Glutamate for Metabolic Intervention in Coronary Surgery II (GLUTAMICSII)

Region Örebro County, University Hospital, Umeå, Sahlgrenska University Hospital, Sweden, Blekinge County Council Hospital, Uppsala University Hospital, Sweden

The aim of GLUTAMICS II is to evaluate whether intravenous glutamate infusion surgery reduces the risk of postoperative heart failure as measured by plasma NT-proBNP in patients undergoing moderate to high-risk coronary artery bypass graft surgery. Patients accepted for coronary artery bypass surgery of at least two vessel disease or left main stenosis with or without concomitant procedure and considered to be at moderate to high surgical risk preoperatively with regard to postoperative heart failure will be studied. The primary endpoint is postoperative increase of NT-proBNP from the day before surgery to the third postoperative day.

In spite of the progress in cardiac surgery and perioperative management postoperative heart failure remains the leading cause of death and organ failure. Although acknowledged as a major problem in cardiac surgery there are no generally accepted criteria for the diagnosis of postoperative heart failure. This in turn could explain why treatment for postoperative heart failure is poorly documented with regard to clinical outcome. Ischemia prior to cardiopulmonary bypass is the main cause of myocardial infarction after CABG. Available data demonstrate that ischemia and evolving myocardial infarction account for a large proportion of patients with postoperative heart failure after CABG. Conventional treatment of postoperative heart failure presents a therapeutic dilemma as inotropic drugs not only aggravate ischemia and increase the size of evolving myocardial infarction, but also stimulate apoptotic processes that may have adverse long-term consequences. The role of inotropes in cardiac surgery is therefore controversial. Some authors claim that liberal use of inotropes and goal-directed haemodynamic therapy can improve outcome whereas other report that liberal use of inotropes is associated with increased morbidity and mortality. Alternative measures that can enhance myocardial recovery and function without putting further strain on the heart are therefore desirable. Glutamate could influence outcome after myocardial ischemia by two different biochemical mechanisms. First, glutamate improves myocardial tolerance to ischemia by facilitated anaerobic metabolism and substrate level phosphorylation during ischemia. The second mechanism is related to the anaplerotic role of glutamate. Glutamate plays a key role for replenishment of Krebs cycle intermediates lost during ischemia, which enhances post-ischemic recovery of myocardial oxidative metabolism and function. Promoting metabolic and functional recovery with metabolic support represents a novel concept in the treatment of heart failure after acute ischemia. Animal experiments suggest that glutamate increases myocardial tolerance to ischemia and that glutamate promotes post-ischemic recovery. Intravenous glutamate improved metabolic and hemodynamic recovery in humans early after CABG. Early clinical experience with intravenous metabolic support showed that the need for inotropes could be substantially reduced while clinical outcomes with regard to postoperative mortality, postoperative renal dysfunction and long-term survival compared favourably with the literature. This encouraging experience contributed to the initiation of the first GLUTAMICS-trial. The first GLUTAMICS-trial investigated if intravenous glutamate infusion given in association with surgery for acute coronary syndrome could prevent myocardial injury, postoperative heart failure and reduce mortality. The study was negative with regard to the primary endpoint, which was a composite of postoperative mortality, perioperative myocardial infarction and left ventricular failure at weaning from cardiopulmonary bypass. However, the study included a high proportion of low risk patients. Furthermore, the design of the primary endpoint suffered from liberal preemptive use of inotropes in patients anticipated to have weaning problems. It became evident at clinical endpoint committee meetings that preemptive use of inotropes prevented detection of weaning problems in patients who later developed severe heart failure. The secondary endpoint severe circulatory failure discriminated mild short-lasting heart failure at weaning from cardiopulmonary bypass from clinically significant heart failure requiring substantial circulatory support and leading to prolonged ICU stay or death. In the glutamate treated patients the relative risk of developing severe circulatory failure was reduced by more than 50% in most risk groups undergoing isolated CABG. The first GLUTAMICS trial also included a substudy consisting of a blinded evaluation of NT-proBNP as a marker for postoperative heart failure. Due to the lack of generally accepted criteria for postoperative heart failure, the evaluation of treatment is difficult. Consequently, comparative studies on different treatment strategies of heart failure after cardiac surgery are sparse given the magnitude of the problem. Natriuretic peptides have been extensively studied in cardiology. In patients with chronic heart failure markedly increased BNP and NT-pro BNP levels are associated with poor prognosis. The response of natriuretic peptides to heart failure treatment has significant prognostic implications, and non-responders have a poor prognosis. In cardiac surgery NT-proBNP increase was more pronounced in patients requiring inotropes. High postoperative levels of BNP and NT-proBNP were associated with worse outcome, both in the short- and long-term. The first GLUTAMICS-trial permitted a blinded prospective evaluation of NT-proBNP by a clinical end-points committee relying on strict prespecified criteria with regard to postoperative heart failure. Data to be published demonstrate that postoperative NT-proBNP (day 1 and day 3) levels were strong predictors for severe heart failure associated with extended ICU stay or death. This implies that postoperative NT-proBNP could serve as a measure to assess efficacy of treatment and preventive strategies for postoperative heart failure. Albeit, a surrogate marker for postoperative heart failure it provides the advantage of a standardized and objective analysis, which makes the study reproducible. AIM The aim is to confirm findings in subgroups from the first GLUTAMICS-trial that intravenous glutamate infusion reduces the risk of postoperative heart failure in moderate to high risk patients undergoing coronary artery surgery by showing a reduced increase of NT-proBNP postoperatively. PATIENTS Patients accepted for coronary artery bypass surgery of at least two vessel disease or left main stenosis with or without concomitant procedure considered to be at moderate to high surgical risk preoperatively with regard to postoperative heart failure. 310 patients are planned to be included after informed written consent. Exclusion criteria: patients with ambiguous food allergies that trigger shortness of breath, headache or flushing; patients> 85 years, previous cardiac surgery, patients who are in such bad condition that they cannot be asked to participate, patients who for linguistic or other reasons are unable to provide informed consent, severe renal failure with preoperative dialysis or calculated GFR <30 mL / min, patients requiring inotropic drugs or mechanical circulatory support (intra-aortic balloon pump) due to circulatory failure even before they enrolled in the study, patients who undergo surgery without the heart-lung machine (off-pump), patients who undergo concomitant Maze-procedure or surgery of ascending aorta. STUDY DESIGN The GLUTAMICS II is an investigator initiated prospective, randomized, placebo controlled, double-blind trial with parallel assignment to glutamate or placebo (saline). The trial is externally randomized and randomization is stratified for patients undergoing isolated CABG and for those having CABG with concomitant procedure. INTERVENTION Patients are randomly allocated to blinded intravenous infusion of 0.125M L-glutamic acid solution or saline at a rate of 1.65 ml/kg and hour commencing at or up to 20 minutes before the release of aortic cross-clamp. The infusion is continued for two hours after declamping the aorta after which an additional 50 ml is given at a halved infusion rate. PRIMARY ENDPOINT The primary endpoint is a postoperative increase of NT-proBNP from the day before surgery to the third postoperative day. SECONDARY ENDPOINTS Secondary endpoints are the absolute postoperative plasma levels of NT-proBNP day 1 and day 3. SAFETY VARIABLES Postoperative mortality (30 days + hospitals), stroke within 24 hours and SUSARs SAMPLE SIZE Sample size is based on available results from the first GLUTAMICS study. In that study, the following increase of NT-proBNP from the preoperative value to third postoperative day (mean ± SD) were observed in patients with LVEF ≤ 0.30 or EuroSCORE II ≥ 3.0 undergoing coronary artery surgery for with or without concomitant procedure. Glutamate (n=71): 5261 ± 4409 Placebo (n=62): 7112 ± 6454 Sample size assessment by external statistical expertise (80% power, 5% risk level; two-sided test) suggests 141 patients in each group. To account for failed sampling and other loss we plan a total of 310 patients. INTERIM ANALYSIS Interim analysis will be performed by an external independent statistician after 160 patients by an adaptive design as reported in detail to the Swedish Medical Product Agency. Update August 30, 2020: Interim analysis in December 2017 supported the original sample size assessment and the aim was set to reach 300 patients with complete data for the primary endpoint. The original goal of 280 patients with complete data has been reached and the study is approaching 300 but as study solutions will expire September 30, 2020 this will be the last date for inclusion of patients into the trial. ETHICAL CONSIDERATIONS A concern with the use of glutamate is that it may act as an excitotoxin under certain conditions and participate in events leading to neurological damage. However, brain tissue concentrations of glutamate are more than fifty-fold higher than in blood whereas the dosage used only elevates blood levels three-fold. Neurological outcome has been carefully monitored when intravenous infusions have been used in clinical practice without evidence of adverse effects. No evidence of subclinical neurological injury associated with intravenous glutamate infusion could be detected by the S-100B measurements and no differences in neurological outcome or other adverse events were found in the GLUTAMICS trial. After written informed consent eligible patients will be enrolled in the study. The study will be performed according to the Helsinki Declaration of Human Rights and is approved by the Regional Ethical Review Board in Linköping (Dnr 2011/498-31; Dnr 2015/333-32). The Swedish Medical Products Agency requests surveillance and unblinding in cases of CT-verified stroke within 24 hours of surgery, mortality and suspected unexpected serious adverse reactions (SUSAR). External monitoring of all key data, written informed consent and unblinding procedures will be done.

Intravenous infusion of 0.125M L-glutamic acid solution at a rate of 1.65 ml/kg BW and hour commencing at or up to 20 minutes before the release of aortic cross-clamp. The infusion is continued for two hours after declamping the aorta after which an additional 50 ml is given at a halved infusion rate.

Intravenous infusion of saline at a rate of 1.65 ml/kg BW and hour commencing at or up to 20 minutes before the release of aortic cross-clamp. The infusion is continued for two hours after declamping the aorta after which an additional 50 ml is given at a halved infusion rate.

Intravenous infusion of 0.125M L-glutamic acid solution at a rate of 1.65 ml/kg BW and hour commencing at or up to 20 minutes before the release of aortic cross-clamp. The infusion is continued for two hours after declamping the aorta after which an additional 50 ml is given at a halved infusion rate.

Intravenous infusion of saline at a rate of 1.65 ml/kg BW and hour commencing at or up to 20 minutes before the release of aortic cross-clamp. The infusion is continued for two hours after declamping the aorta after which an additional 50 ml is given at a halved infusion rate.

Inclusion Criteria: Patients accepted for coronary artery bypass surgery of at least two vessel disease or left main stenosis with or without concomitant procedure considered to be at moderate to high surgical risk preoperatively with regard to postoperative heart failure due to: • EuroSCORE II ≥ 3.0 with at least one of the following cardiac or procedure related risk factors: LVEF ≤ 0.50 CCS class IV Recent Myocardial Infarct (≤ 90 days) Emergency / Urgent procedure (as defined in EuroSCORE II) CABG with aortic or mitral valve procedure OR • LVEF ≤ 0.30 regardless of EuroSCORE II Exclusion Criteria: age > 85 years ambiguous food allergies that trigger shortness of breath, headache or flushing previous cardiac surgery patients who are in such bad condition that they cannot be asked to participate patients who because of linguistic or other reasons are unable to provide informed consent severe renal failure with preoperative dialysis or calculated GFR <30 mL / min patients requiring mechanical circulatory support (intra-aortic balloon pump) due to circulatory failure before they are enrolled in the study surgery without heart-lung machine (off-pump) concomitant Maze-procedure surgery of ascending aorta surgery of both aortic and mitral valve

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