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ANESTHETIC PHARMACOLOGY

The Effect of Mild Hypothermia on Plasma Fentanyl Concentration and Biotransformation in Juvenile Pigs

Harald G. Fritz, MD^*, Martin Holzmayr, Bernd Walter, MD, Klaus-Uwe Moeritz, PhD^||, Amelie Lupp, MD, and Reinhard Bauer, MD, PhD

Departments of *Anesthesiology and Intensive Care Medicine and Pathobiochemistry, Institute for Pathophysiology and Pathobiochemistry, Department of Neurosurgery and Institute for Pharmacology and Toxicology, Friedrich-Schiller-University, Jena; and || Institute of Pharmacology, Ernst Moritz Arndt University, Greifswald, Germany

Address correspondence and reprint requests to Harald G. Fritz, MD, Department of Anesthesiology and Intensive Care Medicine, Martha-Maria Hospital Halle D*lau gGmbH, Roentgenstr. 1, D-06120 Halle/S., Germany. Address e-mail to harald_fritz_2000{at}yahoo.de.

Therapeutic hypothermia may alter the required dosage of analgesics and sedatives, but no data are available on the effects of mild hypothermia on plasma fentanyl concentration during continuous, long-term administration. We therefore assessed in a porcine model the effect of prolonged hypothermia on plasma fentanyl concentration during 33 h of continuous fentanyl administration. Seven female piglets (weight: 11.8 ± 1.1 kg) were anesthetized by IV fentanyl (15 µg · kg^–1 · h^–1) and midazolam (1.0 mg · kg^–1 · h^–1). After preparation and stabilization (12 h), the animals were cooled to a core temperature of 31.6° ± 0.2°C for 6 h and were then rewarmed and kept normothermic at 37.7° ± 0.3°C for 6 more hours. Plasma fentanyl concentrations were measured by radioimmunoassay, cardiac index by thermodilution, and blood flows of the kidney, spleen, pancreas, stomach, gut, and hepatic artery by a colored microspheres technique. Furthermore, in an additional 4 pigs, temperature dependency of hepatic microsomal cytochrome P450 3A4 (CYP3A4) was determined in vitro by ethylmorphine N-demethylation. Plasma fentanyl concentration increased by 25% ± 11% (P < 0.05) during hypothermia and remained increased for at least 6 h after rewarming. Hypothermia reduced the cardiac index (41% ± 15%, P < 0.05), as well as all organ blood flows except the hepatic artery. A strong temperature dependency of CYP3A4 was found (P < 0.01). Mild hypothermia induced a distribution and/or elimination-dependent increase in plasma fentanyl concentration which remained increased for several hours after rewarming. Consequently, a prolonged increase of the plasma fentanyl concentration should be anticipated for appropriate control of the analgesia/sedatives during and early after therapeutic hypothermia.

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