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

November 9, 2023 updated by: I Made Adi Parmana, National Cardiovascular Center Harapan Kita Hospital Indonesia

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.

Study Overview

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.

Study Type

Interventional

Enrollment (Actual)

60

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Jakarta, Indonesia, 11420
        • National Cardiovascular Center Harapan Kita Hospital Indonesia

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Glutamine
Intravenous L-alanyl-L-glutamine 0.5 mg/kgbw
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.
Other Names:
  • Dipeptiven
Placebo Comparator: Control
Intravenous NaCl 0.9%
Intravenous infusion of 500 mL normal saline, started after induction of anesthesia for 24 hours.
Other Names:
  • Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Plasma Troponin I at Baseline
Time Frame: Before induction to anesthesia
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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: Before induction to anesthesia
Plasma glutamine were measured using colorimetric tests in unit of µmol/L
Before induction to anesthesia
Plasma Glutamine at 24 Hour After Cardiopulmonary Bypass
Time Frame: 24 hour after cardiopulmonary bypass
Plasma glutamine were measured using colorimetric tests in unit of µmol/L
24 hour after cardiopulmonary bypass

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Right Atrial Appendage Alpha-ketoglutarate
Time Frame: 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.
5 minute after cardiopulmonary bypass
Right Atrial Appendage Myocardial Injury Score
Time Frame: 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
5 minute after cardiopulmonary bypass
Right Atrial Appendage Apoptosis Index
Time Frame: 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
5 minute after cardiopulmonary bypass
Anti Cardiac Troponin I Expression
Time Frame: 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
5 minute after cardiopulmonary bypass
Ejection Fraction
Time Frame: Immediately after induction of anesthesia
Ejection fraction were measured by transesophageal echocardiography using Simpson method in percentage (%)
Immediately after induction of anesthesia
Ejection Fraction
Time Frame: 5 minutes after cardiopulmonary bypass
Ejection fraction were measured by transesophageal echocardiography using Simpson method in percentage (%)
5 minutes after cardiopulmonary bypass
Cardiac Index
Time Frame: 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
Immediately after induction of anesthesia, 5 minute, 2 hour, 6 hour, 24 hour after cardiopulmonary bypass
Plasma Lactate Before Induction to Anesthesia
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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.
28 days (or until hospital discharge)
Intensive Care Unit Length of Stay
Time Frame: 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
28 days (or until hospital discharge)
Vasoactive Inotropic Score
Time Frame: 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.
28 days (or until hospital discharge)

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Coronary Graft
Time Frame: Intraoperative
Number of coronary arteries grafted during operation
Intraoperative
Total Surgical Procedure Time
Time Frame: Intraoperative
Total time taken for the surgical procedure. Measured in minutes.
Intraoperative
Cardiopulmonary Bypass Time
Time Frame: Intraoperative
Total time measured the patient went under cardiopulmonary bypass. Measured in minutes.
Intraoperative
Aortic Cross-clamping Time
Time Frame: Intraoperative
Total time the patient underwent aortic cross-clamping during the surgical procedure. Measured in minutes.
Intraoperative

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: I Made Adi Parmana, National Cardiovascular Center Harapan Kita Indonesia

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2021

Primary Completion (Actual)

October 30, 2021

Study Completion (Actual)

November 23, 2021

Study Registration Dates

First Submitted

September 7, 2020

First Submitted That Met QC Criteria

September 17, 2020

First Posted (Actual)

September 23, 2020

Study Record Updates

Last Update Posted (Estimated)

November 13, 2023

Last Update Submitted That Met QC Criteria

November 9, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

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.

IPD Sharing Time Frame

Data will be made available after publication until 36 months following article publication

IPD Sharing Access Criteria

Researchers needs to state their aims of analyses and provide a methodologically sound proposal. Proposals should be directed to the corresponding author.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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