Changes in cerebral venous prostanoids during midazolam-induced cerebrovascular hypotension in newborn piglets

Abstract

Objectives: We hypothesized that the effects of midazolam are associated with altered prostanoid synthesis in the newborn piglet during continuous infusion. To test this hypothesis, we examined the effect of midazolam on prostanoid production in the carotid artery and sagittal sinus vein before and during midazolam infusion.

Design: Prospective, randomized, controlled, experimental study.

Setting: Research laboratory at Long Beach Memorial Medical Center.

Subjects: Fourteen newborn piglets (1-3 days old, 1-1.5 kg) randomly assigned to receive either midazolam or vehicle (5% dextrose) infusion for 6 hrs.

Interventions: Two groups of animals received either a) a loading dose of 300 microg/kg of midazolam over 15 mins, followed by a continuous intravenous infusion of 100 microg/kg/hr (n = 6), or b) equivalent volume bolus and intravenous infusions of 5% dextrose (control, n = 8).

Measurements and main results: Changes in systemic and cerebral venous hemodynamics, blood gases, and prostanoid (prostaglandin E2, 6-ketoprostaglandin F1 alpha, thromboxane B2) production were measured at baseline, postbolus, and at 0.5, 2, 4, and 6 hrs. Systemic and cerebral venous midazolam concentrations were measured at 0.5, 1, 2, 3, 4, 5, and 6 hrs. Midazolam infusion did not affect systemic hemodynamics or blood gases. In contrast, midazolam infusion significantly reduced sagittal sinus vein blood pressure, PO2, oxygen saturation, and oxygen content. Cerebral fractional oxygen extraction increased and was positively correlated with cerebral fractional midazolam extraction. Concurrently, systemic and sagittal sinus vein plasma prostaglandin E2 concentrations decreased, whereas 6-ketoprostaglandin F1 alpha concentrations increased with midazolam infusion. Thromboxane B2 concentrations increased transiently in the systemic plasma.

Conclusions: Midazolam infusion preceded by a high bolus dose in newborn piglets alters systemic and sagittal sinus vein prostanoid production. It is also associated with changes in sagittal sinus vein blood pressure and cerebral fractional oxygen extraction. These changes may reflect decreased brain perfusion and metabolism during midazolam infusion.