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

Perioperative Nitric Oxide Prevents Acute Kidney Injury in Cardiac Surgery Patients With Chronic Kidney Disease

Acute Kidney Disease

Chronic Kidney Disease

Cardiac Surgery

Cardiopulmonary Bypass

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.

Sham treatment

80-ppm NO

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)

Difference between groups in the incidence of AKI in patients with CKD are assessed as
percentage after cardiac surgery according to KDIGO criteria.

MD, PhD, Head of Laboratory

Difference between groups in the incidence of low cardiac output syndrome (decrease in
the incidence of low cardiac output syndrome) with the definition of its type (with
dysoxia, without dysoxia, microcirculatory distress). It is a combined point and includes
an increase (or various combinations of these parameters according to the cardiovascular
profile in shock) of serum lactate more than 2 mmol/L, a decrease in central venous blood
saturation of less than 70%, an increase in the arterio-venous carbon dioxide difference
of more than 6 mm Hg, and the need for intra-aortic balloon counterpulsation or other
extracorporeal methods of circulatory support within 24 hours after surgery.

Difference between groups in regional kidney near-infrared oximetry (rSO2, %): before
sternotomy, at the CPB, 6 hours and 24 hours after surgery.

Difference between groups in terms of ΔPCO2/ΔContO2: before sternotomy, 6 hours and 24
hours after surgery.

Difference between groups in severity of AKI as defined by the KDIGO guidelines:

Stage 1 AKI is diagnosed when serum creatinine rises 1.5 to 1.9 times its baseline and
preoperative values within seven days postoperatively, or when it rises ≥0.3 mg/dL (≥26.5
μm/l) within 48 hours after the intervention, and also if urine output is <0.5 ml/kg/h
for 6-12 hours in the first postoperative period.

Stage 2 AKI is diagnosed when serum creatinine increases 2.0 to 2.9 times its
preoperative baseline values within 7 days postoperatively and urine output is <0.5
ml/kg/h more than 12 hours after surgery.

Stage 3 AKI is diagnosed when serum creatinine rises 3 times its preoperative baseline
values within seven days post-intervention, or when it rises to ≥ 4.0 mg/dl (≥ 353.6
μm/L) within 48 hours after the intervention, or if there is a need for renal replacement
therapy, and also, if the urine output was <0.3 ml / kg / h within 24 hours after
surgery.

Difference between groups in the duration of AKI: transient (less than 48 hours) and
persistent.

Difference between groups in the level of NO in exhaled air at baseline, on admission to
the ICU, 6 hours later and 24 hours after surgery.

Difference between groups in the frequency of need for renal replacement therapy during
hospitalization.

Difference between groups in the frequency of major kidney complications during
hospitalization. Major adverse kidney events (MAKE) are a composite endpoint and include
death, new episodes of kidney replacement therapy, and deterioration in renal function
(GFR decrease of 25% or more from baseline).

Difference between groups in the incidence of incomplete recovery of renal function
(decrease in GFR by more than 10% compared with preoperative levels), or persistent renal
dysfunction (defined as an increase in serum creatinine 1.5 times the baseline values or
≥0.5 mg / dL (44 µmol/L) compared with preoperative level) at discharge from the
hospital.

Difference between groups in the level of organ dysfunction and mortality risk measured
on a scale Sequential Organ Failure Assessment (SOFA) in the first 24 hours after
surgery. Minimum score is 0, maximum score is 24. A higher score indicates an increased
risk of mortality.

Difference between groups in the maximum requirement for inotropic and vasopressor drugs
assessed as the vasoactive-inotropic score (VIS). VIS is calculated as follows: dose of
dopamine (mcg/kg/min) + dose of dobutamine ( mcg/kg/min) + 100 x dose of epinephrine
(mcg/kg/min) + 10 x dose of milrinone (mcg/kg/min) + 10,000 x dose of vasopressin
(u/kg/min) + 100 x dose of norepinephrine (mcg /kg/min) + 10 × dose of phenylephrine
(mcg/kg/min).

Difference between groups in the duration of mechanical ventilation (hours).

Difference between groups in the length of ICU stay (days).

Difference between groups in the length of hospital stay (days).

Difference between groups in hospital mortality rate.

Difference between groups in mortality rate within 30 days after surgery.

Difference between groups in the incidence of neurological complications of type 1
(stroke, transient ischemic attack, coma) during hospitalization.

Difference between groups in the incidence of neurological complications of type 2
(delirium, early postoperative cognitive dysfunction, first-onset seizures) during
hospitalization.

Difference between groups in platelet counts 24 hours after surgery.

Difference between groups in the volume of postoperative bleeding, which is calculated as
the total blood loss through drains during the stay in the ICU.

Difference between groups in the frequency of blood transfusion or transfusion of blood
components during the period of stay in the ICU.

Differences between groups in the incidence of major adverse cardiac events (MACE) during
hospitalization and within 30 days after surgery. Major adverse cardiac events - combined
endpoint: myocardial infarction, pacing requirement for >48 hours, cardiac arrest.

Differences between groups in the incidence of other postoperative complications (acute
respiratory failure requiring noninvasive ventilation or reintubation, pneumonia,
vasoplegia, wound infections, sepsis, readmission to the ICU) to be determined according
to standard ESA/ESICM definitions where possible.

Oxygen-air mixture without NO after intubation, during CPB, and six hours after surgery.

NO will be supplemented at 80-ppm concentration to cardiac surgery patients perioperative
after trachea intubation, during CPB, and six hours after surgery.

Perioperative Nitric Oxide Prevents Acute Kidney Injury in Cardiac Surgery Patients With Chronic Kidney Disease

About this trial

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Type

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Placebo

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What is this trial about?

What are the participation requirements?

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