Role of Glutamine as Myocardial Protector in Elective On-Pump CABG Surgery With Low EF

Phase 3

Completed

Conditions: Coronary Artery Bypass
Cardiopulmonary Bypass
Coronary Artery Disease

Interventions: Drug: L-alanyl-L-glutamine dipeptide
Drug: Placebo

Registration Number: NCT04560309

Lead Sponsor: National Cardiovascular Center Harapan Kita Hospital Indonesia

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 60

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Glutamine	L-alanyl-L-glutamine dipeptide	Intravenous L-alanyl-L-glutamine 0.5 mg/kgbw
Control	Placebo	Intravenous NaCl 0.9%

Primary Outcome Measures

Name	Time	Method
Plasma Troponin I at 24 Hour After Cardiopulmonary Bypass	24 hour after cardiopulmonary bypass	Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL
Plasma Glutamine at Baseline	Before induction to anesthesia	Plasma glutamine were measured using colorimetric tests in unit of µmol/L
Plasma Glutamine at 24 Hour After Cardiopulmonary Bypass	24 hour after cardiopulmonary bypass	Plasma glutamine were measured using colorimetric tests in unit of µmol/L
Plasma Troponin I at 5 Minute After Cardiopulmonary Bypass	5 minute after cardiopulmonary bypass	Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL
Plasma Troponin I at 6 Hour After Cardiopulmonary Bypass	6 hour after cardiopulmonary bypass	Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL
Plasma Troponin I at Baseline	Before induction to anesthesia	Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL
Plasma Troponin I at 48 Hour After Cardiopulmonary Bypass	48 hour after cardiopulmonary bypass	Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL

Secondary Outcome Measures

Name	Time	Method
Anti Cardiac Troponin I Expression	5 minute after cardiopulmonary bypass	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
Plasma Lactate Before Induction to Anesthesia	Before induction to anesthesia	Plasma lactate were measured using enzymatic method by blood gas analyser machine in unit of mmol/L
Intensive Care Unit Length of Stay	28 days (or until hospital discharge)	Intensive care unit length of stay were measured from length of time participant spent in intensive care unit in unit of hours
Right Atrial Appendage Alpha-ketoglutarate	5 minute after cardiopulmonary bypass	Right atrial appendage alpha-ketoglutarate were measured from right atrial appendage tissue biopsy using colorimetric tests in unit of g/mol.
Right Atrial Appendage Myocardial Injury Score	5 minute after cardiopulmonary bypass	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
Right Atrial Appendage Apoptosis Index	5 minute after cardiopulmonary bypass	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
Ejection Fraction	5 minutes after cardiopulmonary bypass	Ejection fraction were measured by transesophageal echocardiography using Simpson method in percentage (%)
Plasma Lactate 48 Hours After Cardiopulmonary Bypass	48 hours after cardiopulmonary bypass	Plasma lactate were measured using enzymatic method by blood gas analyser machine in unit of mmol/L
Plasma Lactate 5 Minute After Cardiopulmonary Bypass	5 minute after cardiopulmonary bypass	Plasma lactate were measured using enzymatic method by blood gas analyser machine in unit of mmol/L
Plasma Lactate 6 Hours After Cardiopulmonary Bypass	6 hours after cardiopulmonary bypass	Plasma lactate were measured using enzymatic method by blood gas analyser machine in unit of mmol/L
Vasoactive Inotropic Score	28 days (or until hospital discharge)	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.
Cardiac Index	Immediately after induction of anesthesia, 5 minute, 2 hour, 6 hour, 24 hour after cardiopulmonary bypass	Cardiac index were measured from pulmonary artery catheter using thermodilution method in unit of L/min/m\^2
Plasma Lactate 24 Hours After Cardiopulmonary Bypass	24 hours after cardiopulmonary bypass	Plasma lactate were measured using enzymatic method by blood gas analyser machine in unit of mmol/L
Intensive Care Unit Ventilation Time	28 days (or until hospital discharge)	Intensive care unit ventilation time were measured from length of time participant was on ventilator in intensive care unit in minutes.