By Ji, B; Liu, J; Liu, M; Feng, Z; Et al
Aim. The aim of this investigation is to evaluate the effect of enriched with potassium-magnesium aspartate cold-blood cardioplegia on early reperfusion injury and postoperative arrhythmias in patients with ischemic heart disease undergoing coronary artery bypass grafting (CABG), using measurements of cardiac troponin I (CTnI), hemodynamic indexes and clinical parameters. Methods. Forty patients with three-vessel coronary artery disease (CAO) and stable angina, receiving firsttime elective CABG, were randomly divided into 2 groups: patients in control group (C group n=20) received routine institutional cold blood cardioplegia (4 C) concentration of Mg2+4 mmol/L, Ca2+1.2 mmol/L and K+ 24mmol/L during myocardial arrest Patients in P group (n=20) received modified cold blood cardioplegia enriched with potassium-magnesium aspartate and maintained concentration of Mg2+10 mmol/L, Ca2+1.2 mmol/L and K+20mmol/L in the final blood cardioplegia solution. Clinical outcomes were observed during operation and postoperatively. Serial venous blood samples for CTnI were obtained before induction, after cardiopulmonary bypass (CPB), and postoperative 6, 24, and 72 hours. Hemodynamic indexes were obtained before and after bypass by the radial catheter and SwanGanz catheter.
Results. In both groups, there were no differences regarding preoperative parameters. There were no cardiac related deaths in either group. The time required to achieve cardioplegic arrest after cardioplegia administration was significantly shorter in P group (47.516.3 s) than in C group (62.517.6 s) (P
KEY WORDS: Potassium – Magnesium aspartate – Coronary artery bypass grafting – Myocardial infarction – Troponin.
Cardioplegia is a very important component during cardiopulmonary bypass (CPB) surgery, not only supplying a bloodless field for the surgeon, but also decreasing myocardial injury from ischemia/ reperfusion. Instead of crystalloid cardioplegia, cold blood cardioplegia was regarded as a clinical practice in 1994 in our hospital for adult patients and provided benefits over cold crystalloid cardioplegia1. Over 30 000 open-heart operations were performed with cold blood cardioplegia from 1994-2005. However, mortality and morbidity related to myocardial ischemia/reperfusion injury remained. Significant evidence now exists that the primary mediators of reversible and irreversible myocardial ischemia/ reperfusion injury include intracellular Ca2+ overload during ischemia and reperfusion, and oxidative stress induced by reactive oxygen species (ROS) generated at the onset of reperfusion2-4. The molecule nitric oxide (NO) can also interact with ROS to generate various reactive nitrogen species that appear capable of both contributing to and reducing injury5,6. In addition, metabolic alterations occurring during ischemia can contribute directly and indirectly to Ca^sup 2+^ overload and ROS formation. An understanding of intracellular events that occur secondary to ischemia and reperfusion injury stimulated a search for modifying our cardioplegic solution, in an attempt to improve myocardial recovery postoperative.
Potassium-magnesium aspartate is composed of magnesium aspartate 140 mg (equivalent a 11.8 mg Mg^sup 2+^), potassium aspartate 158 mg (equivalent to 36.2 K^sup +^) and can be effective in stimulating myocardial metabolism, and producing an anti-arrhythmic effect7. In addition, it is well known that magnesium is a natural blocker of the L-type calcium channels and therefore prevents the rise in intracellular calcium during ischemia;8,9 thus, it is likely to reduce energy demands and preserve intracellular metabolites. There are, therefore, strong theoretical reasons to support the addition of magnesium to this cardioprotective strategy. Magnesium also has been widely used in the management of reperfusion-induced ventricular arrhythmias10. In addition, some investigations have shown that metabolic supplementation with aspartate in the cardioplegic solution improves tolerance of normal hearts to global ischemia at normothermia or hypothermia. Possible mechanisms are prevention of ischemia-induced depletion of tricarboxylic acid cycle intermediates and stimulation of the malate-aspartate shuttle11.
The purpose of this study is to investigate whether enriched potassium-magnesium aspartate in the cold blood cardioplegia solution could reduce myocardial injury and prevent postoperative arrhythmias when compared with simple cold blood cardioplegia.
Material and methods
Patient selection and cardioplegia preparation
Our hospital and local ethical community approved the study. Forty consecutive patients who underwent first-time elective coronary artery bypass grafting (CABG) under CPB were enrolled in the present study: 28 men and 12 women, and their ages at operation ranged from 47 to 68 years with a mean of 57.67.5 years. All patients gave their informed consent for the study. The patients were prospectively randomized into one of two groups according to cardioplegic solution used for intraoperative myocardial protection. Randomization was performed by the method described by Altman and Bland12. Control group (C group n=20) received routine institutional cold blood cardioplegia (4 C), which has been used in our hospital since 1994. The cardioplegia formula consists of K+ 20 mmol/L, Mg^sup 2+^ 4 mmol/L, Ca^sup 2+^ 1.2 mmol/L, procaine 0.9 mmol/L, pH 6.9, osmoality 340 mOsm/L. The potassium-magnesium aspartate group (P group n=20) received modified cold blood cardioplegia enriched with 90 mL potassium-magnesium aspartate and concentration of Mg^sup 2+^ maintained at 10 mmol/L and K+ 20 mmol/L in the cardioplegic solution. Preoperative patient characteristics are shown in Table I. All were patients having three-vessel coronary artery disease without valve disease, receiving first time CABG. Excluded were patients with an ejection fraction (EF) below 0.30, recent myocardial infarction (
Operation method
All patients were operated on by the same group in our hospital including the surgeon, anesthesiologist and perfusionist.
Table I. – Preoperative patient characteristics.
ANESTHESIA
The patients were placed in the supine position and anesthesia was induced by the intravenouos administration of fentanyl citrate and vecuroniumbromide, maintained with intravenously administered propofol and inhalation of isofurane. The left radial artery and the right internal jugular vein were catheterized for hemodynamic monitoring. The electrocardiogram and temperature were also monitored. All patients received a high-dose anti-fibrinolytic treatment with aprotinin (5 million KIU).
CARDIOPULMONARY BYPASS
The Stockert-II heart-lung machine (Germany) with roller pump and Medtronic membrane oxygenator Affinity (USA) was used. Continuous non-pulsatile CPB was adjusted at a flow rate of 2.8-3 L/min/kg at 30 C. Mean arterial pressure was maintained 65100mmHg.
SURGICAL PROCEDURE
Following mid-sternotomy and left internal mammary artery (LIMA) preparation, CPB was started under full heparinization (4 mg/kg heparin). The two groups had cardioplegia arrest maintained by two kinds of cold (4 C) blood cardioplegic solutions that were reinfused intermittently every 30 minutes. The route of delivery was exclusively antegrade. The initial dose of cardioplegia was 15 ml/ kg of body weight, and each subsequent dose was half of the initial dose. The a-stat method was used for pH management during hypothermie CPB. When surgical procedures were finished, CPB was stopped. When patient hemodynamics were stable, heparin was neutralized by an infusion of 1 mg protamine sulfate/100 IU of heparin administration.
Laboratory assay
Plasma level marker of myocardial damage (CTnI) was obtained from serial venous blood samples before induction, after CPB, and postoperatively 6, 12, 24, and 72 hours. CTnI concentrations were measured by a specific immunoenzymometric assay developed and has been described in our previous study13.
Electrocardiographic changes
A 12-lead electrocardiogram was recorded 2 hours preoperatively, postoperatively and then daily postoperatively. The electrocardiographic diagnosis criteria for perioperative myocardial infarction (PMI) were new Q-waves more than 0.04 ms or a reduction in R-waves more than 25% in at least two leads.
Statistical analysis
Statistical analysis was performed with SPSS (9.0 version) statistical software. One-way analysis variance (ANOVA) was performed to test the effect of the type of cardioplegia and time on CTnI concentration. Two-way analysis of covari\ance with repeated measures was performed to test the effect of the different type of cardioplegia on CTnI concentrations. Statistical significance accepted at a P
Results
Preoperative and intraoperative data
The major preoperative variables were similar in the two groups (Table I). There were no significant differences between the mean values of age, sex ratio, New York Heart Association (NYHA) classification, body surface area (BSA) and EF.
Operative data
There was no significant difference between the two groups in CPB time, clamp time, graft number, total amount of cardioplegic solution and lowest temperature during bypass. The time required to achieve cardioplegic arrest after starting initial cardioplegia administration was significantly shorter in P group (47.516.3 s, P
Postoperative data
There were no operative deaths (to one month postoperatively) in both groups. Eight patients in C group and one patient in P group (P
Table II. – Operative data and postoperative data.
Leakage of CTnI
CTnI level were similar in both groups before induction. But increased in both groups postoperatively 6 hours. In P group, leakage of CTnI was reduced after CPB. Differences in CTnI concentration between two groups could be inspected at 6 and 12 hours postoperatively (P
Changes of electrocardiograpby
One patient in C group developed new Q waves on the EGG postoperatively. In P group ST segment changes were present in one patient postoperatively (in P group). These data did not show any statistical significance.
Discussion
This study demonstrated that cold-blood cardioplegia solution enriched with potassium-magnesium aspartate decreased early reperfusion injury and preventing postoperative arrhythmias in patients with ischemic heart disease undergoing CABG.
Figure 1.-Cardiac troponin (CTnI) concentration time courses in P group and C group. Data are presented as means standard deviation. Th figure shows that CTnI concentrations are significantly lower in P group than in C group at 6 hours and 12 hours (* = P≤.05).
Mg^sup 2+^ has been reported to afford myocardial contractile protection, particularly in patients with acute myocardial infarction. Potential mechanisms for this protection include a reduction in oxygen demand, an improvement of collateral blood supply, and membrane stabilization. Although there is growing evidence to suggest that the administration of Mg^sup 2+^ to patients undergoing CABG and to patients after myocardial infarction is beneficial, the concentration of Mg^sup 2+^ in cardioplegic solutions remains controversial. Hearse et al.14 have shown that a cardioplegic solution with 16 mmol/L of Mg^sup 2+^ and 1.2 mmol/L Ca^sup 2+^ provided significant postischemic ventricular protection. St. Thomas solution includes 16 mmol/L of magnesium-dichloride. In our previous study, magnesium supplementation could generate the detrimental effects of blood cardioplegia by using a relatively high concentration of magnesium (14-16 mmol/L)15. Caputo16 proposed intermittent antegrade warm blood cardioplegia containing 1.25-2.5 mmol/L of Mg^sup 2+^, and Tyers solution has 1.5 mmol/L of magnesium. Miyoshi et al. have demonstrated that the optimal magnesium concentration is between 2.4 and 4.8 mmol/L for the prevention of reperfusion arrhythmias in isolated rat hearts17. In Yoshitaka’s study, 2 mmol/L of magnesium in the minimally-diluted blood cardioplegia provided more effective myocardial protection than the standard 4:1-diluted blood cardioplegia18.
Potassium-magnesium aspartate supplied not only sufficient Mg^sup 2+^. In addition, although the mechanism of action of aspartate in the ischmie myocardium was not addressed in this study, some studies find that aspartate improved functional recovery by augmenting myocardial energy production mainly during early post-ischemic reperfusion. Replacing extracellular magnesium by enriching cardiologie solutions has been shown to decrease the incidence of postoperative arrhythmias, as well as improve myocardial protection by a variety of pathways19-21. The most important of these is probably magnesium’s ability to modulate intracellular calcium levels by inhibiting calcium entry across the cellular membrane, as well as displacing calcium from the binding sites of the sarcolemmal membrane14,19,22. This prevents mitochondrial calcium uptake, which can lead to uncoupling of oxidative phosphorylation with a decrease in ATP production. Post-ischemic calcium entry is further limited because magnesium prevents an influx of sodium, which during reperfusion is exchanged for calcium. Supplemental magnesium can also facilitate asystole at lower potassium concentrations10. This is important because high potassium concentrations can damage vascular endothelial cells directly, as well as enhance endothelial and myocyte calcium entry.
Conclusions
Although the present study has methodical limitations and there remain several issues to be examined, cold blood cardioplegia enriched with potassiummagnesium aspartate is beneficial on reducing reperfusion injury. It could be a reliable and effective technique for intra-operative myocardial protection.
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B. JI 1-2, J. LIU1, M. LIU3, Z. FENG1, G. WANG3, F. LU4, C. LONG1
1 Department of Cardiopulmonary Bypass,
Cardiovascular Institute and Fuwai Hospital,
Beijing, China
2 Department of Pediatrics, Hershey Medical Center, Penn
State College of Medicine, USA
3 Department of Anesthesiology, Cardiovascular Institute
and Fuwai Hospital, Beijing, China
4 Department of Cardiac Surgery Cardiovascular Institute
and Fuwai Hospital, Beijing, Ch\ina
Address reprint requests to: Ji, MD., Pediatrics Cardiology, Penn State College of Medicine, Department of Pediatrics-085, 500 University Drive, P.O. Box 850, Hershey, PA 17033-0850, USA. E- mail: [email protected]
Copyright Edizioni Minerva Medica Dec 2006
(c) 2006 Journal of Cardiovascular Surgery. Provided by ProQuest Information and Learning. All rights Reserved.
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