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

Coronary Artery Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04560309
• Other study ID #: LB.02.01/VII/466/KEP059/202
• Secondary ID: LB.02.01/VII/466
• Status: Completed
• Phase: Phase 3
• Start date: January 1, 2021
• Est. completion date: November 23, 2021

Study information

• Verified date: November 2023
• Source: National Cardiovascular Center Harapan Kita Hospital Indonesia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: November 23, 2021
• Est. primary completion date: October 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cardiopulmonary Bypass
• Coronary Artery Bypass
• Coronary Artery Disease

Intervention

Drug:
• 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.
• Placebo
Intravenous infusion of 500 mL normal saline, started after induction of anesthesia for 24 hours.

Locations

Country	Name	City	State
Indonesia	National Cardiovascular Center Harapan Kita Hospital Indonesia	Jakarta

Sponsors (1)

Lead Sponsor	Collaborator
National Cardiovascular Center Harapan Kita Hospital Indonesia

Country where clinical trial is conducted

Indonesia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Coronary Graft	Number of coronary arteries grafted during operation	Intraoperative
Other	Total Surgical Procedure Time	Total time taken for the surgical procedure. Measured in minutes.	Intraoperative
Other	Cardiopulmonary Bypass Time	Total time measured the patient went under cardiopulmonary bypass. Measured in minutes.	Intraoperative
Other	Aortic Cross-clamping Time	Total time the patient underwent aortic cross-clamping during the surgical procedure. Measured in minutes.	Intraoperative
Primary	Plasma Troponin I at Baseline	Plasma troponin I were measured using enzyme immunoassay (ELISA) in unit of ng/mL	Before induction to anesthesia
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Plasma Glutamine at Baseline	Plasma glutamine were measured using colorimetric tests in unit of 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	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.	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	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	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	5 minute after cardiopulmonary bypass
Secondary	Ejection Fraction	Ejection fraction were measured by transesophageal echocardiography using Simpson method in percentage (%)	Immediately after induction of anesthesia
Secondary	Ejection Fraction	Ejection fraction were measured by transesophageal echocardiography using Simpson method in 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	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	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	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	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	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	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.	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	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.	28 days (or until hospital discharge)