betadex and Heart-Arrest

Sulfobutylether-β-cyclodextrin (SBE-CD) is a pharmaceutical excipient known to bind verapamil. After intravenous administration, clearance of SBE-CD approximates glomerular filtration rate. We hypothesized that SBE-CD would complex with verapamil in vivo, enhance renal elimination, and increase time to death in a rat model of verapamil toxicity. Ten Wistar rats were allocated to control or intervention groups. All received isoflurane anesthesia followed by verapamil infusion (32 mg/kg) over 1 hour. The control group received saline bolus 7.5 mL/kg at 5 minutes. The intervention group received SBE-CD infusion 7.5 mL/kg (2.25 g/kg) at 5 minutes. Heart rate, respiratory rate, oxygen saturation, and temperature were monitored. The primary endpoint was time to death measured separately as time to asystole and time to apnea. There was no benefit derived from cyclodextrin infusion. Average time to death was significantly longer in the control group as measured by time to apnea (P < 0.05). Control group survival was significantly better as measured by time to asystole and time to apnea (Breslow P < 0.05). SBE-CD infusion resulted in a shorter time to death measured by time to apnea and asystole. Preliminary work demonstrated no effect in isoflurane anesthetized rats receiving only SBE-CD bolus. Verapamil poisoned rats treated with 2.25 g/kg of SBE-CD showed increased toxicity. We propose that this effect was related to the large hyperosmolar CD infusion combined with verapamil-induced cardiogenic shock. Additional studies are warranted to clarify the mechanism of increased toxicity in our study and to assess for potential beneficial effects at lower SBE-CD concentrations.

Topics: Animals; Apnea; beta-Cyclodextrins; Disease Models, Animal; Heart Arrest; Male; Osmolar Concentration; Oxygen; Rats; Rats, Wistar; Shock, Cardiogenic; Survival Rate; Time Factors; Verapamil

We studied the aqueous solution of propofol dissolved in hydroxypropyl-beta-cyclodextrin (HP beta CD) 20% to determine whether the cardiovascular profile differed from that measured for propofol prepared in Intralipid 10% (Diprivan). Conscious male rats were given an intravenous bolus of propofol, 5.0 mg/kg, the minimum dose that induces a loss of righting. Immediately severe bradycardia occurred which was the result of a combination of sinus arrest and atrioventricular block; a significant decrease of blood pressure resulted. A bolus of HP beta CD produced no significant changes in heart rate rhythm. The severe bradycardia produced by propofol in HP beta CD was blocked by both atropine and bilateral cervical vagotomy. Therefore, the effects of propofol in HP beta CD are cholinergic and neurally mediated. These results are consistent with the hypothesis that propofol reduces sympathetic tone prior to reduction in vagal tone, and thereby produces a period of time during which vagal tone is dominant.

Topics: Anesthetics, Intravenous; Animals; Arrhythmia, Sinus; Atropine; beta-Cyclodextrins; Bradycardia; Cholinergic Agents; Cyclodextrins; Drug Interactions; Fat Emulsions, Intravenous; Heart; Heart Arrest; Heart Block; Heart Rate; Injections, Intravenous; Male; Pharmaceutical Vehicles; Propofol; Rats; Rats, Sprague-Dawley; Vagotomy; Vagus Nerve