This experimental protocol, to be conducted in newborn dogs, was designed to elucidate the manner and extent to which the immature brain is protected from ischemic damage during hypothermic circulatory arrest. The rationale for this line of research relates to the well-established approach to the surgical repair of congenital cardiac defects.
Specific aims i nclude: 1) to characterize the early evolution of ischemic brain damage which results from prolonged hypothermic circulatory arrest in newborn dogs and to determine whether or not a delayed neuronal necrosis occurs; 2) to investigate underlying mechanisms which protect the perinatal ischemic brain from injury during hypothermic circulatory arrest other than or in addition to a suppression of oxidative metabolism; 3) to compare the extent to which incomplete versus complete cerebral ischemia is protective (or deleterious) to newborn dog brain during hypothermia; 4) to ascertain the beneficial or deleterious effect of hyperglycemia on the brain damage which results from hypothermic circulatory arrest in newborn dogs; and 5) to determine the protective influence of specific therapeutic modalities on ischemic brain damage resulting from hypothermic circulatory arrest in newborn dogs. Experimental procedures will involve the induction of hypothermia by surface cooling in anesthetized, paralyzed and artifically ventilated newborn dogs to 20degreesC followed by cardiac arrest for up to 120 minutes. Thereafter, the animals will be resuscitated, following which they will undergo neuropathologic analysis at specific intervals of recovery. Regional oxidative and energy metabolism will be determined during and following hypothermic circulatory arrest by the in situ analysis of concentrations of selected glycolytic and Krebs cycle intermediates and high-energy phosphate compounds, using enzymatic, fluorometric techniques. 31P MR spectroscopy also will be used to measure sequentially cerebral high-energy phosphate reserves and intracellular pH (pHi) during and following hypothermic circulatory arrest. Extracellular concentrations of excitatory and inhibitory neurotransmitters also will be measured using a microdialysis technique. Lastly, the regional accumulation of calcium in brain during and following hypothermic circulatory arrest will be accomplished using [45Ca]-autoradiography. Therapeutic interventions to potentially reduce the extent of brain damage during hypothermic circulatory arrest will include thiopental sodium, the xanthine oxidase inhibitor, oxypurinol, and the calcium channel blocker, nimodipine. Additional experimental protocols include the induction of a 'low flow' rather that a 'no flow' state and the determination of the effect of hyperglycemia on hypothermic ischemic brain damage. It is anticipated that these investigations will provide insight into the physiochemical mechanism(s) and duration of the protective influence of hypothermia on circulatory arrest.
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