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

Medical Aspects of Chemical WarfareThe anesthetic dose range in humans is 5 to 10 mg/kg, IV. 146,159 For a nerve agent victim on the battlefield,a ketamine dosage below 2 mg/kg, IV, should provesafe in combination with the high dosages of diazepamthat are likely to be administered. While possibly nothigh enough to augment the anticonvulsant effects ofdiazepam and arrest SE, anesthetic or subanestheticdosages of ketamine should provide considerable additionalneuroprotection, compared to diazepam alone.Moreover, the ketamine dosage can be increased oncepatients reach a medical facility where intubation andventilation can be provided.Additional Neuroprotective ApproachesFree Radical ScavengersDamage produced by reactive oxygen species orfree radicals is a component of seizure and SE-relatedneurotoxicity, 47,160,161 including damage resulting fromnerve agent poisoning. 160 The liberation of catalytic ironfrom extravasated hemoglobin may generate reactiveoxygen species. 160,161 Reactive oxygen species couldalso be generated by xanthine oxidase or impairedmitochondrial electron transport, 161–163 offering thehope that nerve-agent–induced neurotoxicity could bemitigated by antioxidants or free radical scavengers.Nitrone-based free radical traps, such as alphaphenyl-N-tert-butylnitrone(PBN), which react withreactive oxygen species, have proven to be neuroprotectivefollowing cholinesterase inhibition. Pretreatmentwith PBN prevented seizures induced bydiisofluorophosphate, an organophosphonate andnerve agent simulant. 164 Moreover, PBN (150 mg/kg,IP, 5 min after seizure onset) produced significant neuroprotectionin the piriform cortices and other corticalareas of rats following lithium pilocarpine-inducedSE. 165 Unfortunately (and reminiscent of the findingswith HU-211 discussed above), thalamic damage waseither exacerbated or not diminished by PBN in thelatter study. Another report describes neuroprotectiveeffects by PBN 12 hours after ischemic insult. 166A pilot study of PBN did not show neuroprotectionagainst soman-induced injury. 167 A new, centrally acting,nitrone-based free radical scavenger, S34176, hasshown superior neuroprotective properties comparedto PBN in stroke and other glutamate excitotoxicitymodels. 168 S34176 may prove useful against nerveagent–inducedinjury.Mitochondrial Permeability Transition InhibitorsAs mentioned above, damaging stimuli can induceneuronal mitochondria to undergo permeability transition,forming pores that allow the release of storedcalcium into the neuronal cytoplasm. This is accompaniedby curtailment of ATP synthesis, mitochondrialswelling, exacerbation of calcium overload, and neuronaldeath. 59–62 The assembly of mitochondrial transitionpores can be blocked by cyclosporin A, an FDA-approved drug used in cancer chemotherapy. There isevidence that cyclosporin A and topiramate (anothertransition pore blocker) are neuroprotective in variousmodels of excitotoxic brain injury. 169–174 Bauman andcolleagues 169 found that cyclosporin A dramaticallyreduced brain injury in rats following seizures andSE induced by the organophosphate paraoxon. Thereis also evidence of neuroprotection by topiramate followingpilocarpine-induced seizures and SE. 170Neuroprotective HypothermiaTotal-body cooling is an effective nonpharmacologicmethod of treating cerebrovascular disease. Severalstroke experts have advanced this approach as holdinggreat promise in reducing the amount of ischemic braindamage, and in 2004 the FDA approved a catheter forstroke and other specific uses that cools the blood ina penetrating artery. Less technologically complicatedapproaches to total-body cooling have been successfulin limited numbers of animal studies. 175,176 Whether thisapproach would be practical in a battlefield situation,especially with mass casualties, is questionable, but itshould be kept in mind as a possibility.SummaryA variety of neuroprotective compounds have provenuseful in alleviating brain damage caused by nerveagent–inducedseizures and SE. Of these, ketamine, memantine,and dantrolene have received FDA approvalfor other indications, and several other compounds arein clinical trials. Based on the evidence, ketamine, incombination with diazepam, is the top candidate andmost viable neuroprotectant for nerve agent survivorsexhibiting seizures and SE. A dantrolene and diazepamcombination is a viable possibility as well, though lessefficacious. In addition, free radical scavengers (eg,S34176) and transition pore blockers (eg, cyclosporinA) show great promise. It is conceivable that the bestpossible neuroprotective approach will be a “cocktail” oftwo or more agents that affect, in a synergistic fashion,different legs of the excitotoxic pathway. 177232