Effects of Hypoxic-hyperoxic Preconditioning in Cardio-surgical Patients

Effects of Hypoxic-hyperoxic Preconditioning on Myocardial Protection Against Ischemia-reperfusion Injury in Cardio-surgical Patients

Coronary artery bypass grafting (CABG) with cardiopulmonary bypass is a common surgical therapy for patients suffering from coronary artery diseases. The heart is subjected to a long period of ischemia due to the occlusion of the aorta. The heavy burden of myocardial ischemia-reperfusion injury (IRI) thus induces cardiomyocyte death, which can paradoxically reduce the beneficial effect of CABG. Preconditioning by moderate hypoxia or hyperoxia serves as an effective drug-free method to increase the organism's resistance to negative effects, including IRI.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease; Hypoxia; Myocardial Reperfusion Injury; Hyperoxia
• Intervention / Treatment: Procedure: Hypoxic-hyperoxic preconditioning; Procedure: Placebo

Detailed Description

It has been firmly established that the diminished oxygen delivery to the tissues in response to hypoxia is countered by a combination of the increased regional blood flow and the enhanced functional capillary density in the microcirculation. In experimental studies, exposure to hyperoxia for a limited time before ischemia induces a low-grade systemic oxidative stress evokes a preconditioning-like effect on the myocardium and reduces the infarction area by 20%, and the number of arrhythmias after ischemia-reperfusion. One hundred twenty patients were randomly assigned into two equal groups: hypoxic-hyperoxic preconditioning before the surgery (HHP group) and the control group (without preconditioning). Safety control of the preconditioning procedure included ECG monitoring, invasive blood pressure, cardiac output, pulse oximetry, capnography, cerebral oximetry, measurement of anaerobic threshold; acid-base status and metabolic state of arterial and venous blood were assessed once every 10 min during the preconditioning procedure; oxygen balance parameters were calculated. Seventy-two hours before the surgery, an anaerobic threshold was determined to establish a safe oxygen concentration in the respiratory gas mixture during the hypoxic preconditioning phase from 10 to 14%, followed by 75-80% oxygen concentration during the hyperoxic phase.

The hypoxic-hyperoxic preconditioning with individual parameters selection based on the anaerobic threshold in patients with coronary artery diseases before the main stage of cardiac surgery with a cardiopulmonary bypass should reduce the duration of mechanical ventilation, catecholamine support, and frequency of perioperative complications.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• the need for coronary artery bypass grafting (CABG)

Exclusion Criteria:

• age over 75 years
• emergency surgery
• diabetes mellitus
• exacerbation of a chronic disease 1 week before surgery
• any oncological disease at the time of the examination

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hypoxic-hyperoxic preconditioning (HHP); HHP was carried out as follows: breathing with a hypoxic gas mixture for 10 min with the development of hypoxemia, then breathing with a hyperoxic gas mixture for 30 minutes, and at the last stage, a period of breathing with atmospheric air until the cardio-pulmonary bypass is connected. The anaerobic threshold was determined 72 hours before surgery to establish a safe oxygen concentration in the respiratory gas mixture during the hypoxic phase of preconditioning.	Procedure: Hypoxic-hyperoxic preconditioning; Patients were intubated and mechanically ventilated with the target values of PaO2 and PaCO2 (80 - 120 mm Hg and 35 - 45 mm Hg, respectively) under the inhalation anesthesia. HHP was carried out as follows: breathing with a hypoxic gas mixture for 10 min with the development of hypoxemia, then breathing with a hyperoxic gas mixture for 30 minutes, then a period of breathing with atmospheric air (normoxia and normocapnia) until the cardio-pulmonary bypass is connected.; Other Names: HHP
Placebo Comparator: Control; The anaerobic threshold was determined, however, patients in the control group were not preconditioned. Mechanical ventilation was carried out with individual settings maintaining the target values of PaO2 and PaCO2 (80 - 120 mm Hg and 35 - 45 mm Hg, respectively), until the cardio-pulmonary bypass was connected.	Procedure: Placebo; Patients were intubated and mechanically ventilated with the target values of PaO2 and PaCO2 (80 - 120 mm Hg and 35 - 45 mm Hg, respectively) under the inhalation anesthesia until the cardio-pulmonary bypass is connected.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with complications	Any type of complications in postoperative period	60 days
Mechanical ventilation	Mechanical ventilation time	60 days
Rate of spontaneous sinus rhythm recovery	Spontaneous sinus rhythm recovery after surgery	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Catecholamine support	Catecholamine support time	60 days
Troponin T	Troponin T concentration	12 hours
Endothelin-1	Endothelin-1 concentrations	1 day before surgery
Endothelin-1 dynamics 1	Endothelin-1 concentrations	at the end of surgery
Endothelin-1 dynamics 2	Endothelin-1 concentrations	24 hours after surgery
NOx total	NOx total concentrations	1 day before surgery
NOx total dynamics 1	NOx total concentrations	at the end of surgery
NOx total dynamics 2	NOx total concentrations	24 hours after surgery
Asymmetric dimethylarginine (ADMA)	ADMA concentrations	1 day before surgery
ADMA dymanics 1	ADMA concentrations	at the end of surgery
ADMA dymanics 2	ADMA concentrations	24 hours after surgery

Collaborators and Investigators

• Sponsor: Federal Research Clinical Center of Federal Medical & Biological Agency, Russia
• Collaborators: I.M. Sechenov First Moscow State Medical University; Tomsk National Research Medical Center of the Russian Academy of Sciences; Siberian State Medical University
• Investigators: Principal Investigator: Irina A Mandel, PhD, Federal Research Clinical Center FMBA Russia

Publications and helpful links

General Publications

• Mandel IA, Podoksenov YK, Suhodolo IV, An DA, Mikheev SL, Podoksenov AY, Svirko YS, Gusakova AM, Shipulin VM, Yavorovskiy AG. Influence of Hypoxic and Hyperoxic Preconditioning on Endothelial Function in a Model of Myocardial Ischemia-Reperfusion Injury with Cardiopulmonary Bypass (Experimental Study). Int J Mol Sci. 2020 Jul 27;21(15):5336. doi: 10.3390/ijms21155336.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2015
• Primary Completion (Actual): January 15, 2016
• Study Completion (Actual): February 22, 2016

Study Registration Dates

• First Submitted: April 26, 2022
• First Submitted That Met QC Criteria: April 26, 2022
• First Posted (Actual): April 29, 2022

Study Record Updates

• Last Update Posted (Actual): May 9, 2022
• Last Update Submitted That Met QC Criteria: May 6, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: cardiopulmonary bypass; hypoxia; preconditioning; ischemia-reperfusion injury; hyperoxia; myocardial protection; oxygen transport
• Additional Relevant MeSH Terms: Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Postoperative Complications; Signs and Symptoms, Respiratory; Coronary Disease; Cardiomyopathies; Coronary Artery Disease; Reperfusion Injury; Myocardial Reperfusion Injury; Hypoxia; Hyperoxia
• Other Study ID Numbers: HHP-cardio

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No