Submitted on February 7, 2008
Revised on November 26, 2008
Accepted on December 15, 2008
Endotoxin Has Acute and Chronic Effects on the Cerebral Circulation of Fetal Sheep
Susan YS Feng1, David J Phillips, Elaine M Stockx, Victor YH Yu2, and Adrian M Walker1*
1 Monash Institute of Medical Research
2 Monash Medical Centre
* To whom correspondence should be addressed. E-mail: adrian.walker{at}med.monash.edu.au.
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, 1µg/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 ~ +50%) was followed by vasodilatation maximal at 5-6 h (CVR ~ -50%) when CBF had increased (~ +60%) despite reduced ABP (~ -20%). Decreased CVR and increased CBF persisted 24 h post-LPS, and the two subsequent LPS infusions. Cerebral O2 transport was sustained, though SaO2 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 ~ -20%, P < 0.05) was abolished after LPS. Fetuses which 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.
