Domestic swine model for the assessment of chemical warfare agent-anesthetic interactions: Some effects of sulfur mustard

Military Medicine, Aug 2000 by Sawyer, Thomas W

A domestic swine model was developed to examine the interaction of chemical warfare agents with anesthetics and other drugs used during general anesthesia. Animals were fully instrumented, and clinically relevant physiological parameters were monitored throughout the experimental procedures. Exposure of animals under halothane anesthesia to the chemical warfare agent sulfur mustard (HD; 1 mg/kg intravenous) produced mild signs of systemic intoxication during the subsequent 5 hours. Induction doses of ketamine 1 hour after HD exposure resulted in periods of profound apnea, with continued respiratory distress for the next 2 hours. When animals were treated with HD 1 hour after the initiation of ketamine anesthesia, severe and persistent convulsion-like muscular activity was observed within 45 minutes of HD administration. This nonpurposeful activity was not ameliorated by diazepam but was dramatically reduced or eliminated by resumption of halothane anesthesia. Treatment of IiD-intoxicated pigs with succinylcholine produced a prolonged apnea resulting in death. In these apparently mildly HD-intoxicated animals, the introduction of ketamine or succinylcholine can rapidly induce potentially life-threatening situations.

Introduction

Historically, plans for the medical treatment of battlefield casualties have tended to polarize around injuries consideyed either conventional or chemical agent-related. Contingency plans devoted to the treatment of combined casualties have received relatively little attention despite the very real possibility that such a situation may occur. Combined casualties of these types would present unique and challenging problems for medical treatment and have a great impact on available resources. Of particular interest are the potential problems related to anesthetic management, including endotracheal intubation, anesthetic induction and maintenance, and the emergence of poisoned individuals with accompanying traumatic injuries requiring urgent or emergent surgery. In patients poisoned with agents that target the central nervous and respiratory systems, the potential for adverse interactions with anesthetics and neuromuscular blocking agents is likely to be high.

This laboratory has had a continuing interest in sulfur mustard [bis(2-chloroethyl)sulfide; NATO Standard Agreement code HD], a chemical warfare agent that has been well documented as being toxic to a variety of tissue and organ systems.'-4 Although, historically, its primary military use has been as a vesicant (blister-causing) agent, it is also capable of exerting systemic effects on the immune, cardiovascular, and central nervous systems at high concentrations.2,5-9 During studies designed to investigate the vesicant actions of this agent (unpublished data), we noted that in ketamine-anesthetized rats, topical challenges of HD (2 x I wL, 200-g animals) caused signs of intoxication that closely mimmicked those of organophosphatepoisoned animals, including mastication, muscle fasciculation, straub tail, and respiratory distress. These animals often died, apparently of respiratory failure, even though similarly treated but unanesthetized animals never presented any signs of stress or discomfort. In an effort to further investigate the adverse interaction between HD and ketamine, we used domestic swine. These animals have been used extensively in the study of action of anesthetics and have been shown to be an excellent model system for humans.'o.l' We describe here a domestic swine model for the study of anesthetic-chemical warfare agent interactions as well as the adverse interactions between HD and ketamine, and HD and the neuromuscular blocking agent succinylcholine (SDC).

Methods

Animals

Castrated male York-Landrace cross pigs were obtained from a local supplier and housed indoors at the Defence Research Establishment Suffield animal facilities. The pigs were fed on standard 16% hog grower and allowed tap water ad libitum. The mean body weight at the time of experimentation was 21.3 1.0 kg (n = 12), and all test groups consisted of three animals per group. In conducting this research, the authors adhered to the "Guide to the Care and Use of Experimental Animals" and "The Ethics of Animal Experimentation" published by the Canadian Council on Animal Care.

Anesthesia

Animals were fed until the evening before surgery and allowed tap water ad libitum until the time of the experiment. The animals were not premedicated, and general anesthesia was induced by mask with halothane (3%) in a carrier gas mixture of oxygen and nitrous oxide (1:1) using a Boyle anesthesia machine with a circle patient anesthesia circuit while the animal was still in the transport container. After induction, the animals were transferred to the operating table and placed in the supine position. Anesthesia was maintained with halothane (2.0%) and oxygen/nitrous oxide (1:1), and the animals were never allowed to regain consciousness once anesthesia was established. An ear vein was catheterized, the animals were intubated with a 6.0-mm cuffed oral endotracheal tube, and the cuff was inflated with room air to achieve a seal.