Glutamate for Metabolic Intervention in Coronary Surgery (GLUTAMICS)

May 21, 2024 updated by: Rolf Svedjeholm, University Hospital, Linkoeping

Phase III Study of Intravenous Glutamate Infusion for Metabolic Protection of the Heart in Surgery for Unstable Coronary Artery Disease

The main purpose of this study is to determine whether intravenous glutamate infusion given in association with surgery for unstable coronary artery disease can protect the heart from myocardial injury, postoperative heart failure and death.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Myocardial preservation in cardiac surgery has mainly focused on the period when the heart is arrested (cross-clamp time). Today the heart can be arrested for up to 2-3 hours without major consequences. However, in spite of comparatively short cross-clamp times approximately 10% of the patients undergoing coronary surgery sustain significant myocardial injury whereas perioperative myocardial infarction is rare in aortic valve surgery despite longer cross-clamp times. The reason for this is that preoperative ischemia, and to some extent postoperative ischemia, remain major risk factors for development of myocardial infarction in patients with ischemic heart disease. In light of this, we suggest that efforts to improve outcome and reduce permanent myocardial damage should focus on the preoperative and the postoperative phase of coronary surgery. Furthermore, efforts should be instituted to reduce reperfusion injury and minimize permanent myocardial damage in long-standing or severe myocardial ischemia.

Metabolic intervention with intravenous glutamate infusion, offers the prospect of addressing the issues above and extending myocardial protection into the pre- and postoperative phase. Glutamate is an important substrate for the intermediary metabolism of the heart, particularly in association with ischemia. The effects of glutamate are partly related to its role in the malate-aspartate shuttle, transporting reducing equivalents across the mitochondrial membrane, regulating the NAD/NADH balance in the cytosol of the cells, and thereby enhancing anaerobic glycolysis during ischemia. Furthermore, glutamate contributes to an alternative anaerobic pathway for regeneration of high-energy phosphates, by substrate level phosphorylation in the Krebs cycle. Glutamate also improves clearance of metabolic waste produced during ischemia such as lactate and NH3, by taking part in the reactions involving transamination of pyruvate to alanine and of glutamate to glutamine. During reperfusion glutamate contributes to the replenishment of Krebs cycle intermediates lost during ischemia, which is essential for recovery of oxidative metabolism.

Administration of glutamate to patients with stable angina pectoris has been found to increase tolerance to stress-induced ischemia. Ischemia before onset of cardiopulmonary bypass has been established as a major risk factor for postoperative myocardial infarction. Patients with unstable coronary artery disease may have critical ischemia at rest and are particularly vulnerable to the increased oxygen demands during the early stages of coronary surgery. In a pilot study on patients operated urgently for unstable angina we found metabolic signs compatible with improved tolerance to ischemia before surgery and improved recovery of oxidative metabolism during early reperfusion. These results warrant further studies to evaluate the potential clinical benefit of preoperative glutamate infusion extended into the early postoperative period.

Comparisons: Intravenous infusion of 0.125 M glutamic acid solution v saline at a rate of 1.65 ml/hour and kg body weight beginning with institution of anesthesia and stopping 2 hours after unclamping of aorta in patients operated for unstable coronary artery disease.

Preliminary power analysis (80% power; p<0.05) suggests that 2214 patients will be required with regard to primary end-point assuming 30% reduction of events occurring in 12% of untreated patients.

Stage I of the study comprises 800 patients* and will lead to an interim analysis with report of secondary end-points** and recalculation of sample-size with regard to primary end-point. An adaptive design with regard to primary end-point and analysis performed by external statistician blinded to the investigators will be used to avoid increasing the risk for type I error.

*Patient number 800 is anticipated to be enrolled during the summer of 2009 and for practical reasons all patients enrolled until the end of August 2009 will comprise the interim analysis.

**Secondary end-points include analysis of markers for myocardial injury (CK-MB, troponin-T), markers for hemodynamic adequacy (mixed venous oxygen saturation), renal function (p-creatinine, p-Cystatin C), brain injury (S100B, clinical signs). As a substudy a blinded analysis of the value of NT-pro BNP (obtained immediately before surgery, 24 hours postoperatively and on the 3rd postoperative day) as marker of postoperative heart failure and outcome will be conducted. NT-pro BNP will also be related to treatment with glutamate or placebo. Similar evaluation will involve markers troponin-T, p-Cystatin C and mixed venous oxygen saturation. For further details see outcome measures.

Substudies will involve subgroup analyses of patients with regard to combined CABG + valve procedures, severely unstable patients requiring emergency surgery / intravenous nitrates, preoperative LV-dysfunction and patients with diabetes. For further details see outcome measures.

Study Type

Interventional

Enrollment (Actual)

865

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

  • Sweden
      • Karlskrona, Sweden, SE-371 85
        • Blekingesjukhuset, Karlskrona
      • Linköping, Sweden, SE-581 85
        • University Hospital, Linköping
      • Örebro, Sweden, SE 701 85
        • University Hospital, Örebro

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

No older than 85 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • surgery for unstable coronary artery disease (unstable angina, non-STEMI)
  • accepted for surgery < 2 weeks after STEMI
  • coronary surgery for indications above performed with or without cardiopulmonary bypass
  • coronary surgery for indications above with or without simultaneous valve procedure

Exclusion Criteria:

  • informed consent not possible because of critical condition or other reason
  • preoperative use of inotropes or mechanical circulatory assist
  • preoperative dialysis
  • redo-procedure
  • unexpected intraoperative finding / event that increased the dignity of the procedure to overshadow the originally planned operation
  • body weight > 125 kg
  • food allergy known to have caused flush, rash or asthma

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: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Intravenous glutamate
Intravenous infusion of 0.125 M glutamic acid solution at a rate of 1.65 ml/hour and kg body weight beginning with institution of anesthesia and stopping 2 hours after unclamping of aorta in patients operated for unstable coronary artery disease.
Other: Intravenous glutamate infusion
Intravenous infusion of 0.125 M glutamic acid solution at a rate of 1.65 ml/hour and kg body weight beginning with institution of anesthesia and stopping 2 hours after unclamping of aorta in patients operated for unstable coronary artery disease.
Placebo Comparator: Saline infusion
Intravenous infusion of saline at a rate of 1.65 ml/hour and kg body weight beginning with institution of anesthesia and stopping 2 hours after unclamping of aorta in patients operated for unstable coronary artery disease.
Drug: Intravenous infusion of saline
Intravenous infusion of isotonic saline at a rate of 1.65 ml/hour and kg body weight beginning with institution of anesthesia and stopping 2 hours after unclamping of aorta in patients operated for unstable coronary artery disease.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Number of Participants With Perioperative Myocardial Infarction, Postoperative Heart Failure or Postoperative Mortality
Time Frame: 30 days
30 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Degree of Perioperative Myocardial Injury
Time Frame: perioperative
p-CK-MB postoperative day 1, p-troponin-T postoperative day 3
perioperative
Postoperative Hemodynamic State
Time Frame: Until arrival to ICU
Mixed venous oxygen saturation (SvO2) measured at weaning from cardiopulmonary bypass and on arrival to ICU
Until arrival to ICU
Postoperative Hemodynamic State in Patients With Severely Reduced Left Ventricular Ejection Fraction (LVEF<0.40)
Time Frame: End of surgery
Hemodynamic instability despite inotropes or need for IABP at the end of surgery in patients with severely reduced left ventricular ejection fraction (LVEF<0.40)
End of surgery
Postoperative Renal Function
Time Frame: 30 days
maximum p-creatinine value recorded postoperatively < 30 days
30 days
Number of Participants With Postoperative Stroke < 24 Hours
Time Frame: 24 hours
Incidence of Postoperative stroke < 24 hours of surgery verifed by CT-scan
24 hours
ICU Stay
Time Frame: ICU stay
ICU duration of stay (hours)
ICU stay
Atrial Fibrillation
Time Frame: Hospital stay
Number of patients with atrial fibrillation recorded postoperatively
Hospital stay
Severe Circulatory Failure in CCS Class IV Patients
Time Frame: 30 days
Severe circulatory failure according to prespecified criteria as judged by a blinded endpoints committee in CCS class IV patients
30 days
10-year Survival
Time Frame: 10 year - survival (crude)
10-year survival - related to intervention. Last follow-up August 3, 2022. Follow-up time ranged from 12.7-16.8 years.
10 year - survival (crude)
Postoperative Mortality
Time Frame: 30 days
Postoperative mortality within 30 days of surgery
30 days

Collaborators and Investigators

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

Sponsor

University Hospital, Linkoeping

Collaborators

Region Örebro County
Blekingesjukhuset, Karlskrona

Investigators

  • Study Director: Rolf Svedjeholm, MD PhD, University Hospital, Linkoeping

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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

October 1, 2005

Primary Completion (Actual)

December 1, 2009

Study Completion (Actual)

August 1, 2022

Study Registration Dates

First Submitted

June 19, 2007

First Submitted That Met QC Criteria

June 20, 2007

First Posted (Estimated)

June 21, 2007

Study Record Updates

Last Update Posted (Actual)

May 22, 2024

Last Update Submitted That Met QC Criteria

May 21, 2024

Last Verified

May 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 151:2003/70403
  • 20030595 (Registry Identifier: 151/2003/70403 Swedish Medical Product Agency))
  • M76-05 (Other Identifier: Regional Ethical Review Board in Linkoping)

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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