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

Medical Aspects of Chemical Warfareof pyridostigmine in the genesis of these problemshas been questioned. A full discussion of this issuelies beyond the scope of this volume. Some studiesperformed since the Gulf War give reassurance thatpyridostigmine used as called for in military doctrinedoes not by itself give rise to lasting neuromuscularproblems such as fatigue, probably the most commonlyrelated complaint. In one human study, aretrospective analysis showed that handgrip strengthwas not associated with pyridostigmine intake (P =0.558). 272 In another study using animal muscle cellsin culture, ultrastructural alterations seen by electronmicroscopy after 2 weeks of exposure to low-dosepyridostigmine were reversible following withdrawalof the drug. 273On the other hand, a more worrisome concern aboutpyridostigmine in a battlefield context is the situationin which a soldier who has been on the drug in accordancewith pretreatment doctrine needs surgeryacutely. Because pyridostigmine is a ChE inhibitor,one might expect that recovery from anesthesia usinga neuromuscular blocking agent, such as succinylcholine,would be prolonged, and according to aprospective human study, such is the case. 274 This is ofparticular concern in those rare patients with mutantBuChE, as mentioned above. 271 Anesthesia providersin a combat zone must anticipate increased time torecovery of normal function, including that of themuscles of respiration, in troops on pyridostigmine,but the magnitude of the increase does not imply thatthis should affect the decision to go to surgery usingthese anesthetic agents.It is now clear that pyridostigmine can be used effectivelyin large military populations under combatconditions without impairing mission performance.On the other hand, soldiers must have a clear understandingof the threat and the need for this medication.Otherwise, it seems unlikely that they will bewilling to accept the associated gastrointestinal andurinary symptoms or to comply with an 8-hour dosageschedule.Regulatory StatusBefore the 1990 Persian Gulf War, the regulatorystatus of pyridostigmine for nerve agent pretreatmentwas as an off-label use of an approved medication.Additionally, the 30 mg dose was not approved, sincethe only on-label indication was for myasthenia gravisand the smallest adult dose was 60 mg. Because ofthe impending war, in 1991 the FDA waived informedconsent for its use to make the best medical treatmentavailable in a specific combat situation. 275,276 TheFDA based this waiver on two factors. First, it reliedon data from animal studies conducted in both theUnited States and other NATO countries that foundthat pyridostigmine increases survival when usedas pretreatment against challenge by certain nerveagents (data on efficacy in humans challenged bynerve agents is not experimentally obtained). Second,it determined a long history of safety when thedrug was used for approved indications at dosesseveral-fold higher than the doses administered inthe military.The waiver of informed consent was withdrawn in1992. From then until 2003, the status of pyridostigmineused for nerve agent pretreatment was that ofan investigational new drug. This status resultedin the Department of Defense creating an informedconsent protocol should the need again arise to ordertroops to take it. At no time was it illegal for a licensedphysician to prescribe pyridostigmine to a patient,whether military or not, wishing to use the drug forthis purpose.In February 2003, on the eve of the invasion of Iraq,the FDA approved pyridostigmine as a nerve agentpretreatment for soman only. This was the first time theFDA applied the “animal rule” to approve a medicationfor use against chemical or biological warfare agentswithout Phase 2 and Phase 3 human clinical trial data.Technically, no other nerve agent is covered by thisapproval. Realistically, however, from a tactical standpoint,knowledge of the specific agent may not be availablewhen a commander must decide whether or not toorder troops to take it. Pyridostigmine is not suited forany population group not in imminent danger of exposureto a rapidly aging nerve agent. Despite increasedconcerns about chemical terrorism, no first-responderagency in the United States has seriously consideredordering responders to take pyridostigmine.SUMMARYNerve agents are the most toxic chemical warfareagents known. They cause effects within seconds anddeath within minutes. These agents are in the militarystockpiles of several countries, but have been used inonly one war. They can be manufactured by terroristgroups and have been used in terrorist attacks.Nerve agents cause biological effects by inhibitingthe enzyme AChE, causing an excess of the neurotransmitterto accumulate. Hyperactivity in those organsinnervated by cholinergic nerves results, with increasedsecretions from exocrine glands, hyperactivity of skeletalmuscles leading to fatigue and paralysis, hyperac-204