Cerebral Oxidative Metabolism during Hypothermia and Circulatory Arrest in Newborn Dogs

Abstract

ABSTRACT. To ascertain the alterations in cerebral oxiHypothermic circulatory arrest has become an established dative and energy metabolism that occur during hypother-procedure for the operative correction of congenital heart anommic circulatory arrest, nitrous oxide-anesthetized, para-alies in infants and children (1). Despite the prevalence of its use lyzed, and artificially ventilated newborn dogs were surface in clinical practice, little basic research has been conducted to cooled to 18-20°C, after which their hearts were arrested investigate the protective influence of hypothermia superimposed with KCI. At 10, 30,60, and 105 min of circulatory arrest, upon systemic hypoxia, hypotension, or cardiac arrest in peritheir brains were prepared by in situ freezing for the natal animals (2-5). Accordingly, we have developed a model of regional analysis of glycolytic intermediates and high-hypothermic circulatory arrest in the newborn dog; the neuroenergy phosphate reserves. Hypothermia alone was asso-pathologic consequence thereof is now well documented (6, 7). ciated with optimal preservation of labile metabolites in Specifically, newborn dogs subjected to hypothermic circulatory brain, even in caudal brainstem and cerebellum, compared arrest of 1.0 h duration exhibit no brain damage at 4 or 24 h of with barbiturate-anesthetized littermates. After onset of recovery, whereas puppies arrested for 1.5 h or longer show hypothermic circulatory arrest, glucose decreased progres-progressively increasing ischemic injury to selectively vulnerable sively in cerebral cortex, caudate nucleus, hippocampus, structures. It is not known just how long a human infant can and subcortical white matter to negligible levels by 30 min. tolerate hypothermic circulatory arrest, although clinical studies Pyruvate increased transiently (+SO%) at 10 min, whereas suggest a "safe" interval (60-75 min) similar to that of the lactate increased and plateaued (10-11 mmol/kg) at 30 newborn dog (8-10). min. The disproportionate increases in pyruvate and lactateIn the present communication, we describe the results of an resulted in a progressive rise in the lactate/pyruvate ratio. investigation conducted in parallel with neuropathologic studies Phosphocreatine fell precipitously to ~0 . 5 mmol/kg in all to ascertain the nature and extent of alterations in cerebral structures, with a preservation of ATP for the first 10 min carbohydrate and energy metabolism during hypothermia alone of cerebral ischemia. Thereafter, ATP decreased to C0.1 and during hypothermic circulatory arrest. A major objective of mmol/kg in cerebral cortex and between 0.1 and 0.2 mmol/ the study was to correlate changes in regional metabolic activity kg in caudate nucleus, hippocampus, and white matter. during hypothermic cerebral ischemia with the known sensitivity Total adenine nucleotides (ATP + ADP + AMP) were (or resistance) of specific brain structures to ischemic damage. partially depleted by 30 min in the gray matter structures but were unchanged from control for 60 min in...

Changes in Cerebral Hemodynamics and Oxygenation during Hypothermic Cardiopulmonary Bypass in Neonates and Infants

“…Moreover, the normally low-energy requirement of the newborn brain may mask fluctuations in the oxidation-reduction level of the enzyme and effect the reliability of ACytaa3 as a marker of actual changes in oxidation of the enzyme Cytaa3 [35], In this respect, however, it is important to mention the results of a recent study in hypoxic newborn pigs which showed that reduction of Cytaa3, measured by NIRS, predicted indeed cerebral energy loss in these animals [36], Although the value of ACytaa3 as a marker of brain cell oxygenation remains uncertain so far, our results suggest a role for ACytaa3 as a relative measure for cerebral oxi dation. Yager et al [7] showed in newborn dogs major perturbations in the energy status of the brain early after the start of hypother mic circulatory arrest: ATP was preserved only during the first 10 min after the start of circulatory arrest in the parietal cortex, sug gesting alterations in oxidative and energy metabolism thereafter. This is in concert with the decrease in Cytaa3 in all 3 patients shortly after the beginning of the circulatory arrest (mean decrease 4.20 prnol/1).…”

“…The drop of Cytaa3 was small in this patient, but this was probably related to the short duration of the circulatory arrest. Experimen tal studies in newborn dogs showed indeed that especially extended periods of circulatory arrest (> 1 h) were related with cerebral (sub)-cortical and hippocampal damage [6,7], whereas the seizure incidence in 171 neonates and young infants undergoing an arterial switch procedure, was significantly higher in those patients who had circulatory arrest as compared to those without circulatory arrest [27], Recently, several investigators advo cated low-flow cardiopulmonary bypass as an alternative for circulatory arrest to prevent perturbations in cerebral metabolism during deep hypothermic CPB in infants undergoing open-heart surgery [27,30,31], Cytaa3 is the terminal enzyme of the mito chondrial electron transport chain. If oxygen delivery to the brain cell drops to low levels, this intracerebral enzyme becomes progres sively reduced [20].…”

“…Although it is not clear yet whether or not CPB impairs future brain function and developmental outcome, recent experimental and clinical data strongly suggest that deep hypothermic CPB and espe cially circulatory arrest longer than 60 min may be detrimental [5][6][7], In previous studies, we and others showed that especially at deep hypothermic CPB, brain perfusion is very low and cerebral autoregulation seems to be easily disturbed [2,4], Moreover, Greely et al [8] found that the intracellular brain oxygenation of pediatric patients decreased significantly during circulatory arrest and remained im paired after rewarming and CPB despite nor malization of the oxygen availability.…”

Novel treatment options for lysosomal acid lipase deficiency: critical appraisal of sebelipase alfa

“…Low cholesterol/reduced saturated fat diets have been used in pediatric and adult CESD, although this has also demonstrated low efficacy. 39 , 40…”

Treatment of hypoxic-ischaemic brain damage by moderate hypothermia

“…28 The mechanisms by which cooling after hypoxia–ischaemia prevent cell death are less clear. Hypothermia prevents the delayed decline in phosphocreatine and adenosine triphosphate, as well as the simultaneous increase in cerebral lactate concentration, seen 8–12 hours after hypoxia–ischemia in newborn piglets 22…”