Levosimendan does not improve survival time in a rat model of verapamil toxicity.
OBJECTIVE
Calcium channel blocker (CCB) toxicity, in particular that induced by verapamil and diltiazem, presents clinical challenges with no true antidote. Levosimendan, a calcium sensitizer, improves cardiac contractility in patients with heart failure. We tested the hypothesis that calcium channel sensitization will prolong survival in a rat model of severe verapamil poisoning.


METHODS
This was a blinded, randomized, controlled animal study. Wistar rats (mean weight, 371 +/- 50 g) were used. Verapamil (2.5 mg/ml) was infused at a rate of 37.5 mg/kg per hour. Bolus doses of levosimendan (5 microg/mL) were given at 0 min (12 microg/kg) and 5 min (18 microg/kg); saline control was of equal volume. The rats were intubated and maintained under general anesthesia with isoflurane. Electrocardiographic activity and core temperature were monitored during the poisoning and treatment phases. Each rat underwent femoral vein cannulation and was then randomized, in blinded fashion, to receive either levosimendan or an equal volume of saline at 0 and 5 minutes. Death, defined as 1 minute of asystole, was used as the primary endpoint.


RESULTS
Rats treated with levosimendan died before the control group (7.37 +/- 0.7 min [n=7] vs. 16.4 +/- 4.2 [n=7] [ p=.053]). All animals experienced bradycardia prior to asystole.


CONCLUSIONS
Although levosimendan has the ability to sensitize and enhance binding of troponin C to Ca2+, this study did not show an improvement in survival time in the setting of verapamil toxicity. This may be attributed to levosimendan's inhibition of phosphodiesterase, which possibly exacerbated the CCB-induced hypotension.


CONCLUSIONS
In this rat model, levosimendan as a solitary antidotal treatment for verapamil toxicity was not beneficial.
Abraham
Michael K
MK
Department of Emergency Medicine, University of Maryland Medical Center, Baltimore, MD 21201, USA.
Scott
Sara B
SB
Meltzer
Andrew
A
Barrueto
Fermin
F
D000818:Animals; D000931:Antidotes / Q000494:pharmacology* / Q000633:toxicity; D001831:Body Temperature / Q000187:drug effects; D001919:Bradycardia / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D002121:Calcium Channel Blockers; D004347:Drug Interactions; D004562:Electrocardiography; D006323:Heart Arrest / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006835:Hydrazones / Q000494:pharmacology* / Q000633:toxicity; D007022:Hypotension / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D023421:Models, Animal; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D011724:Pyridazines / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D000077464:Simendan; D013997:Time Factors; D014700:Verapamil
D000931:Antidotes; D002121:Calcium Channel Blockers; D006835:Hydrazones; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D000077464:Simendan; D014700:Verapamil