Prevention of Renal Failure by Nitric Oxide in Prolonged Cardiopulmonary Bypass.

Prevention of Renal Failure by Nitric Oxide in Prolonged Cardiopulmonary Bypass: A Double Blind Randomized Controlled Trial.

Prolonged periods of cardiopulmonary bypass (CPB) cause high levels of plasma free haemoglobin(Hb) and are associated with increased morbidity. We hypothesized that repletion of nitric oxide (NO) during and after the surgical procedure on CPB may protect against endothelium dysfunction and organ failure caused by plasma-Hb induced NO scavenging.

Study Overview

• Status: Completed
• Conditions: Heart Valve Diseases; Heart; Complications, Valve, Prosthesis; Cardiac Valve Replacement Complication
• Intervention / Treatment: Other: inhaled Nitrogen; Other: inhaled nitric oxide

Detailed Description

Prolonged periods of cardiopulmonary bypass (CPB) cause high levels of plasma free haemoglobin(Hb) and are associated with increased morbidity. We hypothesized that repletion of nitric oxide (NO) during and after the surgical procedure on CPB may protect against endothelium dysfunction and organ failure caused by plasma-Hb induced NO scavenging. There are three possible beneficial mechanisms of delivering NO:

1. Nitric oxide reduces ischemia-reperfusion injury (such as in acute myocardial infarction, stroke, and acute tubular necrosis).
2. Nitric oxide has anti-inflammatory properties. As antioxidants, exogenous NO may reduce injury by counteracting the cytotoxic effects of reactive oxygen species, modulating leukocyte recruitment, edema formation and tissue disruption.
3. Exogenous nitric oxide prevents noxious effects of hemolysis-associated NO dysregulation. During hemolysis, nitric oxide gas oxidized of plasma oxyhemoglobin to methemoglobin, thereby inhibiting endogenous endothelium NO scavenging by cell-free Hb.

NO depletion during hemolysis and its sequelae. The release of plasma free Hb (with Fe2+ iron) by hemolysis avidly scavenges nitric oxide (NO) by the dioxygenation reaction. Elevated plasma ferrous Hb levels can induce a "NO deficiency" state. Reduced vascular nitric oxide levels can contribute to vasoconstriction, inflammation, and thrombosis, potentially contributing to systemic endothelial dysfunction after cardiac surgery with CPB.

• Study Type: Interventional
• Enrollment (Actual): 217
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Shaanxi
    • Xi'an, Shaanxi, China, 710032
      • Xijing Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provide written informed consent
• Are > 18 years of age
• Elective cardiac or aortic surgery with CPB, when the surgeon plans double valve replacement.
• Stable pre-operative renal function, without dialysis.

Exclusion Criteria:

• Emergent cardiac surgery
• Life expectancy < 1 year
• Hemodynamic instability as defined by a systolic blood pressure <90 mmHg
• Administration of ≥1 Packed Red Blood Cell transfusion in the week before surgery
• X-ray contrast infusion less than 1 week before surgery
• Anticipate administration of nephrotoxic agents, such as hydroxyethyl starch
• Evidence of intravascular or extravascular hemolysis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: inhaled nitrogen; Using an Inovent (Ikaria Inc, N.J., USA) or volumetrically-calibrated flowmeters, pure nitrogen (placebo) is mixed with pure O2 or air. During CPB the gas mixture is delivered through the extracorporeal oxygenator, after CPB the NO is delivered through the inspiratory limb of the anesthetic or ventilator circuit.	Other: inhaled Nitrogen; Standard gas including nitrogen (the vehicle of the Nitric oxide) administration will commence at the onset of CPB and last for 24 hours. At the end of 24 hours, inhaled gases will be weaned and discontinued while carefully monitoring hemodynamics for a period of 2-4 hours.
EXPERIMENTAL: inhaled nitric oxide; Using an Inovent (Ikaria Inc, N.J., USA) or volumetrically-calibrated flowmeters, 800 ppm NO gas is mixed with pure O2 or air to obtain a final concentration of 80 ppm NO. During CPB the gas mixture is delivered through the extracorporeal oxygenator, after CPB the gas is delivered through the inspiratory limb of the anesthetic or ventilator circuit. NO, NO2 and O2 and methemoglobin levels are monitored by an unblinded observer.	Other: inhaled nitric oxide; Nitric oxide administration will commence at the onset of CPB and last for 24 hours. At the end of 24 hours, inhaled NO will be weaned and discontinued while carefully monitoring hemodynamics for a period of 2-4 hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
acute kidney injury	acute kidney injury was defined by the KDIGO criteria	an increase of serum creatinine by 50% within 7 days after surgery, or an increase of serum creatinine by 0.3 mg/dl within 2 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Chronic kidney disease	defined as eGFR<60 mL/min/1.73m2	at 30 days, 90 days, and 1 year following ICU admission
Loss of 25% of eGFR compared to baseline	Loss of 25% of eGFR compared to baseline	at 30 days, 90 days, and 1 year following ICU admission
Major adverse kidney events (MAKE)	a composite outcome of loss of 25% of eGFR from baseline, end stage renal disease requiring a continuous renal replacement therapy and mortality.	at 30 days, 90 days, and 1 year following ICU admission
Renal Replacement Therapy	the incidence of need for Renal Replacement Therapy	at 30 days, 90 days, and 1 year following ICU admission
Incidence of nonfatal stroke and nonfatal myocardial infarction.	Nonfatal stroke will be assessed by the NIH Stroke Scale at baseline before surgery and at 28 days, 60 days, 90 days and 1 year after surgery. Nonfatal myocardial infarction is defined by the third universal definition of MI released in 2012 by the ESC/ACCF/AHA/WHF.	at 30 days, 90 days, and 1 year following ICU admission
Quality of life	The quality of life will be evaluated by the Katz Index of In dependence in Activities of Daily living	at 30 days, 90 days, and 1 year following ICU admission
overall mortality	all cause mortality	at 30 days, 90 days, and 1 year following ICU admission

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
In-hospital stay	It is the length of hospital stay	Normally within 30 days, when patients was discharged from ICU
ICU-stay	It is the length of stay in ICU	Normally within 30 days, when patients was discharged from ICU
Incidence of prolonged ventilation	Prolonged ventilation is defined as patients remaining on the ventilator for more than 48 hours	During hospital stay, normally within 30 days

Collaborators and Investigators

• Sponsor: Xijing Hospital
• Investigators: Study Chair: lize Xiong, M.D.,Ph.D., Xijing Hospital

Publications and helpful links

General Publications

• Hu J, Rezoagli E, Zadek F, Bittner EA, Lei C, Berra L. Free Hemoglobin Ratio as a Novel Biomarker of Acute Kidney Injury After On-Pump Cardiac Surgery: Secondary Analysis of a Randomized Controlled Trial. Anesth Analg. 2021 Jun 1;132(6):1548-1558. doi: 10.1213/ANE.0000000000005381.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 1, 2013
• Primary Completion (ACTUAL): June 1, 2015
• Study Completion (ACTUAL): June 1, 2016

Study Registration Dates

• First Submitted: February 25, 2013
• First Submitted That Met QC Criteria: February 27, 2013
• First Posted (ESTIMATE): March 1, 2013

Study Record Updates

• Last Update Posted (ACTUAL): February 13, 2018
• Last Update Submitted That Met QC Criteria: February 10, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Renal Insufficiency; Heart Valve Diseases; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Antioxidants; Free Radical Scavengers; Endothelium-Dependent Relaxing Factors; Gasotransmitters; Nitric Oxide
• Other Study ID Numbers: 20121025-8; 81000232 (OTHER_GRANT: National Natural Science Foundation of China)