Fentanyl pharmacokinetics in hemorrhagic shock - A porcine model

Background It is common clinical practice to administer reduced doses of op ioid to patients suffering from hemorrhagic shock to minimize adverse hemod ynamic consequences and to prevent prolonged opioid effect. However, the sc ientific foundation supporting this practice is not well established. The a im of this study was to test the hypothesis that hemorrhagic shock alters b oth the distribution and clearance of opioids using fentanyl in a porcine i sobaric hemorrhage model. Methods: Eighteen pigs were randomized to shock or control groups. The anim als in the shock group were subjected to hemorrhage using an isobaric metho d. Pigs in both groups received fentanyl (50 mu g/kg) intravenously over 5 min. Frequent arterial blood samples were obtained for radioimmunoassay. Ea ch animal's pharmacokinetic parameters were estimated by fitting a three-co mpartment model to the concentration versus time data Nonlinear mixed-effec ts population pharmacokinetic models examining the influence of mean arteri al pressure and cardiac index were also constructed Clinical simulations us ing the final population model were performed. Results: The shock cohort reached substantially higher fentanyl concentrati ons. The shack group's central clearance and central- and second-compartmen t distribution volumes were significantly reduced The most useful populatio n model scaled all pharmacokinetic parameters to mean arterial pressure. Th e simulations illustrated that hemorrhagic shock results in higher fentanyl concentrations for any given dosage scheme. Conclusion: The essential finding of the study is that fentanyl pharmacokin etics are substantially altered by hemorrhagic shock. The reduced opioid re quirement commonly observed during hemorrhagic shock is at least partially attributable to pharmacokinetic mechanisms.