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| ID | Type | Description | Link |
|---|---|---|---|
| LB.02.01/VII/466/KEP059/202 | Other Identifier | National Cardiovascular Center Harapan Kita Indonesia |
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Coronary artery disease has the highest mortality rate worldwide and coronary artery bypass grafting (CABG) is the most common cardiac surgery performed in patients with coronary artery disease to revascularize the heart. Despite of improvement in operation techniques, cardioplegia, cardiopulmonary bypass (CPB), myocardial injury related to on-pump CABG is still prominent. In patient with low ejection fraction undergone on-pump CABG, myocardial injury is related to worse outcome and prognosis during peri-operative and post-operative period. On-pump CABG patients with low ejection fraction has increased (up to four times higher) post-operative in hospital mortality rate compared to patient with normal ejection fraction. Administration of intravenous glutamine had been documented in reducing myocardial damage during cardiac surgery and previous studies indicated that glutamine can protect against myocardial injury by various mechanism during ischemia and reperfusion. The purpose of this study to determine whether intravenous glutamine could prevent the decline of plasma glutamine level, reduce myocardial damage, improve hemodynamic profile, and reduce morbidity of on-pump CABG in patients with low ejection fraction.
The study was a double-blind randomized controlled trial to assess the role of glutamine as a myocardial protection during coronary artery bypass grafting under cardiopulmonary bypass in patients with left ventricle ejection fraction of 31-50%. This study was approved by Institutional Review Board of National Cardiovascular Center Harapan Kita and informed consent was obtained before randomization for patient eligible for this study. Allocation of participant to the treatment group was done by block randomization by staff who was not involved in the study. The intervention drug was prepared by pharmacist who also was not involved in the study. Glutamine solution was supplied as L-alanyl-L-glutamine dipeptide (Dipeptiven, 200 mg/mL, Fresenius Kabi, Bad Homburg, Germany) and was prepared to contain 0.5gr/kgbw glutamine diluted in NaCl 0.9% to a final volume of 500 mL. Placebo was supplied as 500 ml of NaCl 0.9%, prepared in similar fashion and packaging as glutamine solution. Principal investigator, care provider, outcome assessor, and participant were blinded to the assigned group until after the end of the study.
Baseline participant characteristics were collected before the intervention included age, sex, body weight, body height, body mass index, and documented pre-operative left ventricle ejection fraction. Coronary artery bypass grafting and cardiopulmonary bypass was done in concordance to standard operating procedure in National Cardiovascular Center Harapan Kita, followed by transit time flow meter measurement to ensure quality of the graft. Modifying factor of the study, the investigators measured duration of surgery, duration of cardiopulmonary bypass, and duration of aortic cross clamp.
The primary outcome of the study was plasma troponin I level. The investigators anticipated plasma troponin I level difference of 20% with standard deviation of 0.04 ng/mL, and for statistical power of 80% and level of significance of 0.05, the required sample size was 24.5 participants per group. As anticipation for participant drop out, the investigators planned to recruit a total of 60 participants.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Glutamine | Experimental | Intravenous L-alanyl-L-glutamine 0.5 mg/kgbw |
|
| Control | Placebo Comparator | Intravenous NaCl 0.9% |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| L-alanyl-L-glutamine dipeptide | Drug | Intravenous infusion of 0.5 mg/kgbw L-alanyl-L-glutamine dipeptide diluted in normal saline to volume of 500 mL, started after induction of anesthesia for 24 hours. |
| Measure | Description | Time Frame |
|---|---|---|
| Plasma Troponin I at Baseline | Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL | Before induction to anesthesia |
| Plasma Troponin I at 5 Minute After Cardiopulmonary Bypass | Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL | 5 minute after cardiopulmonary bypass |
| Plasma Troponin I at 6 Hour After Cardiopulmonary Bypass | Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL | 6 hour after cardiopulmonary bypass |
| Plasma Troponin I at 24 Hour After Cardiopulmonary Bypass | Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL | 24 hour after cardiopulmonary bypass |
| Plasma Troponin I at 48 Hour After Cardiopulmonary Bypass | Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL | 48 hour after cardiopulmonary bypass |
| Plasma Glutamine at Baseline | Plasma glutamine were measured using colorimetric tests in unit of µmol/L | Before induction to anesthesia |
| Plasma Glutamine at 24 Hour After Cardiopulmonary Bypass | Plasma glutamine were measured using colorimetric tests in unit of µmol/L | 24 hour after cardiopulmonary bypass |
| Measure | Description | Time Frame |
|---|---|---|
| Right Atrial Appendage Alpha-ketoglutarate | Right atrial appendage alpha-ketoglutarate were measured from right atrial appendage tissue biopsy using colorimetric tests in unit of g/mol. | 5 minute after cardiopulmonary bypass |
| Right Atrial Appendage Myocardial Injury Score |
| Measure | Description | Time Frame |
|---|---|---|
| Coronary Graft | Number of coronary arteries grafted during operation | Intraoperative |
| Total Surgical Procedure Time | Total time taken for the surgical procedure. Measured in minutes. |
Inclusion Criteria:
Exclusion Criteria:
Drop out Criteria
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| Name | Affiliation | Role |
|---|---|---|
| I Made Adi Parmana | National Cardiovascular Center Harapan Kita Indonesia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Cardiovascular Center Harapan Kita Hospital Indonesia | Jakarta | 11420 | Indonesia |
Individual deidentified participant data reported in this study will be made available on request after publication and ending 36 months following article publication. Researchers needs to state their aims of analyses and provide a methodologically sound proposal. Proposals should be directed to the corresponding author.
Data will be made available after publication until 36 months following article publication
Researchers needs to state their aims of analyses and provide a methodologically sound proposal. Proposals should be directed to the corresponding author.
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Sixty patients with a left ventricle EF of 31-50% who underwent on-pump CABG were included in this study and randomized to treatment. Two patients were dropped out in this study
Participants were recruited based on inclusion criteria. This study was carried out at National Cardiovascular Center Harapan Kita. Written informed consent was obtained from all eligible patients. This study was conducted from January to October 2021.
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| ID | Title | Description |
|---|---|---|
| FG000 | Glutamine | Intravenous L-alanyl-L-glutamine 0.5 mg/kgbw L-alanyl-L-glutamine dipeptide: Intravenous infusion of 0.5 mg/kgbw L-alanyl-L-glutamine dipeptide diluted in normal saline to volume of 500 mL, started after induction of anesthesia for 24 hours. |
| FG001 | Control | Intravenous NaCl 0.9% Placebo: Intravenous infusion of 500 mL normal saline, started after induction of anesthesia for 24 hours. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Glutamine | Intravenous L-alanyl-L-glutamine 0.5 mg/kgbw L-alanyl-L-glutamine dipeptide: Intravenous infusion of 0.5 mg/kgbw L-alanyl-L-glutamine dipeptide diluted in normal saline to volume of 500 mL, started after induction of anesthesia for 24 hours. |
| BG001 | Control |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Plasma Troponin I at Baseline | Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL | Posted | Median | Full Range | ng/mL | Before induction to anesthesia |
|
48 hours
No adverse event reported
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Glutamine | Intravenous L-alanyl-L-glutamine 0.5 mg/kgbw L-alanyl-L-glutamine dipeptide: Intravenous infusion of 0.5 mg/kgbw L-alanyl-L-glutamine dipeptide diluted in normal saline to volume of 500 mL, started after induction of anesthesia for 24 hours. |
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This study has some limitations. Limitations includes the sampling time of right atrial appendage tissue which was only at 5 minutes after CPB. Right atrial appendage tissue was used for apoptotic index assessment using TUNEL staining. Right atrial appendage tissue could not be sampled at 6 hours after CPB because sternal closure was performed prior to 6 hours.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| I Made Adi Parmana, M.D. | Nationcal Cardiovascular Center Harapan Kita | +62 812-4601-212 | adiparmana13@gmail.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP_ICF | Yes | Yes | Yes | Study Protocol, Statistical Analysis Plan, and Informed Consent Form | Dec 1, 2020 | Jan 7, 2023 | Prot_SAP_ICF_000.pdf |
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| ID | Term |
|---|---|
| D003324 | Coronary Artery Disease |
| ID | Term |
|---|---|
| D003327 | Coronary Disease |
| D017202 | Myocardial Ischemia |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| C054122 | alanylglutamine |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
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|
| Placebo | Drug | Intravenous infusion of 500 mL normal saline, started after induction of anesthesia for 24 hours. |
|
|
Right atrial appendage myocardial injury score were measured from tissue section stained with hematoxylin-eosin and examined under by light microscopy in score of 0 (no change) to 3 (major changes with necrosis and diffuse inflammation). Higher scores mean worse outcome |
| 5 minute after cardiopulmonary bypass |
| Right Atrial Appendage Apoptosis Index | Right atrial appendage apoptosis index were measured from tissue section stained with in situ terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and examined under light microscopy in average number of apoptotic cells (positively stained) from 6 random fields per section | 5 minute after cardiopulmonary bypass |
| Anti Cardiac Troponin I Expression | Right atrial appendage anti cardiac troponin I expression were measured from tissue section stained with anti-cardiac troponin I antibody and examined under light microscopy in score of 0 (no change) to -3 (no area observed with anti-cardiac troponin I expression). Higher score mean better outcome | 5 minute after cardiopulmonary bypass |
| Ejection Fraction | Ejection fraction were measured by transesophageal echocardiography using Simpson method in percentage (%) | Immediately after induction of anesthesia |
| Ejection Fraction | Ejection fraction were measured by transesophageal echocardiography using Simpson method in percentage (%) | 5 minutes after cardiopulmonary bypass |
| Cardiac Index | Cardiac index were measured from pulmonary artery catheter using thermodilution method in unit of L/min/m^2 | Immediately after induction of anesthesia, 5 minute, 2 hour, 6 hour, 24 hour after cardiopulmonary bypass |
| Plasma Lactate Before Induction to Anesthesia | Plasma lactate were measured using enzymatic method by blood gas analyser machine in unit of mmol/L | Before induction to anesthesia |
| Plasma Lactate 5 Minute After Cardiopulmonary Bypass | Plasma lactate were measured using enzymatic method by blood gas analyser machine in unit of mmol/L | 5 minute after cardiopulmonary bypass |
| Plasma Lactate 6 Hours After Cardiopulmonary Bypass | Plasma lactate were measured using enzymatic method by blood gas analyser machine in unit of mmol/L | 6 hours after cardiopulmonary bypass |
| Plasma Lactate 24 Hours After Cardiopulmonary Bypass | Plasma lactate were measured using enzymatic method by blood gas analyser machine in unit of mmol/L | 24 hours after cardiopulmonary bypass |
| Plasma Lactate 48 Hours After Cardiopulmonary Bypass | Plasma lactate were measured using enzymatic method by blood gas analyser machine in unit of mmol/L | 48 hours after cardiopulmonary bypass |
| Intensive Care Unit Ventilation Time | Intensive care unit ventilation time were measured from length of time participant was on ventilator in intensive care unit in minutes. | 28 days (or until hospital discharge) |
| Intensive Care Unit Length of Stay | Intensive care unit length of stay were measured from length of time participant spent in intensive care unit in unit of hours | 28 days (or until hospital discharge) |
| Vasoactive Inotropic Score | Vasoactive inotropic score (VIS) were maximum vasoactive and inotropic dose required by participant after surgery measured by VIS=dopamine dose in mg/kgbw/min + dobutamine dose in mg/kgbw/min + 100 x epinephrine dose in mg/kgbw/min + 10 x milrinone dose in mcg/kgbw/min + 10.000 x vasopressin dose in units/kgbw/min + 100 x norepinephrine dose in mcg/kgbw/min. Higher scores means worse outcomes. VIS >= 20 is considered as high VIS and is associated with poor outcomes. | 28 days (or until hospital discharge) |
| Intraoperative |
| Cardiopulmonary Bypass Time | Total time measured the patient went under cardiopulmonary bypass. Measured in minutes. | Intraoperative |
| Aortic Cross-clamping Time | Total time the patient underwent aortic cross-clamping during the surgical procedure. Measured in minutes. | Intraoperative |
Intravenous NaCl 0.9% Placebo: Intravenous infusion of 500 mL normal saline, started after induction of anesthesia for 24 hours. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
|
| Pre-op Ejection Fraction | Median | Full Range | percent |
|
| Units | Counts |
|---|---|
| Participants |
|
|
|
| Primary | Plasma Troponin I at 5 Minute After Cardiopulmonary Bypass | Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL | Posted | Mean | Standard Deviation | ng/mL | 5 minute after cardiopulmonary bypass |
|
|
|
|
| Primary | Plasma Troponin I at 6 Hour After Cardiopulmonary Bypass | Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL | Posted | Mean | Standard Deviation | ng/mL | 6 hour after cardiopulmonary bypass |
|
|
|
|
| Primary | Plasma Troponin I at 24 Hour After Cardiopulmonary Bypass | Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL | Posted | Median | Full Range | ng/mL | 24 hour after cardiopulmonary bypass |
|
|
|
|
| Primary | Plasma Troponin I at 48 Hour After Cardiopulmonary Bypass | Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL | Posted | Median | Full Range | ng/mL | 48 hour after cardiopulmonary bypass |
|
|
|
|
| Primary | Plasma Glutamine at Baseline | Plasma glutamine were measured using colorimetric tests in unit of µmol/L | Posted | Mean | Standard Deviation | μmol/L | Before induction to anesthesia |
|
|
|
|
| Primary | Plasma Glutamine at 24 Hour After Cardiopulmonary Bypass | Plasma glutamine were measured using colorimetric tests in unit of µmol/L | Posted | Mean | Standard Deviation | μmol/L | 24 hour after cardiopulmonary bypass |
|
|
|
|
| Secondary | Right Atrial Appendage Alpha-ketoglutarate | Right atrial appendage alpha-ketoglutarate were measured from right atrial appendage tissue biopsy using colorimetric tests in unit of g/mol. | Posted | Mean | Standard Deviation | g/mol | 5 minute after cardiopulmonary bypass |
|
|
|
|
| Secondary | Right Atrial Appendage Myocardial Injury Score | Right atrial appendage myocardial injury score were measured from tissue section stained with hematoxylin-eosin and examined under by light microscopy in score of 0 (no change) to 3 (major changes with necrosis and diffuse inflammation). Higher scores mean worse outcome | Posted | Mean | Standard Deviation | score on a scale | 5 minute after cardiopulmonary bypass |
|
|
|
|
| Secondary | Right Atrial Appendage Apoptosis Index | Right atrial appendage apoptosis index were measured from tissue section stained with in situ terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and examined under light microscopy in average number of apoptotic cells (positively stained) from 6 random fields per section | Posted | Median | Full Range | cell | 5 minute after cardiopulmonary bypass |
|
|
|
|
| Secondary | Anti Cardiac Troponin I Expression | Right atrial appendage anti cardiac troponin I expression were measured from tissue section stained with anti-cardiac troponin I antibody and examined under light microscopy in score of 0 (no change) to -3 (no area observed with anti-cardiac troponin I expression). Higher score mean better outcome | Posted | Median | Full Range | score on a scale | 5 minute after cardiopulmonary bypass |
|
|
|
|
| Secondary | Ejection Fraction | Ejection fraction were measured by transesophageal echocardiography using Simpson method in percentage (%) | Posted | Median | Full Range | percentage | Immediately after induction of anesthesia |
|
|
|
|
| Secondary | Ejection Fraction | Ejection fraction were measured by transesophageal echocardiography using Simpson method in percentage (%) | Posted | Mean | Standard Deviation | percentage | 5 minutes after cardiopulmonary bypass |
|
|
|
|
| Secondary | Cardiac Index | Cardiac index were measured from pulmonary artery catheter using thermodilution method in unit of L/min/m^2 | Posted | Mean | Standard Deviation | L/min/m^2 | Immediately after induction of anesthesia, 5 minute, 2 hour, 6 hour, 24 hour after cardiopulmonary bypass |
|
|
|
|
| Secondary | Plasma Lactate Before Induction to Anesthesia | Plasma lactate were measured using enzymatic method by blood gas analyser machine in unit of mmol/L | Posted | Median | Full Range | mmol/L | Before induction to anesthesia |
|
|
|
|
| Secondary | Plasma Lactate 5 Minute After Cardiopulmonary Bypass | Plasma lactate were measured using enzymatic method by blood gas analyser machine in unit of mmol/L | Posted | Mean | Standard Deviation | mmol/L | 5 minute after cardiopulmonary bypass |
|
|
|
|
| Secondary | Plasma Lactate 6 Hours After Cardiopulmonary Bypass | Plasma lactate were measured using enzymatic method by blood gas analyser machine in unit of mmol/L | Posted | Median | Full Range | mmol/L | 6 hours after cardiopulmonary bypass |
|
|
|
|
| Secondary | Plasma Lactate 24 Hours After Cardiopulmonary Bypass | Plasma lactate were measured using enzymatic method by blood gas analyser machine in unit of mmol/L | Posted | Mean | Standard Deviation | mmol/L | 24 hours after cardiopulmonary bypass |
|
|
|
|
| Secondary | Plasma Lactate 48 Hours After Cardiopulmonary Bypass | Plasma lactate were measured using enzymatic method by blood gas analyser machine in unit of mmol/L | Posted | Mean | Standard Deviation | mmol/L | 48 hours after cardiopulmonary bypass |
|
|
|
|
| Secondary | Intensive Care Unit Ventilation Time | Intensive care unit ventilation time were measured from length of time participant was on ventilator in intensive care unit in minutes. | Posted | Mean | Standard Deviation | minutes | 28 days (or until hospital discharge) |
|
|
|
|
| Secondary | Intensive Care Unit Length of Stay | Intensive care unit length of stay were measured from length of time participant spent in intensive care unit in unit of hours | Posted | Median | Full Range | hours | 28 days (or until hospital discharge) |
|
|
|
|
| Secondary | Vasoactive Inotropic Score | Vasoactive inotropic score (VIS) were maximum vasoactive and inotropic dose required by participant after surgery measured by VIS=dopamine dose in mg/kgbw/min + dobutamine dose in mg/kgbw/min + 100 x epinephrine dose in mg/kgbw/min + 10 x milrinone dose in mcg/kgbw/min + 10.000 x vasopressin dose in units/kgbw/min + 100 x norepinephrine dose in mcg/kgbw/min. Higher scores means worse outcomes. VIS >= 20 is considered as high VIS and is associated with poor outcomes. | Posted | Median | Full Range | score on a scale | 28 days (or until hospital discharge) |
|
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|
|
| Other Pre-specified | Coronary Graft | Number of coronary arteries grafted during operation | Posted | Median | Full Range | grafts | Intraoperative |
|
|
|
| Other Pre-specified | Total Surgical Procedure Time | Total time taken for the surgical procedure. Measured in minutes. | Posted | Mean | Standard Deviation | minutes | Intraoperative |
|
|
|
| Other Pre-specified | Cardiopulmonary Bypass Time | Total time measured the patient went under cardiopulmonary bypass. Measured in minutes. | Posted | Median | Full Range | minutes | Intraoperative |
|
|
|
| Other Pre-specified | Aortic Cross-clamping Time | Total time the patient underwent aortic cross-clamping during the surgical procedure. Measured in minutes. | Posted | Mean | Standard Deviation | minutes | Intraoperative |
|
|
|
| 0 |
| 30 |
| 0 |
| 30 |
| 0 |
| 30 |
| EG001 | Control | Intravenous NaCl 0.9% Placebo: Intravenous infusion of 500 mL normal saline, started after induction of anesthesia for 24 hours. | 0 | 30 | 0 | 30 | 0 | 30 |
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| D001161 |
| Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
| 2 hours after cardiopulmonary bypass |
|
| 6 hours after cardiopulmonary bypass |
|
| 24 hours after cardiopulmonary bypass |
|
| Unpaired T-Test |
| 0.352 |
The threshold of statistical significance was p < 0.05 |
| Superiority |
| 2 hours after cardiopulmonary bypass | Unpaired T-Test | 0.544 | The threshold of statistical significance was p < 0.05 | Superiority |
| 6 hours after cardiopulmonary bypass | Unpaired T-Test | 0.022 | The threshold of statistical significance was p < 0.05 | Superiority |
| 24 hour after cardiopulmonary bypass | Unpaired T-Test | 0.038 | The threshold of statistical significance was p < 0.05 | Superiority |