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The effect of acutely induced hepatic failure on remifentanil and fentanyl blood levels in a pig model

Published online by Cambridge University Press:  01 March 2006

G. Kostopanagiotou ,
S. L. Markantonis ,
N. Arkadopoulos ,
I. Andreadou ,
G. Charalambidis ,
J. Chondroudaki ,
C. Costopanagiotou  and
V. Smyrniotis
G. Kostopanagiotou
Affiliation:
University of Athens School of Medicine, Attikon Hospital, Second Department of Anaesthesiology, Haidari, Greece
S. L. Markantonis
Affiliation:
University of Athens School of Pharmacy, Laboratory of Biopharmaceutics and Pharmacokinetics, Athens, Greece
N. Arkadopoulos
Affiliation:
University of Athens School of Medicine, Second Department of Surgery, Athens, Greece
I. Andreadou
Affiliation:
University of Athens School of Pharmacy, Laboratory of Biopharmaceutics and Pharmacokinetics, Athens, Greece
G. Charalambidis
Affiliation:
University of Athens School of Pharmacy, Laboratory of Biopharmaceutics and Pharmacokinetics, Athens, Greece
J. Chondroudaki
Affiliation:
University of Athens School of Medicine, Attikon Hospital, Second Department of Anaesthesiology, Haidari, Greece
C. Costopanagiotou
Affiliation:
University of Athens School of Medicine, Attikon Hospital, Second Department of Anaesthesiology, Haidari, Greece
V. Smyrniotis
Affiliation:
University of Athens School of Medicine, Second Department of Surgery, Athens, Greece
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Summary

Background and objective: Opioids and especially fentanyl are widely used during the intensive care unit management of intracranial pressure in fulminant hepatic failure patients as well as during and after liver transplantation. The newer synthetic opioid remifentanil is also increasingly being used in critical care patients. Due to a lack of data relating to the influence of acute hepatic failure on remifentanil and fentanyl pharmacokinetics, this study was designed in order to determine the impact of this condition on the blood levels of these opioids using a pig model. Methods: Twenty pigs were randomly assigned to one of two groups: A group with surgically induced acute hepatic failure by hepatic devascularization (acute hepatic failure, n = 10) and a control group (SHAM, n = 10), subjected to a SHAM operation. Postoperatively, five animals in each group were administered remifentanil (1 μg kg−1 min−1) or fentanyl (0.2 μg kg−1 min−1) by continuous intravenous infusion. Blood samples for determination of drug concentrations were withdrawn at 0 h and 0.5, 1, 5, 7, 9 h after initiation of dosing. Results: Significantly higher blood concentrations were found in animals with acute hepatic failure compared to SHAM-operated animals receiving remifentanil at 5 h (P = 0.003), 7 h (P = 0.007) and 9 h (P = 0.004) and fentanyl at 7 h (P < 0.0005) and 9 h (P = 0.05). The small number and the great variability in drug concentrations did not allow a detailed kinetic analysis to be performed. Approximate clearance values were found to be greater for the SHAM compared with the acute hepatic failure animals for both fentanyl and remifentanil. Conclusions: Hepatic devascularization in our porcine acute hepatic failure model, appears to have significantly altered the disposition of fentanyl and unexpectedly remifentanil. These changes were thought to be brought about by severe disruption of blood flow and biotransformation in the liver, as well as by haemodynamic changes in the acute hepatic failure animals.

Keywords

ACUTE LIVER FAILURE, OPIOID ANALGESICS, fentanyl, remifentanilPHARMACOKINETICSPIG MODEL
Type
Original Article
Information
European Journal of Anaesthesiology , Volume 23 , Issue 7 , July 2006 , pp. 598 - 604
Copyright
© 2006 European Society of Anaesthesiology

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