Intralipid Prolongs Survival in a Rat Model of Verapamil Toxicity

We previously demonstrated in rats that intravenous infusion of a lipid emulsion increases survival in resuscitation from severe bupivacaine cardiac toxicity. The present studies were undertaken to determine if this method is similarly effective in a non-rodent model using a larger animal. Bupivacaine, 10 mg/kg, was administered intravenously over 10 seconds to fasted dogs under isoflurane general anesthesia. Resuscitation included 10 minutes of internal cardiac massage followed with either saline or 20% lipid infusion, administered as a 4-mL/kg bolus followed by continuous infusion at 0.5 mL/kg/min for 10 minutes. Electrocardiogram (EKG), arterial blood pressure (BP), and myocardial pH (pHm) and pO2 (pmO2) were continuously measured. Survival after 10 minutes of unsuccessful cardiac massage was successful for all lipid-treated dogs (n = 6), but with no survivors in the saline controls (n = 6) (P <.01). Hemodynamics, PmO2, and pHm were improved during resuscitation with lipid compared with saline treatment in which dogs did not recover. We found that infusing a lipid emulsion during resuscitation from bupivacaine-induced cardiac toxicity substantially improved hemodynamics, pmO2, and pHm and increased survival in dogs.

Myocardial depression from verapamil toxicity may result from alterations in carbohydrate metabolism as well as calcium-channel antagonism. We hypothesized that pharmacologic doses of insulin may be effective in reversing both of these deficits. Randomized, controlled, prospective study. Laboratory of an urban hospital. Thirty mongrel dogs. Thirty mongrel canines were anesthetized with alpha-chloralose. Toxicity was induced by the administration of 0.1 mg/kg/min iv of verapamil, until there was a 50% reduction in mean arterial pressure, for 30 mins (titration), followed by a continuous verapamil infusion of 1 mg/kg/hr. Animals (n = 6 per group) were randomized to the control group (saline only) or to one of four treatment protocols: a) calcium chloride (20 mg/kg), then 0.6 mg/kg/hr; b) hyperinsulinemia-euglycemia (4.0 U/min of recombinant insulin, with arterial glucose concentration clamped to +/- 10 mg/dL [+/- 0.5 mmol/L] of the basal value); c) epinephrine, with a starting rate of 1.0 microgram/kg/min, titrated to maintain left ventricular pressure at basal values; or d) glucagon, a 0.2-mg/kg bolus, followed by a 150-microgram/kg/hr infusion. Animals were monitored until death or 240 mins; infusate volumes were held constant for all groups. During verapamil titration, the myocardial respiratory quotient increased from 0.84 +/- 0.05 to 1.07 +/- 0.11 (p < .05, paired t-test) and myocardial glucose uptake doubled, despite a reduction in cardiac work (p < .05, paired t-test). Net myocardial lactate uptake also increased significantly, excluding myocardial ischemia. In controls, this trend continued, indicating preferential carbohydrate metabolism during untreated verapamil toxicity. Despite hyperglycemia, the plasma insulin concentration was not significantly different in controls (basal value 11 +/- 2 vs. 39 +/- 21 microU/mL at 30 mins). Hyperinsulinemia-euglycemia increased both myocardial glucose and lactate uptake five-fold, and significantly increased the ratio of myocardial oxygen delivery/work, along with superior improvements in maximal left ventricular elastance at end systole compared with other treatments (p < .05 vs. other treatments, contrast analysis). Verapamil toxicity renders the heart dependent on carbohydrate metabolism. Inasmuch as the positive inotropic effects of all treatments were coincident with increased indices of myocardial carbohydrate uptake, adequate treatment of verapamil toxicity appeared to require maximal myocardial carbohydrate utilization. Hyperinsulinemia-euglycemia allows larger increases in myocardial carbohydrate metabolism and myocardial contractility than calcium chloride, epinephrine, or glucagon, resulting in improved survival rates during severe verapamil toxicity.