High-Dose Insulin for the Treatment of Amlodipine-Induced Toxicity: Initial Findings From a Porcine Model

The utility of high-dose insulin (HDI) to treat amlodipine overdose is not well understood; both amlodipine and HDI cause vasodilation than can worsen shock. We are performing a pilot study to assess the effect of HDI on survival time and other parameters using an established porcine model of amlodipine-induced toxicity. We performed control experiments to confirm the model’s toxicity, and evaluated if dimethyl sulfoxide (DMSO), the solvent for amlodipine for intravenous (IV) infusion, confounds hemodynamic measurements.

Five Yorkshire swine weighing 30-40 kilograms were sedated and continuously anesthetized, intubated, and central arterial/venous catheters and cardiac monitors were placed. After recording baseline cardiac parameters, IV amlodipine infusion was initiated starting at 0.25 mg/kg/hr, and increased by 0.25 mg/kg/hr increments every 15 minutes. Upon reaching the point of toxicity, defined as a 25% drop in mean arterial pressure (MAP) from baseline, the infusion was held at the current rate, and a 20 g/kg IV bolus of normal saline was given. Animals were monitored until expiration, or euthanized at 6 hours. For 3 animals, prior to the IV amlodipine infusion, a DMSO bolus equal to 1/6 the total IV volume of DMSO used in the 6-hour study period was given over 1 hour, followed by 1 hour of monitoring.

4 of 5 animals expired prior to the end of the 6-hour study period, with a mean time to death of 250 minutes, confirming adequate model toxicity. The mean IV amlodipine dose given was 342 mg, with a mean lethal dose of 8.58 mg/kg. One animal that survived to the end of the study reached PoT at 70 minutes, but had experienced unexpected hemodynamic instability with resuscitation prior to experimentation, and had similar toxicity once the amlodipine infused approached the mean toxic dose. The baseline mean HR and MAP for lethal cases were 132 and 110 respectively, with mean values of 201 and 74 at PoT, suggesting vasodilation as a contributor for shock. DMSO alone caused an increase in HR and MAP, but the mechanism and statistical significance of this is uncertain.

Our porcine model is adequately toxic for continued experimentation with HDI. DMSO appears to cause an increase in HR and MAP - while the significance of this finding is uncertain, it may be a confounder to all studies using this model. Our next 10 animals will test if HDI has any effect on animal survival time with respect to our controls.