Resuscitation with 100% oxygen increases injury and counteracts the neuroprotective effect of therapeutic hypothermia in the neonatal rat

Abstract

IntroductIon: Mild therapeutic hypothermia (hT) reduces brain injury in survivors after perinatal asphyxia. Recent guidelines suggest that resuscitation of term infants should be started with air, but supplemental oxygen is still in use. It is not known whether supplemental oxygen during resuscitation affects the protection offered by subsequent hT. results: Wilcoxon median (95% confidence interval) hippocampal injury scores (range 0.0-4.0; 0 to ≥90% injury) were 21% O 2 normothermia (NT): 2.00 (1.25-2.50), 21% O 2 hT: 1.00 (0.50-1.50), 100% O 2 NT: 2.50 (1.50-3.25), and 100% O 2 hT: 2.00 (1.25-2.50). although hT significantly reduced hippocampal injury (B = -0.721, seM = 0.297, P = 0.018), reoxygenation with 100% O 2 increased injury (B = +0.647, seM = 0.297, P = 0.033). Regression constant B = 1.896, seM = 0.257 and normally distributed residuals. dIscussIon: We confirm an ~50% neuroprotective effect of therapeutic hT in the neonatal rat. Reoxygenation with 100% O 2 increased injury and worsened reflex performance. hT was neuroprotective whether applied after reoxygenation with air or 100% O 2 . however, hT after 100% O 2 gave no net neuroprotection. Methods: In an established neonatal rat model, hypoxiaischemia (hI) was followed by 30-min reoxygenation in either 21% O 2 or 100% O 2 before 5 h of NT (37 °c) or hT (32 °c). The effects of hT and 100% O 2 on histopathologic injury in the hippocampus, basal ganglia, and cortex, and on postural reflex performance 7 d after the insult, were estimated by linear regression.P erinatal asphyxia occurs in 1 to 6 per 1,000 term human births (1) and is an important cause of severe neurologic impairment and neonatal mortality. Therapeutic hypothermia (HT) has emerged as a neuroprotective therapy in both newborn animal models (2-4) and clinical trials (5-7). The collective evidence from these studies confirms that mild therapeutic HT improves outcome in hypoxic-ischemic encephalopathy, a condition in which ~50% of cooled infants normally die or have significant neurologic disability (8) as compared with before the advent of HT treatment when ~65% had poor outcome. In the UK, the National Institute for Health and Clinical Excellence has declared that HT should be used as standard of care after perinatal asphyxia (9). HT after perinatal asphyxia is also recommended by the recent 2010 International Resuscitation Guidelines (International Liaison Committee on Resuscitation) (10). HT suppresses many of the pathways that lead to delayed energy failure and cell death after hypoxia (11,12), including generation of reactive oxygen species (13), excitotoxicity (14), and the inflammatory response (15).Supplemental oxygen was previously recommended for resuscitation of the asphyxiated newborn infant, but after the changes in the 2010 International Liaison Committee on Resuscitation guidelines, it is now recommended that resuscitation of the term infant is best started with air, rather than pure oxygen (10). Evidence from animal studies shows that supplemental oxygen during resuscitation...

Immediate Hypothermia Is Not Neuroprotective After Severe Hypoxia-Ischemia and Is Deleterious When Delayed by 12 Hours in Neonatal Rats

“…Currently, it may not be possible with certainty to identify which newborns will have development of significant encephalopathy until some hours after birth. If these experimental results In our previous neuroprotection studies, 15,19,25,26 brains were assessed and scored by 2 pediatric neuropathologists. In this study, we show that computerized area measurements correlate well with our global neuropathology score.…”

“…The ratio of the measured brain area was calculated for the 2 sections per brain and the average percentage of area loss was calculated, respectively (1 − [area ratio (left vs right)] × 100). 27 We validated this computerized method against our neuropathology score 18,[25][26] with P14 rat brains, previously scored by a neuropathologist using our validated scoring system with a 9-step scale from 0.0 (no injury) to 4.0 (≥90% injury). 26 A pathology score of ≈50% correlated with a computer-calculated area loss of ≈40%.…”

“…15,25,26 After a maximum delay of 180 minutes, while pups were with their dam, pups were exposed to 8% oxygen for 90 minutes at T rectal of 36.0°C in a temperature-controlled chamber, which was described to result in moderate HI insult. 25,26 Twenty-three pups died during this moderate insult. Twelve animals carrying a temperature probe were excluded from further analysis.…”

“…We validated this computerized method against our neuropathology score 18,[25][26] with P14 rat brains, previously scored by a neuropathologist using our validated scoring system with a 9-step scale from 0.0 (no injury) to 4.0 (≥90% injury).…”

Brain inflammation induced by severe asphyxia in newborn pigs and the impact of alternative resuscitation strategies on the newborn central nervous system

“…Our group has previously reported detrimental brain effects caused by hyperoxia (1,14,(23)(24)(25). Those pigs were bradycardic and hypotensive but not as extremely sick as the asphyxiated pigs reported here with base excess <−30 mmol/l, pH 6.7, and high PaCO 2 (18) at asystole.…”