of neurotoxicity and cardiotoxicity that results from a variety of cardiovascular and psychoactive drug classes. Animal studies have established benefit from ILE in various models of toxicity including verapamil [5,6], propranolol [7], amiodarone [8], and clomipramine [9]. Case studies have demonstrated successful use of ILE in haloperidol induced cardiac arrest [10], lamotrigine overdose [11], and in resuscitations of patients with combination ingestions of quetiapine/sertraline [12] and buproprion/lamotrigine [13].…”

Pilot Trial of Intravenous Lipid Emulsion Treatment for Severe Nifedipine-Induced Shock

“…Lipid emulsion therapy has been studied for verapamil toxicity with impressive results in several animal models [4][5][6]. It has also been used to treat calcium channel antagonist toxicity in at least 20 published human cases, primarily involving verapamil and diltiazem [7][8][9][10][11][12][13][14][15][16].…”