Glutamate for Metabolic Intervention in Coronary Surgery (GLUTAMICS)

• ClinicalTrials.gov Identifier: NCT00489827
• Recruitment Status: Completed
• First Posted: June 21, 2007
• Results First Posted: June 7, 2019
• Last Update Posted: June 16, 2022
• Sponsor: University Hospital, Linkoeping
• Collaborators: Region Örebro County; Blekingesjukhuset, Karlskrona
• Information provided by (Responsible Party): Rolf Svedjeholm, University Hospital, Linkoeping

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Coronary Artery Bypass; Myocardial Ischemia; Myocardial Infarction; Coronary Artery Disease	Drug: Intravenous infusion of saline; Other: Intravenous glutamate infusion	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 865 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Phase III Study of Intravenous Glutamate Infusion for Metabolic Protection of the Heart in Surgery for Unstable Coronary Artery Disease
• Study Start Date: October 2005
• Actual Primary Completion Date: December 2009
• Actual Study Completion Date: October 2015

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Perioperative Myocardial Infarction, Postoperative Heart Failure or Postoperative Mortality [ Time Frame: 30 days ]

Secondary Outcome Measures :

1. Degree of Perioperative Myocardial Injury [ Time Frame: perioperative ]
   p-CK-MB postoperative day 1, p-troponin-T postoperative day 3
2. 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
3. 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)
4. Postoperative Renal Function [ Time Frame: 30 days ]
   maximum p-creatinine value recorded postoperatively < 30 days
5. Number of Participants With Postoperative Stroke < 24 Hours [ Time Frame: 24 hours ]
   Incidence of Postoperative stroke < 24 hours of surgery verifed by CT-scan
6. ICU Stay [ Time Frame: ICU stay ]
   ICU duration of stay (hours)
7. Atrial Fibrillation [ Time Frame: Hospital stay ]
   Number of patients with atrial fibrillation recorded postoperatively
8. 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
9. Long-term Survival [ Time Frame: 6 months - 10 years ]
   Late mortality - related to biochemical markers (troponin-T, mixed venous oxygen saturation, NT-proBNP) and intervention

Eligibility Criteria

• Ages Eligible for Study: up to 85 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Sweden

Blekingesjukhuset, Karlskrona

Karlskrona, Sweden, SE-371 85

University Hospital, Linköping

Linköping, Sweden, SE-581 85

University Hospital, Örebro

Örebro, Sweden, SE 701 85

Sponsors and Collaborators

University Hospital, Linkoeping

Region Örebro County

Blekingesjukhuset, Karlskrona

Investigators

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

More Information

Publications:

Slogoff S, Keats AS. Does perioperative myocardial ischemia lead to postoperative myocardial infarction? Anesthesiology. 1985 Feb;62(2):107-14. doi: 10.1097/00000542-198502000-00002.

Dahlin LG, Olin C, Svedjeholm R. Perioperative myocardial infarction in cardiac surgery--risk factors and consequences. A case control study. Scand Cardiovasc J. 2000 Oct;34(5):522-7. doi: 10.1080/140174300750064710.

Mudge GH Jr, Mills RM Jr, Taegtmeyer H, Gorlin R, Lesch M. Alterations of myocardial amino acid metabolism in chronic ischemic heart disease. J Clin Invest. 1976 Nov;58(5):1185-92. doi: 10.1172/JCI108571.

Thomassen AR, Nielsen TT, Bagger JP, Henningsen P. Myocardial exchanges of glutamate, alanine and citrate in controls and patients with coronary artery disease. Clin Sci (Lond). 1983 Jan;64(1):33-40. doi: 10.1042/cs0640033.

Pisarenko OI, Baranov AV, Aleshin OI, Studneva IM, Pomerantsev EA, Nikolaeva LF, Savchenko AP, Pavlov NA. Features of myocardial metabolism of some amino acids and ammonia in patients with coronary artery disease. Eur Heart J. 1989 Mar;10(3):209-17. doi: 10.1093/oxfordjournals.eurheartj.a059468.

Thomassen A, Botker HE, Nielsen TT, Thygesen K, Henningsen P. Effects of glutamate on exercise tolerance and circulating substrate levels in stable angina pectoris. Am J Cardiol. 1990 Jan 15;65(3):173-8. doi: 10.1016/0002-9149(90)90080-k.

Thomassen A, Nielsen TT, Bagger JP, Pedersen AK, Henningsen P. Antiischemic and metabolic effects of glutamate during pacing in patients with stable angina pectoris secondary to either coronary artery disease or syndrome X. Am J Cardiol. 1991 Aug 1;68(4):291-5. doi: 10.1016/0002-9149(91)90821-2.

Thomassen AR. Myocardial uptake and effects of glutamate during non-ischaemic and ischaemic conditions. A clinical study with special reference to possible interrelationships between glutamate and myocardial utilization of carbohydrate substrates. Dan Med Bull. 1992 Dec;39(6):471-88. No abstract available.

Beyersdorf F, Kirsh M, Buckberg GD, Allen BS. Warm glutamate/aspartate-enriched blood cardioplegic solution for perioperative sudden death. J Thorac Cardiovasc Surg. 1992 Oct;104(4):1141-7.

Pisarenko OI, Portnoy VF, Studneva IM, Arapov AD, Korostylev AN. Glutamate-blood cardioplegia improves ATP preservation in human myocardium. Biomed Biochim Acta. 1987;46(6):499-504.

Suleiman MS, Fernando HC, Dihmis WC, Hutter JA, Chapman RA. A loss of taurine and other amino acids from ventricles of patients undergoing bypass surgery. Br Heart J. 1993 Mar;69(3):241-5. doi: 10.1136/hrt.69.3.241.

Kimose HH, Ravkilde J, Helligso P, Knudsen MA, Thomassen AR, Nielsen TT, Djurhuus JC. Myocardial loss of glutamate after cold chemical cardioplegia and storage in isolated blood-perfused pig hearts. Thorac Cardiovasc Surg. 1993 Apr;41(2):93-100. doi: 10.1055/s-2007-1013829.

Smith RC, Leung JM, Mangano DT. Postoperative myocardial ischemia in patients undergoing coronary artery bypass graft surgery. S.P.I. Research Group. Anesthesiology. 1991 Mar;74(3):464-73. doi: 10.1097/00000542-199103000-00013.

Pisarenko OI, Lepilin MG, Ivanov VE. Cardiac metabolism and performance during L-glutamic acid infusion in postoperative cardiac failure. Clin Sci (Lond). 1986 Jan;70(1):7-12. doi: 10.1042/cs0700007.

Svedjeholm R, Ekroth R, Joachimsson PO, Ronquist G, Svensson S, Tyden H. Myocardial uptake of amino acids and other substrates in relation to myocardial oxygen consumption four hours after cardiac operations. J Thorac Cardiovasc Surg. 1991 Apr;101(4):688-94.

Svedjeholm R, Vanhanen I, Hakanson E, Joachimsson PO, Jorfeldt L, Nilsson L. Metabolic and hemodynamic effects of intravenous glutamate infusion early after coronary operations. J Thorac Cardiovasc Surg. 1996 Dec;112(6):1468-77. doi: 10.1016/S0022-5223(96)70005-3.

Vanhanen I, Hakanson E, Jorfeldt L, Svedjeholm R. Intravenous aspartate infusion after a coronary operation: effects on myocardial metabolism and hemodynamic state. Ann Thorac Surg. 1998 May;65(5):1296-302. doi: 10.1016/s0003-4975(98)00155-6.

Vanhanen I, Svedjeholm R, Hakanson E, Joachimsson PO, Jorfeldt L, Nilsson L, Vanky F. Assessment of myocardial glutamate requirements early after coronary artery bypass surgery. Scand Cardiovasc J. 1998;32(3):145-52. doi: 10.1080/14017439850140102.

Vanhanen I, Hakanson E, Jorfeldt L, Svedjeholm R. Myocardial uptake and release of substrates in patients operated for unstable angina: impact of glutamate infusion. Scand Cardiovasc J. 2003 May;37(2):113-20. doi: 10.1080/14017430310001230.

Svedjeholm R, Hakanson E, Szabo Z, Vanky F. Neurological injury after surgery for ischemic heart disease: risk factors, outcome and role of metabolic interventions. Eur J Cardiothorac Surg. 2001 May;19(5):611-8. doi: 10.1016/s1010-7940(01)00664-9.

Svedjeholm R, Hakanson E, Vanhanen I. Rationale for metabolic support with amino acids and glucose-insulin-potassium (GIK) in cardiac surgery. Ann Thorac Surg. 1995 Feb;59(2 Suppl):S15-22. doi: 10.1016/0003-4975(94)00917-v.

Rau EE, Shine KI, Gervais A, Douglas AM, Amos EC 3rd. Enhanced mechanical recovery of anoxic and ischemic myocardium by amino acid perfusion. Am J Physiol. 1979 Jun;236(6):H873-9. doi: 10.1152/ajpheart.1979.236.6.H873. No abstract available.

Engelman RM, Rousou JA, Flack JE 3rd, Iyengar J, Kimura Y, Das DK. Reduction of infarct size by systemic amino acid supplementation during reperfusion. J Thorac Cardiovasc Surg. 1991 May;101(5):855-9.

Lazar HL, Buckberg GD, Manganaro AJ, Becker H, Maloney JV Jr. Reversal of ischemic damage with amino acid substrate enhancement during reperfusion. Surgery. 1980 Nov;88(5):702-9.

Bittl JA, Shine KI. Protection of ischemic rabbit myocardium by glutamic acid. Am J Physiol. 1983 Sep;245(3):H406-12. doi: 10.1152/ajpheart.1983.245.3.H406.

Haas GS, DeBoer LW, O'Keefe DD, Bodenhamer RM, Geffin GA, Drop LJ, Teplick RS, Daggett WM. Reduction of postischemic myocardial dysfunction by substrate repletion during reperfusion. Circulation. 1984 Sep;70(3 Pt 2):I65-74.

Pisarenko OI, Solomatina ES, Studneva IM, Ivanov VE, Kapelko VI, Smirnov VN. Protective effect of glutamic acid on cardiac function and metabolism during cardioplegia and reperfusion. Basic Res Cardiol. 1983 Sep-Oct;78(5):534-43. doi: 10.1007/BF01906464.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Jiang H, Holm J, Friberg O, Vanky F, Vidlund M, Tajik B, Yang Y, Svedjeholm R. Utility of NT-proBNP as an objective marker of postoperative heart failure after coronary artery bypass surgery: a prospective observational study. Perioper Med (Lond). 2021 Jul 13;10(1):21. doi: 10.1186/s13741-021-00194-4.

Jiang H, Holm J, Vidlund M, Vanky F, Friberg O, Yang Y, Svedjeholm R. The impact of glutamate infusion on postoperative NT-proBNP in patients undergoing coronary artery bypass surgery: a randomized study. J Transl Med. 2020 May 11;18(1):193. doi: 10.1186/s12967-020-02351-7.

Vidlund M, Tajik B, Hakanson E, Friberg O, Holm J, Vanky F, Svedjeholm R. Post hoc analysis of the glutamics-trial: intravenous glutamate infusion and use of inotropic drugs after cabg. BMC Anesthesiol. 2016 Aug 2;16(1):54. doi: 10.1186/s12871-016-0216-z.

Holm J, Vidlund M, Vanky F, Friberg O, Hakanson E, Walther S, Svedjeholm R. EuroSCORE II and N-terminal pro-B-type natriuretic peptide for risk evaluation: an observational longitudinal study in patients undergoing coronary artery bypass graft surgery. Br J Anaesth. 2014 Jul;113(1):75-82. doi: 10.1093/bja/aeu088. Epub 2014 Apr 11.

Holm J, Vidlund M, Vanky F, Friberg O, Hakanson E, Svedjeholm R. Preoperative NT-proBNP independently predicts outcome in patients with acute coronary syndrome undergoing CABG. Scand Cardiovasc J Suppl. 2013 Feb;47(1):28-35. doi: 10.3109/14017431.2012.731518. Epub 2012 Oct 10.

Vidlund M, Holm J, Hakanson E, Friberg O, Sunnermalm L, Vanky F, Svedjeholm R. The S-100B substudy of the GLUTAMICS trial: glutamate infusion not associated with sustained elevation of plasma S-100B after coronary surgery. Clin Nutr. 2010 Jun;29(3):358-64. doi: 10.1016/j.clnu.2009.09.007. Epub 2009 Oct 22.

• Responsible Party: Rolf Svedjeholm, Professor, University Hospital, Linkoeping
• ClinicalTrials.gov Identifier: NCT00489827
• 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 )
• First Posted: June 21, 2007
• Results First Posted: June 7, 2019
• Last Update Posted: June 16, 2022
• Last Verified: May 2022

Keywords provided by Rolf Svedjeholm, University Hospital, Linkoeping:

Coronary Artery Bypass; Myocardial Protection; Angina, Unstable; Myocardial Ischemia; Myocardial Infarction; Unstable Coronary Artery Disease; Glutamate

Additional relevant MeSH terms:

Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Myocardial Infarction; Infarction; Ischemia; Pathologic Processes; Necrosis; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases