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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: Nitric oxide reduces ischemia-reperfusion injury (such as in acute myocardial infarction, stroke, and acute tubular necrosis). 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. 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.

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

Conditions
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Heart Valve Diseases, Heart; Complications, Valve, Prosthesis, Cardiac Valve Replacement Complication

Intervention / Treatment
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* Other: inhaled nitric oxide
* Other: inhaled Nitrogen


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: inhaled nitrogen<br>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<br>* 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.<br>|
| Experimental: inhaled nitric oxide<br>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<br>* 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.<br>|

What is the study measuring?
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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 |