DEVELOPMENT OF NRORQPROTECTIVE STRATEGY BY THE COMBIMTIQN THERAPY OF MILD HYPOTHERMIA AND NEURQNAL NITRIC OXIDE INHIBITOR ADMINISTRATION AGAINST NEONATAL BRAIN DAMAGE

2002 Fiscal Year Final Research Report Summary

• Project/Area Number: 13670840
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tokyo Medical University
• Principal Investigator: TAKEI Yukito Medicine, Lecturer, 医学部, 講師 (20256259)
• Co-Investigator(Kenkyū-buntansha): YAMADA Naoto Medicine, Clinical assistant, 医学部, 助手 (20276950) ; TAKAMI Takeshi Medicine, Clinical assistant, 医学部, 助手 (20287147)
• Project Period (FY): 2001 – 2002
• Keywords: HYPOXIA ISCHEMIA / HYPOTHERMIA / 7-NITROINDAZOLE / NEONATAL ASPHYXIA / CEREBRAL BLOOD FLOW

Research Abstract

The goal of this study was to investigate the clinical neuroprotective strategy by means of the combination therapy of mild hypothermia and the neuronal nitric oxide inhibitor (7-nitroindazole) administration against hypoxic-ischemic (HI) brain damage in neonatal piglets. We investigated the effects of the different mode of cooling on the cerebral and systemic hemodynamics using HI neonatal brain damage models.
Neonatal piglets, aged less than two days, were anesthetized, paralyzed and mechanically ventilated. We continuously measured cortical electroencephalogram (EEG) , cerebral oxygenation index (TOI) by near-infrared spectroscopy, regional cerebral blood flow (rCBF) by laser Doppler flowmetry, mean arterial blood pressure (MABP) , heart rate (HR), peripheral arterial blood oxygen saturation (Sp02) , rectal and cerebral (nasopharyngeal) temperatures. We also measured blood gases and blood glucoses. The piglets were subjected to temporary occulusion of the common carotid arteries and hypoxemia (Fi02^0. 15, respiratory rate: 15 beaths/min) for 60 min. The piglets were then resuscitated by releasing the carotid occluders and providing the Fi02 of 1. 0 and respiratory rate of 60 breaths/min. Piglets were divided into either the selective brain cooling (nasopharyngeal temperature; 35. 51, ectal temperature; 38. 5 t for 24 hours), whole-body cooling (nasopharyngeal and rectal temperatures; 35. 5 ^C, for 24 hours) or the normothermia (nasopharyngeal and rectal temperatures; 38. 5 ーC) soon after resuscitation. Thereafter, the cooled piglets were slowly rewarmed at 1. 0 ーC per hour until their temperature was within the normal temperature range.
HI insult indicated decreases in TOI, rCBF, Sp02, EEG amplitude, which were returned to baseline after resuscitation in all piglets. The EEG amplitude was then observed to be gradually decreasing (like the delayed "secondary" energy failure). The nasopharyngeal temperature was decreased by 0. 5~1. 0 "C in the selective brain cooling. There were no significant differences in rCBF, TOI, Sp02, EEG amplitude, MABP, HR, blood gase, and blood glucose during cooling and rewarming phase in both selective and whole-body cooling, compared with no were no significant differences in these parameters between the selective rmo bra thermia. There in cooling and whole-body cooling during cooling and rewarming phase, which indicated that the adverse effects in the whole-body cooling were not significant, compared with selective brain cooling.