Role of Glutamine as Myocardial Protector in Elective On-Pump Coronary Artery Bypass Graft Surgery With Low Ejection Fraction

Role of Glutamine as Myocardial Protector in Elective On-Pump Coronary Artery Bypass Graft Surgery With Low Ejection Fraction

Role of Glutamine as Myocardial Protector in Elective On-Pump Coronary Artery Bypass Graft Surgery With Low Ejection Fraction

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.

Glutamine, Myocardial protection, Coronary artery bypass grafting, Cardiopulmonary bypass, Low ejection fraction, Myocardial injury

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.

Right atrial appendage alpha-ketoglutarate were measured from right atrial appendage tissue biopsy using colorimetric tests in unit of nmol/mg.

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).

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

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)

Ejection fraction were measured by transesophageal echocardiography using Simpson method in percentage (%)

Cardiac index were measured from pulmonary artery catheter using thermodilution method in unit of mL/min/m^2

Intensive care unit ventilation time were measured from length of time participant was on ventilator in intensive care unit in unit of hours

Intensive care unit length of stay were measured from length of time participant spent in intensive care unit in unit of hours

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

Inclusion Criteria: Patients with coronary heart disease indicated for elective coronary artery bypass grafting under cardiopulmonary bypass Patients with left ventricle ejection fraction 31% -50% confirmed by echocardiography or radio nuclear study. Patients age ≥18 years Never had heart surgery before Agree to participate in the study and signed informed consent Exclusion Criteria: Emergency coronary artery grafting bypass Having additional procedures other than coronary artery bypass grafting History of myocardial infarction with onset less than 3 months Patients with serum creatinine level more than 2 g/dL Patients with ALT/AST levels more than 1.5 times the upper limit of normal value Required to use intra-aortic balloon pump pre-operatively History of stroke with onset less than 3 months History of pre-operative atrial fibrillation History of heart conduction problem and/or using a pacemaker Patients with HIV Contraindications to pulmonary artery catheter insertion Drop out Criteria Experiencing stroke after surgery Experiencing surgery related complication (haemorrhage) requiring re operation Requiring continuous veno-venous hemofiltration or haemodialysis after surgery Delayed sternal closure Aortic cross clamp duration more than 120 minutes and/or cardiopulmonary bypass time more than 180 minutes