Nitric Oxide in Cardiopulmonary Bypass for Renal Protection in Cardiac Surgery

Study Overview
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Brief Summary
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This prospective randomized study evaluates the nephroprotective effects of exogenous nitric oxide delivered to the extracorporeal circulation circuit during cardiac surgery with cardiopulmonary bypass.

Detailed Description
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The aim of this work is to study nephroprotective effects of nitric oxide (NO) supplementation to the cardiopulmonary bypass (CPB) circuit during cardiac surgery with normothermic CPB in adult patients. The prospective randomized study is performed in the settings of Federal Cardiology Center. A total of 96 adult patients who underwent cardiac surgery with CPB are enrolled in the study. Patients are randomized to two groups: main group receive NO treatment; control group undergoes sham procedure. In the main group, NO is supplied to the CPB line in a dose of 40 ppm throughout the entire CPB period. The primary endpoint is the frequency of acute kidney injury (AKI). The secondary endpoints are urine output during CPB; uNGAL level 4 h after surgery; plasma concentration of free hemoglobin (Hb); concentrations of NO metabolites (nitrite (NO2-) and nitrate (NO3-)) and the total concentration of metabolites of NO (NOx, μM/mL) in blood plasma in the intraoperative period; concentration of proinflammatory (TNF-α, IL-1β, -6, and -8) and anti-inflammatory mediators (IL-1ra, IL-4) in blood plasma in the intraoperative period. Cumulative fluid balance, diuresis, and Lasix doses are assessed within the first 48 h of the postoperative period. The dynamics of serum creatinine is assessed during the first week following the intervention.

Official Title
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Nitric Oxide Supplementation to the Extracorporeal Circulation Line as a Method of Nephroprotection in Cardiac Surgery

Conditions
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Coronary Artery Disease, Heart Valve Diseases, Cardiomyopathies, Acute Kidney Injury

Intervention / Treatment
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* Drug: Nitric Oxide
* Other: Standard CPB


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age above 18 years; planned primary cardiac intervention with cardiopulmonary bypass including coronary artery bypass grafting, valve surgery, and surgical reconstructions of the left ventricle. Exclusion Criteria: Preoperative anemia; the intake of nephrotoxic drugs or the use of X-ray contrast within 72 h before surgery; active phase of endocarditis; emergency surgery; chronic kidney disease; hematologic diseases accompanied by hemolysis; complications of the surgery and the early postoperative period.

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
Interventional Model Description: Single-center prospective, randomized, placebo-controlled study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nitric Oxide<br>Patients of this group receive treatment with exogenous gaseous nitric oxide supplied directly to the oxygenator in the cardiopulmonary bypass circuit during cardiac surgery. | Drug: Nitric Oxide<br>* 40 ppm of exogenous gaseous nitric oxide is supplied directly to the oxygenator in the cardiopulmonary bypass circuit during cardiac surgery.<br>|
| Placebo Comparator: Standard CPB<br>Patients of this group receive sham-treatment without supplying nitric oxide to the cardiopulmonary bypass circuit (Standard CPB) during cardiac surgery. Considering dilution of nitric oxide at a high ratio of 1 to 25,000 in the gas mixture of the cardiopulmonary bypass circuit (CPB), no addition of any inert gas to the CPB circuit is required in sham-treatment group. | Other: Standard CPB<br>* Standard CPB protocol of delivery of air gas mixture to the cardiopulmonary bypass circuit during cardiac surgery.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute kidney injury rate measure | The presence of acute kidney injury (AKI) is assessed during 48 hours after surgery. AKI is defined as follows: an increase in serum creatinine ≥ 0.3 mg/dL (≥ 26.5 μM/L) during 48 hours after surgery; an increase in serum creatinine by ≥ 1.5 times compared with the initial preoperative level for seven days after intervention; and urine output < 0.5 mL/kg/h for 6 hours during the first 48 h after surgery. | 48 hours after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urine output measure | Urine output values (mL/kg/h) are assessed during cardiopulmonary bypass (CPB). | During cardiopulmonary bypass | 
| Urine neutrophil gelatinase-associated lipocalin concentration measure (uNGAL) | The level of uNGAL (ng/mL) is assessed 4 hours after the surgery. | 4 hours after surgery | 
| Free hemoglobin (Hb) concentration measure | Plasma concentrations of Hg (g/L) are assessed during intraoperative period: before sternotomy, 5 minutes after aortic clamping, 5 minutes after aortic declamping, at the end of surgery, and 24 hours after surgery. | 24 hours after surgery | 
| Nitric oxide metabolite concentration measure | Concentrations of NO metabolites (nitrite (NO2-) and nitrate (NO3-)) (μM/mL) and the total concentration of metabolites of NO (NOx) (μM/mL) in blood plasma are assessed in the intraoperative period: before sternotomy, 5 minutes after aortic clamping, 5 minutes after aortic declamping, at the end of surgery, and 24 hours after surgery. | 24 hours after surgery | 
| Proinflammatory mediator concentration measure | Concentrations of proinflammatory (TNF-α, IL-1β, -6, and -8) (pg/mL) in blood plasma are assessed in the intraoperative period: before sternotomy, at the end of surgery, 6 hours after surgery, and 24 hours after surgery. | 24 hours after surgery | 
| Anti-inflammatory mediator concentration measure | Concentrations of anti-inflammatory mediators (IL-1ra, IL-4) (pg/mL) in blood plasma are assessed in the intraoperative period: before sternotomy, at the end of surgery, 6 hours after surgery, and 24 hours after surgery. | 24 hours after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiopulmonary Bypass, Nitric Oxide, Kidney Function Tests, Renal Insufficiency, Protective Agents, Coronary Artery Bypass, Cardiac Surgery