Multiple Centrally Acting Antidotes Protect against Severe O

[Ace844]

(Acad Emerg Med Volume 13 @ Number 4 359-364,

published online before print March 10, 2006, doi: 10.1197/j.aem.2005.10.018

© 2006 Society for Academic Emergency Medicine BASIC INVESTIGATION

Multiple Centrally Acting Antidotes Protect against Severe Organophosphate Toxicity

Marco L.A. Sivilotti, MD, MSc, Steven B. Bird, MD, Jean C.Y. Lo, MS and Eric W. Dickson, MD

From the Departments of Emergency Medicine and of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada; Ontario Regional Poison Information Centre (MLAS), Toronto, Ontario, Canada; Division of Medical Toxicology, Department of Emergency Medicine, University of Massachusetts (SBB), Worcester, MA; and Department of Emergency Medicine, University of Iowa (JCYL, EWD), Iowa City, IA.

Address for correspondence and reprints: Marco L. A. Sivilotti, MD, Department of Emergency Medicine, Queen's University, 76 Stuart Street, Kingston, Ontario, Canada, K7L 2V7. Fax: 613-548-1374; e-mail: sivilotm@meds.queensu.ca.)

Background: Accumulation of acetylcholine in the central nervous system is believed to account for the rapid lethality of organophosphate pesticides and chemical nerve agents. Diazepam is known to supplement atropine therapy, but its specific mechanism of action is uncertain.

Objectives: To test four centrally acting agents for early antidotal efficacy in severe dichlorvos poisoning in the murine model.

Methods: The up-and-down method was used to dose four candidate antidotes: diazepam, xylazine, morphine, and ketamine. Antidotes were administered subcutaneously to unsedated adult Sprague-Dawley rats who were pretreated with 3 mg/kg intraperitoneal glycopyrrolate. All animals received 20 mg/kg of dichlorvos subcutaneously 5 minutes later. A blinded observer adjudicated the outcomes of 10-minute mortality and survival time.

Results: All animals pretreated with either no antidote (8/8 deaths) or glycopyrrolate alone (8/8) died within 10 minutes of dichlorvos injection. Pretreatment with diazepam (3/9 deaths), or xylazine (3/9), decreased lethality substantially (Fisher p = 0.007; median effective doses, 0.12 mg/kg and 3.0 mg/kg, respectively). Intermediate doses of morphine (3.1 to 5.5 mg/kg) resulted in survival, but higher doses did not, presumably because of excessive respiratory depression (7/11 deaths; p = 0.09). Ketamine (7/8 deaths) was ineffective as an antidote. Survival times also were prolonged in the diazepam and xylazine groups (log-rank p < 0.001) and, to a lesser degree, the morphine group (p = 0.07).

Conclusions: Doses of diazepam, xylazine, and morphine below those used for deep sedation protect against severe dichlorvos poisoning, implying that several distinct central mechanisms are each sufficient to avert lethality. These findings suggest new possibilities for prophylaxis or therapy.