Effect of glutamate infusion on NT-proBNP after coronary artery bypass grafting in high-risk patients (GLUTAMICS II): A randomized controlled trial

Abstract

Background Animal and human data suggest that glutamate can enhance recovery of myocardial metabolism and function after ischemia. N-terminal pro-brain natriuretic peptide (NT-proBNP) reflects myocardial dysfunction after coronary artery bypass surgery (CABG). We investigated whether glutamate infusion can reduce rises of NT-proBNP in moderate- to high-risk patients after CABG. Methods and findings A prospective, randomized, double-blind study enrolled patients from November 15, 2015 to September 30, 2020, with a 30-day follow-up at 4 academic cardiac surgery centers in Sweden. Patients underwent CABG ± valve procedure and had left ventricular ejection fraction ≤0.30 or EuroSCORE II ≥3.0. Intravenous infusion of 0.125 M L-glutamic acid or saline at 1.65 mL/kg/h started 10 to 20 minutes before releasing the aortic cross-clamp, then continued for another 150 minutes. Patients, staff, and investigators were blinded to the treatment. The primary endpoint was the difference between preoperative and day-3 postoperative NT-proBNP levels. Analysis was intention to treat. We studied 303 patients (age 74 ± 7 years; females 26%, diabetes 47%), 148 receiving glutamate group and 155 controls. There was no significant difference in the primary endpoint associated with glutamate administration (5,390 ± 5,396 ng/L versus 6,452 ± 5,215 ng/L; p = 0.086). One patient died ≤30 days in the glutamate group compared to 6 controls (0.7% versus 3.9%; p = 0.12). No adverse events linked to glutamate were observed. A significant interaction between glutamate and diabetes was found (p = 0.03). Among patients without diabetes the primary endpoint (mean 4,503 ± 4,846 ng/L versus 6,824 ± 5,671 ng/L; p = 0.007), and the incidence of acute kidney injury (11% versus 29%; p = 0.005) was reduced in the glutamate group. These associations remained significant after adjusting for differences in baseline data. The main limitations of the study are: (i) it relies on a surrogate marker for heart failure; and (ii) the proportion of patients with diabetes had almost doubled compared to the cohort used for the sample size estimation. Conclusions Infusion of glutamate did not significantly reduce postoperative rises of NT-proBNP. Diverging results in patients with and without diabetes agree with previous observations and suggest that the concept of enhancing postischemic myocardial recovery with glutamate merits further evaluation. Trial registration ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02592824. European Union Drug Regulating Authorities Clinical Trials Database (Eudra CT number 2011-006241-15).

Glutamate infusion associated with reduced rises of p‐Copeptin after coronary surgery: Substudy of GLUTAMICS II

“…The sample size must be considered as glutamate was associated with a significantly lower incidence of acute kidney injury in the main study, which included patients from all participating centres. 14 Elevated p-Copeptin has previously been reported to be associated with acute kidney injury. 23 Renal function is sensitive to circulatory failure and some degree of renal failure is frequently seen after cardiac surgery.…”

“…The main limitation of this study is that although it was prespecified the findings among patients without diabetes were exploratory, and only motivated by the interaction between glutamate and diabetes detected in the main study. 14 The time points for sampling were adapted to the main study which focused on NT-proBNP and, hence, the early peak of p-Copeptin was not caught. Other limitations include sample size and the unexpectedly high proportion of patients with diabetes.…”

“…The full study protocol has been published. 14 The GLUTAMICS II trial including the substudy was registered at ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02592824.…”

“…However, subgroup analyses and post hoc analyses of the first GLUTAMICS trial suggested that glutamate infusion mitigated postoperative myocardial dysfunction in high-risk groups except in patients with diabetes. [10][11][12][13][14] In the second GLUTAMICS trial, postoperative rise of NT-proBNP was significantly reduced in patients without diabetes. 14 Copeptin is a 39 amino acid glycopeptide and the C-terminal part of pro-Arginine Vasopressin.…”

“…[10][11][12][13][14] In the second GLUTAMICS trial, postoperative rise of NT-proBNP was significantly reduced in patients without diabetes. 14 Copeptin is a 39 amino acid glycopeptide and the C-terminal part of pro-Arginine Vasopressin. [15][16][17] The Arginine Vasopressin (AVP) system is activated in critical illness by changes in blood volume, plasma osmolarity and cardiac output.…”