Effect of cyclodextrin infusion in a rat model of verapamil toxicity.

Sulfobutylether-ß-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.

Dose-dependent response to cyclodextrin infusion in a rat model of verapamil toxicity.

INTRODUCTION: Sulfobutylether-ß-cyclodextrin (SBE-CD) is a pharmaceutical excipient known to bind verapamil. Following intravenous administration, clearance of SBE-CD approximates glomerular filtration rate. We hypothesized that infusion of SBE-CD would increase time to asystole in a rat model of verapamil toxicity in a dose-dependent manner. The objective was to demonstrate the effect of a range of SBE-CD concentrations in a rat model of verapamil toxicity. METHODS: Twenty-five Wistar rats were allocated to control or 1 of 4 intervention groups. All received ketamine and diazepam anesthesia followed by verapamil infusion 32 mg/kg/h. The verapamil infusion for the intervention groups was premixed with SBE-CD in a 1:1, 1:2, 1:4, or 1:8 molar ratio (verapamil to SBE-CD). The control group infusion did not contain SBE-CD. Additional saline or water was added to the infusion so that the total volume infused was the same across groups, and the osmolality was maintained as close to physiologic as possible. Heart rate, respiratory rate, and temperature were monitored. The primary endpoint was time to asystole. RESULTS: Verapamil coinfused with SBE-CD in a molar ratio of 1:4 resulted in prolonged time to asystole compared to control (21.2 minutes vs 17.6 minutes, P < 0.05). There were no differences in time to asystole between control and any other intervention group. There was no significant difference in time to apnea between control and any intervention group. We assessed the effect of a range of SBE-CD concentrations and identified 1 concentration that prolonged time to asystole. Mechanisms that may explain this effect include optimal volume expansion with a hyperosmolar cyclodextrin containing solution, complexation of verapamil within the hydrophobic cyclodextrin pore, and/or complexation within micelle-like aggregates of cyclodextrin. However, mechanistic explanations for the observed findings are speculative at this point. CONCLUSION: The 1:4 verapamil to SBE-CD concentration was modestly effective with SBE-CD concentrations above and below this range demonstrating nonstatistically significant improvements in time to asystole.

Rhythm disturbances.

Patients with cardiac rhythm disturbances may present in a variety of conditions. Patients may be unstable, requiring immediate interventions, or stable, allowing for a more deliberate approach. Rapid assessment of patient stability, underlying rhythm, and determination of appropriate interventions guides timely therapy. This article discusses the differential diagnosis and treatment of adult patients presenting with primary bradyarrhythmias and tachyarrhythmias, with the exception of atrial fibrillation and atrial flutter, covered elsewhere in this issue. A concise approach to diagnosis and determination of appropriate therapy is presented.

Fatty acids antagonize bupivacaine-induced I(Na) blockade.

Theories regarding the mechanism of intravenous fat emulsion for bupivacaine cardiotoxicity include creation of an intravascular lipid sink into which the cardiotoxic drug is sequestered, an improvement of impaired cardiac metabolism, and restoration of cardiomyocyte function by increasing intracellular calcium. However, work in this area is inconclusive and a more mechanistic explanation is desirable. We used a heterologous expression system (HEK-293 cells) and voltage clamp techniques to study the electrophysiologic effects of bupivacaine, polyunsaturated, and saturated fatty acids on sodium current (I(Na)) in stable cell lines expressing human cardiac sodium channels. Linolenic (polyunsaturated) and stearic (saturated) fatty acids were selected for study as they are components of commonly used lipid infusions. Bupivacaine-induced significant tonic and use dependent I(Na) block, as expected. Linolenic and stearic fatty acids directly modulated I(Na), inducing primarily tonic block. Greater block was seen with linolenic acid as compared with stearic acid. Simultaneous exposure to bupivacaine and fatty acids reduced both the tonic and use dependent block compared with bupivacaine alone. Reduction of bupivacaine-induced I(Na) block was greatest in cells treated with linolenic acid. These results suggest that the salutary effects of intravenous fat emulsion may be, in part, due to a direct modulatory effect of fatty acids on cardiac sodium channels.

Lepiota subincarnata J.E. Lange induced fulminant hepatic failure presenting with pancreatitis.

A 43-year-old woman with a medical history significant only for hepatitis B carrier status presented to an emergency department with generalized weakness, dizziness, nausea, and diarrhea 36 h after eating an estimated 170 g of sautéed Lepiota subincarnata J.E. Lange (basionym Lepiota josserandii). Laboratory evaluation revealed profound metabolic acidosis with mild transaminitis, mild coagulopathy, and renal insufficiency. Marked biochemical evidence of pancreatitis was present prior to significant hepatotoxicity. The patient ultimately required liver transplantation on hospital day 7 and was discharged home on hospital day 12.