Jonas Holm, Gabriele Ferrari, Anders Holmgren, FarkasVanky, ÖrjanFriberg, MårtenVidlund, Rolf Svedjeholm
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.
Introduction
The contractile function of the heart is directly linked to substrate metabolism [1]. Glutamate plays a key role in myocardial metabolism during ischemia and reperfusion [2–6]. Ischemic heart disease is characterized by an increase in the myocardial consumption of glutamate [7,8]. The high fractional extraction rates of glutamate observed across the myocardium early after coronary artery bypass surgery suggest that a transient substrate deficiency occurs in these conditions [9]. In animal models, glutamate administration has been reported to facilitate the recovery of myocardial metabolism and contractile function after severe ischemia [3–6]. In cardiac surgery, glutamate has been used as an additive in cardioplegic solutions, but as cold cardioplegia has been reported to be associated with myocardial loss of glutamate other forms of administration might be preferable [10].
Materials and methods
Study design
The GLUTAmate for Metabolic Intervention in Coronary Surgery II (GLUTAMICS II) trial was investigator initiated and designed as a prospective, externally randomized, placebo-controlled, double-blind trial with parallel assignment to glutamate or placebo (saline). The study and its amendments were approved by the Swedish Medical Products Agency (Dnr 151:2011/96689; Dnr 5.1-2015-77379; Dnr 5.1-2016-62288; Dnr 5.1-2017-71108). The latest study protocol is presented in the S1 Protocol. The trial was registered at the European Union Drug Regulating Authorities Clinical Trials Database (Eudra CT number 2011-006241-15) and at ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02592824.
This trial is reported according to the Consolidated Standards of Reporting Trials statement (S1 Checklist).
Results
Patient characteristics
We analyzed a total of 303 patients, 148 in the glutamate group and 155 in the control group. The mean ages were, respectively, 73 ± 7 years versus 75 ± 7 years; p = 0.004. The glutamate group had a lower mean EuroSCORE II than the control group (4.6 ± 2.1% versus 5.2 ± 2.5%; p = 0.02), and a higher estimated creatinine clearance (69 ± 24 mL/min versus 63 ± 23 mL/min; p = 0.01). The proportions of patients with diabetes were high in both groups (49% versus 46%). Detailed patient characteristics are given in Table 1.
Discussion
The main finding of this study in moderate- to high-risk patients undergoing CABG is that intravenous glutamate infusion during the first hours of reperfusion did not significantly reduce rise of plasma NT-proBNP from preoperative level to the third postoperative day. However, a significant interaction was found between diabetes and glutamate that affected the primary endpoint.
Acknowledgments
The authors thank M Fredriksson (Linköping University statistical adviser) for assistance with statistical analyses. The authors acknowledge assistance from research nurses IngerHuljebrant (Linköping), Mika Hickisch (Örebro), TittiTollefsen and AnnelieSandström (Umeå), Eva Linde and Linda Thimour-Bergström (Gothenburg). Forum Östergötland in Linköping coordinated external monitoring aided by AvdelningenförKliniskaPrövningar, AKP in Örebro, and KlinisktForskningscentrum, KFC in Umeå.
Citation: Holm J, Ferrari G, Holmgren A, Vanky F, Friberg Ö, Vidlund M, et al. (2022) Effect of glutamate infusion on NT-proBNP after coronary artery bypass grafting in high-risk patients (GLUTAMICS II): A randomized controlled trial. PLoS Med 19(5): e1003997. https://doi.org/10.1371/journal.pmed.1003997
Academic Editor: Martin Schreiber, Oregon Health and Science University, UNITED STATES
Received: January 17, 2022; Accepted: April 22, 2022; Published: May 9, 2022
Copyright: © 2022 Holm et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Data cannot be shared publicly because of patient confidentiality under current Swedish legislation. Data are available for researchers who meet the criteria for access to confidential data. Requests for data access should be directed to the Head of the Division of Diagnostics and Specialist Medicine at Linköping University: https://liu.se/en/organisation/liu/hmv/disp.
Funding: This work was supported by grants from The Swedish Heart-Lung Foundation(RS) [Grant 20140633] https://www.hjart-lungfonden.se/om-oss/in-english/ and by grants from Region Östergötland (RS) [RÖ 796412, RÖ 693091, RÖ 610951] https://www.regionostergotland.se/Forskning-och-innovation/Forskningsstrategi-och-malbild/Forskningsfinansiering/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation fo the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: AKI, acute kidney injury; CABG, coronary artery bypass grafting; CCS, Canadian Cardiovascular Society; CK-MB, creatine kinase-MB isoenzyme; COVID-19, Coronavirus Disease 2019; CPB, cardiopulmonary bypass; CRF, case report form; CT, computed tomography; EuroSCORE II, European System for Cardiac Operative Risk Evaluation II; GLUTAMICS, GLUTAmate for Metabolic Intervention in Coronary Surgery; IABP, intra-aortic balloon pump; ICU, intensive care unit; IQR, interquartile range; NT-proBNP, N-terminal pro-brain natriuretic peptide; SUSAR, suspected unexpected adverse reaction
https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003997#abstract0
