The neuropathologic effects in rats and neurometabolic effects in humans of large-dose remifentanil

Given in clinically relevant large doses to rats, mu-opioids produce limbic system hypermetabolism and histopathology. This investigation extends these observations, in both rats and humans, for the short-acting drug remifentanil, which allows more precise control and assessment of the effects of duration of opioid exposure. We performed two series of experiments: one in rats for neuropathologic effects and the second in humans for neurometabolic effects. Fifty mechanically ventilated rats received saline solution or remifentanil 20-160 mug . kg(-1) . min(-1) for 3 h, followed bv neuropathologic evaluation 7 days later. Four volunteers underwent induction of anesthesia and endotracheal intubation with propofol and rocuronium administration followed bv remifentanil infusion at 1-3 mug . kg(-1) . min(-1) with positron emission tomography evaluation of cerebral metabolic rate for glucose. In rats, dose-related electroencephalogram activation was evident and 19 of 40 remifentanil-treated rats showed brain damage, primarily in the limbic system (P < 0.01). In humans, cerebral metabolic rate for glucose in the temporal lobe increased from 6.29 +/- 0.32 to 7.68 +/- 1.05 mg . 100 g(-1) . m(-1) (P < 0.05). These data indicate that prolonged large-dose remifentanil infusion is neuro toxic in rats with congruent metabolic effects with brief infusion in humans and suggest that some adverse effects reported in rats may be clinically relevant.