Effects of continuous infusion fentanyl citrate on cerebrovascular and systemic prostanoids in postsurgical newborn piglets

Abstract

Background: Newborns admitted to the intensive care unit undergo multiple painful procedures. Fentanyl citrate (FC) is one of the most commonly used drugs for pain relief in the newborn. Although it has been reported that one of the biological effects of fentanyl is hemodynamic stability, the response of systemic and/or cerebrovascular prostanoids to FC infusions have not been studied.

Methods: To examine the effects of continuous intravenous (IV) infusion of FC on systemic and cerebrovascular prostanoid concentrations, two groups of spontaneously breathing newborn piglets (1-3 days old) were studied. The study group (n = 6) and the control group (n = 8) were respectively given a loading dose of 30 micrograms/kg IV over 15 minutes, immediately followed by a continuous IV infusion of 10 micrograms/kg/hr for 6 hours, or a placebo (PB) solution of 5% dextrose in a similar fashion. Cerebrospinal fluid (0.5 mL) from cisterna magna puncture and blood samples (1.0 mL) from the sagittal sinus vein and carotid artery were collected serially before and after FC or PB infusion for drug and PG determinations. FC was measured by high pressure liquid chromatography (HPLC), and the prostanoids were measured using enzyme immunoassay (EIA) kits.

Results: FC infusion induced marked elevations in 6-ketoPGF1 alpha (300%, p < 0.001) and TXB2 (150%, p < 0.001) at 30 minutes, and remained elevated up to 2 hours of infusion. In addition, systemic 6-ketoPGF1 alpha increased by 180% (p < 0.001) and PGE2 concentrations fell dramatically at 30 minutes (87%, p < 0.001) and did not return to normal levels during the infusion time (83% to 81%, p < 0.001 to p < 0.01). CSF 6-ketoPGF1 alpha and TXB2 levels increased by 152% and 80%, respectively (p < 0.001), but PGE2 decreased by 76% (p < 0.001), at 6 hours of infusion. An inverse relationship existed between FC, and sagittal sinus PGE2 levels (r = 0.46, p < 0.03) and systemic PGE2 levels (r = 0.602, p < 0.02).

Conclusion: The data suggest FC is rapidly transported across the blood brain barrier and the effects on cerebrovascular prostanoids, particularly PGE2 is rapid and prolonged. PGE2 appears to be the primary responsive prostanoid. The magnitude of the response, as evidenced by the early and sharp reductions in systemic and cerebrovascular concentrations, suggest vasoconstriction, with possible adverse effects on organ blood flow and metabolic activity. However, further studies are required to evaluate the effects on organ blood flow and metabolism.