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

Medical Aspects of Chemical Warfareagainst the side effects of antidotes in an unpoisonedindividual.Antidotes should be administered until ventilationis adequate and secretions are minimal. In a mildly tomoderately symptomatic individual complaining ofdyspnea, relief is usually obtained with 2 or 4 mg ofatropine (the amount of atropine in one or two MarkI kits or ATNAA). In a severely exposed person whois unconscious and apneic or nearly apneic, at least6 mg of atropine (the amount in three Mark I kits orATNAA), and probably more, should be administeredinitially, and ventilatory support should be started.Atropine should be continued at appropriate intervalsuntil the casualty is breathing adequately witha minimal amount of secretions in the mouth andlungs. The initial 2 or 4 mg has proven adequate inconscious casualties. Although 6 to 15 mg has beenrequired in apneic or nearly apneic casualties, the needfor continuing atropine has not extended beyond 2 to3 hours (although distressing but not life-threateningeffects, such as nausea and vomiting, have necessitatedadministering additional atropine in the following 6–36h). This is in contrast to the use of atropine to treatintoxication by organophosphorus insecticides, whichmay cause cholinergic crises (such as an increase insecretion and bronchospasm) for days to weeks afterthe initial insult. 179–181The US military developed an inhaled form ofatropine, called “medical aerosolized nerve agent antidote(MANAA),” which was approved by the FDAin 1990. It is not widely used but is still available inthe national stockpile. The official doctrine for its useis as follows:MANAA is used mainly in medical treatment facilitiesby the individual casualty under medical supervisionfor symptomatic relief of nerve agent-inducedsecretions and muscle twitches. It is intended foruse after the casualty has been decontaminated andevacuated to a clean environment where there is noneed for MOPP, including the mask. The MANAA allowsthe patient to self-medicate on an “as needed”basis. 184MANAA has a limited role in patients recoveringfrom nerve agent poisoning who still require someobservation but who can self-medicate. It has not beenstockpiled to any great extent in the civilian sector.In hospital management of both vapor and liquidcasualties, and, in many cases, in management en routeto a hospital, such as in an ambulance, the preferredroute of administration of atropine will be intravenousafter the initial IM field doses. The clinical endpoint,that of patients breathing comfortably on their ownwithout the complication of respiratory secretions, willbe the same. A longer period of IV atropine administrationshould be expected in patients exposed throughthe skin than in vapor-exposed patients.The management of patients exposed to nerve agentthrough open wounds will probably fall between thatof vapor-exposed casualties and casualties exposed tonerve agent liquid on intact skin.Oxime TherapyOximes are nucleophilic substances that reactivatethe organophosphate-inhibited ChE (the phosphonylatedenzyme) by removing the phosphyl moiety. Oximesmay be considered a more physiologic method oftreating nerve agent poisoning than atropine becausethey restore normal ChE enzyme function. However,several features limit their utility.Mechanism of ActionAfter the organophosphorus compound attachesto the enzyme to inhibit it, one of the following twoprocesses may occur:1. The enzyme may be spontaneously reactivatedby hydrolytic cleavage, which breaksthe organophosphonyl–ChE bond, reactivatingthe enzyme.2. The complex formed by the enzyme-ChE maylose a side group and become negativelycharged, or “age,” becoming resistant to reactivationby water or oxime.Both of these processes are related to the size ofthe alkyl group attached to the oxygen of the organophosphoruscompound, the group attached to the firstcarbon of this alkyl group, and other factors. Once theorganophosphonyl–enzyme complex ages, it cannot bebroken by an oxime. 14,15 Consequently, oxime therapyis not effective after aging occurs.Because the nerve agents differ in structure, theirrates of spontaneous reactivation and aging differ. Forexample, when complexed with VX, RBC-ChE spontaneouslyreactivates at a rate of roughly 0.5% to 1%per hour for about the first 48 hours. The VX–enzymecomplex ages very little during this period. 44,47,113 Thesoman-enzyme complex does not spontaneouslyreactivate; the half-time for aging is about 2 minutes.The half-time for aging of the sarin-RBC-ChE complexis about 5 hours, and a small percentage (5%) of theenzyme undergoes spontaneous reactivation. 113 Thehalf-time for aging of the tabun-enzyme complex issomewhat longer.In the mid 1950s, Wilson and coworkers reported186