Efficacy of Nitric Oxide Administration in Attenuating Ischemia/Reperfusion Injury During Neonatal Cardiopulmonary Bypass

Section Editors

 Viviane Nasr – Boston





Rania Abbasi – Indianapolis




Efficacy of Nitric Oxide Administration in Attenuating Ischemia/Reperfusion Injury During Neonatal Cardiopulmonary Bypass

Chawki Elzein 1Cynthia Urbas 2Bonnie Hughes 3Yi Li 4Cheryl Lefaiver 5Michel Ilbawi 1Luca Vricella 1

World J Pediatr Congenit Heart Surg. 2020 Jul;11(4):417-423.

doi: 10.1177/2150135120911034.

PMID: 32645771; DOI: 10.1177/2150135120911034


Take Home Points:

  • Administration of nitric oxide (NO) during cardiopulmonary bypass (CPB) resulted in lower troponin levels after weaning from CPB than those who did not receive NO, with lower level prior to modified ultrafiltration (MUF) and significantly lower levels after conclusion of MUF
  • Compared to the control group, there was no significant difference in inotropic scores or ventricular function during the 24-hour postoperative study period in those who received NO during CPB
  • Systemic administration of NO during CPB for the Norwood procedure has myocardial protective effects (lower Troponin levels) but no observed effect on postoperative recovery

Rajeev Wadia, MD, Assistant Professor, Pediatric Anesthesiology

Commentary from Dr. Rajeev Wadia, Assistant Professor of Pediatric Cardiac Anesthesiology at Johns Hopkins University: Cardiopulmonary bypass (CPB) creates morbidity in all patient populations. The absence of pulsatile flow, episodes of circulatory arrest or low-flow periods, complexity of congenital heart surgery with long bypass times, and the immature organs of a neonate all result in systemic inflammation in the neonate. Ischemia/reperfusion injury is a known producer of pro-inflammatory mediators that cause systemic organ dysfunction. Nitric oxide (NO) can provide protection to ischemia/reperfusion injuries. In adult patients undergoing CPB surgery, NO has been shown to blunt the release of markers of cardiac injury and decrease ventricular dysfunction during and immediately after CPB (1, 2). Furthermore, it has been shown that infants undergoing repair of tetralogy of Fallot who received NO during CPB had evidence of better myocardial protection, improved fluid balance, and improved postoperative intensive care unit course (3).

The authors of this manuscript hypothesized that systemic delivery of NO into the oxygenator of the CPB circuit during the Norwood procedure would ameliorate ischemia/reperfusion injury and improve postoperative recovery. They performed a prospective, randomized, blinded control study of newborns undergoing a Norwood operation with a Sano shunt at a single institution in the United States over an approximate 4-year time period. The study was sponsored by Mallinckrodt Pharmaceuticals (Hampton, NJ). A total of 24 neonates with hypoplastic left heart syndrome or variants participated in the study, with one-half randomly assigned to receive 40 ppm NO through the oxygenator (study group, n=12) and the other one-half to receive a placebo gas (control group, n=12). All patients were required to be > 37 weeks gestation and have a birth weight of > 2.5 kg. Patients were excluded if they had perioperative sepsis, renal dysfunction (creatinine level >1 mg/dL), intracranial hemorrhage, presence of chromosomal abnormalities and/or genetic syndromes, and prior intervention (catheter or surgical).


 The intraoperative care these neonates received is worth noting. All neonates received a total of 20 mg/kg of methylprednisolone prior to surgical incision, in equally divided doses 6-8 hours apart. All patients received continuous cerebral perfusion at 50 ml/kg/min through cannulation of the base of the innominate artery and continuous perfusion of the lower part of the body at 50 ml/kg/min through cannulation of the descending aorta after the distal aspect of the arch patch was sutured. The authors report that in their experience when using this lower body cannulation technique, interruption of blood flow to the lower body is limited to approximately 20 minutes. No patient, therefore, had total circulatory arrest. The heads and groins were routinely covered with ice bags until rewarming was started. All patients were cooled to 28⁰C. Cooling and rewarming were done using pH-stat strategy. Finally, once the patients were weaned off CPB, NO (or placebo gas) administration within the CPB machine was discontinued. All patients, both control and study participants, were then administered inhaled NO through the endotracheal tube. Subsequent inhaled NO management was similar among all patients per routine institutional practice. Only the perfusionist was aware of the randomization process. No other practitioners in either the operative or postoperative location knew who received NO or placebo gas through the CPB circuit. All patients had skin closure in the operating room with delayed sternal closure a few days after adequate diuresis.

There was no difference in demographic characteristics or surgical times between the groups. All operations were performed by the same two surgeons using the same technique. Of note, the total mean time of flow interruption of the lower body was not different between either group (study group: 19.2 ± 6.74 min vs control group: 18.0 ± 3.62 min). No patient died in the study.





Serum samples measuring multiple inflammatory markers were taken at 5 different time points (T0: after induction of general anesthesia but before surgery, T1: after weaning off CPB but before MUF, T2: after MUF, T3: 12 hours after CPB discontinuation, T4: 24 hours after CPB discontinuation). Results for both groups are shown in Table 2. The study group had lower troponin levels at the end of CPB compared to the control group (0.62 ± 0.58 vs 0.87 ± 0.58, p=0.31) and the difference became significant at the end of modified ultrafiltration (MUF) (0.36 ± 0.32 vs 0.97 ± 0.48, p=0.009). Clinical outcome data collected for both groups showed no difference in inotropic scores or ventricular function, despite the lower troponin levels noted in the study group. Furthermore, there was no difference in the duration of mechanical ventilation, pediatric surgical heart unit length of stay, and hospital length of stay.








The authors admit their study has several important limitations. They had a small sample size from a single center, requiring nearly 4 years to recruit enough patients. Despite this, the study still did not meet its primary end point based on the power calculation required to compare the difference in fluid balance, as measured by the total amount of fluid administered in the first 24 and 48 hours. Also, the surgical technique used for selective cerebral and lower body perfusion may have limited the ischemia time, thus decreasing the ischemia/reperfusion injury in the control group. Finally, the routine use of inhaled NO in the postoperative period may have added some protection to both groups and decreased the power of the study. Even so, this pilot study does show that perhaps NO administration during CPB in high-risk, single-ventricle population could confer myocardial protective effect. However, in order to show any long-term clinical benefit, a larger number of patients would be necessary.


Table 2. Comparison Between I/R Injury Markers at Different Time Points Between Both Groups.

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  2. Lefer AM. Attenuation of myocardial ischemia-reperfusion injury with nitric oxide replacement therapy. Ann Thorac Surg. 1995;60(3):847-851
  3. Checchia PA, Bronicki RA, Muenzer JT, DixonD. Nitric oxide delivery during cardiopulmonary bypass reduces postoperative morbidity in children – a randomized trial. J Thorac Cardiovasc Surg. 2013;146(3):530-536