Inhaled nitric oxide for reducing major adverse events requiring intensive life support in adults undergoing cardiac surgery with cardiopulmonary bypass: protocol for a phase III, double-blind, multicenter randomized controlled trial (NORISC Trial).

INTRODUCTION

Cardiac surgery remains a high-risk intervention, with postoperative complications, including ischemic events (myocardial infarction and stroke), acute kidney injury, respiratory failure, and neurocognitive dysfunction, affecting up to 30% of patients and resulting in increased mortality. While inhaled nitric oxide (NO) is traditionally used for pulmonary hypertension and right ventricular dysfunction, recent experimental and clinical studies suggest its organ-protective potential may mitigate ischemia-reperfusion injury and hemolysis induced toxicity. However, whether these physiological and mechanistic effects translate into improved patient-centered outcomes remains unproven in a large-scale setting. The NORISC trial aims to determine whether perioperative NO administration reduces major complications requiring intensive life support following cardiac surgery.

METHOD AND ANALYSIS: This is an international, multicenter, double-blind, randomized (1:1), parallel-arm superiority trial. We will enroll 3650 patients undergoing elective cardiac surgery with cardiopulmonary bypass (CPB). The intervention group will receive NO at 80 parts per million (ppm) via the oxygenator sweep gas during CPB, followed by inhaled NO at 40-80 ppm via mechanical ventilation for up to 6 h postoperatively or until extubation, whichever occurs first. The control group will receive standard care with placebo gas. The primary outcome is a 30-d composite of all-cause mortality and major adverse events (MAEs) necessitating intensive life support (e.g., stage 3 AKI, mechanical circulatory support, or prolonged ventilation, etc). Based on a hypothesized 20% relative risk reduction (from 20% to 16%), a sample size of 3650 provides 80% power at a one-sided α of 0.025. Conclusion/Expected Impact: The NORISC trial will provide high-quality, definitive evidence on the clinical efficacy of NO in cardiac surgery. By targeting hemolysis-mediated organ injury through a standardized delivery strategy, this study has the potential to redefine perioperative management and reduce the global burden of postoperative morbidity.

ETHICS AND DISSEMINATION: The protocol has received Institutional Review Board approval at all participating centers. Recruitment commenced in May 2025. Results will be disseminated through peer-reviewed publications and international scientific congresses.

TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT06702553.