Effect of Nitric Oxide via Cardiopulmonary Bypass on Ventilator-Free Days in Young Children Undergoing Congenital Heart Disease Surgery: The NITRIC Randomized Clinical Trial

Luregn J Schlapbach; Kristen S Gibbons; Stephen B Horton; Kerry Johnson; Debbie A Long; David H F Buckley; Simon Erickson; Marino Festa; Yves d’Udekem; Nelson Alphonso; David S Winlaw; Carmel Delzoppo; Kim van Loon; Mark Jones; Paul J Young; Warwick Butt; Andreas Schibler

doi:10.1001/jama.2022.9376

. 2022 Jun 27;328(1):38–47. doi: 10.1001/jama.2022.9376

Effect of Nitric Oxide via Cardiopulmonary Bypass on Ventilator-Free Days in Young Children Undergoing Congenital Heart Disease Surgery

The NITRIC Randomized Clinical Trial

Luregn J Schlapbach ^1,^2,³, Kristen S Gibbons ¹, Stephen B Horton ^4,^5,⁶, Kerry Johnson ^1,², Debbie A Long ^1,⁷, David H F Buckley ⁸, Simon Erickson ⁹, Marino Festa ^10,¹¹, Yves d’Udekem ^5,^12,¹³, Nelson Alphonso ^1,^14,¹⁵, David S Winlaw ^16,¹⁷, Carmel Delzoppo ^5,¹⁸, Kim van Loon ¹⁹, Mark Jones ²⁰, Paul J Young ²¹, Warwick Butt ^5,^6,^18,^22,^23,^✉, Andreas Schibler ²⁴, for the NITRIC Study Group, the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG), and the ANZICS Paediatric Study Group (PSG)

¹Child Health Research Centre, The University of Queensland, Brisbane, Queensland, Australia

²Paediatric Intensive Care Unit, Queensland Children’s Hospital, Children’s Health Queensland, Brisbane, Queensland, Australia

³Department of Intensive Care and Neonatology, and Children’s Research Center, University Children’s Hospital Zurich, University of Zurich, Zurich, Switzerland

⁴Cardiac Surgical Unit, Royal Children’s Hospital, Melbourne, Victoria, Australia

⁵Faculty of Medicine, Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia

⁶Clinical Sciences Theme, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia

⁷School of Nursing, Centre for Healthcare Transformation, Queensland University of Technology, Brisbane, Queensland, Australia

⁸Paediatric Intensive Care Unit, Starship Children’s Hospital, Auckland, New Zealand

⁹Paediatric Critical Care, Perth Children’s Hospital, Western Australia and The University of Western Australia, Crawley, Western Australia, Australia

¹⁰Kids Critical Care Research, Paediatric Intensive Care Unit, Children’s Hospital at Westmead, Westmead, New South Wales, Australia

¹¹Sydney Children’s Hospital Network, Sydney, New South Wales, Australia

¹²Children’s National Hospital and The George Washington University School of Medicine and Health Sciences, Seattle, Washington

¹³Heart Research, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia

¹⁴Cardiac Surgery, Queensland Children's Hospital, Brisbane, Queensland, Australia

¹⁵School of Medicine, Children’s Health Clinical Unit, University of Queensland, Brisbane, Queensland, Australia

¹⁶Heart Centre for Children, The Children’s Hospital at Westmead, Westmead, New South Wales, Australia

¹⁷Sydney Children’s Hospital Network and Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia

¹⁸Paediatric Intensive Care Unit, Royal Children’s Hospital Melbourne, Melbourne, Victoria, Australia

¹⁹Department of Anaesthesiology, University Medical Center Utrecht, Wilhelmina Children’s Hospital, Utrecht, the Netherlands

²⁰Institute of Evidence Based Healthcare, Bond University, Gold Coast, Australia

²¹The Intensive Care Research Programme, Medical Research Institute of New Zealand, Wellington, New Zealand

²²Department of Critical Care, Melbourne Medical School University of Melbourne, Victoria, Australia

²³Central Clinical School Faculty of Medicine Monash University, Melbourne, Victoria, Australia

²⁴Critical Care Research Group, Wesley Medical Research, St Andrew’s War Memorial Hospital, Brisbane, Queensland, Australia

^✉

Corresponding Author: Warwick Butt, MD, Paediatric Intensive Care Unit, Royal Children’s Hospital Melbourne, 50 Flemington Rd, Parkville, VIC, Australia 3052 (Warwick.Butt@rch.org.au).

Group Information: The members of the NITRIC Study Group, the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG), and the ANZICS Paediatric Study Group (PSG) appear in Supplement 4.

Accepted for Publication: May 19, 2022.

Published Online: June 27, 2022. doi:10.1001/jama.2022.9376

Author Contributions: Drs Schlapbach and Gibbons had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Butt and Schibler contributed equally.

Concept and design: Schlapbach, Gibbons, Horton, Johnson, Long, Erickson, Festa, d’Udekem, Alphonso, Jones, Butt, Schibler.

Acquisition, analysis, or interpretation of data: Schlapbach, Gibbons, Horton, Johnson, Long, Buckley, Erickson, Festa, d’Udekem, Winlaw, Delzoppo, van Loon, Jones, Young, Schibler.

Drafting of the manuscript: Schlapbach, Gibbons, Horton, Long, Buckley, Erickson, Young, Schibler.

Critical revision of the manuscript for important intellectual content: Schlapbach, Gibbons, Horton, Johnson, Long, Erickson, Festa, d’Udekem, Alphonso, Winlaw, Delzoppo, van Loon, Jones, Young, Butt, Schibler.

Statistical analysis: Schlapbach, Gibbons, Jones, Schibler.

Obtained funding: Schlapbach, Horton, Long, Buckley, Erickson, Festa, Winlaw, van Loon, Schibler.

Administrative, technical, or material support: Schlapbach, Gibbons, Horton, Johnson, Long, Buckley, Festa, Alphonso, Winlaw, Delzoppo, van Loon, Schibler.

Supervision: Schlapbach, Gibbons, Horton, Johnson, Festa, d’Udekem, Winlaw, van Loon, Butt, Schibler.

Conflict of Interest Disclosures: Dr Schlapbach reported receiving a National Health and Medical Research Council Clinical Practitioner Fellowship. Dr Festa reported receiving grants from the National Health and Medical Research Council during the conduct of the study and grants from Hearts and Minds outside the submitted work. Dr d’Udekem reported receiving personal fees from Actelion outside the submitted work. Dr van Loon reported receiving grants from Dutch National Health Insurance Innovation Fund and nonfinancial support from EKU Electronics during the conduct of the study and grants from Wilhelmina Research, LivaNova, and Janivo Stichting outside the submitted work. Dr Young reported receiving grants from Health Research Council of New Zealand (Clinical Practitioner Research Fellowship) and personal fees from AM Pharma (member of the REVIVAL trial international trial steering committee) outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by grants from the National Health and Medical Research Council (NHMRC; GNT1140322), Australia; HeartKids Foundation, Australia; Children’s Hospital Foundation, Brisbane, Australia; Perth Children’s Hospital Foundation, Australia; and Green Lane Research and Educational Fund, New Zealand. Drs Schlapbach, d’Udekem, and Schibler were supported by NHMRC Clinical Practitioner Fellowships. Dr Young was supported by a Clinical Practitioner Fellowship from the Health Research Council of New Zealand. The Operational Infrastructure Support Program, Victorian Government, supported this study. The Utrecht site was funded by the Department of Anesthesiology, University Medical Center Utrecht, and supported by the Dutch National Health Insurance Innovation Fund. Mallinckrodt Pharmaceuticals and EKU Electronics provided nitric oxide delivery devices to study centers.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The members of the NITRIC Study Group, the Australian and New Zealand Intensive Care Society Clinical Trials Group, and the ANZICS Paediatric Study Group are listed in Supplement 4.

Data Sharing Statement: See Supplement 5.

Additional Contributions: We thank the parents and children participating in this trial and the medical, nursing, and research teams in the participating sites for their help in study setup, recruitment, data collection, and monitoring of study data. We thank the members of the data and safety monitoring board (Tom Karl, MD, The University of Queensland, Brisbane, Australia; Philip Sargent, MD, Gold Coast University Hospital, Southport, Australia; Ben Gelbart, MBBS, Royal Children’s Hospital, Melbourne, Australia; and Lahn Straney, PhD, Monash University, Melbourne, Australia). No compensation was received by data and safety monitoring board members for their role in the study.

^✉

Corresponding author.

PMCID: PMC9237803 PMID: 35759691

Key Points

Question

Does nitric oxide applied into the cardiopulmonary bypass oxygenator compared with standard care result in more ventilator-free days in children younger than 2 years undergoing surgery for congenital heart disease?

Findings

In this randomized clinical trial that included 1371 children undergoing cardiopulmonary bypass surgery, treatment with nitric oxide into the cardiopulmonary bypass at 20 ppm resulted in 26.6 ventilator-free days vs 26.4 ventilator-free days, a difference that was not statistically significant.

Meaning

Among infants undergoing heart surgery, delivery of nitric oxide into the cardiopulmonary bypass did not increase ventilator-free survival censored at 28 days.

Abstract

Importance

In children undergoing heart surgery, nitric oxide administered into the gas flow of the cardiopulmonary bypass oxygenator may reduce postoperative low cardiac output syndrome, leading to improved recovery and shorter duration of respiratory support. It remains uncertain whether nitric oxide administered into the cardiopulmonary bypass oxygenator improves ventilator-free days (days alive and free from mechanical ventilation).

Objective

To determine the effect of nitric oxide applied into the cardiopulmonary bypass oxygenator vs standard care on ventilator-free days in children undergoing surgery for congenital heart disease.

Design, Setting, and Participants

Double-blind, multicenter, randomized clinical trial in 6 pediatric cardiac surgical centers in Australia, New Zealand, and the Netherlands. A total of 1371 children younger than 2 years undergoing congenital heart surgery were randomized between July 2017 and April 2021, with 28-day follow-up of the last participant completed on May 24, 2021.

Interventions

Patients were assigned to receive nitric oxide at 20 ppm delivered into the cardiopulmonary bypass oxygenator (n = 679) or standard care cardiopulmonary bypass without nitric oxide (n = 685).

Main Outcomes and Measures

The primary end point was the number of ventilator-free days from commencement of bypass until day 28. There were 4 secondary end points including a composite of low cardiac output syndrome, extracorporeal life support, or death; length of stay in the intensive care unit; length of stay in the hospital; and postoperative troponin levels.

Results

Among 1371 patients who were randomized (mean [SD] age, 21.2 [23.5] weeks; 587 girls [42.8%]), 1364 (99.5%) completed the trial. The number of ventilator-free days did not differ significantly between the nitric oxide and standard care groups, with a median of 26.6 days (IQR, 24.4 to 27.4) vs 26.4 days (IQR, 24.0 to 27.2), respectively, for an absolute difference of −0.01 days (95% CI, −0.25 to 0.22; P = .92). A total of 22.5% of the nitric oxide group and 20.9% of the standard care group developed low cardiac output syndrome within 48 hours, needed extracorporeal support within 48 hours, or died by day 28, for an adjusted odds ratio of 1.12 (95% CI, 0.85 to 1.47). Other secondary outcomes were not significantly different between the groups.

Conclusions and Relevance

In children younger than 2 years undergoing cardiopulmonary bypass surgery for congenital heart disease, the use of nitric oxide via cardiopulmonary bypass did not significantly affect the number of ventilator-free days. These findings do not support the use of nitric oxide delivered into the cardiopulmonary bypass oxygenator during heart surgery.

Trial Registration

anzctr.org.au Identifier: ACTRN12617000821392

This clinical trial compares the efficacy of nitric oxide applied into the cardiopulmonary bypass oxygenator vs standard care on ventilator-free days in children younger than 2 years undergoing surgery for congenital heart disease.

Introduction

Congenital heart disease affects about 1 in 100 live-born children.¹ Reported estimates, published in 2021,² indicated that 40 000 children would be born with congenital heart disease in the United States this year. Annual inpatient hospital costs for these children were expected to exceed $5.6 billion.³ Studies published over the last 2 decades have confirmed that congenital heart disease was a leading cause of infant mortality and morbidity, with many survivors manifesting physical, developmental, or cognitive problems.^4,5

Approximately 25% of children with congenital heart disease require corrective surgery during infancy. Most of these surgeries are performed using cardiopulmonary bypass, which triggers a widespread endothelial, inflammatory, and coagulation system response.⁶ This response, in combination with myocardial ischemia and reperfusion, can cause low cardiac output syndrome. This syndrome is characterized by an inability of the heart to meet the perfusion requirements of the patient’s organs. It occurs in 25% to 40% of children undergoing cardiopulmonary bypass surgery and is associated with higher mortality, prolonged mechanical ventilation, and unfavorable long-term outcomes.⁷ The burden imposed by congenital heart disease contrasts with the paucity of evidence on perioperative management.⁸

Nitric oxide has been proposed as an adjunctive therapy for children undergoing cardiopulmonary bypass surgery⁹ based on preclinical and clinical data suggesting beneficial effects on myocardial ischemia and reperfusion.^10,11,12,13 Studies have suggested that nitric oxide added to the gas inflow of the cardiopulmonary bypass oxygenator may decrease postoperative troponin levels, reduce low cardiac output syndrome, and shorten duration of invasive mechanical ventilation in young children.^14,15

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 nitric oxide applied into the cardiopulmonary bypass oxygenator would result in more ventilator-free days than standard care in children undergoing surgery for congenital heart disease.

Methods

Study Design and Oversight

This was an investigator-initiated multicenter, randomized, double-blind, parallel-group trial endorsed by the Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group and the ANZICS Paediatric Study Group. The trial was registered before the start of recruitment. The Child Health Research Center at The University of Queensland managed the trial and monitored the data quality (eMethods 1 in Supplement 3). An independent data and safety monitoring board oversaw the trial and reviewed the planned interim analyses after 660 and 1000 patients had reached 28 days of follow-up (eMethods 2 and 3 in Supplement 3). Mallinckrodt Pharmaceuticals and EKU Electronics provided nitric oxide delivery devices to study centers but had no involvement in study design, analyses, or interpretation of the results.

The protocol, which was reported before enrollment had been completed,¹⁶ was approved by the ethics committees for participating institutions (Trial Protocol in Supplement 1 and eMethods 4 in Supplement 3). Written informed consent was provided by parents or guardians prior to surgery.

Patients

Children younger than 2 years undergoing elective open congenital heart disease surgery with cardiopulmonary bypass were eligible for inclusion in the trial. 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. A full list of exclusion criteria is provided in eMethods 5 in Supplement 3. Ethnicity was collected to describe the cohort of participants, particularly focusing on groups at increased risk, for each participant based on the patient registration form on admission to the hospital, based on fixed preexisting categories determined by the hospital. If the ethnicity data were missing, research coordinators at each site would review the notes in the medical record to obtain this information.

Randomization

Eligible and consented participants were randomized by the perfusionists once the decision to operate on cardiopulmonary bypass was confirmed, but before bypass commenced. Participants were randomly assigned to receive nitric oxide applied into the cardiopulmonary bypass oxygenator or standard care cardiopulmonary bypass without nitric oxide using a secure REDCap trial database hosted at The University of Queensland.¹⁷ Random permuted block randomization (block sizes of 4, 6, 8, and 10) with a 1:1 ratio to the 2 study groups was used to generate the randomization schedule, with stratification according to age at randomization (<6 weeks vs 6 weeks to 24 months), univentricular vs biventricular lesions, and trial center.

Interventions

In the nitric oxide group, nitric oxide was applied into the cardiopulmonary bypass oxygenator to achieve a concentration of 20 ppm, verified by continuous sampling. Nitric oxide was started with the initiation of cardiopulmonary bypass 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, nitric oxide was not applied into the cardiopulmonary bypass oxygenator. In both groups, other aspects of care (ie, perfusion management, surgery, anesthesia, and postoperative care including inhaled nitric oxide use, ventilator weaning, and extubation practices) were at the discretion of the treating clinician.

The trial group assignment was known to the study perfusionist who performed the randomization but was not disclosed to patients’ families, nor to clinical or research staff. In the operating theater, the nitric oxide delivery system was covered and nitric oxide delivery rates were only visible to the perfusionist.

End Points

The primary outcome was the number of ventilator-free days from initiation of cardiopulmonary bypass to day 28.¹⁸ Ventilator-free days were defined as the total number of calendar days or portions of calendar days spent without mechanical ventilation through an endotracheal tube during the first 28 days after randomization. All the patients who had died by day 28 were considered to have had zero ventilator-free days. Ventilator-free days were chosen as the primary outcome because they were an objective and pragmatic measure of postoperative morbidity and recovery. The duration of postoperative ventilation is associated with requirements for intensive care unit (ICU) support and sedation and has direct impacts on the child and family.¹⁶

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 cardiopulmonary bypass; duration of ICU length of stay; hospital length of stay; and postoperative troponin levels as markers of myocardial injury. Low cardiac output syndrome was defined as a blood lactate level greater than 4 mmol/L with a concurrent oxygen extraction gradient of at least 35 percentage points, or high inotrope and/or vasopressor requirements.^7,19,20 The oxygen extraction gradient was calculated as arterial oxygen saturation minus the central venous oxygen saturation using paired blood gas samples obtained at ICU admission and 6, 12, 24, and 48 hours after the operation or until ICU discharge, whichever was sooner. The dose of inotropes and vasopressors was measured using the vasoactive-inotropic score, which combines the doses of dopamine, dobutamine, epinephrine, norepinephrine, milrinone, and vasopressin in a single score, with a higher score indicating a greater level of cardiovascular support.²⁰ A score of 15 or more constituted high support requirements for the purposes of defining low cardiac output syndrome.

In addition to these defined study outcomes, a range of physiological variables and process of care measures were recorded, although not prespecified in the formal protocol. Process-of-care measures included the vasoactive-inotropic score, inhaled nitric oxide, and kidney replacement therapy after initiation of bypass. Physiological variables included oxygen extraction gradients, blood lactate levels, serum creatinine levels, acute kidney injury,²¹ and severity and duration of postoperative organ dysfunction measured on admission to ICU and at 6, 12, 24, and 48 hours after admission. Analyses on health care costs, long-term outcomes, levels of systemic inflammatory markers, and host transcriptomics are not reported in this article.

Power Analysis and Sample Size Calculation

A mean (SD) of 22.5 (8.10) ventilator-free days was assumed in the standard care group.¹⁴ Allowing for a 15% inflation in the sample size to account for rank-based testing and 10% inflation to account for withdrawals and interim analyses, a sample of 1320 was estimated to provide the trial with a power of 90% to detect a small effect size (Cohen d = 0.2),²² which corresponds to an absolute between-group difference of 1.66 ventilator-free days (40 hours) at day 28 after commencement of bypass, with a 2-sided type I error rate of .05. The difference of 40 hours was two-thirds of the effect estimate observed in the previous study and was considered plausible by the study management committee.¹⁴

Statistical Analysis

The statistical analysis plan was reported, and the full Stata analysis code was uploaded on GitHub before completion of enrollment (Supplement 2).²³ All analyses were performed on the cohort of consented and randomized patients, according to their randomization group, except those who were randomized but did not receive cardiac surgery with cardiopulmonary bypass. Multiple imputation was preplanned for the primary outcome measure in the case of missing data; however, because there were no missing data relating to ventilator-free days, imputation was not required.

For the primary analysis, a Wilcoxon rank-sum test was used for unadjusted analysis, with differences between medians calculated by means of quantile regression using a simplex algorithm, with the inversion method used to calculate 95% CIs after adjustment for stratification variables (age group, single ventricle physiology, and site) as fixed effects.

Several prespecified secondary analyses were performed. First, for the preplanned secondary outcome measures, logistic regression analyses were used for binary outcomes; Cox proportional hazard models for length of stay outcomes using a shared frailty model (proportionality assumption inspected visually using Kaplan-Meier plots and log-log plot, with no clear evidence of divergence); and linear or quantile regression for continuous outcomes, dependent on the distribution of the variable. Models were adjusted for age at randomization and lesion type (as per randomization strata) as fixed effects, and site as a random effect. Second, 2 predefined subgroup analyses restricted to the study strata were performed (age <6 weeks vs ≥6 weeks; and univentricular vs biventricular physiology). Interaction was assessed through inclusion of interaction terms between the stratification variable and randomization group in the model. Third, a predefined sensitivity analysis was performed, with adjustment for treatment group, duration of cardiopulmonary bypass, surgical complexity (recorded using the risk adjustment for congenital heart surgery score),²⁴ blood prime use during surgery, sex and strata variables as fixed effects, and site as a random effect. A post-hoc analysis was undertaken to examine potential heterogeneity between study sites, limited to the primary outcome and key secondary outcome measure (composite of the incidence of low cardiac output syndrome or postoperative extracorporeal life support within 48 hours, or death within 28 days of initiation of cardiopulmonary bypass), with analytic methods mirroring those for the primary analysis, excluding site from the model and reporting only effect estimates with 95% CIs.

Statistical significance for the primary outcome was indicated by a P value of .05 and was determined with use of a 2-sided hypothesis test. No correction for multiple comparisons was applied in the evaluation of secondary or other outcomes. Thus, such results are exploratory and are reported as point estimates with 95% CIs. All analyses were performed with Stata/SE version 17.0 (StataCorp Pty Ltd).

Results

Patients

From July 2017 through April 2021, 1371 patients were enrolled in 6 pediatric cardiac surgical centers in Australia, New Zealand, and the Netherlands (eFigure 1 and eTable 1 in Supplement 3). Seven consented, randomized patients did not undergo surgery with cardiopulmonary bypass, which left a population of 1364, with 679 assigned to the nitric oxide group and 685 assigned to standard care (Figure 1). Patient characteristics at baseline are shown in Table 1 (eTables 2 and 3 in Supplement 3).

Figure 1. — ARDS indicates acute respiratory distress syndrome; NITRIC, Nitric Oxide During Cardiopulmonary Bypass to Improve Recovery in Infants With Congenital Heart Defects.

^aParticipants could have 1 or more reasons for ineligibility/nonenrollment.

^bCommon reasons included non–English-speaking parents and child under care.

^cRandomization stratified by age, lesion type, and site.

Table 1. Baseline Characteristics of Infants Enrolled in the Trial.

Characteristic	No. (%)
Characteristic	Nitric oxide	Standard care
No.	679	685
Age at randomization, median (IQR), wk^a	13.6 (2.3-27.0)	14.2 (1.8-30.6)
<6	227 (33.4)	232 (33.9)
≥6	452 (66.6)	453 (66.1)
Weight, median (IQR), kg	4.7 (3.5-6.6)	4.8 (3.4-7.0)
Sex
Female	266 (39.2)	317 (46.3)
Male	413 (60.8)	368 (53.7)
Ethnicity^b
Aboriginal/Torres Strait Islander	77 (11.3)	67 (9.8)
Asian	19 (2.8)	21 (3.1)
Māori/Pacific Island Peoples	67 (9.9)	68 (9.9)
Multiethnic/other^c	90 (13.3)	78 (11.4)
White	426 (62.7)	451 (65.8)
Congenital heart disease^d
Univentricular^a	77 (11.3)	76 (11.1)
Biventricular^a	602 (88.7)	609 (88.9)
History of cardiac surgery on CPB	58 (8.5)	57 (8.3)
Shunt lesions	454 (66.9)	451 (65.8)
Ventricular septal defect	271 (39.9)	279 (40.7)
Transposition of the great arteries	105 (15.5)	96 (14.0)
Atrial septal defect	102 (15.0)	116 (16.9)
Atrioventricular septal defect	67 (9.9)	56 (8.2)
Truncus arteriosus	6 (0.9)	14 (2.0)
Persistent ductus arteriosus	3 (0.4)	2 (0.3)
Other^e	8 (1.2)	5 (0.7)
Right-sided obstructive lesions	196 (28.9)	216 (31.5)
Tetralogy of fallot	105 (15.5)	119 (17.4)
Pulmonary stenosis/atresia	69 (10.2)	78 (11.4)
Double outlet right ventricle	13 (1.9)	5 (0.7)
Other^e	19 (2.8)	21 (3.1)
Left-sided obstructive lesions	133 (19.6)	153 (22.3)
Hypoplastic aortic arch	70 (10.3)	98 (14.3)
Hypoplastic left heart syndrome	30 (4.4)	32 (4.7)
Coarctation	5 (0.7)	4 (0.6)
Interrupted aortic arch	3 (0.4)	4 (0.6)
Other^e	31 (4.6)	38 (5.6)
Various lesions	39 (5.7)	32 (4.7)
Total anomalous pulmonary venous drainage	24 (3.5)	18 (2.6)
Double-inlet left ventricle	7 (1.0)	8 (1.2)
Other^e	10 (1.5)	8 (1.2)
Presurgical ICU admission	142 (20.9)	137 (20.0)
Duration of presurgical ICU stay, median (IQR), d	2.5 (1.5-4.2)	2.5 (1.5-4.3)
Treatments prior to heart surgery
Prostaglandin	132 (19.4)	152 (22.2)
Invasive ventilation	49 (7.2)	56 (8.2)
Afterload reducing agents	34 (5.0)	25 (3.7)
Inotropes	13 (1.9)	13 (1.9)
Steroids	3 (0.4)	7 (1.0)
Inhaled nitric oxide	1 (0.2)	1 (0.2)
Comorbid congenital syndromes
Congenital syndrome^d	123 (18.1)	120 (17.5)
Trisomy 21	61 (9.0)	58 (8.5)
22q11	16 (2.4)	18 (2.6)
VACTERL	6 (0.9)	6 (0.9)
Noonan	1 (0.2)	5 (0.7)
Turner	3 (0.4)	0
CHARGE	1 (0.2)	1 (0.2)
Other syndrome	37 (5.5)	32 (4.7)

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Abbreviations: CHARGE, coloboma, heart defects, atresia choanae (also known as choanal atresia), growth retardation, genital abnormalities, and ear abnormalities; CPB, cardiopulmonary bypass; ICU, intensive care unit; VACTERL, vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities.

^{^a}

Used for stratification.

^{^b}

Ethnicity was self-reported by the parent or guardian of the child.

^{^c}

Ethnicities included in the “multiethnic/other” category were predominantly multiethnic children, with the primary “other” ethnicities reported as Arabian (n = 39), Indian (n = 25), and African (n = 14).

^{^d}

Patients may have more than 1 type of congenital heart disease and more than 1 type of congenital syndrome.

^{^e}

Details of “other” lesions are provided in eTable 3 in Supplement 3.

Interventions

The median cardiopulmonary bypass time was 113 minutes (IQR, 71 to 167) in the nitric oxide group and 114 minutes (IQR, 75 to 166) in the standard care group. Nitric oxide was delivered into the cardiopulmonary bypass oxygenator for a median of 100% of bypass time (IQR, 100% to 100%) in the nitric oxide group and was not used in the standard care group. Inhaled nitric oxide was used intraoperatively in 6.6% of the nitric oxide group and 6.0% of the standard care group. The characteristics of cardiopulmonary bypass and other aspects of intraoperative management were not significantly different by treatment group (eTable 4 in Supplement 3).

Primary End Points

At day 28, there was no significant between-group difference in the number of ventilator-free days, with a median of 26.6 days (IQR, 24.4 to 27.4) in the nitric oxide group and 26.4 days (IQR, 24.0 to 27.2) in the standard care group (adjusted estimate of absolute difference, −0.01 days [95% CI, −0.25 to 0.22]; P = .92) (Table 2; Figure 2).

Table 2. Primary and Secondary Outcomes.

Outcome	Nitric oxide	Standard care	Estimate of difference (95% CI)
Outcome	Nitric oxide	Standard care	Unadjusted	Adjusted^a
No.	679	685
Primary outcome
Ventilator-free days, median (IQR)	26.6 (24.4 to 27.4)	26.4 (24.0 to 27.2)	0.18 (−0.11 to 0.48)^b	−0.01 (−0.25 to 0.22)^c
Secondary outcomes
Low cardiac output syndrome, need for extracorporeal life support, or death^d	153 (22.5)	143 (20.9)	1.10 (0.85 to 1.43)	1.12 (0.85 to 1.47)
Length of stay, median (IQR), d
ICU	3.0 (1.9 to 5.9)	3.0 (1.9 to 6.3)	0.98 (0.88 to 1.10)	1.00 (0.90 to 1.12)
Hospital	9.0 (6.0 to 17.1)	9.1 (6.7 to 17.8)	0.97 (0.87 to 1.09)	0.97 (0.87 to 1.09)
Troponin level postoperatively, μmol/L^e
At ICU admission, median (IQR)	9.67 (4.62 to 22.98)	8.80 (4.16 to 20.90)	0.90 (−0.59 to 2.39)	1.21 (−1.66 to 4.08)
No.	374	385
At 24 h post-ICU admission, median (IQR)	3.09 (1.66 to 6.10)	3.20 (1.62 to 7.21)	−0.11 (−0.75 to 0.53)	−0.23 (−0.88 to 0.42)
No.	347	344
Outcomes not prespecified in the formal protocol
Duration of time with open chest postoperatively, median (IQR), h	44.2 (24.6 to 89.6)	45.2 (26.0 to 88.7)	−0.95 (−10.73 to 8.84)	−0.17 (−13.01 to 12.67)
No.	143	151
Treated with inhaled nitric oxide postoperatively	80 (11.8)	92 (13.4)	0.86 (0.62 to 1.19)	0.86 (0.62 to 1.19)
Duration of inhaled nitric oxide, median (IQR), h	45 (20 to 92)	45 (24 to 89)	0 (−17.9 to 17.9)	−3.6 (−25.2 to 18.0)
Treated with kidney replacement postoperatively	112 (16.5)	119 (17.4)	0.94 (0.71 to 1.25)	0.94 (0.68 to 1.30)
Duration of kidney replacement, median (IQR), h	28 (14 to 68)	27 (18 to 55)	1 (−8.2 to 10.2)	0.5 (−10.6 to 11.6)
Organ dysfunction postoperatively (PELOD-2), mean (SD)^f
At ICU admission	7.7 (2.6)	7.4 (2.5)	0.3 (0.04 to 0.57)	0.32 (0.073 to 0.56)
At 24 h	2.4 (2.2)	2.4 (2.2)	0.022 (−0.21 to 2.53)	0.024 (−0.20 to 0.25)
At 48 h	1.9 (2.3)	1.9 (2.4)	0.00080 (−0.25 to 0.25)	0.0059 (−0.23 to 0.25)
Creatinine level postoperatively, μmol/L^g
At ICU admission, mean (SD)	35.3 (12.8)	33.9 (12.2)	1.37 (0.011 to 2.74)	1.52 (0.51 to 2.54)
No.	645	649
At 24 h post-ICU admission mean (SD)	42.2 (21.5)	41.6 (20.7)	0.56 (−2.21 to 3.33)	1.24 (−1.06 to 3.53)
No.	444	445
Acute kidney injury^h
At ICU admission	150 (22.1)	117 (17.1)	1.38 (1.05 to 1.80)	1.47 (1.10 to 1.98)
At 24 h	187 (27.5)	162 (23.7)	1.23 (0.96 to 1.57)	1.25 (0.97 to 1.60)
At 48 h	129 (19.0)	115 (16.8)	1.16 (0.88 to 1.53)	1.16 (0.88 to 1.55)
Safety measure
Any adverse eventⁱ	75 (11.1)	72 (10.5)	1.06 (0.75 to 1.49)	1.07 (0.75 to 1.55)

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Abbreviations: ICU, intensive care unit; PELOD-2, Pediatric Logistic Organ Dysfunction–2.

^{^a}

Adjusted for age at randomization, lesion type, and site.

^{^b}

P = .23.

^{^c}

P = .92.

^{^d}

The presence of low cardiac output syndrome (LCOS) was calculated as a binary variable by evaluating the relevant data items at the following time points: admission to pediatric intensive care unit (PICU), and after 6 hours, 12 hours, 24 hours, and 48 hours post-PICU admission, or until the patient is discharged from the PICU (whichever occurs first). Criteria for LCOS include a blood lactate level (arterial where available, if not then venous) greater than 4 mmol/L and the presence of an oxygen extraction of greater than 35% (arterial oxygen saturation–central venous oxygen saturation gradient >35%), or a high inotrope requirement operationalized as vasoactive-inotrope score of 15 or greater. If these criteria are met for at least 1 of the above listed time points, the presence of LCOS is confirmed. If individual data items required for the calculation of LCOS are missing, then the patient will be assumed not to have had LCOS.

^{^e}

Normal range of troponin less than 0.02 μg/L.

^{^f}

PELOD-2 is a weighted score with values of zero indicating absence of organ dysfunction, and higher values indicating increasing severity of organ dysfunction.

^{^g}

For normal range of creatinine, the age-specific thresholds used in PELOD-2 were applied.

^{^h}

Postoperative acute kidney injury was assessed using serum creatinine levels to classify according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria.²¹ Because no baseline creatinine values were available, we applied the age-specific thresholds used in PELOD-2 to define the presumed baseline creatinine values. KDIGO stage 1 was defined as an increase in creatinine to 1.5 to 1.9 times the presumed baseline; stage 2 as an increase 2.0 to 2.9 times; and stage 3 as an increase 3.0 or more times baseline and/or the use of kidney replacement therapy.

^ⁱ

See eTables 10 and 11 in Supplement 3 for additional details on adverse events.

Figure 2. — In this graphic presentation, patients who died are included as extubated. Patients extubated immediately after operation are plotted in the initial steep curve.

Secondary End Points

A total of 153 patients (22.5%) in the nitric oxide group and 143 (20.9%) in the standard care group developed low cardiac output syndrome within 48 hours after initiation of bypass, received postoperative extracorporeal life support within 48 hours after initiation of bypass, or died within 28 days after initiation of bypass (adjusted odds ratio, 1.12 [95% CI, 0.85 to 1.47]). The duration of ICU and hospital lengths of stay and postoperative troponin levels were not significantly different by treatment group (Table 2; eFigure 2 in Supplement 3).

End Points Not Prespecified in the Formal Protocol

Physiological variables, including oxygen extraction gradient, lactate levels, and organ dysfunction measured during the first 48 hours after initiation of bypass, were not significantly different by treatment group (Table 2). The vasopressor-inotropic score and other process-of-care measures were also not significantly different by treatment group (eFigure 3 in Supplement 3). There were no significant between-group differences in any of the components of the key composite outcome (eTable 5 in Supplement 3).

Subgroup Analyses and Sensitivity Analyses

There was no evidence of heterogeneity of treatment effect with respect to the primary outcome for any of the a priori–defined subgroups of interest (Figure 3; eTables 6 and 7, and eFigure 4 in Supplement 3). Among infants younger than 6 weeks, a median of 24.7 ventilator-free days (IQR, 21.9 to 25.9) were observed in the nitric oxide group compared with 24.9 ventilator-free days (IQR, 22.0 to 26.0) in the standard care group; and the composite outcome of low cardiac output syndrome, extracorporeal life support, or death occurred in 42.3% in the nitric oxide group as compared with 32.8% in the standard care group. Additional analyses for secondary outcomes were not indicative of a benefit from nitric oxide in any subgroup (eTables 6 and 7 in Supplement 3). Preplanned sensitivity analyses adjusting for an extended set of baseline covariates were comparable (eTable 8 in Supplement 3). Post-hoc analyses by study site did not reveal substantial heterogeneity (eTable 9 in Supplement 3).

Figure 3. — Findings are shown for the overall cohort and subgroups.

^aAdjusted for age at randomization, lesion type, and site.

^bAdjusted for lesion type and site.

^cAdjusted for age at randomization and site.

Adverse Events

Adverse events occurred in 75 patients (11.1%) in the nitric oxide group and 72 patients (10.5%) in the standard care group (adjusted odds ratio, 1.07 [95% CI, 0.75 to 1.55]). Only 1 adverse event, an unexpected cardiac arrest in the postoperative period in a patient assigned to nitric oxide, was considered possibly related to study treatment. Details of adverse events and protocol deviations are provided in eTables 10, 11, and 12 of Supplement 3.

Discussion

In this international randomized clinical trial involving children younger than 2 years undergoing cardiopulmonary bypass surgery for congenital heart disease, there was no significant difference in the number of ventilator-free days between those who received nitric oxide delivered into the cardiopulmonary bypass circuit and those who received standard care cardiopulmonary bypass without nitric oxide. There were no significant between-group differences in a composite of the incidence of low cardiac output syndrome or postoperative extracorporeal life support within 48 hours of the start of cardiopulmonary bypass, death within 28 days, or in the individual components of this outcome.

These findings are at variance with 2 previous single-center trials that evaluated the use of nitric oxide delivered at 20 ppm into the cardiopulmonary bypass circuit in children having surgery for congenital heart disease and 2 adult trials.^25,26 The first of these trials included 16 children and reported that children allocated to nitric oxide had a significantly shorter duration of mechanical ventilation, shorter ICU length of stay, and lower postoperative troponin levels than those assigned to standard care.¹⁵ The second trial included 198 children and reported a lower incidence of low cardiac output syndrome in children younger than 2 years, with the most marked reduction in low cardiac output syndrome found in children younger than 6 weeks.¹⁴ Based on these 2 positive pediatric trials involving a total of 214 children, in recent years, nitric oxide was considered to be a potentially effective therapy for improving perioperative outcomes in this patient group. This has led to some units introducing the use of nitric oxide during cardiopulmonary bypass as standard of care despite the lack of high-grade evidence.

In adults, a trial of 60 patients undergoing coronary artery bypass grafting reported lower postoperative cardiac enzymes and vasopressor scores in patients randomized to nitric oxide delivered at 40 ppm into the cardiopulmonary bypass vs standard care.²⁶ Another recent adult trial that enrolled 244 patients who underwent valve replacement surgery found a lower incidence of acute kidney injury in patients where nitric oxide was delivered at 80 ppm into the cardiopulmonary bypass followed by 24 hours of inhalative nitric oxide vs standard care.²⁵

No clinically or statistically significant heterogeneity of treatment effect was observed in the primary outcome based on age older than or younger than 6 weeks, nor in the other preplanned subgroup analyses comparing univentricular with biventricular physiology. However, this result is viewed with caution because the study was not powered for statistical assessment of heterogeneity in these groups. A priori exploratory analyses on markers of organ dysfunction and recovery after cardiopulmonary bypass were not suggestive of benefits in end points such as acute kidney injury for any subgroup.

Strengths

This trial had several strengths. It assessed a potential intervention to reduce the effects of cardiopulmonary bypass on early recovery, which was identified as a research priority for congenital heart disease.^{4,7,27,28,29,30}

The trial included participants who required cardiopulmonary bypass for a broad range of congenital heart disease in children younger than 2 years and recruited in 3 countries. Additional strengths of the trial included the pragmatic setting reflecting contemporary epidemiology of congenital heart disease.^1,31,32 Supporting the generalizability of these findings, overall rates of ventilator-free survival, ICU and hospital length of stay, requirements for extracorporeal life support, and 28-day mortality were comparable with those reported by the North American Pediatric Heart Network.³³

Limitations

This trial had several limitations. First, while study personnel including surgeons, anesthetists, ICU staff, and parents were blinded to the intervention, for technical reasons, the perfusionist applying the intervention was unblinded.²³ Despite this, the characteristics of cardiopulmonary bypass delivered to patients appeared similar by treatment group, apart from the use of nitric oxide. Second, delivery of nitric oxide was fixed at 20 ppm based on existing safety data and there remains the possibility that different doses of nitric oxide may have altered the effect of the intervention. Third, nitrosothiol levels were not measured. Fourth, some patients in both treatment groups received open-label inhaled nitric oxide treatment, which may have reduced the ability to detect a between-group difference. Fifth, the study protocol did not mandate ventilator weaning or extubation readiness assessment procedures. Sixth, follow-up of study patients will be required to determine whether the intervention was associated with differences in long-term outcomes.^4,5,30,34,35

Conclusions

Section Editor: Christopher Seymour, MD, Associate Editor, JAMA (christopher.seymour@jamanetwork.org).

Supplement 1.

Trial Protocol

Click here for additional data file.^{(700.4KB, pdf)}

Supplement 2.

Statistical Analysis Plan

Click here for additional data file.^{(454.8KB, pdf)}

Supplement 3.

eMethods 1. List of Ethics Approval Numbers and Approved Protocol Modifications

eMethods 2. Data Monitoring Plan

eMethods 3. Data and Safety Monitoring Board Charter

eMethods 4. Results of Interim Analyses

eMethods 5. Inclusion and Exclusion Criteria

eFigure 1. Recruitment Graph

eFigure 2. Kaplan-Meier Curves for Length of Stay in a) ICU and b) Hospital

eFigure 3. Composite Figure of a) Bar Chart Depicting Proportion of Patients With LCOS, b) Mean (and 95% CI) SaO2-ScvO2 Difference, c) Boxplot of Lactate Levels, d) Boxplot of VIS Score, e) Mean (and 95% CI) of Creatinine Values, Over Time Points 0, 6, 12, 24, 48 Hours After ICU Admission, f) PELOD-2 Score At 0, 24, 48 Hours After ICU Admission, Separated by Treatment Group

eFigure 4. Cumulative Incidence Functions for Extubation (Accounting for Mortality) for a) Age <6 Weeks, b) Age ≥6 Weeks, c) Univentricular Physiology, d) Biventricular Physiology

eTable 1. Enrolment Statistics by Site

eTable 2. Additional Baseline Characteristics of the Study Groups

eTable 3. Listing of Cardiac Lesions Contained in “Other” Categories

eTable 4. Surgical and Perioperative Characteristics of Enrolled Infants

eTable 5. Post Hoc Analyses of Components of Composite Outcome Measures for Study Cohort and Subgroups

eTable 6. Age Subgroup Analyses for Primary and Secondary Outcomes

eTable 7. Pathophysiology Subgroup Analyses for Primary and Secondary Outcomes

eTable 8. Sensitivity Analysis of Primary and Secondary Outcomes

eTable 9. Post Hoc Subgroup Analyses by Site for Ventilator-Free Days (Primary Outcome) and Composite Low Cardiac Output Syndrome, Need for ECLS or Death Secondary Outcome

eTable 10. Description of Adverse Events

eTable 11. List of Adverse Events

eTable 12. Description of Protocol Deviations

Click here for additional data file.^{(841KB, pdf)}

Supplement 4.

Nonauthor Collaborators. NITRIC Study Group, the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG), and the ANZICS Paediatric Study Group (PSG)

Click here for additional data file.^{(115.1KB, pdf)}

Supplement 5.

Data Sharing Statement

Click here for additional data file.^{(18.5KB, pdf)}

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