Abstract
Carbon monoxide (CO) at low concentrations imparts protective effects in numerous preclinical small animal models of brain injury. Evidence of protection in large animal models of cerebral injury, however, has not been tested. Neurologic deficits following open heart surgery are likely related in part to ischemia reperfusion injury that occurs during cardiopulmonary bypass surgery. Using a model of deep hypothermic circulatory arrest (DHCA) in piglets, we evaluated the effects of CO to reduce cerebral injury. DHCA and cardiopulmonary bypass (CPB) induced significant alterations in metabolic demands, including a decrease in the oxygen/glucose index (OGI), an increase in lactate/glucose index (LGI) and a rise in cerebral blood pressure that ultimately resulted in increased cell death in the neocortex and hippocampus that was completely abrogated in piglets preconditioned with a low, safe dose of CO. Moreover CO-treated animals maintained normal, pre-CPB OGI and LGI and corresponding cerebral sinus pressures with no change in systemic hemodynamics or metabolic intermediates. Collectively, our data demonstrate that inhaled CO may be beneficial in preventing cerebral injury resulting from DHCA and offer important therapeutic options in newborns undergoing DHCA for open heart surgery.
Highlights
Neurologic abnormalities occur in neonates undergoing cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) for correction of congenital heart defects
Neuroprotective studies by Mezrow et al suggest that disturbances in cerebral blood flow and cerebral vascular resistance correlate with clinical findings of neurologic injury after hypothermic circulatory arrest and that cerebral metabolism is maintained by increases in oxygen and glucose extraction, a relationship viewed as potentially very important. [38,39] In order to define effects of inhaled carbon monoxide (CO) on neuroprotection during DHCA, this study investigated differences in cerebral blood flow, cerebral hemodynamics, cerebral metabolism, and cerebral pathology in piglets preconditioned with inhaled CO before undergoing CPB and DHCA
Statistical significance was observed for Mean pulmonary artery pressure (MPAP) immediately after CPB and for mean superior sagittal sinus pressure (MSSSP) 6 hours after CPB
Summary
Neurologic abnormalities occur in neonates undergoing cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) for correction of congenital heart defects. Preconditioning as a preoperative therapy to protect the brain prior to DHCA has not been studied, but has otherwise been shown to be useful in other clinical indications [1,2,3,4,5,6,7] such as organ transplantation to improve function post transplant [8,9,10,11,12,13]. Among a host of protective genes is heme oxygenase-1 (HO-1), which is increased dramatically in response to stress and importantly, when elevated, imparts potent salutary effects [22,23,24,25,26,27,28,29,30,31,32,33,34]. Recent efforts have identified CO as the primary mechanism by which HO-1 imparts its beneficial effects in animals
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