Medical Aspects of Chemical Warfare (2008) - The Black Vault

Medical Aspects of Chemical Warfaredamage were not seen in the anesthetized animals.In this study, there were no significant differences inthe cardiovascular and respiratory effects when theagent was given intravenously, percutaneously, or byinhalation. In a study 71 of rabbits poisoned with sarin,bronchoconstriction appeared to be a minor factor,while neuromuscular block (particularly at the diaphragm)and central failure were the primary factorsin respiratory failure.In a review 72 describing studies in anesthetized catsgiven tabun, sarin, soman, or VX, the loss of centralrespiratory drive was found to be the predominantcause of respiratory failure with each of the agents, andthe contribution of bronchoconstriction was apparentlyinsignificant (in contrast to the severe bronchoconstrictionnoted in the earlier study 67 ). Respiratory failurewas the predominant cause of death in the speciesstudied because significant cardiovascular depressionoccurred only after cessation of respiration. 71,72 Whenatropine was administered in adequate amounts beforethe failure of circulation, it reversed the centraldepression and bronchoconstriction but not the neuromuscularblock, a finding that might be expected,because the neuromuscular effects of poisoning withthese nerve agents occur at a nicotinic site. 67,71In one study, 73 pyridostigmine was administered toprimates, which were then exposed to a nerve agentand given the standard therapeutic drugs, atropine and2-pyridine aldoxime methyl chloride (2-PAM Cl, alsocalled 2-pralidoxime chloride; pyridine-2-aldoximemethyl chloride; 2-formyl-1-methylpyridinium chloride;Protopam chloride, manufactured by Wyeth-Ayerst Laboratories, Philadelphia, Pa). Pyridostigminedoes not appear to enter the CNS because it is a quaternarycompound and thus would not be expectedto protect central sites of respiratory stimulation fromthe effects of a nerve agent. The pretreated animalscontinued to breathe, however, in contrast to controlsthat did not receive pyridostigmine pretreatment butwere otherwise treated in the same manner.The results of this study suggest that pyridostigmineprotects against the cessation of respiration. Sincepyridostigmine does not appear to enter the CNS, itis suggested that peripheral mechanisms of breathing(skeletal muscles and airways) must predominate insustaining breathing. Alternatively, the blood–brainbarrier may change in the presence of a nerve agent(as with other types of poisoning or hypoxia) to allowthe penetration of drugs it otherwise excludes. Forexample, when 2-PAM Cl, which is also a quaternarycompound, is administered to animals poisoned witha ChE inhibitor, it can be found in the animals’ centralnervous systems, but it is not found in the brains ofnormal animals after they receive 2-PAM Cl. 74Skeletal MusculatureThe neuromuscular effects of nerve agents havebeen the subject of hundreds of studies since nerveagents were first synthesized in 1936. Much of ourinformation on the mechanism of action of nerveagents and potential therapeutic measures has comefrom these studies. Because this chapter is primarilyconcerned with clinical effects of nerve agent poisoning,a comprehensive review of these studies is notpresented here.The effects of nerve agent intoxication on skeletalmuscle are caused initially by stimulation of musclefibers, then by stimulation of muscles and musclegroups, and later by fatigue and paralysis of theseunits. These effects on muscle may be described asfasciculations, twitches or jerks, and fatigue.Fasciculations are the visible contractions of asmall number of fibers innervated by a single motornerve filament. They are normally painless, and smallfasciculations often escape the patient ’ s notice. Theyappear as ripples under the skin. They can occur as alocal effect at the site of a droplet of agent on the skinbefore enough agent is absorbed to cause systemiceffects; the patient is not likely to notice these if thearea affected is small. Fasciculations can also appearsimultaneously in many muscle groups after a largesystemic exposure. A casualty who has sustained asevere exposure will have generalized fasciculations,a characteristic sign of poisoning by a ChE inhibitor.Fasciculations will typically continue long after thepatient has regained consciousness and has voluntarymuscle activity.After a severe exposure, there are intense and suddencontractions of large muscle groups, which causethe limbs to flail or become momentarily rigid or thetorso to arch rigidly in hyperextension. Whether thesemovements, which have been described as convulsivejerks, are part of a generalized seizure or originatelower in the nervous system has been a matter of debate.Occasionally, these disturbances may be a localeffect on the muscle groups below or near the site ofexposure (for instance, the marked trismus and nuchalrigidity in an individual who has pipetted soman intohis or her mouth; see Exhibit 5-1). 20 Nerve agents alsoproduce convulsions that are associated with frankepileptiform seizure activity as measured by EEGrecordings. 75–77 In cases of severe poisoning, convulsivemovements and associated epileptiform seizureactivity may stop or become episodic as respiratorystatus becomes compromised and oxygenation is depressed.It may be impossible to clinically distinguishconvulsive activity because of frank central seizuresfrom the purely peripheral neuromuscular symptoms174