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Abstract

Introduction: The time interval after experimental traumatic brain injury (TBI) during which exposure to hyperthermia (HT) exacerbates brain injury is unknown. Hypothesis: Hippocampal neuronal death correlates inversely with the time interval between TBI and a single brief exposure to HT within 72h of injury. Methods: Anesthetized, normothermic C57BL6J adult male mice underwent TBI by controlled cortical impact (6m/s, 1.2mm). All injured mice underwent a single 2h period of post-TBI temperature manipulation, with brain temperature targeted to 37°C (normothermia, NT) or 39°C (HT) at 15min, 24h, 72h or 96h. Mice were divided into 7 groups (n = 5 – 6/group): na? (no TBI), 15NT, 15HT, 24NT, 24HT, 72HT and 96HT. During temperature regulation, isoflurane and femoral catheters were used. Vital signs were recorded every 5min and Lactated Ringer’s (LR) given if MAP < 70mmHg. Mice were sacrificed 7d after TBI and brains stained with H&E. Hemodynamics and blood gases (median [IQR]) were compared with Wilcoxon Rank Sum; CA1/CA3 neuron counts (mean [SEM]) were compared using ANOVA with Holm-Sidak, all with significance at p < 0.05. Results: During temperature manipulation, HT mice had increased temperature (38.93 [38.80–38.95] vs. 37.10 [37.02–37.13] °C), heart rate (600.0 [577.3 – 618.6] vs. 524.8 [522.3 – 584.3] bpm) and MAP (92.9 [84.4 – 95.4] vs. 85.6 [81.9 – 88.6] mmHg), but there were no differences in LR requirement, lactate or base deficit. Neuron density per 0.1mm of CA1 was decreased in 15HT (9.87 [2.66]), 24HT (8.68 [2.47]) and 72HT (9.54 [2.97]) vs. na? (27.25 [2.37]). Neuron density per 0.1mm of CA3 was decreased in 24NT (5.98 [2.42]), 24HT (7.74 [2.89]), 72HT (5.74 [2.04]) and 96HT (10.97 [1.18]) vs. na? (26.21 [0.56]). Conclusions: Our data suggest that brief exposure to a clinically relevant HT insult up to at least 72h after experimental TBI produces a marked exacerbation of neuronal death in CA1. Our findings also surprisingly suggest that, even with protocolized resuscitation, exposure to anesthesia and monitoring after TBI can have deleterious effects in CA3. Defining the duration of post-traumatic vulnerability to HT and/or anesthesia is needed to optimize clinical management. Supported by T32 HD040686.