Endotoxin has acute and chronic effects on the cerebral circulation of fetal sheep.
We studied the impact of endotoxemia on cerebral blood flow (CBF), cerebral vascular resistance (CVR), and cerebral oxygen transport (O(2) transport) in fetal sheep. We hypothesized that endotoxemia impairs CBF regulation and O(2) transport, exposing the brain to hypoxic-ischemic injury. Responses to lipopolysaccharide (LPS; 1 microg/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 (DeltaCVR approximately +50%) was followed by vasodilatation maximal at 5-6 h (DeltaCVR 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 O(2) transport was sustained, although arterial O(2) 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 (DeltaCVR 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 O(2) 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 O(2) transport being maintained by elevated cerebral perfusion; thus sustained O(2) transport does not prevent brain injury in endotoxemia. In contrast, cerebral hypoperfusion and reduced O(2) transport occur in fetuses destined to die, emphasizing the importance of sustaining O(2) transport for survival.
Feng
Susan Y S
SY
Ritchie Centre for Baby Health Research, Monash Institute of Medical Research, Monash Medical Centre, Clayton, Melbourne, Victoria, Australia.
Phillips
David J
DJ
Stockx
Elaine M
EM
Yu
Victor Y H
VY
Walker
Adrian M
AM
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002555:Cerebrospinal Fluid / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D016207:Cytokines / Q000096:biosynthesis; D003627:Data Interpretation, Statistical; D042783:Endothelial Cells / Q000502:physiology; D004731:Endotoxins / Q000097:blood / Q000494:pharmacology*; D005260:Female; D005313:Fetal Death; D005333:Fetus / Q000098:blood supply*; D008070:Lipopolysaccharides / Q000097:blood / Q000494:pharmacology*; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D010101:Oxygen Consumption / Q000502:physiology; D011247:Pregnancy; D012756:Sheep; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014664:Vasodilation / Q000187:drug effects
D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; C044101:endotoxin, Escherichia coli