Diazepam replacement

Military Medicine,  Aug 2000  by Little, James S

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Dear Editor:

We are writing in response to the letter of November 11, 1999 by Major Harris and Captain Gausman, published in the February 2000 issue, in which they advocate the replacement of diazepam with lorazepam as the field anticonvulsant treatment for nerve agent-induced seizures.

The authors are correct to point out that soldiers pretreated with pyridostigmine are much more likely to go into prolonged status epilepticus when exposed subsequently to nerve agents and promptly treated with atropine and 2-PAM CI (MARK 1), rather than die, than are soldiers not so pretreated. Work at the U.S. Army Medical Research Institute of Chemical Defense has shown that any nerve agent can produce status epilepticus. This can occur regardless of pyrodostigmine pretreatment, which only assures greater protection against acute lethal effects of certain agents such as soman. Therefore, the problems of status epilepticus are not unique to the nerve agent soman. It was for this very reason that diazepam was fielded as an immediate anticonvulsant treatment.

All drugs used to treat nerve agent casualties must be Food and Drug Administration (FDA) approved, and under terms of the Department of Defense budget signed September 1999. It is in fact illegal to use any FDA approved drug on the battlefield as a matter of doctrine if the indication is not itself also FDA approved. The decision to field diazepam must be viewed in the context of the time (1988-1990) when approval for the use of diazepam to treat nerve agent-induced seizures was first sought from the FDA. At that time, diazepam was the drug best researched as demonstrating anticonvulsant activity in animal studies of nerve agent-induced seizures. Only three drugs (diazepam, pentobarbital, and phenytoin) were FDA approved (i.e., approved indications) for treatment of status epilepticus. Of these three drugs, phenytoin is ineffective against nerve agent-induced seizures, it could not

be given by the intramuscular (IM) route (a necessity for self/buddy aid of a nerve agent casualty), and pentobarbital produces anticonvulsant effects against nerve agent seizures at only near-anesthetic doses. Although it was recognized that IM use of diazepam had erratic bioavailability, it did have demonstrable anticonvulsant effects against nerve agentinduced seizures.

It was because of the limitations of diazepam as an immediate field treatment that a research effort was launched at this Institute in 1994 to evaluate other drugs for use as an advanced anticonvulsant for the treatment of nerve agentinduced seizures. Lorazepam has been evaluated head-to-head with diazepam, clonazepam, midazolam, and other benzodiazepines in a guinea pig model of nerve agent-induced (soman) seizures that closely approximates and incorporates the military doctrinal use of pyridostigmine pretreatment and postexposure treatment with atropine, 2-PAM Cl and the test benzodiazepine. All therapeutic drugs (atropine, 2-PAM CI, test benzodiazepine) were given IM as they would be given in a field treatment situation. Under these conditions, lorazepam was statistically no more potent (EDT: diazepam = 4.81 mg/kg; lorazepam = 3.53 mg/kg) nor more rapidly acting in terminating soman-induced EEG seizure activity than diazepam (time for EEG seizure termination: diazepam = 51.16 min.; lorazepam = 109.68 min.) (McDonough et al, Arch. Toxicol., 1999, 73:473-478). Thus, based on these date there is no clear improvement in the control of nerve agent seizures by lorazepam when compared directly with diazepam, using the IM route of treatment.

Major Harris and Captain Gausman correctly identify the fact that most benzodiazepines are poorly absorbed and are slow to produce therapeutic blood levels following IM administration. When nerve agent seizures can be treated under standard emergency room conditions, where IV delivery of anticonvulsant drugs is the norm, diazepam (or lorazepam if it had been used) was fully sufficient to control the epileptiform activity, as was demonstrated in the clinical treatment of the victims of the terrorist attacks with nerve agents in Japan. However, field treatment of nerve agent casualties with therapeutic drugs is constrained by the use of the IM route. Recent animal work in both guinea pigs and rhesus monkeys has shown that midazolam is significantly both more potent and more rapidly acting in controlling soman-induced seizures than is diazepam or lorazepam when given by this route. Unfortunately, there currently is no FDA-approved clinical indication for the treatment of seizures with midazolam. This is an issue that is currently being addressed in an effort to develop an advanced anticonvulsant for treatment of nerve agent-induced seizures.

Information submitted by: Lieutenant Colonel Jonathan Newmark, Medical Corps, Chief, Operations Branch of the Chemical Casualty Care Division; and John McDonough, PhD, Science and Technology Objective Coordinator, Advance Anticonvulsants.

James S. Little, Colonel, U.S. Army Commanding 8 May 2000

Copyright Association of Military Surgeons of the United States Aug 2000
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