Determining the optimal dose of intravenous fat emulsion for the treatment of severe verapamil toxicity in a rodent model.
OBJECTIVE
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.
Perez
Eric
E
St. Luke's Roosevelt Hospital Center, Columbia University, College of Physicians and Surgeons, New York, NY, USA. eperez95@yahoo.com
Bania
Theodore C
TC
Medlej
Kamal
K
Chu
Jason
J
D000136:Acid-Base Equilibrium / Q000187:drug effects; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose / Q000628:therapy; D005217:Fat Emulsions, Intravenous / Q000008:administration & dosage*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D051381:Rats; D016019:Survival Analysis; D016896:Treatment Outcome; D014700:Verapamil / Q000633:toxicity*
D002121:Calcium Channel Blockers; D005217:Fat Emulsions, Intravenous; D014700:Verapamil