Just Say No to NO (Nitric Oxide) Delivered in the Cardiopulmonary Bypass Oxygenator During Cardiac Surgery in Young Children
Susan Nicolson MD, Lindsey Loveland Baptist MD, James DiNardo MD, and Viviane Nasr MD
Original article
Schlapbach LJ, Gibbonds KS, Horton S et al. for the NITRIC Study Group, the Australian and New Zeland Intensive Care Society Clinical Trials Group (ANZICSCTG) and ANZICS Paediatric Study Group (PSG). Effect of Nitric Oxide via Cardiopulmonary Bypass On Ventilator-Free Days in Young Children Undergoing Congenital Heart Disease Surgery. JAMA. 2022 Jul 5;328(1):38-47. doi: 10.1001/jama.2022.937 PMID: 35759691
Nitric oxide (NO) has been proposed as an adjunctive therapy for young children undergoing cardiac surgery with cardiopulmonary bypass (CPB) based on preclinical and clinical data suggesting beneficial effects on myocardial ischemia and reperfusion. Two pediatric studies, with a total of 214 patients, have suggested that NO administered into the gas flow of the CPB oxygenator may reduce postoperative low cardiac output syndrome, decrease postoperative troponin levels, and shorten the duration of mechanical ventilation (ref 1,2). The international NITRIC (Nitric Oxide During Cardiopulmonary Bypass to Improve Recovery in Infants with Congenital Heart Defects) trial was conducted to test the hypothesis that NO applied into the CPB oxygenator would result in more ventilator-free days than standard care on CPB. The study, the largest randomized controlled trial performed to date on children undergoing cardiac surgery, was a double-blind, multicenter trial where 1371 children under 2 years of age were randomized between July 2017 and April 2021 to receive NO at 20 ppm delivered in the CPB oxygenator or standard care CPB without NO. Children with persistently elevated pulmonary vascular resistance, chronic ventilator dependency, severe preoperative shock states and sepsis, acute respiratory distress syndrome, and methemoglobinemia and those after cardiac arrest receiving extracorporeal life support or deemed unlikely to survive the next hours without surgery were excluded. The primary outcome was ventilatory-free days (days alive, free from mechanical ventilation from commencement of CPB until postop day 28). Ventilator-free days were chosen as the primary outcome as endotracheal extubation is an objective and pragmatic measure of postoperative morbidity and recovery. Secondary outcomes were a composite of the incidence of low cardiac output syndrome, postoperative extracorporeal life support within 48 hours, or death within 28 days of initiation of CPB; duration of ICU and hospital length of stay; and postoperative troponin levels as markers of myocardial injury.
NO was started with the initiation of CPB and maintained until weaning of bypass (the same procedure was repeated if a patient underwent multiple bypass runs during their operation). In the standard care group, NO was not applied into the oxygenator. In both groups, other aspects of care (ie, perfusion management, surgery, anesthesia, and postoperative care including inhaled NO use, ventilator weaning, and extubation practices) were at the discretion of the treating clinicians. The trial group assignment was known only to the study perfusionist who performed the randomization and was not disclosed to the clinical or research staff.
Among the 1371 randomized children 587 were female (42.8%) with a mean [SD] age of 21.2 [23.5] weeks. 99.5% of patients completed the trial. The number of ventilator-free days did not differ between the NO and standard care groups with a median of 26.6 days (IQR 24.4. to 27.4) versus 26.4 days (IQR 24.0 to 27.2) respectively. A total of 22.5% of the NO group and 20.9% of the standard group developed low cardiac output syndrome within 48 hours or died by day 28 for an adjusted odds ratio of 1.12. Other secondary outcomes were no different between the groups.
The authors concluded that for children younger than 2 years undergoing cardiopulmonary bypass surgery for congenital heart disease, the use of NO in a dose of 20 ppm via CPB did not significantly affect the number of ventilator-free days. These findings do not support the use of NO delivered into the CPB oxygenator during heart surgery on young children.
There were several limitations of the study including:
1. Delivery of NO was fixed at 20 ppm, thus the possibility exists that different doses of NO may alter the effect of the intervention.
2. Some patients in both treatment groups received open-label inhaled NO, which may have reduced the ability to detect between-group differences.
3. The anesthetic and sedation drugs and doses chosen were at the discretion of the anesthesia and ICU teams and may influence timing of extubation.
References:
1. James C, Millar J, Horton S, et al. Nitric oxide administration during paediatric cardiopulmonary bypass. Intensive Care Med. 2016;42(11):1744-52.
2. Checchia PA, Bronicki RA, Muenzer JT, et al. Nitric oxide delivery during cardiopulmonary bypass reduces postoperative morbidity in children: a randomized trial. J Thorac Cardiovasc Surg. 2013;146(3):530-6.