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

Neuroprotection as a Treatment for Nerve Agent Survivorsthe mean cross-sectional area of temporal lobe necrosis(ie, piriform cortex and surrounding structures)was reduced by 85.5% compared to soman-positivecontrols (P = 0.018). The mean reduction produced bydiazepam alone was only 39.9% and was not significant.In the lateral dorsal thalamus and surroundingthalamic nuclei, diazepam plus ketamine reducedsevere damage by 91.4% compared to soman controls(P < 0.001). The reduction in lateral dorsal thalamusdamage by diazepam alone was only 27.4% and wasnot significant. Neuronal pathological assessments,using haematoxylin and eosin stain, confirmed thesequantitative findings. It is likely that reduced seizureintensities contributed to the observed neuroprotection;however, this speculation is unconfirmed becauseEEGs were not obtained from these animals.Taken together, the preponderance of evidenceindicates that ketamine is a viable neuroprotectant candidateagainst nerve-agent–induced SRBD. However,ketamine is not FDA approved for this purpose. Therehave been no human or nonhuman primate studies todetermine the optimal dose of ketamine to be used incombination with diazepam or other benzodiazepinesto alleviate nerve-agent–induced SE. On the otherhand, several case reports describe the effectivenessof ketamine, following benzodiazepine therapy, forrefractory human SE from different causes. Therefore,off-label use of ketamine, as adjunct neuroprotectivetherapy following nerve agent intoxication, should beundertaken with caution and consideration of the bestavailable evidence.Because ketamine would be administered in conjunctionwith diazepam, and because of an increasedrisk of respiratory insufficiency by the combined treatments(see below), it is important to review treatmentrecommendations for diazepam. The autoinjector issuedby the US military contains 10 mg diazepam. Fora 70-kg (154-lb) individual, one autoinjector delivers adose (0.14 mg/kg, IM) consistent with the diazepamloading dosage (0.15 mg/kg, IV) recommended by therecent Belgian Consensus on SE. 148 The autoinjectordose is also consistent with the diazepam dose (5–20mg/70 kg) recommended by Durham 152 as initial treatmentfor SE, and is in agreement with the 20-mg diazepamdose (per rectum) recommended in “Treatmentof Status Epilepticus in Adults: Columbia UniversityProtocol,” as first line therapy when IV access is notavailable. 153 The Belgian Consensus 148 further recommends4 to 8 mg per hour IV maintenance dosingwith diazepam. On the battlefield, medics and unitlifesavers are permitted to administer two additional10-mg dosages of diazepam. Overall there is regularityin the recommended use of diazepam in the initialtreatment of adult SE, regardless of cause. The mainadverse effects of diazepam, and benzodiazepines ingeneral, are respiratory depression, hypotension, anddecreased consciousness. 148For intractable SE, the Belgian Consensus advocatesan adult dosage of 50 to 100 mg ketamine as a followup to diazepam for its “theoretical neuroprotectiveeffects.” 148 This dosage is consistent with Durham’s 152recommendation of 50 to 100 mg ketamine followedby 50 to 100 mg per hour, as a “second-line” treatmentfor refractory SE. Walker et al 154 report successfullytreating an adult patient exhibiting “partial motor SE”with an anesthetic dosage of ketamine (ie, 100 mg/h).In a 13-year-old girl whose SE failed to respond to allstandard treatments, control of clinical and electrographicSE was obtained within 90 seconds followinga bolus injection (IV) of 2 mg/kg ketamine; control wasmaintained by continuous infusion of ketamine up toa maximum of 7.5 mg/kg per hour. 155Adverse effects of ketamine include a transientdecrease in respiratory rate with bolus administration(ie, ≥ 2 mg/kg, IV), pulmonary secretions (controllablewith atropine), transient cardiovascular stimulationand possible tachycardia, intracranial hypertension(making it contraindicated for closed head injury),and undesired psychic effects. 148,156 In field situations,ketamine is preferred above other anesthetics becauseit is relatively unlikely to cause respiratory depression.It is generally accepted that ketamine does not producesignificant ventilatory depression in humans. 156Ketamine may also produce neurotoxicity typicalof NMDA receptor antagonists. As mentioned above,NMDA receptor antagonists have been shown to causeneurotoxicity in the cingulate and retrosplenial corticesas well as cerebellar Purkinje cells. 117,118,157,158 A case ofpossible ketamine toxicity was seen in a 44-year-oldman treated for refractory SE. 158 Control of his SE wasachieved with an initial bolus injection of 2 mg/kgketamine (IV, over 2 min), followed by a continuousinfusion of 2 mg/kg per hour. Infusion dosages wereprogressively increased until achieving a final dose of7.5 mg/kg per hour after 48 hours. Dosages were thentitrated down over the next 72 hours. The patient exhibiteddiffuse cerebellar and cerebral atrophy consistentwith animal models of NMDA antagonist-mediatedneurotoxicity. 158 Studies have reported that the mechanismof this toxicity is indirectly mediated by excessivecholinergic stimulation, 119–121 and supplementalatropine could have an ameliorative effect. In addition,GABAergic stimulation is reportedly protective againstthis specific form of neurotoxicity. 119–121However, high dosages of both diazepam and ketaminecould exacerbate respiratory distress alreadypresent in nerve agent casualties. Therefore, a conservativedose range for ketamine is advisable. In humans,a ketamine dose less than 1 mg/kg, IV, provides effectiveanalgesia against acute and chronic pain. 146,156,159231