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The Supportive Value of Pre-Bypass L-Glutamate Loading in Patients Undergoing Coronary Artery Bypass Grafting

Posted on: Wednesday, 29 March 2006, 09:00 CST

By Bitzikas, G; Papakonstantinou, C; Lazou, A; Bougioukas, G; Et al

Aim. Experimental studies have demonstrated that an exogenous supply of glutamate improves mechanical function and recovery of ischemic myocardium. The aim of the present study was to investigate the effect of myocardial pre-bypass loading with glutamate on myocardial protection during global ischemia and reperfusion of patients undergoing coronary artery bypass grafting (CABG).

Methods. The study was double blinded. Twenty patients undergoing elective CABG were randomized to receive L-glutamate (n=10) or normal saline (n=10). Intracellular levels of glutamate, ATP and lactate were measured in left ventricular biopsies collected 10 min after aortic clamp release. Hemodynamic data, and postoperative release of CK-MB and troponin T were also measured.

Results. Pre-bypass administration of glutamate resulted in myocardial glutamate loading since glutamate levels were significantly higher in the glutamate group of patients than in controls (18.6 3.1 versus 8.7 1.2 g/g tissue, P<0.001). In the same group ATP levels were also significantly higher (2.4 0.7 versus 1.5 0.4 g/g tissue, P<0.05) and lactate levels significantly less than in controls (6.9 1.9 versus 12.0 2.1 g/g tissue, P<0.001). Glutamate patients had statistically significantly superior post-bypass hemodynamic performance (cardiac index, left ventricular stroke work index, systemic vascular resistance and pulmonary vascular resistance). Statistically significantly lower levels of CK-MB (6 h postoperative), total and peak CK-MB, troponin T (24 h postoperative), and total troponin T were found in the glutamate group.

Conclusion. The results of this preliminary study indicate that pre-bypass intravenous administration of glutamate in patients undergoing CABG has a supportive effect on myocardial metabolism during global ischemia and reperfusion, improves patients' postoperative hemodynamic performance and reduces postoperative cardiac enzyme release.

Key words: Glutamate * Coronary artery bypass * Myocardial metabolism * Ischemia * Reperfusion.

The consequences of insufficient myocardial protection, during cardiac surgery under extracorporeal circulation, are severe but not always directly evident. Furthermore, changing trends in the population at risk have resulted in increasing numbers of high-risk patients presented for coronary artery bypass grafting (CABG).1 The cardiac functional reserve of these patients is limited, increasing the demand for intraoperative myocardial protection.2

Metabolic myocardial support in the form of substrate-enriched blood cardioplegia aims to increase energy production during ischemia, irrespective of oxygen needs, and improves mechanical function after global heart ischemia. Certain amino acids, especially glutamate, are important in this respect playing well- defined metabolic roles.3-5 Glutamate exhibits unique uptake by human myocardium, its uptake is elevated in patients with coronary disease, and is consumed during aortic clamping during CABG.6-9 Preclinical and clinical data suggest that exogenous supply of glutamate improves myocardial recovery post-global ischemia and reperfusion.10-16

In this study, we aimed to load the myocardium with glutamate, by intravenous administration before the introduction of extracorporeal circulation. The efficacy with respect to the protective value for the myocardium was studied in patients undergoing elective myocardial revascularization.

Materials and methods

The institutional review board of the hospital approved this study and each patient has given written informed consent. The study was performed in accordance to the European guidelines for good clinical practice. During the period October 2000-February 2001, 20 patients who underwent a first time coronary by-pass operation under extracorporeal circulation (ECC) were included. Patients undergoing urgent myocardial revascularization, with ejection fraction of the left ventricle <30%, or with one vessel disease were excluded from the study. The study was double blinded. Patients who fulfilled the inclusion criteria were randomised to receive in Group A: 0.05_ L- glutamic acid IV via a central venous catheter before commencement of ECC; the solution was prepared with the addition of 2 ampules containing 10 mL or 1.8 g L-glutamic acid each (Vioser, Greece) in 480 mL normal saline (N/S); the dosage was 25 mg/kg body weight (BW) for every patient; after estimation of the amount per patient, the infusion was commenced just after anesthesia induction and terminated after 1 h with the use of a volumetric infusion pump. Group B patients received an equal amount of N/S.

Operative technique

All patients underwent a CABG operation using extracorporeal circulatory support, cold-blood cardioplegic arrest, with the use of the left internal thoracic artery and 1 to 3 saphenous vein grafts. The proximal anastomoses of the vein grafts were performed during reperfusion, under partial aorta crossclamping. Cardiopulmonary bypass was performed with non-pulsatile flow from a membrane oxygenator. The perfusate was cooled to 30-32 C. The circuit was primed with 1000 mL Ringer lactate and 200 mL 20% mannitol. Cold (4- 6 C) blood antegrade cardioplegia 800-1 000 mL was administered, at a 4:1 ratio of blood to cardioplegic solution; 1 L of the cardioplegic solution consisted of 850 mL Ringer lactate, 50 mL sodium bicarbonate 8%, 40 mL KCL, 60 mL St Thomas II sol (20 mL St Thomas II consists of 3.25 g magnesium, 272.8 mg procaine, 1.19g potassium). After each distal anastomosis, additional cardioplegia was delivered (over 2 min) through the aortic root and the vein graft. After aortic declamping, warm blood was delivered through the vein grafts until the completion of all proximal anastomoses. Anesthesia was initiated with the supply of midazolam 0.1-0.2 mg/ kgBW, fentanyl 6-10 pg/kgBW, pancuronium 0.1 mg/kgBW and maintained with propofol 50-80 pg/kgBW/min, fentanyl 0.04-0.06 g/kgBW/min and pancuronium 0.03 mg/kgBW every hour.

Evaluations

Complete history and physical examination including predisposing factors, clinical characteristics and angiographie data were recorded for all patients. During surgery the number of grafts, use of internal thoracic artery, time of extracorporeal circulation and aortic clamping, weaning from cardiopulmonary bypass (CPB), use of inotropic drugs or means of mechanical support of circulation were recorded. Patients were also followed postoperatively for complications.

The following parameters were also measured:

a) Hemodynamic parameters: heart rate (HR), mean arterial pressure (MAP), central venous pressure (CV_), mean pulmonary artery pressure (MPA), pulmonary capillary wedge pressure (PCWP), cardiac output (CO), cardiac index (CI), left ventricular stroke work index (LVSWI), saturation of mixed venous blood (SVO^sub 2^), systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR), were determined after induction of anesthesia (To), 10 min after weaning from ECC (Tx) and 4 h after weaning from ECC (T^sub 4^). Cardiac output was determined with thermodilution and SVO^sub 2^, LVSWI, SVR, PVR were calculated on an Abbot-Critical Care System, Q- vue monitor using a Swan-Ganz (Abbott lab-8 Fr) catheter.

b) Creatine phosphokinase-rnyocardial branch (CK-MB) was sampled at 6 h (T^sub 6^), 24 h (T^sub 24^) and 48 h (T^sub 48^) post weaning from ECC; levels of troponin T (TnT) were sampled at 8 h (T^sub 8^), 24 h (T^sub 24^) and 48 h (T^sub 48^) post 'weaning from ECC in total venous blood. In addition, total CK-MB and TnT levels were determined and the peak enzyme value recorded. TnT was determined quantitatively using a commercially available ELISA kit (Roche/Boehringer Mannheim).

c) Myocardial biopsies: transmyocardial biopsies of the free left ventricular wall were collected 10 min post aortic clamp release using a special biopsy needle (true-cut needle, 14 G). The biopsy sample was immediately submerged in liquid nitrogen and stored at - 70 C for later determinations of ATP, lactate and glutamate levels.

Measurment of ATP, lactate and glutamate levels

Biopsies were homogenized in 1 mL ice-cold PCA 4% w/v (perchloric acid) and centrifuged at 12 000 g for 5 min at 4 C. The supernatant was neutralized with the addition of NaOH, centrifuged at 12 000g for 10 min at 4 C and the supernatant was used for the determination of metabolites. Quantification of ATP and Lactate was performed photometrically using commercially available kits (ATP: Sigma- Aldrich, Lactate and Glutamate: Roche) and was based on the change of absorbance at 340 nm due to NADH oxidation or NAD reduction. Glutamate was measured sequentially to lactate after the addition of glutamate-pyruvate transaminase.

Statistical analysis

For the variables of interest the mean values SD were assessed; Student's t-test was used to study the parity of 2 mean values, while a non parametric Mann-Whitney test was used for mean values derived from samples that did not follow normal distribution. The comparison of percentages and the independence testing of 2 qualitative variables was performed using a χ^sup 2^ test. Analysis of variance for repeated measurements was used for the comparison of the mean values of different parameters for the 3 different sampling times. For the determination of the interact\ion between the group and different samplings, analysis of variance (for repeated measurements), with 2 factors was employed. A P-value of 0.05 or less was considered to indicate statistical significance. Statistical analysis was performed using the computational package SPSS 10.0.

Results

The 2 groups were evenly matched with respect to their demographic and clinical characteristics (pre- or postoperatively) (Table I). A low dose of dopamine (2-4 g/kg/min) was administered to all patients, while a low dose of adrenaline (≤0.04 g/kg/min) was supplied to 3 patients of Group A and 5 patients of Group B. Only 1 patient of Group A required a higher dose of adrenalin (0.08 g/kg/min), to support circulation during the first postoperative hours. One patient in Group A, and 2 patients in Group B presented with postoperative atrial fibrillation which was reduced by administration of amiodarone. No further morbidity, or electrocardiographic changes indicative of a perioperative myocardial infarction were observed.

TABLE I.-Comparison of demographic, clinical, angiographie and operational data of patients in 2 groups.

Levels of ATP, glutamate and lactate

The ATP levels in Group A were statistically significantly higher than Group B (glutamate 2.40.7 versus placebo 1.50.4 _g/g tissue, P=0.002; 95% C.I.=0.4-1.4). The mean level of glutamate in Group A was substantially higher than that of Group B (glutamate 18.63.1 versus placebo 8.71.2 g/g tissue, P<0.001; 95%, C.I.=7.6-12.1). The mean levels of lactate were lower for Group A than Group B (glutamate 6.91.9 versus placebo 12.02.1 g/g tissue, P<0.001; 95% C.I.=3.2-6.9).

TABLE II.-Hemodynamicparameters, mean values ( SD).

TABLE III.-Mean values (SD) of troponin-Tand CK-MB.

Hemodynamic measurements

The mean values for the hemodynamic parameters determined during this study are summarized in Table II. Each factor is presented with a relevant P-value within each group indicating statistically significant changes from baseline to 4 h post weaning. An overall comparison between the 2 groups indicates that the hemodynamic factors affected by L-glutamate loading included CI, LVSWI, PVR and SVR.

No statistically significant differences were observed for the mean values of the other hemodynamic parameters studied between the groups of patients.

Enzymatic activity

The mean levels of TnT for all 3 samplings were lower for Group A compared to Group B (P=0.031). The mean total release of TnT for Group A (1.00.2 ng/dL) was significantly lower (P=0.021) than the mean total value for Group B (1.30.4 ng/dL) (Table III). Similarly, the mean levels of CK-MB were lower for the glutamate group than the control group (P=0.035). The mean total CK-MB release for Group A (59.316.1 ng/dL) was significantly lower (P=0.031) than that of Group B (84.429.6 ng/dL).

Discussion and conclusions

Under certain conditions, an exogenous supply of metabolic substrates to the heart may be of vital importance for myocardial function and survival. Although amino acids are quantitatively insignificant for myocardial energy production, specific amino acids such as glutamate and aspartate are qualitatively important for the intermediate myocardial metabolism, especially in conditions of ischemia-reperfusion, as those observed during cardiac surgery with ECC.3, 4, 17 Glutamate transaminates pyruvate to alanine instead of lactate thus reducing lactate accumulation during ischemia, and allowing continuation of anaerobic metabolism.18 Furthermore, alanine can serve as a non-toxic carrier of ammonia, which rapidly accumulates during anoxia.19 Under anaerobic conditions the presence of glutamate plays an important regulatory role in the malate- aspartate pathway affecting the catabolism of glucose and lactate in the heart.3 During reperfusion, glutamate and aspartate are important metabolic substrates for the replacement of Krebs cycle intermediates consumed during ischemia.4 There is also evidence that cardio-protection by glutamate may be achieved via neutralization of free oxygen radicals during reperfusion of ischemic myocardium, with the involvement of the NADP + NADPH coenzyme pair and glutathione.17

Evidence has been accumulating from experimental studies on the importance of exogenous glutamate supply in cardio0 -protection.11, 20-23 In the contrary, the study of Ghomeshi et al. employing magnetic resonance spectroscopy, reported negative findings, with glutamate enriched blood not improving myocardial energy metabolism during reperfusion.24

The design of the present study was based on the work of Boiling et al. suggesting that the time of loading is significant, with exogenous administration of glutamate before ischemia, and not during reperfusion, producing superior results.25 Studies employing warm induction of blood cadioplegia supplied with glutamate in animal models results in metabolic and functional recovery of the myocardium following ischemia.26, 27 Few clinical studies have been reported on the application of blood cardioplegia enriched with glutamate in cardiac surgery.15, 28, 29

According to Mudge et al. patients with coronary disease show a significantly increased glutamate uptake as compared to healthy individuals.6 Relative studies of Pisarenko et al.7 revealed that changes in myocardial metabolism of glutamate are more evident in patients with coronary disease and severe left ventricular dysfunction. Furthermore, cardioplegic arrest using crystalloid cardioplegia leads to a decrease in intracellular glutamate levels, which is maintained even 20 min post reperfusion, and blood cardioplegia does not cause a decrease of glutamate levels at the end of ischemia but a significant decrease during reperfusion.8, 9

Given that glutamate displays increased myocardial uptake in patients with coronary disease and an increased consumption under ischemia-reperfusion during CABG operations with the use of ECC, the administration of exogenous glutamate before ischemia may create conditions of myocardial loading favorable for the myocardial metabolism during cardioplegic arrest and reperfusion.. Indeed, in the present study, the pre-bypass i.v. administration of glutamate led to myocardial uptake, since myocardial glutamate levels post reperfusion in patients of Group A were significantly higher compared to the control group. This uptake had a significant metabolic effect on the ischemic myocardium as it maintained the levels of ATP and significantly decreased the levels of lactate at the end of global cardiac ischemia. These results are in accordance with those of previous experimental studies.11, 17, 21, 25

Although the exogenous supply of glutamate results in myocardial loading, the uptake rate is not unlimited and depends on the levels of glutamate in arterial blood. Vanhanen et al.30 determined that the infusion of 30-40 mg/kgBW/h glutamic acid leads to a maximum uptake of glutamate from myocardium during the immediate postoperative period. Since myocardial glutamate uptake is time- dependent, there is strong evidence that the method of glutamate administration in the present study creates more favorable myocardial loading conditions than the enrichment of blood cardioplegia which is administered for a few minutes.

In another study, Vanhanen et al.31 investigated the impact of pre- and during ECC glutamate infusion on myocardial uptake and release of substrates, measuring arterial-coronary sinus differences, in patients operated for unstable angina. Glutamate infusion was associated with a myocardial uptake of glutamate and in contrast to the control group there was also uptake of lactate before ECC and during late reperfusion.

During infusion of glutamate, no undesirable effects were observed. There was a small decrease in the systemic vascular resistance towards the end of infusion, but this was combined with an increase of the cardiac output. No major neurologic complications were observed in patients receiving glutamate. Although the exogenous supply of glutamate has been proved to provoke a dose- dependent neurotoxicity in rodents 32 this is not the case in primates since it does not cross the blood-brain barrier.33 Furthermore, accumulated experience with amino acid-enhanced blood cardioplegia has not reported any association with increased incidence of cerebral complications.30

The supply of glutamate had a significant protective effect on the degree of intraoperative myocardial damage as determined by the positive effect on CI and LWSWI of the patients receiving glutamate and the lower postoperative levels of TnT and CK-MB. Troponin T constitutes a sensitive biological marker of intraoperative myocardial damage.34, 35

In the postoperative setting a study has revealed that administration of glutamate to patients undergoing coronary bypass 1 to 2 h after weaning from ECC improved their LVSWI and CI.36 In an older study by Pisarenco et al. the intravenous infusion of glutamate in patients with low cardiac output syndrome (LCOS) after open-heart surgery resulted in the augmentation of CO accompanied by cessation of ammonia release and a change from lactate release to lactate uptake by the myocardium.37 Besides blood cardioplegic enrichment and postoperative administration of glutamate the results of the present study show that even pre-bypass glutamate administration in patients undergoing CABG under ECC exerts a protective action on the subsequently ischemic myocardium. The principal limitation of this study is the relatively small and low- risk population. It was proposed as a pilot study primarily focusing on the myocardial metabolic effect of glutamate supply. Further studies including a larger number of patients are necessary to confirm the clinical impact of the method, especially in patients with severe left ventricular dysfunction who present increased myocardial energy demands.

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G. BITZIKAS1, C. PAPAKONSTANTINOU1, A. LAZOU2, G. BOUGIOUKAS1, M.TOUMPOURAS1

G. TRIPSIANIS3, P. SPANOS1

1 Department of Cardipthoracic Surgery

AHEPA Hospital, Aristotles University of Thessaloniki

Thessaloniki, Greece

2 Department of Biology

Aristotles University of Thessaloniki

Thessaloniki, Greece

3 Department of Biostatistics

Democritus University of Thrace

Aiexandroupolis, Greece

Received: April 13, 2005.

Accepetd for publication: December 6, 2005.

Address reprint requests to: G. Bitzikas MD, Trapezountos 43, 55131 Thessalonica, Greece. E-mail:gbitzika@med.duth.gr

Copyright Edizioni Minerva Medica Dec 2005

Source: Journal of Cardiovascular Surgery

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