Phase III Study of Metabolic Intervention With Glutamate in Coronary Surgery II
Phase: PHASE3
Conditions: Coronary Artery Bypass Surgery, Postoperative Complications, Heart Failure
Sponsor: University Hospital, Linkoeping

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Metabolic intervention with glutamate in surgery for ischemic heart 
disease:(GLUTAMICS II = GLUTAmate for Metabolic Intervention 
in Coronary Surgery II)  
 
 
EudraCT number: 2011-006241-15 
 
Sponsor's Protocol Code Number GLUTAMICS2 
 
Sponsor and Principal investigator: Rolf Svedjeholm (consultant cardiac surgeon, professor) 
Dept of Thoracic and Vascular Surgery, Linköping University Hospital, SE 581 85 Linköping, 
Sweden 
 
Telephone: +46101034825 
E-mail: rolf.svedjeholm@regionostergotland.se 
 
 
Participating sites:  
 
Thorax-kärlkliniken, Universitetssjukhuset, Linköping 
 
Thoraxkliniken, Universitetssjukhuset, Örebro 
 
Thoraxkliniken, Sahlgrenska Universitetssjukhuset, Göteborg. 
 
Thoraxkirurgiska enheten, Norrlands Universitetssjukhus, Umeå 
 
Verksamhetsområdet Thoraxkirurgi och Anestesi, Akademiska sjukhuset, Uppsala* 
 
Thoraxcentrum, Blekingesjukhuset, Karlskrona*  
 
*No contribution 
 
 
Synopsis 
 
GLUTAMICS II (EudraCT number: 2011-006241-15) is an externally randomized, placebo-
controlled study with parallel study groups and double-blind masking.  The study drug is a 
0.125M solution of glutamate given intravenously in association with coronary artery bypass 
surgery. Placebo consists of a normal saline.   
 
The aim is to confirm findings from subgroups in a previous study GLUTAMICS and 
demonstrate that glutamate infusion reduces the risk of postoperative heart failure. 
 

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The primary endpoint is the increase of NT-proBNP, a biomarker for heart failure, from 
preoperative level the day before surgery to the third postoperative day. Secondary endpoints are 
the absolute levels of NT-proBNP on the first and third postoperative day. 
 
The study population consists of patients with at least moderate preoperative risk due to cardiac 
risk factors undergoing coronary artery bypass surgery (CABG) of at least two-vessel disease 
with or without concomitant procedure. Specifically, moderate preoperative risk due to cardiac 
risk factors implies at least one prespecified cardiac risk factor contributing to EuroSCORE II ≥ 
3.0 or severe left ventricular dysfunction (Left ventricular ejection fraction ≤ 0.30) regardless of 
EuroSCORE II.  
 
Randomization will be stratified for patients undergoing isolated CABG and those undergoing 
CABG with a concomitant procedure. 
 
Exclusion criteria: patients with ambiguous food allergy known to have triggered shortness of 
breath, headache or flushing, age > 85 years, previous cardiac surgery, informed consent not 
possible because of critical condition, linguistic or other reasons, preoperative use of mechanical 
circulatory assist, preoperative dialysis or calculated GFR < 30 mL/min, surgery without heart-
lung machine (off-pump), concomitant Maze-procedure, surgery of ascending aorta, surgery of 
both aortic and mitral valve. 
  
310 patients are planned to be included and interim analysis will be conducted after 160 patients. 
The study is anticipated to start in the middle of October 2015 and to be completed within 2 
years.  
 
 
Background  
 
Postoperative heart failure is the leading cause of extended intensive care, multiple organ failure 
and death after cardiac surgery(1). Conventional treatment of postoperative heart failure with 
inotropic drugs improves hemodynamics but at the prize of excessive increase in myocardial 
oxygen demand, which could aggravate the underlying myocardial injury(2). 
 
Myocardial metabolism in patients with coronary artery disease is characterized by an increased 
uptake of the amino acid glutamate(3, 4). This amino acid plays a key role in the metabolism of 
cardiomyocytes. In animal experiments glutamate improves myocardial tolerance to 
ischemia*(5, 6). After ischemia glutamate plays an important role for replenishment of Krebs 
cycle metabolites that have been depleted in the mitochondria and can thereby enhance 
normalization of the oxidative metabolism, which is disturbed after severe ischemia(7-9). 
 
 
*  The suggested biochemical explanation is that glutamate can contribute to anaerobic energy 
production in the Krebs cycle through metabolism of -ketoglutarate to succinate, and that anaerobic 
glycolysis is enhanced by the malate-aspartate shuttle by maintenance of the redox potential in the 
cytosol. Accumulation of lactate is inhibited by transamination of pyruvate to alanine.  
 

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A positive effect of glutamate on the metabolic and functional recovery of the heart has also been 
found in small studies in humans(10, 11). In light of this and encouraging clinical experience, 
which compare favorably with the literature both regarding survival and heart failure related 
complications, the first GLUTAMICS trial was initiated(12).  
 
In this multi-center study 861 patients undergoing CABG for acute coronary syndrome were 
randomized to intravenous infusion of glutamate or placebo (normal saline). The primary 
endpoint was a composite of postoperative mortality (≤ 30 days), perioperative myocardial 
infarction and left ventricular failure on weaning from the heart-lung machine. The results did 
not show any difference regarding the primary endpoint between the groups(13). 
 
Regarding secondary endpoints significant differences were observed suggesting a beneficial 
effect on myocardial recovery after ischemia. Significantly fewer patients developed severe 
postoperative heart failure that prolonged intensive care or required treatment with intra-aortic 
balloon pump. The presumed effect of glutamate infusion was observed in the patients with CCS 
class IV angina, which constituted a prespecified subgroup. A relative risk reduction exceeding 
50% was also observed in other high-risk groups (table 1) with the exception of diabetics. 
 
A potential advantage with glutamate is that it works by enhancing normal recovery 
mechanisms, which should be less stressful for the heart than conventional treatment with 
inotropic drugs, which increase myocardial oxygen demand and thereby can aggravate 
underlying myocardial injury(2). Accordingly, we observed that the patients who fulfilled 
criteria for heart failure at weaning from the heart-lung machine had a significantly shorter ICU 
stay and a lower incidence of renal failure if they had received glutamate (table 2). 
 
The first GLUTAMICS trial was originally planned for patients with unstable angina CCS class 
IV but the inclusion criteria were widened to include all patients with acute coronary syndrome, 
which resulted in inclusion of many low-risk patients which diluted the results and reduced the 
power of the study. We also observed that the primary endpoint would have benefited from a 
more robust design with regard to the criteria for heart failure due to liberal use of preemptive 
inotropes.  
 
Another issue the first GLUTAMICS trial had to address was the lack of universally accepted 
criteria for the diagnosis of postoperative heart failure. This was done by using a blinded 
endpoints committee relying on prespecified criteria. Halfway into the trial NT-proBNP became 
available and a substudy was initiated to blindly evaluate this biomarker for heart failure against 
the heart failure classifications made by the endpoints committee. Our analyses demonstrated 
that postoperative high NT-proBNP levels were associated with postoperative heart failure 
(Figure 1). This implies that postoperative NT-proBNP could be used to evaluate prevention and 
treatment of postoperative heart failure after cardiac surgery.  
 
The results suggest that intravenous glutamate potentially provides an important and gentle way 
to enhance myocardial recovery after ischemia, which also might prove useful in cardiology 
practice. However, the results from the first GLUTAMICS trial have received little attention due 
to the fact that the positive results were secondary endpoints in subgroups. For intravenous 
glutamate infusion to receive acceptance as treatment and prevention of heart failure after CABG 
the results need to be confirmed in future studies. 

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Our initial aim with this study was to conclusively demonstrate in a larger cohort (n=1400) that 
intravenous glutamate reduces the risk of severe heart failure after CABG in patients with CCS 
class IV angina or moderate to severe reduction of left ventricular ejection fraction (LVEF ≤ 
0.45). Due to funding the GLUTAMICS II study has been modified and downscaled to rely on 
NT-proBNP as a marker of heart failure. The advantage with this redesign is that fewer patients 
are required and that the primary endpoint can be reproduced in future studies. Inclusion criteria 
have been slightly widened but the study focuses on risk patients in need of CABG. Patients 
accepted for CABG of at least two vessel disease with or without concomitant procedure and 
deemed preoperatively to carry at least a moderately increased risk for postoperative mortality 
(EuroSCORE II ≥ 3.0) will be considered for inclusion. Sample size estimations have been 
performed by an external professional statistician based on data from patients with EuroSCORE 
II ≥ 3.0 in the first Glutamics-trial.  
 
 
Aims   
 
The aim of this clinical trial is to confirm that intravenous glutamate infusion reduces the risk of 
postoperative heart failure in patients undergoing CABG by demonstrating mitigated increase of 
NT-proBNP, a biomarker for heart failure, postoperatively. 
  
 
Trial design   
 
Externally randomized, placebo-controlled trial with parallel study groups and double-blind 
masking. Normal saline, which like the glutamate solution is a clear solution, will be used as 
placebo. 
 
 
Study population 
 
• Patients accepted for CABG of at least two vessel disease or left main stenosis with or 
without a concomitant procedure and who either have:  
 
o EuroSCORE II ≥ 3.0 to which at least one of following risk factors contribute  
 
▪ LVEF ≤ 0.50 
▪ CCS-class IV  
▪ Myocardial infarct ≤ 90 days 
▪ Emergent or urgent procedure 
▪ CABG + aortic or mitral valve procedure 
 
o Left Ventricular Ejection Fraction ≤ 0.30 regardless of EuroSCORE II  
 
• The procedure has to be done with heart-lung machine (on-pump)  
 

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These patients will be informed about the trial and asked to participate. Patients who accept 
participation and are operated with the aid of heart-lung machine will be included in the study.  
 
Exclusion criteria: patients with ambiguous food allergy known to have triggered shortness of 
breath, rash or flushing, age >85 years, previous cardiac surgery, informed consent not possible 
because of critical condition, linguistic or other reason, renal failure with preoperative dialysis or 
calculated GFR < 30 mL/min, preoperative use of mechanical circulatory assist, surgery without 
heart-lung machine (off-pump), concomitant Maze-procedure for atrial fibrillation, surgery of 
ascending aorta, surgery of both aortic and mitral valve. 
 
 
The participating centers Linköping, Örebro, Umeå, Gothenburg, Uppsala and Karlskrona are the 
only cardiac surgical centers within their region and thus account for all cardiac surgical 
procedures. To evaluate sampling bias the aim is to use the databases from each center. 
 
 
Research plan  
 
Randomized double-blind study on 310 patients fulfilling inclusion criteria. Randomization will 
be stratified for those undergoing isolated CABG and those undergoing CABG with concomitant 
procedure. 
 
Half of the patients will receive glutamate infusion intravenously (1.65 mL/ kg bodyweight and 
hour of a 0.125M L-glutamic acid solution), which will be started 10-20 minutes before 
anticipated release of aortic cross-clamp and the start of reperfusion. The infusion will be given 
for 2 hours after release of aortic cross-clamp. Thereafter another 50 mL will be given with the 
infusion rate halved. The maximum total given will not exceed 500 mL. If the volume is 
insufficient due to high body weight or extension of cross-clamp time the last 50 mL should be 
given at half the original infusion rate. The remaining half of the patients will receive normal 
saline in a similar way. 
 
 
Specification of outcomes 
 
 
Primary endpoint:  
 
 
The primary endpoint is postoperative increase of NT-proBNP from the day before surgery to the 
third postoperative day.  
. 
 
Secondary endpoints and substudies 
 
Secondary endpoints are the absolute levels of NT-proBNP on postoperative day 1 and day 3.  
 

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Subgroup analyses and substudies 
 
Patients undergoing isolated CABG or CABG with concomitant procedure will also be analyzed 
separately. 
 
Blood samples from the three sampling time points are planned to be frozen to permit analysis of 
novel markers of heart failure and myocardial injury in the future. 
 
Minor substudies may arise but will be specified and reported to the Swedish MPA and 
ClinicalTrials.gov before they are started. 
 
 
Safety variables  
 
Postoperative mortality (30 days + in-hospital), stroke within 24 hours of surgery and SUSAR.  
 
 
 
Sample size estimation and statistics 
 
The sample size is based on available results on NT-proBNP from the first GLUTAMICS-trial.  
In that study the following increase of NT-proBNP was observed in patients undergoing CABG 
or CABG with concomitant procedure who fulfilled inclusion criteria for the planned trial from 
preoperative values to postoperative day 3 (mean ± Standard Deviation) 
  
Glutamate (n=71): 5261 ± 4409 
  
Placebo (n=62): 7112 ± 6454   
 
 
Sample size estimation by statistical expertise (80% power, 5% risk level; two-sided test) 
suggests 141 patients in each group. To compensate for possible missed sampling and other 
causes for loss of data we plan to include a total of 310 patients.  
 
Interim analysis will be performed by an independent external statistician after 160 patients in a 
way that does not increase the demands regarding statistical significance of the primary 
endpoints. An adaptive design implying that a surrogate variable (increase of NT-proBNP from 
preoperative level to postoperative day 1) known to correlate well with the primary endpoint will 
be used. Furthermore, regardless of if statistical significance is reached the study will proceed 
until 310 patients have been included or until the expiry date of the study solutions. Stopping 
criteria are given on page 12. 
 
 
 
Continuous variables will analyzed with a two-tailed t-test or Mann-Whitney U test depending 
on the distribution of data. 

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Categorical variables will be analyzed with a two-tailed Chi square test unless expected cell 
counts are less than 5, then Fisher’s exact test will be used.  
 
 
 
Dropouts, missed sampling and exclusions  
 
Patients will be analyzed according to intention to treat. 
 
Exclusions are estimated to be less than 1%. In the first Glutamics trial four patients out 865 who 
accepted participation were excluded. Dropouts and exclusions will be described when the study 
is published. 
 
Missed sampling (NT-proBNP) on postoperative day 3 should lead to sampling the following 
day. 
 
 
Schedule and performance  
 
Funding applications to the Swedish Research Council and the Swedish Heart Lung Foundation 
have been submitted several times. Sufficient funding for the original version of the trial has not 
been achieved. The funding received has been approved for the downsized version of 
GLUTAMICS II by the Swedish Heart Lung Foundation. APL has started preparation for 
production of infusion solutions which are estimated to be available for delivery in October 
2015. Because of restricted funding all study solutions (n=400) will be produced in a single batch 
with 24 months expiry date. 
 
Information to patients and written informed consent 
 
All patients eligible for the study will receive oral and written information about the trial. 
Written informed consent will be obtained in which the patient also is asked to permit potential 
independent audit in the future.  
 
 
Ethical considerations  
 
Postoperative heart failure remains the main cause for prolonged intensive care, multiorgan 
failure and death after cardiac surgery(1). Available data suggest that glutamate can enhance the 
normal recovery of the heart after ischemia, which is associated with less strain on the 
myocardium than by stimulating myocardial contractility with conventional inotropic drugs. The 
potential benefits could therefore be substantial. 
 
 
The patients will apart from an intravenous infusion of 300-500 mL of glutamate or normal 
saline receive normal postoperative care. 
 

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Glutamate is an amino acid naturally present in the human body and one of the most abundantly 
present free amino acids in the cardiomyocytes. During ischemia glutamate levels in the 
cardiomyocytes are depleted, which the heart compensates by extracting glutamate from the 
blood(6, 9). The extraction rate from plasma is approximately 50% postoperatively(14). The 
plasma levels increase rapidly during oral and intravenous administration(10, 11, 15, 16). In 
susceptible individuals an adverse reaction called Chinese restaurant syndrome consisting of 
transient flushing, headache and burning chest pain has occasionally been reported(17). In the 
first GLUTAMICS trial no adverse effects that could be directly linked to glutamate were 
observed(13).  
 
In spite of the widespread use of glutamate there is no evidence that exogenous delivery of 
glutamate has caused neurological or other permanent complications in humans or primates(18-
20). A possible cause is that glutamate does not pass the blood-brain barrier(19). Furthermore, 
the level of glutamate found in the central nervous system is up to 50 times higher than in 
blood(21). The glutamate infusion planned in the trial increases whole blood levels by 2-3-fold, 
which has been shown to increase myocardial uptake two-fold(22). Higher infusion rates have 
not been shown to further increase myocardial uptake of glutamate(22). 
 
 
Clinical importance and clinical experience 
 
Experience from the first GLUTAMICS trial suggests that glutamate could halve the risk of 
developing severe postoperative heart failure and thus cardiac mortality(13). According to 
O´Connor postoperative heart failure was the primary cause for mortality in 2/3 of the cases in 
Northern New England and the single most important cause for differences between institutions 
with good and bad results(1). 
 
Our group has used glutamate in clinical practice at Linköping University Hospital for 20 years 
and our experience so far in CABG is associated with a mortality 75% lower than expected 
according to EuroSCORE. Compared with national and international results we noted that the 
risk of renal failure (probably the most sensitive indicator for the quality of postoperative heart 
failure treatment) after CABG has been at least five times lower (regardless of what criteria was 
used)(12, 23). 
 
Patients admitted to surgery with severely depressed left ventricular function is the group of 
patients that has received prophylactic treatment most frequently. In a recently published study 
on 104 patients, we observed a mortality of 1.0% in a cohort with an expected mortality of 8.3% 
according to logistic EuroSCORE(12). As this type of results are influenced by other factors, 
they should be interpreted cautiously but they agree with the results of the first GLUTAMICS 
trial. 
 
The biochemical properties of glutamate suggest that the clinical effects we aim to confirm in the 
GLUTAMICS II trial should be possible to emulate in studies on other patient cohorts with acute 
myocardial ischemia. The major clinical implications in the future may thus be found in acute 
myocardial infarction and other conditions characterized by acute myocardial ischemia(18, 24). 
 
 

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Overall assessment of risk and benefit 
 
Glutamate has metabolic properties that can increase myocardial tolerance to ischemia and 
enhance recovery of metabolism and function after ischemia(2, 6). These properties are desirable 
when conventional pharmacologic al treatment and myocardial protection is insufficient. The 
need for alternative treatment is strengthened by the fact that traditional treatment of 
postoperative heart failure with inotropic drugs increase myocardial oxygen consumption 
excessively in relation to the effect on myocardial contractility and hence carries a risk of 
aggravating underlying ischemic myocardial injury(2, 25, 26). This could explain why 
postoperative heart failure has been identified as the single most important cause for 
postoperative mortality after CABG(1). In the first GLUTAMICS trial a relative risk reduction 
exceeding 50% of developing heart failure leading to extended intensive care or death was 
observed in most high-risk groups (table 1)(13). 
 
Potential hazards include the adverse reactions reported on pages 11-12. The risk of adverse 
reactions, such as Chinese restaurant syndrome, asthma or urticaria is considered small with the 
dosages employed and will be further reduced by excluding patients with ambiguous food 
allergies. In our twenty-year experience with glutamate including the first GLUTAMICS trial we 
have so far not observed any of these adverse reactions. In light of this we consider the potential 
benefits to outweigh the potential hazards. 
 
The investigators manual provides more details and references. 
 
 
Administration of glutamate 
 
Glutamate levels in plasma increase rapidly after both oral and intravenous administration(10, 
15, 16, 22, 27). In association with cardiac surgery glutamate has been administered as an 
additive in cardioplegic solutions or intravenously. Experimental data suggest that transport of 
glutamate across the cellular membrane of cardiomyocytes is impeded by cardioplegia 
(hyperkalemic solution) and that the myocytes actually leak glutamate in the cardioplegic 
state(28). The main reason for choosing the intravenous route for administration of glutamate is 
our objective to enhance recovery during the first hours of reperfusion. 
 
Dosage of glutamate 
 
Available data demonstrate that myocardial uptake of glutamate correlates strongly with arterial 
levels in patients early after CABG(14). We also know that myocardial uptake of glutamate 
increases when plasma levels are increased by intravenous administration(10, 11). However, 
increasing arterial levels (whole blood) by more than 2-3-fold is not associated with a further 
increase of myocardial uptake. These arterial levels can be achieved with an infusion rate of 1.65 
mL/ kg body weight and hour of a 0.125M glutamic acid solution(22). 
 
The total volume to be infused according to plan (see research plan page 5) is estimated as 
follows depending on body weight: 70 kg - 289 mL; 80 kg - 330 ml; 90 kg - 371 mL; 100 kg - 
412 mL. The maximum volume that can be infused is 500 mL. 
 

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Details about the composition of the solution is given in the Pharmaceutical documentation. 
 
Discontinuation of the infusion 
 
Infusion should be terminated if there are signs of allergic reaction (rash, bronchial obstruction, 
anaphylactic reaction) or SUSAR are encountered. 
 
Drug management 
 
Drug management will follow the instructions from the producer APL 
 
 
Randomization, treatment of controls, patient identification 
 
Randomization is planned to be done in varying block sizes by APL in Umeå, the manufacturer 
of the study solutions. 
 
The infusion bottle will have two copies of the randomization code, one will be on a self-
adhesive label which should be removed and transferred to the CRF when the infusion is started. 
This is the point when the patient is included in the trial. 
 
Masking will be double-blind. Placebo consists of normal saline. Both the glutamate solution and 
placebo are clear transparent solutions implying that you cannot tell one from the other visually. 
The study bottles are marked with a patient code that is registered in the CRF and in the 
institutional data base. A patient identification list will permit identification of patients in 
association with data check and quality control 
 
The randomization codes are stored at APL in Umeå. Codes can be broken for individual patients 
in cases of suspect adverse reactions. This decision is made after consultation with the principal 
investigator or his deputy. 
 
Safety monitoring 
 
Postoperatively all patients are continually monitored with invasive hemodynamic monitoring 
(CVP, arterial blood pressure), electrocardiogram, diuresis, level of consciousness, discharge 
from chest tubes. Hemodynamically unstable patients are monitored with pulmonary artery 
catheters and SvO2 measurements. Transesophageal echocardiography is routinely performed 
and whenever patients are hemodynamically unstable. After the first day the level of monitoring 
is adjusted to the needs of the patient with regard to hemodynamic state. Early mobilization is 
desirable. Neurological state is controlled at awakening from anesthesia and a brain scan is 
performed if there are any signs of neurological injury. Biomarkers for myocardial injury (CK-
MB) are checked on the first postoperative morning. Biomarkers for heart failure are checked on 
the first and third postoperative morning (NT-proBNP). 
 
 
Adverse reactions and toxicology 
 

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Glutamate levels in plasma increase rapidly both after oral and intravenous administration. 
Despite widespread use of this substance, mainly as a flavor enhancer but also in infusion 
solutions there is currently no documentation showing that exogenously administered glutamate 
has caused permanent injury in man or primates(18-20). 
 
Conventional toxicity studies on several species have yet to reveal any carcinogenic or 
teratogenic effects. No influence on reproduction has been found(29). 
 
In the central nervous system glutamate is one of the dominating neurotransmitters. Under 
certain conditions glutamate may act as an excitotoxin and contribute to neuron damage and 
neuron death in association with acute and chronic neurological disease. Glutamate has been 
claimed to be involved in the pathogenesis associated with ischemic brain injuries and research is 
directed at finding glutamate receptor antagonists that might mitigate the injury(30). 
 
Damage on the central nervous system has bee induced in certain species, mainly rodents, with 
large doses of exogenously administered glutamate(31). However, despite widespread use there 
is no evidence that exogenously administered glutamate has caused permanent neurological 
injury in humans or primates(18-20). A possible explanation is that glutamate does not pass the 
blood-brain barrier or placenta(19, 20). 
 
Theoretically extracorporeal circulation used during cardiac surgery might influence the 
permeability of the blood brain barrier in a way that could influence the passage of glutamate. 
However, at certain institutions glutamate has been used routinely as an additive in cardioplegic 
solutions (which increases plasma levels much more than what is achieved with the dosage used 
in our study) without any evidence for increased risk of complications from the central nervous 
system(32). A multivariable analysis of central nervous system complications did not reveal any 
tendency to increased risk of sustaining central nervous system complications after cardiac 
surgery related to glutamate. On the contrary a tendency to the opposite was observed(33). 
 
In a neurotrauma cohort conventional amino acid solutions containing glutamate 3.75 gram/L 
was found to increase plasma levels of glutamate twice but no difference in outcome was found 
between patients receiving amino acids vs those not receiving amino acids(34).  
 
In this context it might be worth considering that glutamate concentrations in the central nervous 
system are approximately 50 times higher than in blood(21). The glutamate infusion planned in 
our trial increases blood levels 2-3-fold(22). 
 
In the first GLUTAMICS-trial involving 861 patients the risk for subclinical neurological injury 
was evaluated in a subgroup by sampling of biomarker S-100B. No differences or trends were 
found between the glutamate and control group regarding S-100B or clinical neurological 
events(35). 
 
Despite being a natural amino acid in the human body adverse reactions and allergy has been 
discussed. It is mainly three conditions that has caught the eye in the medical literature. These 
are Chinese restaurant syndrome, glutamate elicited asthma and glutamate elicited urticaria. 
Chinese restaurant syndrome has received most attention (flushing, headache and chest pain). 
Several blinded studies, some of them done on patients who have claimed to have experienced 

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symptoms related to glutamate, have failed to prove the connection as no difference in symptoms 
were found between patients receiving glutamate or not(36-38). Similar findings have been done 
in patients claimed to have glutamate elicited asthma(39, 40). There are studies suggesting that 
glutamate could cause Chinese restaurant syndrome in susceptible individuals(17). Although, 
there is reason to question the latter studies we have decided that ambiguous food allergies 
known to have elicited flushing, headache, rash or asthma will be exclusion criteria in the 
planned trial. 
 
More details and references are given in the supplement about adverse reactions and toxicology. 
 
 
Adverse events (AE) 
 
Adverse events (AE) are common after cardiac surgery as all patients have some degree of 
postoperative pain, bleeding and fever. Serious adverse events (SAE) are defined as AE that have 
been life threatening or deadly or resulted in extended hospital care or permanent sequele. SAE 
are also common after cardiac surgery. Postoperative atrial fibrillation, the most common cause 
for exended hospital stay, is observed in approximately one third of the patients undergoing 
CABG.  
 
In GLUTAMICS II AE will be registered and dived into AE and SAE. To determine if the study 
substance had any influence on AE these events will be compared between treatment group and 
control group. AE will be reported according to what organ has been affected: Central nervous 
system, heart - circulation, lungs, gastrointestinal tract, kidneys, skin. Infections will be reported 
according to would or organ affected. Postoperative nausea will be reported if it required 
antiemetic treatment. 
 
Reporting of Adverse events, side effects and SUSAR 
 
” Serious adverse events” (SAE) and SUSAR will be reported on a dedicated fax form to the 
Sponsor within 24 hours after the investigator gains knowledge about the event. Rules for 
breaking randomization codes are specified in the investigator’s manual. 
 
Suspicion of side effects or SUSAR will be reported to the Swedish Medical Product Agency 
according to their instructions. The Sponsor is responsible for this task and will report SUSAR 
that have been life threatening or deadly withing 7 days and the remaining within 15 days. 
 
Suspicion of side effects will also be reported to the local ethical review board. 
 
Sponsor plans a yearly report of AE to the Swedish Medical Product Agency. 
 
 
Monitoring, quality control and interim analyses  
 
Participating centers will monitor each other 100% with regard to correct inclusion, written 
informed consent, primary and secondary endpoints, SAE and SUSAR. Complete monitoring 
regarding management of infusion solutions and original data is planned 10%. 

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The trial will be monitored internally on a weekly basis with regard to inclusions, completeness 
of sampling, management and storage of CRF and exclusions. 
 
External statistical expertise at Linköping University will perform interim analysis, which is 
planned after 160 patients have been included in the trial. 
 
The Swedish Medical Product Agency can perform an independent audit without prior notice. 
 
 
Clinical Endpoints committee 
 
The need for a clinical endpoints committe has been abolished with the novel downscaled design 
of  GLUTAMICS II.  
 
 
Stopping criteria 
 
If monitoring or interim analysis would give suspicion of an increased risk for stroke or a 
negative impact on mortality the trial will be prematurely stopped. If monitoring indicates 
unexpected and serious adverse sideeffects the trial will be prematurely stopped. Safety aspect 
will thus have priority and the trial will be stopped before the incidence of serious side effects 
reraches statistical significance. In a situation when the next event would give a p-value < 0.10 
with regard to a negative effect on stroke or mortality this issue will be discussed with the 
Swedish Medical Product Agency. 
 
Sample size will be adjusted after interim analysis. If a positive effect on the surrogate marker 
for the primary endpoint has been achieved at interim analysis the study will still continue to a 
total of 310 patients or until the expiry date of the study solutions. The trial will be stopped if 
there is no absolute difference in the surrogate endpoint in favor of the glutamate group at 
interim analysis. Patients will be included in the trial while we await the outcome of the interim 
analysis. 
 
 
Insurances 
 
Heart surgery is associated with risks for complications and postoperative pain. It is, however, 
unlikely that participation in the trial will influence that negatively. The regular patient insurance 
is therefore considered sufficient. 
 
 
 
 
Information to staff 
 

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Staff at all levels will be informed orally about the trial, its background and aims. Contact 
persons will be selected that will be available continuously for questions that arise. Furthermore, 
written information will be available at all units. 
 
 
 
 
Sponsor 
 
Rolf Svedjeholm, Thoraxkir sektionen, Thorax-kärlkliniken, US, Linköping 
 
Investigators  
 
Rolf Svedjeholm, överläkare, Thoraxkir sektionen, Thorax-kärlkliniken, US, Linköping 
Jonas Holm, överläkare, Thoraxkir, Thorax-kärlkliniken, US, Linköping 
Farkas Vanky, överläkare, Thoraxkir sektionen, Thorax-kärlkliniken, US, Linköping 
 
Örjan Friberg, överläkare, Thoraxkir sektionen, Thoraxkliniken, US, Örebro 
Gabriele Ferrari, ST-läkare, Thoraxkir sektionen, Thoraxkliniken, US, Örebro 
 
Lars Algotsson, överläkare, Kliniken för thoraxkirurgi, anestesi och intensivvård, Skånes 
Universitetssjukhus, Lund. 
 
Anders Holmgren, överläkare, Thoraxkirurgiska enheten, Norrlands Universitetssjukhus, Umeå 
David Wariaro, överläkare, Thoraxanestesi, Norrlands Universitetssjukhus, Umeå 
 
Andreas Borsiin, ST-läkare, Thoraxcentrum, Blekingesjukhuset, Karlskrona 
 
Lena Jideus, överläkare, Verksamhetsområdet Thoraxkirurgi och Anestesi, Akademiska 
sjukhuset, Uppsala 
 
 
Responsibilities regarding delegation within the investigator group 
 
Responsible investigator delegates tasks to coworkers within the investigator group 
 
Reporting and publication 
 
The results will be made public regardless of outcome and will be submitted for peer review in 
an international cardiovascular/ cardiology/ heart surgery journal. Choice of journal will be 
discussed by the investigator group when the results are available. 
 
Preliminary report of the results at an international conference is a possibility. 
 
 
Archiving of original data 
 

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Primary data will be archived and will be available for independent externa audit for 15 years. 
Archiving will account for protection of patient secrecy and integrity. CRF:s will be archived in 
a locked space and will not permit identification of individual patients without access to the 
patient identification list which be kept locked in a separate space. 
 
 
 
Selected publications by the investigaors related to the trial 
 
 1. Svensson SE, Svedjeholm R, Ekroth R, Milocco I, Nilsson F, Sabel K G, William-Olsson G. 
Trauma metabolism and the heart; uptake of substrates and effects of insulin early after cardiac 
surgery. J Thorac Cardiovasc Surg 1990; 99: 1063 - 1073. 
2. Svedjeholm R, Svensson SE, Ekroth R, Milocco I, Nilsson F, Vinnars E, Wernerman J. 
Trauma metabolism and the heart; studies of heart and leg amino acid flux after cardiac surgery. 
Thorac Cardiovasc Surgeon. 1990; 38: 1-5. 
3. Svedjeholm R, Ekroth R, Joachimsson PO, Ronquist G, Svensson SE, Tydén H. Myocardial 
uptake of amino acids and other substrates in relation to myocardial oxygen consumption four 
hours after cardiac surgery. J Thorac Cardiovasc Surg 1991; 101: 688 - 694. 
4. Svedjeholm R, Ekroth R, Joachimsson PO, Tydén H. High dose insulin improves the efficacy 
of dopamine early after cardiac surgery. A study of myocardial performance and oxygen 
consumption. Scand J Thorac Cardiovasc Surg. 1991; 25: 215 - 221. 
5. Svedjeholm R, Hallhagen S, Ekroth R, Joachimsson PO, Ronquist G. Dopamine and High-
dose Insulin infusion (Glucose-Insulin-Potassium) after a Cardiac Operation. Effects on 
Myocardial Metabolism. Ann Thorac Surg 1991; 51: 262 - 270. 
6. Svedjeholm R, Huljebrant I, Håkanson E, Vanhanen I. The Rationale for Metabolic Support 
with Amino Acids and GIK  (Glucose-Insulin-Potassium) in Cardiac Surgery. Ann Thorac 
Surg.1995; 59:S15-22. 
7. Svedjeholm R, Huljebrant I, Håkanson E, Vanhanen I. Glutamate and high-dose glucose-
insulin-potassium (GIK) in the treatment of severe cardiac failure after cardiac operations. Ann 
Thorac Surg. 1995; 59: S23-30.  
8. Svedjeholm R, Vanhanen I, Håkanson E, Joachimsson PO, Jorfeldt L, Nilsson L. Metabolic 
and hemodynamic effects of intravenous glutamate infusion early after coronary surgery. 
J.Thorac.Cardiovasc.Surg. 112(6):1468-1477, 1996. 
9. Vanhanen I, Svedjeholm R, Håkanson 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: 145-152. 
10. Vanhanen I, Håkanson 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; 37: 113-120. 
11. Rolf Svedjeholm, Mårten Vidlund, Ingemar Vanhanen, Erik Håkanson. A metabolic 
protective strategy could improve long-term survival in patients with LV-dysfunction undergoing 
CABG. Scand Cardiovasc J 2010; 44: 45-58. 
12. Mårten Vidlund, Jonas Holm, Erik Håkanson, Örjan Friberg, Lena Sunnermalm, Farkas 
Vanky, Rolf Svedjeholm. 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; 
29: 358-64. 

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Product Agency                                                                                                                               
13. Mårten Vidlund, Erik Håkanson, Örjan Friberg, Sören Juhl-Andersen, Jonas Holm, Farkas 
Vanky, Lena Sunnermalm, Jan-Olov Borg, Rajiv Sharma, Rolf Svedjeholm. GLUTAMICS – a 
randomized clinical trial on glutamate infusion in patients operated for acute coronary syndrome. 
American College of Cardiology, New Orleans, April 2-5, 2011.  (JACC Volume: 57   Issue: 
14   Supplement: 1   Pages: E938-E938   Published: APR 5 2011) 
14. Mårten Vidlund: Glutamate for metabolic intervention in coronary surgery – with special 
reference to the GLUTAMICS-trial. Thesis 2011: Örebro Studies of medicine 58.  
 
 
Table 1 
 
 
  
Number 
Control/ 
Glutamate 
Control 
Glutamate 
RR 
95% CI 
p-
value 
Isolated CABG 
413/411 
16 (3.9%) 
6 (1.5%) 
0.38 
0.15-0.95 
0.04 
NSTEMI only 
68/59 
1 (1.5%) 
1 (1.7%) 
1.15 
0.07-18 
0.92 
Diabetics 
108/98 
4 (3.7%) 
4 (4.1%) 
1.10 
0.28-4.3 
0.89 
Non-diabetics 
305/313 
12 (3.9%) 
2 (0.6%) 
0.16 
0.04-0.72 
0.02 
CSS class IV 
233/225 
16 (6.9%) 
3 (1.3%) 
0.19 
0.06-0.66 
0.008 
Left main stenosis 
>50% 
141/174 
10 (7.1%) 
1 (0.6%) 
0.08 
0.01-0.63 
0.02 
Female gender 
77/70 
7 (8.5%) 
2 (2.7%) 
0.31 
0.26-1.2 
0.14 
EuroSCORE≥8 
63/83 
9 (14.3%) 
4 (4.8%) 
0.34 
0.11-1.05 
0.06 
Severe LV-
dysfunction 
 
20/14 
5 (25%) 
1 (7.1%) 
0.29 
0.04-2.2 
0.23 
Emergency*  
13/14 
4 (31%) 
1 (7.1%) 
0.23 
0.03-1.6 
0.16 
LV-failure 
at weaning 
14/18 
8 (57%) 
2 (11%) 
0.19 
0.05-0.78 
0.02 
 

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Table 1.  The incidence of severe postoperative circulatory failure in the control group and 
glutamate group in different subgroups undergoing isolated CABG. The relative risk ± 95% 
confidence interval of developing severe postoperative circulatory failure associated with 
glutamate treatment. Results are approximative given the small number of events. * Emergency 
according to EuroSCORE definition. RR= relative risk; CI= confidence interval. 
 
 
 
Table2. Outcome data for patients with LV-failure at weaning from CPB (median+ 
interquartile range, mean±SD or count n %).  
 
 
Placebo 
n=18 
Glutamate 
n=20 
p-value 
a-Lactate 
mmol/L 
5 
minutes 
after 
protamine 
2.5±1.0  
1.7±0.5 
0.004 
Hemodynamic state at completion of 
surgery 
 
 
 
      -Unstable with inotropes / IABP 
31% (5/16) 
0 
0.01 
 
 
 
 
Severe circulatory failure 
56%(10/18) 15%(3/20) 
0.02 
Postop increase of p-Creatinine ( µmol/L) 
58±87 
19±34 
0.08 
Renal injury (increased creatinine x2 ) 
22% 
0% 
0.03 
Ventilator treatment (hours) 
7.4 [5.8-49] 5.0 [3.3-8.0] 
0.02 
ICU stay (hours) 
92 [41-139] 
25 [18-57] 
0.02 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Product Agency                                                                                                                               
 
 
 
 
 
Figure 1. Postoperative NT-proBNP (day 1) v severe heart failure. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Product Agency                                                                                                                               
 
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