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Glutamate for metabolic intervention in coronary surgery: with special reference to the GLUTAMICS-trial
Örebro University, School of Health and Medical Sciences.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Myocardial ischemia is a major cause of postoperative heart failure and adverse outcome in coronary artery bypass graft surgery (CABG). Conventional treatment of postoperative heart failure with inotropic drugs may aggravate underlying ischemic injury. Glutamate has been claimed to increase myocardial tolerance to ischemia and promote metabolic and hemodynamic recovery after ischemia. The aim of this work was to investigate if intravenous glutamate infusion given in association with CABG for acute coronary syndrome can reduce mortality and prevent or mitigate myocardial injury and postoperative heart failure. We also wanted to assess neurological safety issues, as a concern with the use of glutamate is that it may act as an excitotoxin under certain conditions.A metabolic strategy for perioperative care was assessed in an observational study on 104 consecutive patients with severe left ventricular dysfunction undergoing CABG. Based on encouraging clinical results, unsurpassed in the literature, the GLUTAMICS-trial was initiated. 861 patients undergoing CABG for acute coronary syndrome were randomly allocated to blinded intravenous infusion of L-glutamicacid solution or saline. The primary endpoint was a composite of postoperative mortality (≤30 days), perioperative myocardial infarction and left ventric ular heart failure in association with weaning from cardiopulmonary bypass. Secondary endpoints included neurological safety issues, degree of myocardial injury,postoperative hemodynamic state, use of circulatory support and cardiac mortality.The event rate was lower than anticipated and the primary endpoint did not differ significantly between the groups. Regarding secondary endpoints there were significant differences compatible with a beneficial effect of glutamate on post-ischemic myocardial recovery. The putative effect of glutamate infusion was seen in more ischemic patients (CCS class IV) and in patients with evident or anticipated LV-failure on weaning from CPB. No evidence for increased incidence of clinical or subclinical neurological injury was found. In conclusion, intravenous glutamate infusion is safe in the dosages employed and could provide a novel and important way of promoting myocardial recovery after ischemic injury.

Place, publisher, year, edition, pages
Örebro: Örebro universitet , 2011. , 87 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 58
Keyword [en]
myocardial ischemia, coronary artery bypass, cardiac surgery, acute coronary syndrome, glutamate, metabolic intervention, postoperative heart failure, myocardial recovery
National Category
Medical and Health Sciences Clinical Medicine Surgery
Research subject
Surgery
Identifiers
URN: urn:nbn:se:oru:diva-19757ISBN: 978-91-7668-824-3 (print)OAI: oai:DiVA.org:oru-19757DiVA: diva2:446486
Public defence
2011-11-11, Wilandersalen, Universitetssjukhuset, Örebro, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2011-10-07 Created: 2011-10-07 Last updated: 2017-10-17Bibliographically approved
List of papers
1. A metabolic protective strategy could improve long-term survival in patients with LV-dysfunction undergoing CABG
Open this publication in new window or tab >>A metabolic protective strategy could improve long-term survival in patients with LV-dysfunction undergoing CABG
2010 (English)In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 44, no 1, 45-58 p.Article in journal (Refereed) Published
Abstract [en]

Objective. Adverse outcome after CABG is closely related to postoperative heart failure precipitated by ischemia and myocardial infarction. Restrictive use of inotropes is therefore desirable. Patients with preoperative left ventricular dysfunction are a high-risk group in this respect. To reduce myocardial oxygen expenditure we evolved a metabolic strategy for perioperative care. Design. Observational study on 104 consecutive patients with severe left ventricular dysfunction undergoing CABG. The metabolic strategy implied physiological measures to minimize myocardial oxygen expenditure including restrictive use of inotropes and specific measures such as extended CPB and metabolic support to facilitate myocardial recovery. Hemodynamic state was primarily assessed by mixed venous oxygen saturation (SvO(2)). Follow-up averaged 9.7 +/- 1.4 years. Results. LVEF was 0.30 +/- 0.05 (range 0.20-0.37) and 3.5 +/- 1.3 vessels were bypassed. Inotropes were used in 6.7% for weaning from CPB. Increase of s-creatinine by >= 50% compared to preoperative values was observed in 2.9%. Logistic EuroSCORE was 8.3% whereas observed 30-day mortality was 1.0%. Crude 5-year survival was 89.4%. Conclusions. The metabolic strategy allowed restrictive use of inotropes and was associated with encouraging long-term survival. Renal function was well preserved suggesting that SvO(2) served as an adequate marker of circulation. Randomized trials with metabolic support are warranted.

Place, publisher, year, edition, pages
Oslo: Taylor & Francis, 2010
Keyword
coronary-artery-bypass, left-ventricular dysfunction, glucose-insulin-potassium, ischemic cardiomyopathy, ejection fraction, cardiac-surgery, myocardial revascularization, cardiopulmonary bypass, follow-up, heart-failure
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-20137 (URN)10.3109/14017430903531008 (DOI)
Available from: 2011-10-21 Created: 2011-10-21 Last updated: 2017-12-08Bibliographically approved
2. The S-100B substudy of the GLUTAMICS-trial: glutamate infusion not associated with sustained elevation of plasma S-100B after coronary surgery
Open this publication in new window or tab >>The S-100B substudy of the GLUTAMICS-trial: glutamate infusion not associated with sustained elevation of plasma S-100B after coronary surgery
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2010 (English)In: Clinical Nutrition, ISSN 0261-5614, E-ISSN 1532-1983, Vol. 29, no 3, 358-364 p.Article in journal (Refereed) Published
Abstract [en]

Background & aimsConcerns have been raised about potential neurological injury related to exogenous glutamate. In cardiac surgery glutamate has been administered as a putative cardioprotective agent by cardioplegia or intravenous infusion. In the GLUTAMICS trial, in addition to surveillance of clinical neurological injuries, a prespecified subgroup was analyzed with regard to postoperative S-100B levels to detect potential subclinical neurological injury related to glutamate infusion.MethodsSixty-nine patients operated on for unstable coronary syndrome were randomized to intravenous infusion of glutamate (n=35) or saline (n=34) perioperatively. Plasma levels of S-100B were obtained on the third postoperative day.ResultsS-100B in the glutamate group and the control group were 0.079±0.034μg/L and 0.090±0.042μg/L respectively (p=0.245). There were no patients with stroke or mortality. Three patients in the control group and two in the glutamate group had postoperative confusion. These patients had significantly elevated S-100B compared with those without confusion (0.132±0.047vs 0.081±0.036μg/L; p=0.003). Overall, 21 patients had S-100B above reference level (≥0.10μg/L) and these patients had significantly more calcifications in the ascending aorta on epiaortic scanning.ConclusionsIntravenous glutamate infusion during surgery for unstable coronary artery disease did not initiate a sustained elevation of plasma S-100B. Thus, no evidence for subclinical neurological injury related to glutamate infusion was found. In contrast, postoperative elevation of plasma S-100B was linked to calcification of the ascending aorta and postoperative confusion.

Keyword
Glutamate, Neurological injury, Nutrition, Coronary artery bypass surgery, Myocardial protection, Stroke
National Category
Medical and Health Sciences Surgery
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-20138 (URN)10.1016/j.clnu.2009.09.007 (DOI)
Note

Mårten Vidlund is also affiliated to Univ Hosp Orebro, Dept Cardiothorac Surg & Anesthesia, Orebro, Sweden.

Available from: 2011-10-21 Created: 2011-10-21 Last updated: 2017-12-08Bibliographically approved
3. GLUTAMICS: a randomized clinical trial on glutamate infusion in patients operated for acute coronary syndrome
Open this publication in new window or tab >>GLUTAMICS: a randomized clinical trial on glutamate infusion in patients operated for acute coronary syndrome
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2011 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Glutamate has been claimed to protect the heart from ischemia and to facilitate metabolic and hemodynamic recovery after ischemia. The GLUTAMICS-trial investigated if intravenous glutamate infusion given in association with surgery for acute coronary syndrome can reduce mortality and prevent or mitigate myocardial injury and postoperative heart failure. Methods: In this investigator-initiated prospective, double-blind study 861 patients undergoing surgery for acute coronary syndrome in three Swedish Hospitals were randomly assigned to intravenous infusion of glutamate (n=428) or saline (n=433) perioperatively. The primary endpoint was a composite of postoperative mortality (30 days), perioperative myocardial infarction and left ventricular heart failure on weaning from cardiopulmonary bypass. Results: Thirty-day mortality was 0.9 % in the glutamate group and 1.2% in the control group. Cardiac mortality was 0.2% in the glutamate group and 0.9% the control group. The incidence of the composite primary end point was 7.2% in the glutamate group and 5.8% in the control group. None of these differences were statistically significant. Regarding secondary end points significantly fewer patients in the glutamate group were hemodynamically unstable at completion of surgery (0.3% v 1.8%; p=0.035) or in need of intra-aortic balloon pump on arrival to the intensive care unit (0.0% v 1.2%; p=0.026). In patients with severe unstable angina (CCS class IV; n=475) the incidence of severe circulatory failure according to prespecified criteria was significantly lower in the glutamate group (2.6% v 6.6%; p=0.036). Conclusions: The primary endpoint did not differ significantly between the groups. Regarding secondary end points there were significant differences compatible with a beneficial effect of glutamate on myocardial recovery. (ClinicalTrials.gov Identifier: NCT00489827)

National Category
Medical and Health Sciences Surgery
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-20140 (URN)10.1016/S0735-1097(11)60938-8 (DOI)
Available from: 2011-10-21 Created: 2011-10-21 Last updated: 2017-10-17Bibliographically approved
4. The influence of inotropic drugs on the outcome of the GLUTAMICS trial
Open this publication in new window or tab >>The influence of inotropic drugs on the outcome of the GLUTAMICS trial
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences Surgery
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-20141 (URN)
Available from: 2011-10-21 Created: 2011-10-21 Last updated: 2017-10-17Bibliographically approved

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