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 microg x kg(-1) x 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 microg x kg(-1) x 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 x 100 g(-1) x 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.


CONCLUSIONS
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.
Kofke
W Andrew
WA
Department of Anesthesia, University of Pennsylvania, Philadelphia, 19104-4283, USA. kofkea@uphs.upenn.edu
Attaallah
Ahmed F
AF
Kuwabara
Hiroto
H
Garman
Robert H
RH
Sinz
Elizabeth H
EH
Barbaccia
John
J
Gupta
Naresh
N
Hogg
Jeffery P
JP
D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010880:Piperidines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists*; D000077208:Remifentanil
D000701:Analgesics, Opioid; D010880:Piperidines; D017450:Receptors, Opioid, mu; D005947:Glucose; D000077208:Remifentanil