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

Abstract

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.

Acute on chronic exposure to endotoxin is associated with enhanced chemoreflex responses in preterm fetal sheep

“…Carotid vascular conductance was significantly increased in LPS-treated animals before occlusion consistent with our previous report (22) and previous studies that found increased carotid blood flow despite hypotension (10,25). Despite this marked central vasodilation, occlusion was associated with a rapid reduction in conductance that was not significantly different to saline-treated fetuses.…”

“…These data are difficult to interpret given that high-dose LPS by itself is associated with severe hypotension and a high risk of death over 4 to 7 h (7,8,10,22,25). Supporting a direct effect, there is evidence of impaired chemoreflex responses in adult patients with sepsis and multiple organ failure (29,30) and after acute LPS injection in anesthetized adult cats and neonatal piglets (11,23).…”

A Critical Review of Models of Perinatal Infection

“…Multiple studies have shown that fetal sheep exposed to acute boluses of Gram-negative LPS commonly develop white matter damage [63,64,65,66,67,68,69,70,71]. Typically, such large doses are associated with acute loss of a third to over 40% of fetuses associated with terminal hypotension [64,67,72], similar to the deaths of 6/11 fetuses in a recent report [73]. …”

Chorioamnionitis: a multiorgan disease of the fetus?

“…23,24 In addition, proinflammatory cytokines may affect the central nervous system by increasing the permeability of the developing blood brain barrier exclusively observed in the cerebral white matter, 25 and by impairing the cerebral blood flow. 26 Second, developing oligodendrocytes are injured by reactive oxygen species and reactive nitrogen species generated by either oligodendrocyte glutamatergic excitotoxicity or microglial activation. The activated microglia generate free radicals and induce the ultimate death of the antioxidant-deficient immature oligodendrocytes.…”