Acute and chronic effects of endotoxin on cerebral circulation in lambs

Abstract

The impact of endotoxemia on cerebral endothelium and cerebral blood flow (CBF) regulation was studied in conscious newborn lambs. Bacterial endotoxin [LPS, 2 μg/kg iv] was infused on 3 consecutive days. Cerebrovascular function was assessed by monitoring CBF and cerebral vascular resistance (CVR) over 12 h each day and by the endothelium-dependent vasodilator bradykinin (BK) ( n = 10). Inflammatory responses were assessed by plasma tumor necrosis factor-α (TNF-α, n = 5). Acutely, LPS disrupted the cerebral circulation within 1 h, with peak cerebral vasoconstriction at 3 h (CBF −28 and CVR +118%, P < 0.05) followed by recovery to baseline by 12 h. TNF-α and body temperature peaked ∼1 h post-LPS. BK-induced vasodilatation (CVR −20%, P < 0.05) declined with each LPS infusion, was abolished after 3 days, and remained absent for at least the subsequent 5 days. Histological evidence of brain injury was found in four of five LPS-treated newborns. We conclude that endotoxin impairs cerebral perfusion in newborn lambs via two mechanisms: 1) acute vasoconstriction (over several hours); and 2) persistent endothelial dysfunction (over several days). Endotoxin-induced circulatory impairments may place the newborn brain at prolonged risk of CBF dysregulation and injury as a legacy of endotoxin exposure.