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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
60
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.
Intravenous infusion of 500 mL normal saline, started after induction of anesthesia for 24 hours.
National Cardiovascular Center Harapan Kita Hospital Indonesia
Jakarta, Indonesia
Plasma Troponin I at Baseline
Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 48 hour after cardiopulmonary bypass
Plasma Glutamine at Baseline
Plasma glutamine were measured using colorimetric tests in unit of µmol/L
Time frame: Before induction to anesthesia
Plasma Glutamine at 24 Hour After Cardiopulmonary Bypass
Plasma glutamine were measured using colorimetric tests in unit of µmol/L
Time frame: 24 hour after cardiopulmonary bypass
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.
Time frame: 5 minute after cardiopulmonary bypass
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
Time frame: 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
Time frame: 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
Time frame: 5 minute after cardiopulmonary bypass
Ejection Fraction
Ejection fraction were measured by transesophageal echocardiography using Simpson method in percentage (%)
Time frame: Immediately after induction of anesthesia
Ejection Fraction
Ejection fraction were measured by transesophageal echocardiography using Simpson method in percentage (%)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 28 days (or until hospital discharge)
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