NCT03748082

Brief Summary

This study is an ancillary (add-on) study to the clinical trial entitled "Effect of Nitric Oxide in Cardiac Surgery Patients With Endothelial Dysfunction", which has Clinical Trials.gov identifier NCT02836899. NCT02836899 trial randomizes cardiac surgical patients to receive either Nitric Oxide (NO) or a placebo during and after cardiac surgery. This ancillary study aims to assess the effects of Nitric Oxide on vascular responsiveness and on endothelial function during hemolysis in patients with pre-operative endothelial dysfunction undergoing cardiac surgery requiring prolonged cardiopulmonary bypass.

Trial Health

30
At Risk

Trial Health Score

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

Trial has exceeded expected completion date
Timeline
Completed

Started Dec 2018

Longer than P75 for phase_2

Geographic Reach
1 country

2 active sites

Status
withdrawn

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

November 16, 2018

Completed
4 days until next milestone

First Posted

Study publicly available on registry

November 20, 2018

Completed
15 days until next milestone

Study Start

First participant enrolled

December 5, 2018

Completed
4.9 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

November 1, 2023

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

November 1, 2023

Completed
Last Updated

December 2, 2025

Status Verified

November 1, 2025

Enrollment Period

4.9 years

First QC Date

November 16, 2018

Last Update Submit

November 24, 2025

Conditions

Endothelial DysfunctionHemolysis IntravascularCardiovascular DiseasesCardiovascular Risk Factor

Keywords

Cardiac SurgeryCardiopulmonary BypassReactive Hyperemia IndexNitric Oxide

Outcome Measures

Primary Outcomes (1)

  • Reactive Hyperemia Index (RHI)

    A finger plethysmograph will measure the transient increase in forearm blood flow (Reactive Hyperemia Index, RHI) in response to a 5 minutes occlusion of the brachial artery with a pressure cuff (Peripheral Artery Tonometry).

    The test will be performed perioperatively before anesthesia induction and at 24 hours after CPB during ICU admission.

Other Outcomes (3)

  • Endothelial Nitric Oxide Synthase (eNOS) enzymatic activity

    Endothelial Cells will be collected perioperatively before anesthesia induction and at 24 hours after CPB during ICU admission.

  • Pulmonary vascular resistances (PVR)

    PVR will be measured every 6 hours after surgery for 24 hours after cardiopulmonary bypass start.

  • Systemic vascular resistances (SVR)

    SVR will be measured every 6 hours after surgery for 24 hours after cardiopulmonary bypass start.

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). Test gas administration will commence at the onset of CPB and last for 24 hours.

Diagnostic Test: Reactive Hyperemia IndexProcedure: Endothelial Cells Collection

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. 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.

Drug: Nitric OxideDiagnostic Test: Reactive Hyperemia IndexProcedure: Endothelial Cells Collection

Interventions

Nitric OxideDRUG

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. 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.

Also known as: iNO
Nitric Oxide
Reactive Hyperemia IndexDIAGNOSTIC_TEST

Vascular responsiveness will be assessed with peripheral arterial tonometry which measures the transient increase in forearm blood flow (Reactive Hyperemia Index, RHI) in response to a five-minute occlusion of the brachial artery with a pressure cuff.

ControlNitric Oxide
Endothelial Cells CollectionPROCEDURE

Endothelial cells are collected before and after surgery from a peripheral vessel using a soft J-shaped wire inserted through an intravascular catheter.

ControlNitric Oxide

Eligibility Criteria

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

You may qualify if:

  • Eligible and randomized in the trial NCT02836899
  • Provide written informed consent
  • Age ≥ 18 years of age
  • Elective cardiac or aortic surgery with CPB \>90 minutes
  • Clinical evidence of endothelial dysfunction assessed by a specifically designed questionnaire

You may not qualify if:

  • Estimated Glomerular Filtration Rate 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 Cell (PRBC) transfusions in the week prior to enrollment
  • X-ray contrast infusion less than 48 hours before surgery
  • Evidence of hemolysis from any other origin:
  • a. Intravascular: i. Intrinsic RBC defects leading to hemolytic anemia (eg, enzyme deficiencies, hemoglobinopathies, membrane defects) ii. 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 b. 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 (2)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Boston Medical Center

Boston, Massachusetts, 02118, United States

Location

Related Publications (4)

  • Lei C, Berra L, Rezoagli E, Yu B, Dong H, Yu S, Hou L, Chen M, Chen W, Wang H, Zheng Q, Shen J, Jin Z, Chen T, Zhao R, Christie E, Sabbisetti VS, Nordio F, Bonventre JV, Xiong L, Zapol WM. Nitric Oxide Decreases Acute Kidney Injury and Stage 3 Chronic Kidney Disease after Cardiac Surgery. Am J Respir Crit Care Med. 2018 Nov 15;198(10):1279-1287. doi: 10.1164/rccm.201710-2150OC.

    PMID: 29932345BACKGROUND

  • Rezoagli E, Ichinose F, Strelow S, Roy N, Shelton K, Matsumine R, Chen L, Bittner EA, Bloch DB, Zapol WM, Berra L. Pulmonary and Systemic Vascular Resistances After Cardiopulmonary Bypass: Role of Hemolysis. J Cardiothorac Vasc Anesth. 2017 Apr;31(2):505-515. doi: 10.1053/j.jvca.2016.06.009. Epub 2016 Jun 8.

    PMID: 27590461BACKGROUND

  • Tabit CE, Shenouda SM, Holbrook M, Fetterman JL, Kiani S, Frame AA, Kluge MA, Held A, Dohadwala MM, Gokce N, Farb MG, Rosenzweig J, Ruderman N, Vita JA, Hamburg NM. Protein kinase C-beta contributes to impaired endothelial insulin signaling in humans with diabetes mellitus. Circulation. 2013 Jan 1;127(1):86-95. doi: 10.1161/CIRCULATIONAHA.112.127514. Epub 2012 Nov 30.

    PMID: 23204109BACKGROUND

  • Hamburg NM, Keyes MJ, Larson MG, Vasan RS, Schnabel R, Pryde MM, Mitchell GF, Sheffy J, Vita JA, Benjamin EJ. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation. 2008 May 13;117(19):2467-74. doi: 10.1161/CIRCULATIONAHA.107.748574. Epub 2008 May 5.

    PMID: 18458169BACKGROUND

MeSH Terms

Conditions

HemolysisCardiovascular Diseases

Interventions

Nitric Oxide

Condition Hierarchy (Ancestors)

Pathologic ProcessesPathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Reactive Nitrogen SpeciesFree RadicalsInorganic ChemicalsNitrogen OxidesNitrogen CompoundsOxidesOxygen CompoundsOrganic Chemicals
0

Study Design

Study Type
interventional
Phase
phase 2
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Purpose
BASIC SCIENCE
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
MD

Study Record Dates

First Submitted

November 16, 2018

First Posted

November 20, 2018

Study Start

December 5, 2018

Primary Completion

November 1, 2023

Study Completion

November 1, 2023

Last Updated

December 2, 2025

Record last verified: 2025-11

Data Sharing

IPD Sharing
Will not share

Locations

US(2)