Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective

Three to 12 h of mild hypothermia (HT) starting after hypoxia-ischemia is n europrotective in piglets that are anesthetized during HT. Newborn infants suffering from neonatal encephalopathy often ventilate spontaneously and ar e not necessarily sedated. We aimed to test whether mild posthypoxic HT las ting 24 h was neuroprotective if the animals were not sedated. Thirty-nine piglets (median weight 1.6 kg, range 0.8-2.2 kg; median age 24 h, range 7-4 8 h) were anesthetized and ventilated and subjected to a 45-min hypoxic (Fi o(2) similar to 6%) global insult (n = 36) or sham hypoxia (n = 3). On reox ygenation, 18 were maintained normothermic (NT, 39.0 degreesC) for 72 h, an d 21 were cooled from 39 (NT) to 35 degreesC (HT) for the first 24 h before NT was resumed (18 experimental, three sham hypoxia). Cardiovascular param eters and intermittent EEG were documented throughout. The brain was perfus ion fixed for neuropathology and five main areas examined using light micro scopy. The insult severity (duration in minutes of EEG amplitude < 7 muV) w as similar in the NT and HT groups, mean +/- SD (28 +/- 7.2 versus 27 +/- 8 .6 min), as was the mean Fio(2) (5.9 +/- 0.7 versus 5.8 +/- 0.8%) during th e insult. Six NT and seven HT piglets developed posthypoxic seizures that l asted 29 and 30% of the time, respectively. The distribution and degree of injury (0.0-4.0, normal-maximal damage) within the brain (hippocampus, cort ex/white matter, cerebellum, basal ganglia, thalamus) were similar in the N T and HT groups (overall score, mean +/- SD, 2.3 +/- 1.5 versus 2.4 +/- 1.3 ) as was the EEG background amplitude at 3 h (13 +/- 3.5 versus 10 +/- 3.3 muV). The HT animals shivered and were more active. The sham control group (n = 3) shivered but had normal physiology and neuropathology. Plasma corti sol was significantly higher in the HT group during the HT period, 766 +/- 277 versus 244 +/- 144 muM at 24 h. Mild postinsult HT for 24 h was not neu roprotective in unsedated piglets and did not reduce the number of animals that developed posthypoxic seizures. Cortisol reached 3 times the NT value at the end of HT. We speculate that the stress of shivering and feeling col d interfered with the previously shown neuroprotective effect of HT. Resear ch on the appropriateness of sedation during clinical HT is urgent.