Fentanyl, an opioid metabolized by hepatic mixed function oxidases, is commonly administered as the primary anesthetic for neonates undergoing surgery. Pharmacokinetic studies have suggested that abdominal surgery in neonates decreases fentanyl clearance, contending that this results from increases in intra-abdominal pressure (IAP) decreasing hepatic blood flow. To examine the effects of IAP on hepatic blood flow and fentanyl clearance, we infused fentanyl to eight neonatal lambs, measured regional blood flows by using the radionuclide-labeled microsphere technique and determined hepatic fentanyl extraction and clearance and hepatic oxygen extraction and consumption at three levels of IAP: 0, 12 and 18 mm Hg. Increased IAP did not affect portal or hepatic blood flow or ductus venosus shunt. Fentanyl extraction was 16.5 +/- 3.0% (mean +/- S.E.) at 0 mm Hg of IAP. Increased IAP decreased hepatic extraction of fentanyl, thereby decreasing fentanyl clearance. Increased IAP did not affect hepatic oxygen extraction or consumption. In two additional animals in which serial measurements of hepatic blood flow were obtained, increased IAP (15 mm Hg) transiently decreased hepatic blood flow with recovery to control values at 2 hr. The authors conclude that fentanyl is poorly extracted by neonatal livers, in contrast to its large extraction ratio in adults. The decrease in fentanyl clearance with increased IAP is consistent with pharmacokinetic studies demonstrating decreased clearance in neonates undergoing abdominal surgery. However, the present study suggests that the mechanism of decreased clearance is decreased hepatic function (decreased fentanyl extraction) rather than decreased hepatic blood flow.