Inhaled Nitric Oxide for Prevention of Postoperative AKI in High-Risk Cardiac Surgery Patients

Intraoperative Inhaled Nitric Oxide to Reduce Postoperative Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass

The goal of this clinical trial is to learn if giving inhaled nitric oxide during heart surgery can prevent acute kidney injury (AKI) in patients who are at high risk of developing this complication. AKI is a serious problem after heart surgery and can lead to longer hospital stays, higher costs, and increased risk of death or long-term kidney disease. Currently, there is no effective medicine to prevent AKI after heart surgery.

The main questions it aims to answer are:

• Does inhaled nitric oxide reduce the chance of developing AKI within 7 days after heart surgery compared to placebo?
• Does inhaled nitric oxide help preserve kidney function up to 90 days after surgery?

Researchers will compare inhaled nitric oxide (the device is turned on) to a placebo (the same device is connected to the breathing circuit but not turned on, so no nitric oxide is given). The device panel is covered so that both participants and the research team do not know who receives active treatment or placebo (double-blind).

Participants in this study will:

• Have the nitric oxide device connected to their breathing circuit during heart surgery; they will receive either active nitric oxide or no nitric oxide (device off)
• Provide blood and urine samples to test kidney function during and after surgery
• Be followed for 90 days after surgery to monitor kidney health and any side effects

Study Overview

• Status: Not yet recruiting
• Conditions: Cardiac Surgery With Cardiopulmonary Bypass; Cardiac Surgery Associated - Acute Kidney Injury
• Intervention / Treatment: Drug: Inhaled Nitric Oxide (iNO); Drug: Placebo

Detailed Description

This is a single-center, prospective, randomized, double-blind, placebo-controlled superiority trial. It evaluates whether intraoperative inhaled nitric oxide (iNO) at 80 ppm reduces the incidence of acute kidney injury (AKI) within 7 days after cardiac surgery with cardiopulmonary bypass (CPB) in high-risk patients (Mayo Clinic renal risk score ≥2).

Intervention: Patients receive inhaled nitric oxide at 80 ppm via the ventilator circuit during CPB and until the end of surgery.

Control: The same device is connected but remains turned off (no iNO delivery). The device screen is covered in both groups to maintain blinding.

Randomization and blinding: Randomization (1:1) uses a blocked scheme with allocation concealment. Patients, surgeons, anesthesiologists, ICU staff, and outcome assessors are blinded. A dedicated gas therapist (not otherwise involved) manages the device.

Standardized management: All patients receive standardized anesthesia, CPB, and KDIGO-recommended AKI prevention bundle (MAP>55 mmHg, goal-directed perfusion).

Safety monitoring: Intraoperative methemoglobin (blood gas) and nitrogen dioxide (device readout) are monitored with predefined safety thresholds for dose adjustment.

Exploratory biomarker substudy (optional): Blood and urine samples are collected at perioperative time points to measure biomarkers of kidney injury and inflammation.

Follow-up: In-hospital outcomes (complications, ventilation duration, length of stay) and telephone follow-up at 30 and 90 days for major adverse kidney and cardiovascular events.

Sample size: Approximately 330 participants (1:1) are planned.

Statistical analysis: The primary analysis compares 7-day AKI incidence between groups with a two-sided α=0.05. Secondary outcomes will be analyzed using appropriate parametric or non-parametric methods.

• Study Type: Interventional
• Enrollment (Estimated): 330
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Kefang Guo, M.D.; Phone Number: 86-021-64041990; Email: dr_guokefang@163.com
• Study Contact Backup: Name: Ying Yu, M.D.; Phone Number: 86-021-64041990; Email: yu.ying1@zs-hospital.sh.cn

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200032
      • Zhongshan Hospital, Fudan University
      • Contact: Kefang Guo, M.D.; Phone Number: 86-021-64041990; Email: dr_guokefang@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥18 years
• Scheduled for elective cardiac surgery with cardiopulmonary bypass, including valve surgery and/or coronary artery bypass grafting (CABG)
• Mayo Clinic renal risk score ≥2

Exclusion Criteria:

• Emergency surgery
• Cardiac or major vascular surgery requiring deep hypothermic circulatory arrest
• Use of potentially nephrotoxic drugs (e.g., radiocontrast agents, aminoglycosides, amphotericin) within 24 hours before surgery
• Preoperative heart failure or low cardiac output syndrome requiring life support devices (ECMO, Impella or other left ventricular assist devices, mechanical ventilation), or left ventricular ejection fraction <30%, or other equivalent severe cardiac dysfunction
• Receipt of inhaled nitric oxide or inhaled prostacyclin within 7 days before randomization
• End-stage renal disease with eGFR <15 mL/min, or currently receiving renal replacement therapy, or prior kidney transplantation
• Hemophilia A or B
• Other end-stage chronic disease with estimated life expectancy <1 year (as assessed by the attending physician)
• Pregnancy
• Active endocarditis or other active infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Group	Drug: Placebo; The same NO device is connected to the ventilator circuit but remains TURNED OFF, so no nitric oxide is delivered. The device screen is covered to maintain blinding. Participants in the placebo group receive no active drug.
Experimental: Inhaled Nitric Oxide (iNO) Group	Drug: Inhaled Nitric Oxide (iNO); Inhaled nitric oxide(iNO) at 80 ppm is delivered via the ventilator circuit during cardiopulmonary bypass and until the end of surgery. The gas is administered using the INOwill N200 delivery device (which is turned ON).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Acute Kidney Injury (AKI) within 7 Days After Surgery	Proportion of participants developing AKI within 7 days post-surgery, defined according to the KDIGO 2012 criteria.	Up to 7 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AKI Stage and Duration	Maximum KDIGO stage (1, 2, or 3) of AKI and total duration (days) of AKI during the first 7 postoperative days.	Up to 7 days after surgery
Major Adverse Kidney Events (MAKE)	Composite of all-cause death, new need for renal replacement therapy, or a ≥25% decline in eGFR from baseline. Assessed during hospital stay and at 30 and 90 days after discharge.	At hospital discharge, and at 30 days and 90 days after surgery
Major Adverse Cardiovascular Events (MACE)	Composite of myocardial infarction, stroke, or all-cause death. Assessed during hospital stay and at 30 and 90 days after discharge.	At hospital discharge, and at 30 days and 90 days after surgery
Postoperative Complications	Occurrence of pneumonia, stroke, myocardial infarction, or other major complications during the postoperative hospital stay.	From end of surgery until hospital discharge (assessed up to 90 days)
Duration of Mechanical Ventilation	Total time (hours) from end of surgery until successful extubation.	During intensive care unit (ICU) stay, up to 30 days
ICU Length of Stay	Total number of days from ICU admission to ICU discharge.	During hospitalization, up to 90 days
Hospital Length of Stay	Total number of days from surgery to hospital discharge.	During hospitalization, up to 90 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intraoperative Methemoglobin Level	Maximum methemoglobin level (%) measured by intraoperative blood gas analysis.	During surgery (from induction until sternal closure)
Nitrogen Dioxide Level	Maximum nitrogen dioxide level (ppm) measured in real time by the NO delivery device.	During surgery (from start of iNO delivery until end of surgery)
Dose Reduction or Discontinuation of Study Gas	Number of participants in whom the study gas was reduced or stopped because methemoglobin exceeded 5% or nitrogen dioxide exceeded 3 ppm.	During surgery (from start of iNO delivery until end of surgery)
Adverse Events Related to Study Gas Administration	Any adverse event that leads to early discontinuation or prolonged use of the study gas, including worsening oxygenation, elevated pulmonary artery pressure causing hypoxemia, systemic hypotension, bradycardia, or right heart failure.	During surgery (from start of iNO delivery until end of surgery)
Urinary NGALLevels	Urinary neutrophil gelatinase-associated lipocalin (NGAL) measured at baseline (pre-anesthesia induction) and at 6, 24, and 72 hours after surgery.	Preoperative (baseline) and postoperative hours 6, 24, 72
Urinary KIM-1 Level	Urinary kidney injury molecule-1 (KIM-1) measured at baseline (pre-anesthesia induction) and at 6, 24, and 72 hours after surgery.	Preoperative (baseline) and postoperative hours 6, 24, 72
Serum Cystatin C Level	Serum cystatin C (mg/L) measured at baseline and at 6, 24, and 72 hours after surgery.	Preoperative (baseline) and postoperative hours 6, 24, 72
Inflammatory Cytokine Levels	Serum levels (pg/mL) of inflammatory cytokines (e.g., interleukin-1 [IL-1], IL-2, IL-6, IL-18, and tumor necrosis factor-alpha [TNF-α]) measured at baseline and at 6, 24, and 72 hours after surgery.	Preoperative (baseline) and postoperative hours 6, 24, 72

Collaborators and Investigators

• Sponsor: Shanghai Zhongshan Hospital
• Investigators: Principal Investigator: Kefang Guo, M.D., Zhongshan hospital, Fudan university,Shanghai, China

Study record dates

Study Major Dates

• Study Start (Estimated): April 30, 2026
• Primary Completion (Estimated): October 31, 2028
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: April 10, 2026
• First Submitted That Met QC Criteria: April 19, 2026
• First Posted (Actual): April 22, 2026

Study Record Updates

• Last Update Posted (Actual): April 22, 2026
• Last Update Submitted That Met QC Criteria: April 19, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Cardiopulmonary Bypass; Acute Kidney Injury; Cardiac surgery; Nitric Oxide
• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Renal Insufficiency; Acute Kidney Injury
• Other Study ID Numbers: B2026-171

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The investigators do not plan to share individual participant data (IPD). The informed consent form signed by participants did not include provisions for sharing de-identified data with external researchers beyond the primary study team.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No