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

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ClinicalTrials.gov Identifier: NCT01802619
Recruitment Status : Completed
First Posted : March 1, 2013
Last Update Posted : February 13, 2018
Sponsor:
Information provided by (Responsible Party):
chonglei, Xijing Hospital

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Heart Valve Diseases Heart; Complications, Valve, Prosthesis Cardiac Valve Replacement Complication Other: inhaled nitric oxide Other: inhaled Nitrogen Phase 1 Phase 2

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  (Clinical Trial)
Actual Enrollment : 217 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: Prevention of Renal Failure by Nitric Oxide in Prolonged Cardiopulmonary Bypass: A Double Blind Randomized Controlled Trial.
Actual Study Start Date : August 2013
Primary Completion Date : June 2015
Study Completion Date : June 2016

Resource links provided by the National Library of Medicine

U.S. FDA Resources

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.



Primary Outcome Measures :
  1. acute kidney injury [ Time Frame: 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 ]
    acute kidney injury was defined by the KDIGO criteria


Secondary Outcome Measures :
  1. Chronic kidney disease [ Time Frame: at 30 days, 90 days, and 1 year following ICU admission ]
    defined as eGFR<60 mL/min/1.73m2

  2. Loss of 25% of eGFR compared to baseline [ Time Frame: at 30 days, 90 days, and 1 year following ICU admission ]
    Loss of 25% of eGFR compared to baseline

  3. Major adverse kidney events (MAKE) [ Time Frame: at 30 days, 90 days, and 1 year following ICU admission ]
    a composite outcome of loss of 25% of eGFR from baseline, end stage renal disease requiring a continuous renal replacement therapy and mortality.

  4. Renal Replacement Therapy [ Time Frame: at 30 days, 90 days, and 1 year following ICU admission ]
    the incidence of need for Renal Replacement Therapy

  5. Incidence of nonfatal stroke and nonfatal myocardial infarction. [ Time Frame: at 30 days, 90 days, and 1 year following ICU admission ]

    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.


  6. Quality of life [ Time Frame: at 30 days, 90 days, and 1 year following ICU admission ]
    The quality of life will be evaluated by the Katz Index of In dependence in Activities of Daily living

  7. overall mortality [ Time Frame: at 30 days, 90 days, and 1 year following ICU admission ]
    all cause mortality


Other Outcome Measures:
  1. In-hospital stay [ Time Frame: Normally within 30 days, when patients was discharged from ICU ]
    It is the length of hospital stay

  2. ICU-stay [ Time Frame: Normally within 30 days, when patients was discharged from ICU ]
    It is the length of stay in ICU

  3. Incidence of prolonged ventilation [ Time Frame: During hospital stay, normally within 30 days ]
    Prolonged ventilation is defined as patients remaining on the ventilator for more than 48 hours



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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01802619


Locations
China, Shaanxi
Xijing Hospital
Xi'an, Shaanxi, China, 710032
Sponsors and Collaborators
Xijing Hospital
Investigators
Study Chair: lize Xiong, M.D.,Ph.D. Xijing Hospital

Responsible Party: chonglei, M.D.& Ph.D., Xijing Hospital
ClinicalTrials.gov Identifier: NCT01802619     History of Changes
Other Study ID Numbers: 20121025-8
81000232 ( Other Grant/Funding Number: National Natural Science Foundation of China )
First Posted: March 1, 2013    Key Record Dates
Last Update Posted: February 13, 2018
Last Verified: February 2018

Additional relevant MeSH terms:
Renal Insufficiency
Heart Valve Diseases
Kidney Diseases
Urologic Diseases
Heart Diseases
Cardiovascular Diseases
Nitric Oxide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Endothelium-Dependent Relaxing Factors
Vasodilator Agents
Gasotransmitters
Protective Agents