title: The effect of mild hypothermia on plasma fentanyl concentration and biotransformation in juvenile pigs.
abstract: 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 microg . 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 degrees +/- 0.2 degrees C for 6 h and were then rewarmed and kept normothermic at 37.7 degrees +/- 0.3 degrees 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.
authors.affiliation: 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.
authors.forename: Harald G
authors.initials: HG
authors.lastname: Fritz
authors.forename: Martin
authors.initials: M
authors.lastname: Holzmayr
authors.forename: Bernd
authors.initials: B
authors.lastname: Walter
authors.forename: Klaus-Uwe
authors.initials: KU
authors.lastname: Moeritz
authors.forename: Amelie
authors.initials: A
authors.lastname: Lupp
authors.forename: Reinhard
authors.initials: R
authors.lastname: Bauer
mesh_terms: D000701:Analgesics, Opioid / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D001784:Blood Gas Analysis; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D005283:Fentanyl / Q000097:blood / Q000493:pharmacokinetics*; D006439:Hemodynamics / Q000187:drug effects; D007035:Hypothermia / Q000378:metabolism*; D019344:Lactic Acid / Q000097:blood; D008099:Liver / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010100:Oxygen / Q000097:blood; D013552:Swine
chemical_list: D000701:Analgesics, Opioid; D001786:Blood Glucose; D019344:Lactic Acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010100:Oxygen; D005283:Fentanyl