Efficacy of the ketamine-atropine combination in the delayed treatment of soman-induced status epilepticus.
Nerve agent poisoning is known to induce full-blown seizures, seizure-related brain damage (SRBD), and lethality. Effective and quick management of these seizures is critical. In conditions of delayed treatment, presently available measures are inadequate calling for optimization of therapeutic approaches. The effects of ketamine/atropine sulfate (KET/AS) combinations were thus assessed as potential valuable delayed therapy in soman-poisoned male guinea pigs. Animals received pyridostigmine (26 microg/kg, i.m.) 30 min before soman (62 microg/kg, i.m.) followed by therapy consisting of atropine methyl nitrate (4 mg/kg) 1 min later. KET was then administered i.m. at different times after the onset of seizures, starting at 30 min post-poisoning. KET was always injected with atropine sulfate, itself given at a dose that was unable to modify seizures (2 to 10 mg/kg). Different treatment schemes (dose and time of injection) were evaluated. Sub-anesthetic doses of KET (10 mg/kg) could prevent lethality and stop ongoing seizures only when administered 30 min after challenge. An extended delay before treatment (up to 2 h) called for an increase in KET dose (up to 60 mg/kg three times), thus reaching anesthetic levels but without the need of any ventilation support. KET proved effective in stopping seizures, highly reducing SRBD and allowing survival with a progressive loss of efficacy when treatment was delayed beyond 1 h post-challenge. Preliminary results suggest that association with the benzodiazepine midazolam (1 mg/kg) might be interesting when treatment is initiated 2 h after poisoning, i.e., when KET efficacy is dramatically reduced. All in all, these observations suggest that KET, in association with atropine sulfate and possibly other drugs, may be highly effective in the delayed treatment of severe soman intoxication.
Dorandeu
Frederic
F
Département de Toxicologie, CRSSA, 24 avenue des Maquis du Gresivaudan, F-38 702 La Tronche, France. fdorandeu@crssa.net
Carpentier
Pierre
P
Baubichon
Dominique
D
Four
Elise
E
Bernabé
Denis
D
Burckhart
Marie-France
MF
Lallement
Guy
G
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage*; D001285:Atropine / Q000008:administration & dosage*; D002619:Chemical Warfare Agents / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004569:Electroencephalography / Q000187:drug effects; D006168:Guinea Pigs; D007649:Ketamine / Q000008:administration & dosage*; D008297:Male; D008874:Midazolam / Q000008:administration & dosage*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D012999:Soman / Q000633:toxicity; D018709:Statistics, Nonparametric; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy*; D013997:Time Factors
D000927:Anticonvulsants; D002619:Chemical Warfare Agents; D007649:Ketamine; D001285:Atropine; D012999:Soman; D008874:Midazolam