Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain

Ketamine, a widely used pediatric anesthetic, has been associated with enhanced neuronal toxicity in the developing brain, but mechanisms and neuronal susceptibility to neurotoxic insult leading to neuronal cell death remain poorly defined. One of the main goals of this study was to determine whether there is a duration of ketamine-induced anesthesia below which no significant ketamine-induced neurodegeneration can be detected. Newborn rhesus monkeys (postnatal day 5 or 6) were administered ketamine intravenously for 3, 9 or 24 h to maintain a steady anesthetic plane, followed by a 6-h withdrawal period. The 9- and 24-h durations were selected as relatively long and extremely long exposures, respectively, while the 3-h treatment more closely approximates a typical duration of pediatric general anesthesia. Animals were subsequently perfused under anesthesia and brain tissue was processed for analyses using silver and Fluoro-Jade C stains and caspase-3 immunostain. The results indicated that no significant neurotoxic effects occurred if the anesthesia duration was 3 h. However, ketamine infusions for either 9 or 24 h significantly increased neuronal cell death in layers II and III of the frontal cortex. Although a few caspase-3- and Fluoro-Jade C-positive neuronal profiles were observed in some additional brain areas including the hippocampus, thalamus, striatum and amygdala, no significant differences were detected between ketamine-treated and control monkeys in these areas after 3, 9 or 24 h of exposure. These data show that treatment with ketamine up to 3 h is without adverse effects as determined by nerve cell death. However, anesthetic durations of 9 h or greater are associated with significant brain cell death in the frontal cortex. Thus, the threshold duration below which no neurotoxicity would be expected is somewhere between 3 and 9 h.