In vivo Monitoring of Cerebral Hemodynamics in the Immature Rat: Effects of Hypoxia-Ischemia and Hypothermia

Abstract

Background: Neonatal hypoxic-ischemic (HI) encephalopathy occurs in 1-4 per 1,000 live term births and can cause devastating neurodevelopmental disabilities. Currently, therapeutic hypothermia (TH) is the only treatment with proven efficacy. Since TH is associated with decreased cerebral metabolism and cerebral blood flow (CBF), it is important to assess CBF at the bedside. Diffuse correlation spectroscopy (DCS) has emerged as a promising optical modality to noninvasively assess an index of CBF (CBF_i) in both humans and animals. In this initial descriptive study, we employ DCS to monitor the evolution of CBF_i following HI with or without TH in immature rats. We investigate potential relationships between CBF and subsequent cerebral damage. Methods: HI was induced on postnatal day 10 or 11 rat pups by right common carotid artery ligation followed by 60-70 min hypoxia (8% oxygen). After HI, the pups recovered for 4 h under hypothermia (HI-TH group, n = 23) or normothermia (HI-N group, n = 23). Bilateral measurements of hemispheric CBF_i were made with DCS in unanesthetized animals at baseline, before HI, and 0, 1, 2, 3, 4, 5, and 24 h after HI. The animals were sacrificed at either 1 or 4 weeks, and brain injury was scored on an ordinal scale of 0-5 (0 = no injury). Results: Carotid ligation caused moderate bilateral decreases in CBF_i. Following HI, an initial hyperemia was observed that was more prominent in the contralateral hemisphere. After initiation of TH, CBF_i dropped significantly below baseline levels and remained reduced for the duration of TH. In contrast, CBF_i in the HI-N group was not significantly decreased from baseline levels. Reductions in CBF_i after 4 h of TH were not associated with reduced damage at 1 or 4 weeks. However, elevated ipsilateral CBF_i and ipsilateral-to-contralateral CBF_i ratios at 24 h were associated with worse outcome at 1 week after HI. Conclusions: Both HI and TH alter CBF_i, with significant differences in CBF_i between hypothermic and normothermic groups after HI. CBF_i may be a useful biomarker of subsequent cerebral damage.