Neuroprotective and antiepileptic activities of ketamine in nerve agent poisoning.

Abstract

To the Editor:—We read with interest the review by Ben Abraham et al. providing guidelines for the care of victims of bioterrorism, in the October issue of Anesthesiology. 1This article is an important contribution at a time when using a nerve agent such as sarin, even in the civilian context, is increasingly likely. 2The authors stress the possibility of dangerous reactions occurring when ketamine is used in sulfur mustard casualties. However, this assessment based on unexplained results would require further investigations. 3Despite this word of caution, we would like to emphasize the benefits of ketamine for nerve agent poisoning.Ketamine has been safely used for more than 35 yr but was gradually banished from usual practice because of psychedelic side effects and was supplanted by new, easier to handle drugs. However, the potential neuroprotective effects linked to the blockade of N -methyl-d-aspartate (NMDA) glutamate receptors prompted a renewed interest in phencyclidine derivatives such as ketamine 4and led to the discussion of one of the major contraindications of the molecule: brain damage.Because of cardiovascular and respiratory favorable properties, ketamine seems to be an anesthetic of choice for military surgery. 5Better oxygen delivery and survival after ketamine anesthesia have been reported in experimental models of hemorrhage. 6Reduced respiratory depression with higher Pao2values, when compared to halothane, makes it particularly safe for analgesia during surgical procedures far from the operating room. 7During combat in a chemical warfare environment, the IV route would be difficult to consider and administration of ketamine by the intramuscular route would clearly be an advantage.Of particular interest is the ketamine induced NMDA receptor-channel noncompetitive blocking, which most probably explains its neuroprotective and anticonvulsant properties. This makes ketamine particularly suitable for induction and maintenance of anesthesia in patients exposed to organophosphorous compounds. 8Although ketamine has occasionally been reported to induce seizures, a larger body of evidence suggests that it actually displays anticonvulsant and neuroprotective properties. 9Not only the accumulation of acetylcholine but also excitatory amino acid neurotransmission is responsible for the nerve agent-induced status epilepticus and brain damage. 10NMDA receptors, which are largely permeable to calcium, are particularly involved. A voltage-dependant magnesium block characterizes the NMDA channel. Depolarization, the final common pathway of multiple neuronal injuries, causes the magnesium block to be lifted, enabling calcium to enter the cell and induce the cascade of neuronal damage. Ketamine or Dizocilpine (MK-801) are noncompetitive antagonists that act inside the canal, at the phencyclidine site and demonstrate use-dependent, open-channel blockade. The first experimental results obtained with NMDA receptor antagonists in soman-poisoned animals demonstrate that only the animals with status epilepticus exhibit neuronal damage, and the longer the convulsions, the worst the neurologic outcome. Limitation of seizures with these antagonists may thus prevent definite neurologic damage. 11Because of an increasing difficulty in stopping nerve agents induced on-going seizures with time, it would be necessary to consider the use of ketamine as early as possible and multiple injections of anesthetic doses. The S(+) isomer, which is two to four times more potent than the R(−) isomer because of a superior pharmacological action on NMDA receptors, may exhibit better neuroprotective properties, although definitive results are still expected. 12