Published online May 1, 2006
PEDIATRICS Vol. 117 No. 5 May 2006, pp. 1549-1559 (doi:10.1542/peds.2005-1649)

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Delayed Whole-Body Cooling to 33 or 35°C and the Development of Impaired Energy Generation Consequential to Transient Cerebral Hypoxia-Ischemia in the Newborn Piglet

Frances E. O'Brien, MRCPCH^a, Osuke Iwata, MD^a, John S. Thornton, PhD^b, Enrico De Vita, PhD^c, Mark W. Sellwood, MRCPCH^a, Sachiko Iwata, MD^a, Yasuko S. Sakata, MD^a, Susan Charman, MSc^d, Roger Ordidge, PhD^b, Ernest B. Cady, FInstP^c, John S. Wyatt, FRCPCH^a and Nicola J. Robertson, FRCPCH, PhD^a

^a Departments of Pediatrics and Child Health and
^b Medical Physics and Bioengineering, University College London, London, United Kingdom
^c Department of Medical Physics and Bioengineering
^d Medical Statistics Unit, Research and Development Directorate, University College London National Health Service Foundation Trust, London, United Kingdom

OBJECTIVES. Fundamental questions remain about the precise temperature providing optimal neuroprotection after perinatal hypoxia-ischemia (HI). Furthermore, if hypothermia delays the onset of the neurotoxic cascade and the secondary impairment in cerebral energy generation, the "latent phase" may be prolonged, thus extending the period when additional treatments may be effective. The aims of this study were to investigate the effects of delayed systemic cooling at either 33°C or 35°C on the following: (1) latent-phase duration, and (2) cerebral metabolism during secondary energy failure itself, in the 48-hour period after transient HI.

METHODS. Piglets were randomly assigned to the following: (1) HI-normothermic (HI-n) rectal temperature (T_rectal; n = 12), (2) HI-T_rectal 35°C (HI-35; n = 7), and (3) HI-T_rectal 33°C (HI-33; n = 10). Groups were cooled to the target T_rectal between 2 and 26 hours after HI. Serial magnetic resonance spectroscopy was performed over 48 hours. The effect of cooling on secondary energy failure severity (indexed by the nucleotide triphosphate/exchangeable phosphate pool [NTP/EPP] and phosphocreatine/inorganic phosphate [PCr/Pi] ratios) was assessed.

RESULTS. Compared with HI-n, HI-35 and HI-33 had a longer NTP/EPP latent phase and during the entire study duration had higher mean NTP/EPP and PCr/Pi. The latent phase (both PCr/Pi and NTP/EPP) and the whole-brain cerebral energetics were similar for HI-35 and HI-33. During the hypothermic period, compared with HI-n, PCr/Pi was preserved in the cooled groups, but this advantage was not maintained after rewarming. Compared with HI-n, HI-35 and HI-33 had higher NTP/EPP after rewarming.

CONCLUSIONS. Whole-body hypothermia for 24 hours at either 35 or 33°C, commenced 2 hours after resuscitation, prolonged the NTP/EPP latent phase and reduced the overall secondary falls in mean PCr/Pi and NTP/EPP during 48 hours after HI. Reducing the temperature from 35 to 33°C neither increased mean PCr/Pi and NTP/EPP nor further lengthened the latent phase.

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Key Words: phosphorus magnetic resonance spectroscopy • hypoxic-ischemic encephalopathy • perinatal asphyxia • whole-body cooling • neuroprotection • hypothermia

Abbreviations: HI—hypoxia-ischemia • NE—neonatal encephalopathy • ³¹P—phosphorus • MRS—magnetic resonance spectroscopy • PCr—phosphocreatine • ATP—adenosine triphosphate • Pi—inorganic phosphate • FID—free induction decay • NTP—nucleotide triphosphate • EPP—exchangeable phosphate pool • T_rectal—rectal temperature • FIO₂—inspired oxygen fraction • AED—acute energy depletion • CI—confidence interval • ANOVA—analysis of variance • NAD—nicotinamide adenine dinucleotide • GM—gray matter

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Accepted Oct 7, 2005.

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