Clinical trial NCT05757557: Perioperative Nitric Oxide Prevents Acute Kidney Injury in Cardiac Surgery Patients With Chronic Kidney Disease
Official title: Perioperative Nitric oxiDE-conditioning, Produced by Plasma-chemical Synthesis Technology, For prevEnt Acute kidNey Injury During carDiac surgEry in Patients With chRonic Kidney Disease (DEFENDER-trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Acute Kidney Disease
Chronic Kidney Disease
Cardiac Surgery
Cardiopulmonary Bypass
Keywords: Acute Kidney Disease
Nitric Oxide
Chronic Kidney Disease
Cardiopulmonary Bypass
Cardiac Surgery
Prevention
Lead sponsor: Tomsk National Research Medical Center of the Russian Academy of Sciences
Sponsor class: OTHER
First posted: 2023-03-07
Enrollment: 136
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The protective nitric oxide (NO) effects are mediated by selective pulmonary vasodilation and improvement of arterial oxygenation in hypoxemic patients by reducing intrapulmonary shunting and improving ventilation-perfusion coordination. Inhaled NO has been used for years to treat acute respiratory failure and pulmonary hypertension in anesthesia and intensive care. The nephroprotective role of NO was studied in an experimental model of contrast-induced nephropathy. The primary aim of this prospective, double-blind, randomized, parallel-group, controlled trial is to test the hypothesis that perioperative conditioning of patients with NO at a dose of 80 ppm, obtained by plasma-chemical synthesis technology, through a ventilator and an extracorporeal circulation circuit reduces the incidence of acute kidney injury (AKI) in patients with an initially high risk of kidney damage due to the presence of preoperative chronic kidney disease (CKD). The study is interventional. Examination and treatment of patients is carried out in accordance with the approved standards of medical care for the relevant diseases. During the study, no experimental or unregistered (not approved for use) medical or diagnostic procedures in the territory of the Russian Federation will be carried out. The study includes patients admitted to the Cardiac Surgery Department of Cardiology Research Institute of Tomsk NRMC for elective surgery with high risk of AKI in the perioperative period

Detailed description: NO abruptly relaxes vascular smooth muscle, leading to pulmonary vasodilation without appreciable hemodynamic effect on extrapulmonary vessels (selective pulmonary vasodilation). In addition, NO expands the smooth muscle of constricted bronchi, which may improve arterial oxygenation in hypoxemic patients by reducing intrapulmonary shunting and improving ventilation-perfusion coordination. NO has been used for many years to treat acute respiratory failure and pulmonary hypertension in anesthesia and intensive care. Several experimental and clinical studies have demonstrated extrapulmonary effects of NO, predominantly on diuresis and natriuresis, platelet function, and modulation of the immune response. The nephroprotective role of NO was studied in an experimental model of contrast-induced nephropathy.

This study is prospective, double-blind, randomized, parallel-group, controlled trial. In regard to medical procedures, this study is interventional. Examination and treatment of patients is carried out in accordance with the approved standards of medical care for the relevant diseases. During this study, no experimental or unregistered (not approved for use) medical or diagnostic procedures in the territory of the Russian Federation is carried out.

The primary aim of the study is to test the hypothesis that perioperative conditioning of patients with NO at a dose of 80 ppm, obtained by plasma-chemical synthesis technology, through a ventilator and an extracorporeal circulation circuit reduces the incidence of AKI in patients with an initially high risk of kidney damage due to the presence of preoperative CKD.

Secondary objectives of the study include the following:

* To test the hypothesis that perioperative conditioning of patients with NO at a dose of 80 ppm, obtained using plasma-chemical synthesis technology, through the ventilator circuit and the extracorporeal circulation circuit is associated with an improvement in regional kidney oximetry.
* To test the hypothesis that the method of monitoring regional kidney oximetry in the para-infrared spectrum is an effective intraoperative method for quantifying the organoprotective effect of NO-therapy.
* To test the hypothesis that perioperative conditioning of patients with NO at a dose of 80 ppm, obtained by plasma-chemical synthesis technology, through the ventilator circuit and the extracorporeal circulation circuit is associated with optimization of endogenous NO homeostasis, determined by the level of NO in the air exhaled by the patient.
* To test the hypothesis that perioperative conditioning of patients with NO at a dose of 80 ppm, obtained using plasma-chemical synthesis technology, through the ventilator circuit and the extracorporeal circulation circuit is associated with an improvement in the global oxygen status of the body, assessed using ΔPCO2/ΔContO2.
* To test the hypotheses that perioperative conditioning of patients with NO at a dose of 80 ppm, obtained using the plasma-chemical synthesis technology through the ventilator circuit and the extracorporeal circulation circuit, reduces the frequency and severity of other organ damage and complications: cardiac, pulmonary, hemorrhagic, neurological, infectious complications, multiple organ failure after surgery, duration of mechanical ventilation, time of stay in the intensive care unit, in-hospital and 30-day mortality in patients with CKD.

Currently, there is no convincing evidence of the benefits or harms of additional NO therapy as part of the anesthesia management of cardiac surgery in patients at high risk of developing AKI. Therefore, there is no reason to believe that randomization into study groups creates additional risks/benefit for patients.

Regardless of the results of randomization, the decision on the relevance of perioperative administration of NO for cardiac surgery in each case is made by a medical consultation, including a cardiac surgeon, an anesthesiologist and a cardiologist immediately after the patient is included in the study.

The study includes patients admitted to the Cardiac Surgery Department of the Research Institute of Cardiology, Tomsk National Research Medical Center for elective surgery, and who have a high risk of AKI in the perioperative period. The frequency of AKI was chosen as the primary endpoint because the manifestation of multiple organ damage in the vast majority of cases begins with renal dysfunction. AKI is a self-perpetuating condition that causes respiratory, cardiac, and cerebral failure.

After patients enter the operating room, they are randomly assigned to the study intervention group (80 ppm NO) or control group. The devices available in the clinic, discussed above, that perform synthesis, supply of inhaled NO, and monitor NO, nitrogen dioxide (NO2) in the supply line directly during therapy, will be used NO. In the NO group, the final concentration of NO is 80 ppm. Patients in the control group will receive a standard NO-free oxygen-air mixture. NO will be supplied immediately after the patient is intubated through the anesthesia machine circuit throughout the operation, followed by the NO delivery through the oxygenator of the cardiopulmonary bypass (CPB) machine throughout the CPB, after weaning from the CPB through the anesthesia machine circuit until the end of the operation and within 6 hours after interventions through the ventilator circuit or through a face mask if the patient will be extubated earlier.

The choice of NO dose and exposure time for clinicians is based on two basic principles:

1. the applied dose of NO and its exposure time are safe for patients;
2. the applied dose of NO and its exposure time are sufficient to provide potential protective effects.

Devices for NO therapy (for the delivery of NO at all stages of the study) are developed at the Research and Production Center for Physics of the Federal State Unitary Enterprise "Russian Federal Nuclear Center - All-Russian Research Institute of Experimental Physics".

For the delivery of nitric oxide at all stages of the study, a device for plasma-chemical synthesis of nitric oxide will be used. For production and for all processes of the product life cycle, the International Certificate of Conformity ISO 13485:2016 Medical Devices - Quality Management Systems, No. GKRU-0072-MD has been received. The device used in this study makes it possible to produce nitric oxide from the air in a gas discharge by generating a repetitively pulsed diffuse discharge excited in an atmospheric pressure air in a gap with a sharply nonuniform electric field. Such a discharge ensures efficient synthesis of nitric oxide in a nonequilibrium low-temperature plasma.

In this study a multimodal approach will be applied to reduce the incidence of acute kidney injury after cardiac surgery. Strategies for optimizing renal outcomes will be applied during the study. Implementation of the Kidney Disease: Improving Global Outcomes guidelines for nephroprotection will be the standard for all patients during the study (Close monitoring of renal function; Functional haemodynamic monitoring; Optimizing fluid status and haemodynamics; Avoidance of hyperglycaemia; Avoidance of radiocontrast and discontinuation of nephrotoxic medications). During CPB, all patients will receive a goal-directed perfusion strategy. In this study it is aimed to maintain a high-normal oxygen delivery target at \> 280 ml min m2.

Thus, this study is supposed to assess the potential benefit of perioperative NO conditioning in the era of proven technologies for preventing AKI and determine its potential relevance in the concept of multimodal protection.

Eligibility criteria: Inclusion Criteria:

* Cardiac surgery with CPB
* Age \> 18 years
* Signed informed consent
* CKD (cGFR \<60 mL/min/1.73 m2)
* Positive decision of council of physicians on individual safety of perioperative administration of NO

Exclusion Criteria:

* Emergency surgery (including that in ACS)
* cGFR \<15 mL/min/1.73 m2
* Administration of potentially nephrotoxic drugs within 24 hours before surgery (radiocontrast agents, antimicrobial therapy with aminoglycosides and / or amphotericin)
* Critical preoperative status (preoperative need for mechanical ventilation, inotropes, circulatory support)
* Pregnancy
* Ongoing enrolment in other randomized clinical trial
* Previous randomization in DEFENDER trial
* Active endocarditis and/or sepsis
* Pulmonary hypertension higher than stage II (systolic pulmonary pressure over 65 mmHg according to data of preoperative transthoracic echocardiography
* Condition after kidney transplantation
* Ongoing AKI caused by glomerulonephritis, interstitial nephritis, renal artery occlusion, or postrenal occlusion
* Cardiac surgery with hypothermic circulatory arrest
* Left ventricular ejection fraction \< 30%
* Single kidney

Primary outcomes:
measure: Incidence of AKI (%)
timeFrame: 7 days
Secondary outcomes:
measure: Incidence of low cardiac output syndrome (%)
timeFrame: 24 hours
measure: Regional tissue oxygen saturation levels (rSO2, %)
timeFrame: 24 hours
measure: ΔPCO2/ΔContO2 (ratio)
timeFrame: 24 hours
measure: AKI Severity (degree)
timeFrame: 7 days
measure: AKI duration (hours)
timeFrame: Seven days
measure: Level of NO in exhaled air (ppm)
timeFrame: 1st day after operation
measure: Renal replacement therapy need (%)
timeFrame: 14 days
measure: Major adverse kidney events (%)
timeFrame: 30 days
measure: Incidence of incomplete recovery of renal function (%)
timeFrame: 30 days
measure: Maximum severity of multiple organ failure (SOFA scale)
timeFrame: 24 hours
measure: Vasoactive-inotropic score (VIS)
timeFrame: 24 hours
measure: Duration of mechanical ventilation (hours)
timeFrame: 21 days
measure: ICU stay (days)
timeFrame: 30 days
measure: Hospital stay (days)
timeFrame: 30 days
measure: Hospital mortality (%)
timeFrame: 14 days
measure: 30-day mortality rate (%)
timeFrame: 30 days
measure: Incidence of neurological complications of type 1 (stroke, transient ischemic attack, coma) (%)
timeFrame: 14 days
measure: Incidence of neurological complications of type 2 (delirium, early postoperative cognitive dysfunction, first-onset seizures) (%)
timeFrame: 14 days
measure: Platelet count
timeFrame: 24 hours
measure: Postoperative bleeding (mL)
timeFrame: 24 hours
measure: Incidence of blood or blood component transfusion (%)
timeFrame: Seven days
measure: Incidence of major adverse cardiac events (MACE) (%)
timeFrame: 30 days
measure: Incidence of other postoperative complications (%)
timeFrame: 30 days
Other outcomes:
measure: Subclinical AKI
timeFrame: 24 hours
measure: Subclinical intestinal injury
timeFrame: 24 hours
measure: Subclinical myocardial damage
timeFrame: 24 hours
Locations:
city: Tomsk
country: Russian Federation
facility: Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences
state: Russia
Study officials:
affiliation: Cardiology Research Institute, Tomsk National Research Medic
name: Nikolay O Kamenshchikov, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: