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

Medical Aspects of Chemical Warfarethis finding in studies of atropine and of Ditran(Lakeside Laboratories, Milwaukee, Wis), a 2 to 1mixture of two similar belladonnoid glycolates. 89In the late 1950s and early 1960s, Ditran coma(like atropine coma, a decade earlier) enjoyed briefpopularity as a treatment for depression. 122–124 InEdgewood studies between 1962 and 1967, physostigmineproved equally effective as an antidoteto the follow-on glycolates described above. Similarfindings were soon reported in civilian studies. 125–128Deliria produced by overdose with other drugs possessinganticholinergic side effects, such as diazepam,tricyclic antidepressants, and antihistamines, were alsofound to be treatable with physostigmine. 128–130 Whengiven by the intravenous route, a dose of 30 µg/kg ofphysostigmine was sufficient to partially reverse theanticholinergic delirium produced by a variety of belladonnoids,although at least 45 µg/kg was the initialdose required to obtain good results.Physostigmine has also been used and reported tobe effective for morphine-induced respiratory depression;alcohol withdrawal; and the effects of heroin,ketamine, and fentanyl. 131 Its mode of action in theseinstances may be partially due to a direct arousal effect,rather than simple inhibition of cholinesterase. Casereports confirming its efficacy have come from the directorof the Rocky Mountain Poison and Drug Center,near Denver, Colorado. 125 The use of physostigmine asan antidote was also favorably reviewed by the directorof the Poison Control Center in Munich, Germany. 132Although in undrugged patients doses of as little as2 to 3 mg of physostigmine alone may cause nauseaand other signs of cholinergic excess (eg, salivation,intestinal cramping, and diarrhea), an intramusculardose of 4 mg is generally well tolerated without anyside effects when given as an antagonist to belladonnoidintoxication. In more than 100 subjects treatedby one of the authors, the only unusual side effectswere transient fasciculations of the platysma (a thinsuperficial neck muscle) in one subject, and transientperiods of nausea and vomiting in a few others. 96If excessive physostigmine is given in the absence ofbelladonnoid intoxication, adverse effects can easily bereversed by injecting 1 to 2 mg of atropine. Physostigmine,if administered intravenously, should be givengradually because a bolus effect may cause cardiacarrhythmias or even cardiac arrest. Most of these untowardoutcomes, however, have occurred in patientswho were in poor general health or suffering fromheart disease. Back titration with atropine can usuallyavert or reverse disturbing anomalies of response.When the diagnosis is in doubt, an intramusculartest dose of 1 to 2 mg of physostigmine, repeatedafter 20 minutes if necessary, is recommended. Oncethe diagnosis of delirium has been established by adefinite clearing of the sensorium, improvement canbe sustained by repeating the treatment at intervalsof 1 to 4 hours. Changes in heart rate and intellectualperformance can provide a guide to dosage. Forexample, if heart rate rises and confusion increases(quickly assessable by asking for serial subtraction of7s from 100), supplemental doses can safely be given.Polish investigators studying the effects of high-doseatropine treatment of psychiatric patients reportedgiving as much as 15 mg of physostigmine in a singleinjection to terminate atropine coma. 133 They did notdescribe any adverse effects.Maintenance treatment of delirium produced byBZ or other long-acting agents is best handled by theuse of oral physostigmine, mixing it with fruit juice tomask its bitter taste. Dosage by the oral route is onlytwo thirds as effective as by the parenteral route andshould be adjusted accordingly. In a combat zone, theoral route may, in fact, be the only practical way to treatlarge numbers of casualties. Medical technicians cando the job under the supervision of a physician.For reasons that are not fully understood, physostigmineis relatively ineffective if given during theonset phase of belladonnoid intoxication. The treatmentteam should therefore not be discouraged if earlyadministration of physostigmine fails to bring aboutimmediate, dramatic improvement. Unfortunately, useof the antagonist does not shorten the duration of theunderlying intoxication. Also, if initial treatment is notmaintained, final recovery may be slightly delayed. 96Although physostigmine is probably not as highly regardedas it was during the 1970s and 1980s, it has predictableeffects, and there are specific indications for itsuse. Test doses of 1 mg may safely be given, and minorimprovement in mental status, or a decrease in tachycardia,can justify the safe use of larger titrated doses.Whether or not physostigmine is available, supportivemeasures are important. It may be proper toevacuate and hospitalize patients with severe cases.Oral tetrahydroaminacridine in doses of 200 mg wasalso tested as an antagonist against BZ and proved tobe moderately effective. 93 Its use as an anticholinesterasetreatment of Alzheimer patients has since beenapproved by the US Food and Drug Administration.In an Edgewood pilot study, tetrahydroaminacridinecaused temporary mild changes in hepatic functiontests, and further testing was discontinued. Similarchanges were noted in civilian patients but did notprevent its approved use.426