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DEVELOPMENTAL PHYSIOLOGY AND PREGNANCY

Endotoxin has acute and chronic effects on the cerebral circulation of fetal sheep

¹Ritchie Centre for Baby Health Research, ²Centre of Reproduction and Development, Monash Institute of Medical Research, Monash University, Clayton; and ³Newborn Services, Monash Medical Centre, Clayton, Victoria, Australia

Submitted 2 February 2008 ; accepted in final form 15 December 2008

We studied the impact of endotoxemia on cerebral blood flow (CBF), cerebral vascular resistance (CVR), and cerebral oxygen transport (O₂ transport) in fetal sheep. We hypothesized that endotoxemia impairs CBF regulation and O₂ transport, exposing the brain to hypoxic-ischemic injury. Responses to lipopolysaccharide (LPS; 1 µg/kg iv on 3 consecutive days, n = 9) or normal saline (n = 5) were studied. Of LPS-treated fetuses, five survived and four died; in surviving fetuses, transient cerebral vasoconstriction at 0.5 h (CVR approximately +50%) was followed by vasodilatation maximal at 5–6 h (CVR approximately –50%) when CBF had increased (approximately +60%) despite reduced ABP (approximately –20%). Decreased CVR and increased CBF persisted 24 h post-LPS and the two subsequent LPS infusions. Cerebral O₂ transport was sustained, although arterial O₂ saturation was reduced (P < 0.05). Histological evidence of neuronal injury was found in all surviving LPS-treated fetuses; one experienced grade IV intracranial hemorrhage. Bradykinin-induced cerebral vasodilatation (CVR approximately –20%, P < 0.05) was abolished after LPS. Fetuses that died post-LPS (n = 4) differed from survivors in three respects: CVR did not fall, CBF did not rise, and O₂ transport fell progressively. In conclusion, endotoxin disrupts the cerebral circulation in two phases: 1) acute vasoconstriction (1 h) and 2) prolonged vasodilatation despite impaired endothelial dilatation (24 h). In surviving fetuses, LPS causes brain injury despite cerebral O₂ transport being maintained by elevated cerebral perfusion; thus sustained O₂ transport does not prevent brain injury in endotoxemia. In contrast, cerebral hypoperfusion and reduced O₂ transport occur in fetuses destined to die, emphasizing the importance of sustaining O₂ transport for survival.

cerebral blood flow; fetus; oxygen transport