NCT02836899

Brief Summary

The purpose of this study is to determine whether nitric oxide is effective in the treatment of acute kidney injury in cardiac surgical patients with sign and laboratory data suggesting endothelial dysfunction undergoing prolonged cardiopulmonary bypass.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
250

participants targeted

Target at P50-P75 for phase_3

Timeline
Completed

Started Feb 2017

Longer than P75 for phase_3

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

July 15, 2016

Completed
4 days until next milestone

First Posted

Study publicly available on registry

July 19, 2016

Completed
7 months until next milestone

Study Start

First participant enrolled

February 8, 2017

Completed
8.5 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

August 15, 2025

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

August 15, 2025

Completed
7 months until next milestone

Results Posted

Study results publicly available

March 10, 2026

Completed
Last Updated

March 10, 2026

Status Verified

February 1, 2026

Enrollment Period

8.5 years

First QC Date

July 15, 2016

Results QC Date

January 30, 2026

Last Update Submit

February 18, 2026

Conditions

Acute Kidney Injury

Keywords

acute kidney injury; nitric oxide; cardiopulmonary bypass; endothelial dysfunction; cardiac surgery

Outcome Measures

Primary Outcomes (1)

  • Number of Participants With Acute Kidney Injury

    Acute kidney injury (AKI) is defined by KDIGO criteria as an abrupt (within 48h) reduction in kidney function correlated to an absolute increase in serum creatinine of 0.3 mg/dL or more (≥26.4 μmol/L) or a percentage increase in serum creatinine of 50% or more (1.5-fold from baseline) at any time during the first 7 days after surgery or, finally, a reduction in urine output with a documented oliguria of \< 0.5 ml/Kg/h for \>6h.

    7 days

Secondary Outcomes (9)

  • AKI Severity

    7 days after cardiac surgery

  • Renal Replacement Therapy

    up to 1 year

  • Major Adverse Kidney Events (MAKE)

    6 weeks after cardiac surgery

  • Organ Dysfunction

    7 days

  • Prolonged Cardiovascular Support

    48 hours after cardiac surgery

  • +4 more secondary outcomes

Other Outcomes (12)

  • Renal Tubular Injury

    Up to 6 weeks

  • Incidence of AKI Related to Risk Factors

    7 days

  • Incidence of Delirium

    7 days after cardiac surgery

  • +9 more other outcomes

Study Arms (2)

Control

PLACEBO COMPARATOR

Inhaled nitrogen will be administered via the cardiopulmonary bypass (CPB) machine and after CPB via the inspiratory limb of the anesthetic or ventilator circuit, and thereafter via the mechanical ventilator in the Intensive Care Unit (ICU). Once patients are extubated they will breathe test gas via a facemask or nasal cannula. Test gas administration will commence at the onset of CPB and last for 24 hours.

Other: Placebo

Nitric Oxide

EXPERIMENTAL

Inhaled nitric oxide (iNO) will be administered via the CPB machine and after CPB via the inspiratory limb of the anesthetic or ventilator circuit, and thereafter via the mechanical ventilator in the ICU. Once patients are extubated they will breathe test gas via a facemask or nasal cannula. Test gas administration will commence at the onset of CPB and last for 24 hours. At the end of 24 hours, iNO will be weaned and discontinued while carefully monitoring hemodynamics for a period of 2-4 hours.

Drug: Nitric Oxide

Interventions

Nitric OxideDRUG

Inhaled nitric oxide will be administered in a final concentration of 80 ppm. The treatment will begin at the onset of the cardiopulmonary bypass until to 24h after Intensive Care Unit (ICU) admission, including 2-4 hours of weaning from nitric oxide and careful hemodynamics monitoring.

Nitric Oxide
PlaceboOTHER

This is the placebo group. Nitrogen will be added instead of nitric oxide.

Control

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Provide written informed consent
  • Age ≥ 18 years of age
  • Elective cardiac or aortic surgery with CPB\>90 minutes
  • Stable pre-operative renal function without evidence of plasma creatinine level increase of ≥ 0.3 mg/dL over the prior 3 months and without renal replacement therapy (RRT).
  • Clinical evidence of endothelial dysfunction assessed by a specifically designed questionnaire.

You may not qualify if:

  • eGFR less than 30 ml/min/1.73 m2
  • Emergent cardiac surgery.
  • Life expectancy \< 1 year at the time of enrollment.
  • Hemodynamic instability as defined by a systolic blood pressure \<90 mmHg.
  • Mean pulmonary artery pressure ≥ 40 mm Hg and PVR \> 4 Wood Units.
  • Left ventricular ejection fraction \< 30% by echocardiography obtained within three months of enrollment
  • Administration of one or more Packed Red Blood Cells (RBCs) transfusion in the week prior to enrollment.
  • X-ray contrast infusion less than 48 hours before surgery.
  • Evidence of intravascular or extravascular hemolysis from any other origin:
  • i. Intravascular: Intrinsic RBCs defects leading to hemolytic anemia (eg, enzyme deficiencies, hemoglobinopathies, membrane defects). Extrinsic: liver disease, hypersplenism, infections (eg, bartonella, babesia, malaria), treatment with oxidizing exogenous agents (eg, dapsone, nitrites, aniline dyes), exposure to other hemolytic agents (eg, lead, snake and spider bites), lymphocyte leukemia, autoimmune hemolytic disorders.
  • ii. Extravascular: Infection (eg, clostridial sepsis, severe malaria), paroxysmal cold hemoglobinuria, cold agglutinin disease, paroxysmal nocturnal hemoglobinuria, iv infusion of Rho(D) immune globulin, iv infusion of hypotonic solutions.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Related Publications (2)

  • Arora P, Di Fenza R, Shetty NS, Giammatteo V, Marrazzo F, Spina S, Zadek F, Gianni S, Fakhr BS, La Vita C, Shann K, Zheng H, Gaonkar M, Yu B, Feelisch M, Thompson TB, Akeju O, Sundt TM, Bonventre J, Ichinose F, Berra L; Cardiac Anesthesia Research Group. Nitric Oxide to Reduce Acute Kidney Injury in Patients with Preexisting Endothelial Dysfunction Requiring Prolonged Cardiopulmonary Bypass: A Randomized Clinical Trial. Anesthesiology. 2026 Mar 1;144(3):652-665. doi: 10.1097/ALN.0000000000005861. Epub 2025 Nov 21.

    PMID: 41270263DERIVED

  • Marrazzo F, Spina S, Zadek F, Lama T, Xu C, Larson G, Rezoagli E, Malhotra R, Zheng H, Bittner EA, Shelton K, Melnitchouk S, Roy N, Sundt TM, Riley WD, Williams P, Fisher D, Kacmarek RM, Thompson TB, Bonventre J, Zapol W, Ichinose F, Berra L. Protocol of a randomised controlled trial in cardiac surgical patients with endothelial dysfunction aimed to prevent postoperative acute kidney injury by administering nitric oxide gas. BMJ Open. 2019 Jul 4;9(7):e026848. doi: 10.1136/bmjopen-2018-026848.

    PMID: 31278097DERIVED

Related Links

MeSH Terms

Conditions

Acute Kidney Injury

Interventions

Nitric Oxide

Condition Hierarchy (Ancestors)

Renal InsufficiencyKidney DiseasesUrologic DiseasesFemale Urogenital DiseasesFemale Urogenital Diseases and Pregnancy ComplicationsUrogenital DiseasesMale Urogenital Diseases

Intervention Hierarchy (Ancestors)

Reactive Nitrogen SpeciesFree RadicalsInorganic ChemicalsNitrogen OxidesNitrogen CompoundsOxidesOxygen CompoundsOrganic Chemicals

Results Point of Contact

Title
Lorenzo Berra, MD
Organization
Massachusetts General Hospital
lberra@mgh.harvard.edu
617-726-3030

Study Officials

  • Lorenzo Berra, MD

    Massachusetts General Hospital

    PRINCIPAL INVESTIGATOR

Publication Agreements

PI is Sponsor Employee
Yes

Study Design

Study Type
interventional
Phase
phase 3
Allocation
RANDOMIZED
Masking
DOUBLE
Who Masked
PARTICIPANT, INVESTIGATOR
Purpose
PREVENTION
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Lorenzo Berra, MD, Assistant Professor, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School

Study Record Dates

First Submitted

July 15, 2016

First Posted

July 19, 2016

Study Start

February 8, 2017

Primary Completion

August 15, 2025

Study Completion

August 15, 2025

Last Updated

March 10, 2026

Results First Posted

March 10, 2026

Record last verified: 2026-02

Data Sharing

IPD Sharing
Will not share

Locations

US(1)