The Effects of Intermittent Hypoxic-hyperoxic Preconditioning for Patients Undergoing Cardiopulmonary Bypass.

Study Overview
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Brief Summary
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The aim of the study is to evaluate the effects of intermittent hypoxic-hyperoxic training (IHHT) to protect myocardium against perioperative myocardial injury during cardiac surgery using cardiopulmonary bypass.

Detailed Description
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This is a prospective, single-center, randomized controlled clinical trial, which will involve patients over 18 years old who would be recruited consecutively during pre-admission consultation at the I.M Sechenov First Moscow State Medical University Cardiac Surgery Department. All patients with a diagnosis of valvular heart disease, or aortic arch disease and indications for cardiac surgery, according to the European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines. Five days before the operation, patients will be randomly assigned into two groups using a computer-generated randomization table: intermittent hypoxic-hyperoxic training and an intermittent hypoxic-hyperoxic training control group. For both groups laboratory testing (specific biomarkers - C-reactive protein, troponin I, fatty acid-binding protein (FABPs) and lactate) will be performed before training and after the surgery, and the hypoxic-inducible factor (HIF 1 alpha) would be implemented before and after the trainings. Patients in the intermittent hypoxic-hyperoxic training group will undergo four daily procedures of interval hypoxic-hyperoxic training before cardiac surgery, using a normobaric device to obtain hypoxic and hyperoxic gas mixtures (ReOxy Cardio; Aimediq S.A., Luxemburg, Registration certificate in RU P3H 2014/1486). Before the start of the training, each patient would undergo a hypoxic test to assess the individual response to hypoxia, and to determine the rate of reduction of blood oxygen saturation (SpO2) with a finger pulse oximeter (Masimo SET, measurement accuracy ±2%). During 5 minutes the patient will receive air with reduced oxygen content (12%), through a mask under constant monitoring of the heart rate (HR) and SpO2. As a safety measure, minimal SpO2 would be set at 82% and maximal accepted increase of heart rate would be set to +50% of the initial heart rate. When these values would be reached, the supply of oxygen automatically would be switched to a hyperoxic gas mixture (35%-40% O2), inhaling of which would be continued until SpO2 reached 100% (even if SpO2 was lower before the procedure), therefore depending on the rate of saturation reduction, will be taken 1 to 3 minutes (mean 1 min and 50 seconds). The intention is to create hyperoxic arterial oxygen tension and not to simply reduce the time required to recover from hypoxia. Intermittent hypoxic hyperoxic training would be considered successful if there were no significant side effects during the procedure such as angina pain, loss of consciousness, severe dizziness or other variants of significant subjective deterioration of the patient's condition. In the case of successfully passing the test, patients will proceed to the basic intermittent hypoxic hyperemic training. During the training, the hypoxic gas mixture will be given to the patient again in intermittent mode, based on the individual test parameters and alternating with the supply of a hyperoxic gas mixture. One cycle of the procedure consists of hypoxic and hyperoxygenated intervals, the duration of which will be regulated automatically according to the biofeedback principle, based on monitoring of individual values of SpO2 and heart rate. The duration of the hypoxic period ranges from 3 to 5 minutes, and the duration of the hyperoxic period ranges from 1 to 3 minutes, depending on the SpO2 recovery rate. The total time of the hypoxic gas mixture inhaled during one procedure will be 20-30 min. A final training would be conducted in the evening before the surgery. Patients in the intermittent hypoxic-hyperoxic training - control group also will undergo four daily procedures before surgery, using 40 min training periods with simulation of intermittent hypoxic-hyperoxic training by using the same equipment, the patient receives moistened air through a placebo mask under constant monitoring of heart rate and SpO2. Only the person who will conduct the training would know about the patient's allocation to a particular intervention group, the anesthesiologists and cardiac surgeons will not have access to this information. Episodes of cardiac arrhythmias, hypotension with a need for inotropic drug prescription, changes in electrocardiogram, pulse values and blood pressure levels will be recorded during surgery and the postoperative period. Patients will be monitored for 7 days in the hospital, and 30 days after discharge to evaluate the complications. Differences between groups will be assessed using the unpaired Student's t-test or the one-tailed Anova test followed by the Bonferroni post-test. Baseline corrected logistic regression models will be used to estimate the training effect in relation to primary and secondary endpoints. Statistical significance will be set at 0.05 to test hypotheses.

Official Title
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The Effects of Intermittent Hypoxic-hyperoxic Preconditioning for Patients Undergoing Cardiac Surgery Using Cardiopulmonary Bypass and Its Impact on Postoperative Complications.

Conditions
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Valvular Heart Disease, Aortic Arch Aneurysm, Surgery

Intervention / Treatment
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* Device: ReOxy Cardio device, intermittent hypoxic-hyperoxic training ( IHHT)
* Device: ReOxy Cardio device


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Written consent to participate in the study 2. Male or female patients over 18 years 3. Indications for planned replacement of the aortic or mitral valves or operations on the aortic arch. Exclusion Criteria: 1. Individual intolerance to the intermittent hypoxic-hyperoxic training 2. Acute coronary syndrome after hospitalization and before the surgery 3. The presence of an acute infectious process after hospitalization and before the surgery (fever, leukocytosis with a shift leukocyte formula to the left, increased erythrocyte sedimentation rate (ESR), increased C-reactive protein) 4. Uncompensated hypertension at the time of the procedure (systolic blood pres-sure more than 160 mm Hg, diastolic blood pressure more than 110 mm Hg) 5. Loss of consciousness, severe dizziness Non-inclusion criteria: Occlusive atherosclerotic disease of lower limbs, Acute coronary syndrome within 4 weeks before entry Preoperative renal insufficiency (serum creatinine higher than 200 mmol/L), Acute infectious diseases Partial and secondary generalized forms of epilepsy, Uncompensated hypertension (Blood pressure at the time of the procedure: systolic blood pressure more than 160 mm Hg, diastolic blood pressure more than 110 mm Hg) Severe bronchial asthma with the development of respiratory failure of the II-III degree and individual intolerance to oxygen deficiency. 9. Severe hepatic impairment (class C child-Pugh) Intervention type 10. Mental illness (if patients are not capable of understanding the nature, significance and implications of the clinical trial) 11. Myocardial insufficiency as a component of multiple organ failure in decompensation of liver and kidney diseases

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: Supportive Care
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: the intervention group intermittent hypoxic-hyperoxic training<br>the intervention group is patients performing intermittent hypoxic-hyperoxic training before operation. ReOxy Cardio device, intermittent hypoxic-hyperoxic training ( IHHT) Intervention Description: Perform 4 trainings daily of intermittent hypoxic hyperoxic trainings before surgery, using 40 min trainings periods, the patient will receive air with reduced oxygen content (12 %) through a mask under constant monitoring of heart rate (HR) and SpO2. As a safety measure, minimal SpO2 was set at 82 % and maximal accepted increase of heart rate was set to + 50 % of the initial HR. When these values would be reached, the supply of oxygen automatically switched to a hyperoxic gas mixture (35% - 40% O2), inhaling of which would be continued until SpO2 reached 100% (even if SpO2 would be lower before the procedure), which, depending on the rate of saturation reduction, will takes 1 to 3 min (mean 1 min and 50 s). | Device: ReOxy Cardio device, intermittent hypoxic-hyperoxic training ( IHHT)<br>* Perform 4 trainings daily of intermittent hypoxic hyperoxic trainings before surgery, using 40 min trainings periods, the patient will receive air with reduced oxygen content (12 %) through a mask under constant monitoring of heart rate (HR) and SpO2. As a safety measure, minimal SpO2 was set at 82 % and maximal accepted increase of heart rate was set to + 50 % of the initial HR. When these values would be reached, the supply of oxygen automatically switched to a hyperoxic gas mixture (35% - 40% O2), inhaling of which would be continued until SpO2 reached 100% (even if SpO2 would be lower before the procedure), which, depending on the rate of saturation reduction, will takes 1 to 3 min (mean 1 min and 50 s).<br>|
| Placebo Comparator: the control group<br>intermittent hypoxic-hyperoxic training control group will be identical to the main group, also underwent four daily procedures before surgery using 40 min training periods with simulation of intermittent hypoxic-hyperoxic trainings by using the same equipment, whereas moistened air will be delivered through a placebo mask | Device: ReOxy Cardio device<br>* Perform 4 trainings daily of intermittent hypoxic-hyperoxic trainings before surgery, using 40 min trainings periods, whereas moistened air will be delivered through a mask under constant monitoring of heart rate (HR) and SpO2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death from a cardiac cause | Death from cardiac causes during the current hospitalization or 30 days after discharge | The first 30 days from the date of discharge | 
| Myocardial infarction | Myocardial infarction after current surgery and one month after discharge | through study completion, an average of 1 month after discharge | 
| Stroke | Stroke in postoperative period until the date of the discharge | through study completion, an average of 1 month after discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Electrocardiogram deterioration caused by myocardial ischemia; | Electrocardiogram deterioration caused by myocardial ischemia (ST segment elevation or depression, Q wave, negative T wave ) during hospitalization or 30 days after discharge | through study completion, an average of 1 month after discharge | 
| Angina pectoris - typical chest pain III - IV functional class (Canadian Cardiovascular Society classification) | Having an angina pectoris during hospitalization or 30 days after discharge | through study completion, an average of 1 month after discharge | 
| Documented episodes of atrial fibrillation/ atrial flutter. | Documented episodes of atrial fibrillation or atrial flutter during hospitalization or 30 days after discharge | through study completion, an average of 1 month after discharge | 
| Ventricular proarrhythmia requiring additional therapy | Detection of ventricular proarrhythmia during hospitalization or 30 days after discharge | through study completion, an average of 1 month after discharge | 
| Atrioventricular block 2-3 degrees | Atrioventricular block 2-3 degree during hospitalization or 30 days after discharge | through study completion, an average of 1 month after discharge | 
| Episodes of hypotension requiring additional therapy | Episodes of hypotension (systolic blood pressure of less than 90 mmHg/ diastolic of less than 60 mmHg) requiring additional therapy during hospitalization or 30 days after discharge | through study completion, an average of 1 month after discharge | 
| Length of stay in the intensive care unit |  | through study completion, an average of 1month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cardiac pulmonary bypass, reperfusion, interval hypoxic-hyperoxic training, preconditioning, valvular heart disease, aortic arch aneurysm