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ANESTHETIC PHARMACOLOGY

The Neuropathologic Effects in Rats and Neurometabolic Effects in Humans of Large-Dose Remifentanil

W. Andrew Kofke, MD FCCM^*, Ahmed F. Attaallah, MD, Hiroto Kuwabara, MD PhD, Robert H. Garman, DVM, Elizabeth H. Sinz, MD, John Barbaccia, MD, Naresh Gupta, MD^||, and Jeffery P. Hogg, MD^||

*Department of Anesthesia, University of Pennsylvania, Philadelphia; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh; and Consultants in Veterinary Pathology, Inc, Murrysville, Pennsylvania; and Departments of Anesthesiology and || Radiology, West Virginia University, Morgantown, West Virginia

Address correspondence and reprint requests to W. Andrew Kofke, MD, FCCM, Department of Anesthesia, University of Pennsylvania, 7 Dulles Bldg., Philadelphia, PA 19104-4283. Address e-mail to kofkea{at}uphs.upenn.edu

Given in clinically relevant large doses to rats, µ-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 µg · kg^-1 · min^-1 for 3 h, followed by neuropathologic evaluation 7 days later. Four volunteers underwent induction of anesthesia and endotracheal intubation with propofol and rocuronium administration followed by remifentanil infusion at 1–3 µg · 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 · min^-1 (P < 0.05). These data indicate that prolonged large-dose remifentanil infusion is neurotoxic in rats with congruent metabolic effects with brief infusion in humans and suggest that some adverse effects reported in rats may be clinically relevant.

IMPLICATIONS: This study demonstrates dose-related remifentanil neurotoxicity in physiologically controlled rats with congruent brain metabolic effects in four humans undergoing positron emission tomography evaluation during brief large-dose remifentanil anesthesia. These data suggest that some adverse effects reported in rats may be clinically relevant.

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