The effect of mild hypothermia on plasma fentanyl concentration and biotransformation in juvenile pigs.
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.
Fritz
Harald G
HG
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.
Holzmayr
Martin
M
Walter
Bernd
B
Moeritz
Klaus-Uwe
KU
Lupp
Amelie
A
Bauer
Reinhard
R
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
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