Abstract Body (Do not enter title and authors here):
Background—Nitric oxide signaling can mediate ischemia-reperfusion injury by altering vascular resistance and inflammatory responses, including the production and degradation of reactive oxygen species (ROS). Excess ROS contributes to oxidative stress and can impair mitochondrial energy synthesis via oxidative phosphorylation (OxPhos). We previously demonstrated that ROS and mitochondrial respiration in the neonatal brain can be adversely affected following deep hypothermic circulatory arrest (DHCA). It is unknown if inhaled nitric oxide (iNO) alters cerebral ROS and OxPhos capacity post-DHCA.

Research Question—Does intraoperative iNO therapy affect cerebral ROS, OxPhos capacity, and neurologic injury or recovery after DHCA?

Methods—Ten neonatal swine underwent DHCA (90min, 18^oC) prior to reperfusion and rewarming, of which half were randomized and blinded to receive iNO (40ppm) intraoperatively (DHCA_90min+iNO, N=5) and half did not (DHCA_90min, N=5). Five additional piglets underwent sham procedures without bypass, DHCA, or iNO. Upon study completion, brain tissue was analyzed using high-resolution mitochondrial respirometry. Immunohistochemistry assessed microglia- and neuron-specific inflammation using antibodies for ionized calcium-binding adaptor molecule 1 (IBA-1) and beta-amyloid precursor protein (β-APP), respectively.

Results—Following DHCA_90min+iNO, cerebral ROS production did not decline compared to DHCA_90min animals (P=0.210, Figure), and OxPhos capacity via mitochondrial complex I was reduced compared to both sham (P=0.041) and DHCA_90min animals (P=0.078, Figure). Rare and frequent β-APP staining was more common after DHCA_90min and DHCA_90min+iNO compared to sham animals (P=0.055), and IBA-1 staining in subcortical white matter increased following DHCA_90min+iNO compared to both sham (P=0.001) and DHCA_90min animals (P=0.013, Figure).

Conclusions—iNO does not attenuate cerebral ROS following DHCA, and may even increase microglial inflammation and post-operative white matter injury by impairing energy synthesis via mitochondrial complex I. Further studies are warranted to elucidate how regional changes in the cerebral microcirculation may affect the delivery, efficacy, and toxicity of targeted therapeutics following DHCA. Improved insights into how microglial inflammation and mitochondrial energy synthesis mediate neurologic injury and recovery post-DHCA might ultimately help improve neurocognitive outcomes in congenital cardiac surgery.