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

Medical Aspects of Chemical Warfareon hospital day 28, and was intubated throughout thecourse. Of the remaining three patients, representingthe most severe cases who survived, intubation wasrequired only for 24 hours or less. This shows that mechanicalventilation in essentially all cases who survivesarin poisoning is a short-term clinical concern. 165In summary, spontaneous respiration will stopwithin several minutes after onset of effects caused byexposure to a lethal amount of nerve agent. Antidotesalone are relatively ineffective in restoring spontaneousrespiration. Attempts at ventilation are hindered by thehigh resistance of constricted bronchiolar muscles andby copious secretions, which may be thick and plug thebronchi. Ventilatory assistance may be required briefly(20–30 min) or for a much longer period. In severalinstances, assistance was required for 3 hours 20,66 ; thisseems to be the longest reported use of ventilation.Atropine TherapyThe antagonism between the ChE-inhibiting substancephysostigmine and a cholinergic blocking substancehas been recognized for well over a century. 166In the early 1950s, atropine was found to reduce theseverity of effects from ChE-inhibitor poisoning, but itdid not prevent deaths in animals exposed to syntheticChE-inhibiting insecticides. 167Cholinergic blocking substances act by blockingthe effects of excess ACh at muscarinic receptors.ACh accumulates at these receptors because it is nothydrolyzed by ChE when the enzyme is inactivatedby an inhibitor. Thus, cholinergic blocking substancesdo not block the direct effect of the agent (ChE inhibition);rather, they block the effect of the resultingexcess ACh.Many cholinergic blocking substances have beentested for antidotal activity. Among the findings arethe following:• Almost any compound with muscarinic cholinergicblocking activity has antidotal activity.• Atropine and related substances reduce theeffects of the ChE inhibitors, primarily in thosetissues with muscarinic receptor sites.• Antidotal substances with higher lipoid solubility,which penetrate the CNS more readily,might be expected to have greater antidotalactivity, since some of the more severe effectsof ChE inhibitor poisoning (such as apnea andseizures) are mediated in the CNS.Several countries use, or have proposed to use,other anticholinergic drugs as adjuncts to atropinefor treating nerve agent poisoning. These anticholinergicshave much more potent and rapid effects onthe CNS than does atropine. For example, Israel usesa mixture of drugs known as TAB as their immediatenerve agent treatment. This mixture contains the oximeTMB-4, atropine, and the synthetic anticholinergicbenactyzine. From 1975–1980 the US military alsoused TAB. The atropine and benactyzine combinationin the TAB mixture is similar in composition to the atropine,benactyzine and 2-PAM combination antidotemixtures investigated by Yugoslav researchers in theearly 1970s. 168,169 Animal studies have shown that benactyzineis much more potent and acts more rapidlyto reverse the CNS effects of nerve agent intoxicationthan does atropine. 170,171 In addition, benactyzine issignificantly less potent in inhibiting sweating or producingmydriasis than atropine, and is therefore lesslikely to induce heat casualties in a warm environmentor compromise near vision in the case of accidentaluse. Military researchers in the Czech Republic haveadvocated the use of the synthetic anticholinergicsbenactyzine and trihexyphenidyl, along with the carbamatepyridostigmine, in a prophylactic mixture theyhave designated as PANPAL. 172 In addition, the Czechsutilize benactyzine and biperiden, as well as atropine,as postexposure antidotal treatments. 172,173While many countries have other anticholinergicdrugs to use as adjuncts to atropine to treat nerveagent poisoning, none of these compounds have beentested or used in human clinical cases of poisoningeither with nerve agents or other organophosphate orcarbamate pesticides.Nevertheless, atropine has been the antidote ofchoice for treating nerve agent intoxication since nerveagents were first discovered and produced duringWorld War II. It was included in the German nerveagent first aid kits 174 and was determined to be an effectiveantidote by British scientists at Porton Downwho first analyzed the pharmacology and toxicologyof tabun obtained from captured German artilleryshells. Since the 1940s, atropine has been adoptedas the first-line antidote to counteract nerve agentpoisoning by the armed forces of most countries. It isalso almost universally used as the antidote to treatanticholinesterase poisoning by organophosphate orcarbamate pesticides. 175,176A dose of 2 mg atropine was chosen for self-administration or buddy-administration (the AtroPenautomatic injector included in the Mark I (MeridianMedical Technologies Inc, Bristol, Tenn) kit contains2 mg; Figure 5-5) by the US and the military of severalother countries because it reverses the effects of nerveagents, the associated side effects of a dose this sizecan be tolerated, and reasonably normal performance182