Physiologic and Neuropathologic Aspects of Hypothermic Circulatory Arrest in Newborn Dogs

Abstract

ABSTRACT. A model of hypothermic circulatory arrest has been developed in the newborn dog. Ten puppies were anesthetized with halothane, paralyzed, and artificially ventilated with 70% nitrous oxide 30% oxygen to arterial oxygen pressure >8.0 kPa (60 mm Hg), arterial carbon dioxide pressure of 4.4-5.6 kPa (33-42 mm Hg), and arterial pH of 7. 35-7.42. Animals were surface cooled to 20°C, after which cardiac arrest was produced with i.v. KCI. Dogs remained asystolic without ventilation for 1.0 (n = 4), 1.5 (n = 3), or 2.0 (n = 3) h. Resuscitation was accomplished with closed-chest compression, mechanical ventilation, i.v. epinephrine and NaHC03, and rewarming to 37°C. Postarrest recovery was maintained for 3-4 h; thereafter, the puppies underwent perfusion-fixation of their brains for pathologic analysis. Plasma glucose (control = 8.3 mmol/L) increased slightly during hypothermic cardiac arrest (+36%) but was markedly elevated at 15 min postarrest (20 mmol/L). Blood lactate (control = 1.1 mmol/L) increased almost 200% during hypothermic circulatory arrest, with a further rise to 9.0 mmol/L at 15 min postarrest. Thereafter, lactate decreased in the 1-h arrested dogs but increased progressively in the other groups. Mean arterial blood pressure returned to baseline (73 mm Hg) by 15 min postarrest, remained stable in the 1-h dogs, but fell at 3 h to 62 and 34 mm Hg in the 1.5-and 2.0-h groups, respectively. No neuropathologic alterations were seen in puppies arrested for 1 h, whereas all puppies arrested for 1.5 or 2 h had varying degrees of cerebral cortical and hippocampal damage. Thus, newborn dogs tolerate 1 h of hypothermic circulatory arrest without brain damage, with graded neuronal injury thereafter. The experimental model has direct clinical relevance and can be used to study mechanisms of cellular injury in brain, heart, and other organs during prolonged ischemia. 3 5 in infants and children. The rationale for this surgical approach relates to the well-known observation that acute brain damage secondary to systemic hypoxia, hypotension, or cardiac arrest is prevented or at least substantially reduced by prior or concurrent hypothermia (1-5). It is the duration of cardiac arrest and its attendant total cerebral ischemia that is limiting for the prevention of brain damage. It is not known how long an infant can tolerate hypothermic circulatory arrest without sustaining ischemic brain injury, although clinical practice suggests a "safe" interval of 60-70 min (6-8). Unfortunately, infants occasionally sustain brain damage even when the duration of cardiac arrest is well within the "therapeutic window" (9, 10). It has not been established whether such brain damage arises as a silent complication of the surgical procedure itself (e.g. postoperative hypotension, air emboli, etc.) or as a result of cerebral ischemia beyond the safety margin for any specific individual infant. Given the fact that 0.5-1.0% of all infants are born with surgically correctable cardiac defects, it is surprising that little research has be...

Differences in intraischemic temperature influence neurological outcome after deep hypothermic circulatory arrest in newborn dogs.

“…In this regard, we previously showed that postischemic hyperglycemia is associated with lactacidemia, which presumably arises from enhanced anaerobic glycolysis by muscle. 13 By 8 hours of recovery, all systemic variables returned to their prearrest, normothermic values.…”

“…These regions of brain were chosen because of their known vulnerability to ischemic damage in the newborn dog. 13 ' 14 To ensure consistency, only the damaged neurons showing eosinophilic perikarya and nuclear karyorrhexis or pyknosis were counted. For cerebral cortex, a coronal section…”

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

“…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.…”

Cerebral Oxidative Metabolism during Hypothermia and Circulatory Arrest in Newborn Dogs

“…In this regard, our neuropathologic studies have shown that cerebral cortex and caudate nucleus are consistently damaged after 1.75 h of cardiac arrest, whereas the hippocampus shows no or only minor injury (7). White matter is spared, even after 2 h of cardiac arrest (6). Given the minor differences in cerebral metabolic rate among the gray matter structures (cerebral cortex, caudate nucleus, and hippocampus) during hypothermia (see Table 3), it is unlikely that differences in preischemic metabolic activity per se account for the apparent resistance especially of the hippocampus to ischemic damage.…”

“…In an investigation published in this journal, nitrous oxideanesthetized and artificially ventilated puppies were subjected to hypothermic circulatory arrest for 1.0, 1.5, and 2.0 h; 3-4 h postresuscitation, they underwent perfusion-fixation of their brains for pathologic analysis (6). No neuropathologic alterations were seen in puppies arrested for 1.0 h, whereas animals arrested for 1.5 h showed mild-to-moderate damage (selective neuronal necrosis) exclusively of the cerebral cortex, and animals arrested for 2.0 h exhibited severe damage of the cerebral cortex and also injury of the caudate nucleus and hippocampus.…”