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Ann Thorac Surg 2002;73:837-841
© 2002 The Society of Thoracic Surgeons

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Original article: cardiovascular

Cardioplegic arrest with L-arginine improves myocardial protection: results of a prospective randomized clinical trial

^a Departments of Surgery, Anesthesia, and Medicine, Montreal Heart Institute and the University of Montreal, Montreal, Quebec, Canada

Accepted for publication December 18, 2001.

* Address reprint requests to Dr Carrier, Montreal Heart Institute, 5000 Belanger St. East, Montreal, Quebec, H1T 1C8, Canada
e-mail: carrier{at}icm.umontreal.ca

	Abstract

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Background. Blood cardioplegic arrest remains the method of choice for myocardial protection. L-arginine has been suggested to improve protection through an increase in nitric oxide production.

Methods. A prospective, randomized, double-blinded clinical trial comparing standard blood cardioplegic solution to L-arginine-enriched solution (7.5 g/500 mL) enrolled 200 patients undergoing coronary artery bypass grafting. Clinical data and biochemical markers of ischemia were recorded. Warm blood cardioplegia (33°C) was administered in 74% of patients and cold blood (20°C) was used in 26% of patients. Both groups averaged three grafts per patient.

Results. There were two (2%) deaths in both groups. There were four (4%) myocardial infarctions (MI) in the control group and six (6%) infarctions in the L-arginine group (p = 0.5). For the 190 patients without MI, serum levels of troponin T averaged 0.40 ± 0.43, 0.38 ± 0.42, and 0.39 ± 0.50 µg/L in control patients compared with 0.28 ± 0.22, 0.24 ± 0.18, and 0.27 ± 0.20 µg/L in L-arginine patients, respectively, 12, 24 and 48 hours after coronary artery bypass grafting (p = 0.03). The cardiac index averaged 2.7 ± 0.8 L · min^-1 · m^-2 in control patients and 2.9 ± 0.7 L · min^-1 · m^-2 in arginine patients immediately after surgery (p = 0.09). Intensive care unit and hospital length of stay averaged 3.5 ± 5 days and 7.3 ± 6 days in control patients compared with 2.5 ± 3 days and 6.1 ± 4 days in arginine patients (p = 0.09).

Conclusions. L-arginine-supplemented blood cardioplegic solution is associated with reduced release of biochemical markers of myocardial damage, suggesting improved myocardial protection.

	Introduction

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Several experimental studies have suggested that supplementation of blood cardioplegia with L-arginine may improve myocardial protection by increasing the release of nitric oxide, improving coronary blood flow with vasodilatation, and by decreasing platelets and leukocytes adhesion to the endothelial surface resulting in an overall decrease in postischemic and reperfusion injury. L-arginine, a simple aminoacid precursor of nitric oxide synthesis, was shown to increase nitric oxide release [1–3], to improve systolic and diastolic function in areas at risk [4], to increase coronary blood flow, and to accelerate myocardial tissue pH recovery [5] after ischemia and reperfusion in animal models.

There are also conflicting laboratory results regarding the optimal timing of administration of L-arginine, before ischemia or during reperfusion, to obtain a beneficial effect on protection of the myocardium [6]. Previously we undertook a phase I pilot clinical study to determine the potential benefits and side effects related to the addition of L-arginine to a standard blood cardioplegic solution, because there was no published clinical experience with L-arginine in blood cardioplegia. A total of 50 patients who underwent coronary artery bypass grafting were randomly assigned either to a treatment group that received 1 g of L-arginine administered during blood cardioplegic arrest, or to a control group. Although there was no difference between the two groups in the release of metabolic markers of myocardial ischemia, no significant side effects related to the addition of L-arginine to the cardioplegic solution were observed [7].

The present study was designed to test the hypothesis that a greater concentration of L-arginine-enriched blood cardioplegic solution will decrease the release of cardiac troponin T, a highly sensitive marker of myocardial ischemia after coronary artery bypass grafting.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Study population
Between 1998 and 2000, a total of 200 patients undergoing primary coronary artery bypass grafting at the Montreal Heart Institute were prospectively randomized into two groups: one with L-arginine supplementation in the cardioplegic solution (treatment group), and the other without L-arginine (control group). After the patients had agreed to participate in the study and signed an informed consent form, they were randomized, just before the beginning of the operation, by blocks of 4 for equal sample size in the two groups. The study sample size was chosen to show a decrease of 50% of the average level of postoperative cardiac troponin T levels in patients who were administered a L-arginine-enriched cardioplegic solution, with an alpha error of 5% and a power of 80%. The study was approved and monitored by the Ethics Committee of the Research Center of the Montreal Heart Institute.

Exclusion criteria were as follows: operation within 21 days of an acute myocardial infarction; urgent operation for acute coronary occlusion at angioplasty; emergent surgical procedures performed outside of normal working hours; reoperation for myocardial revascularization; and coronary operations associated with any other cardiac surgical procedures.

Surgical technique
The operation was performed according to standard surgical techniques. Internal mammary artery and saphenous vein grafts were used in all patients. Proximal anastomoses to the aorta were performed with partial occlusion of the ascending aorta. Cardiopulmonary bypass was performed using moderate hemodilution, with a hematocrit level between 20% and 25%, and mild systemic hypothermia by permitting body temperature to drift down progressively to 33°C, the core temperature being maintained thereafter at that level with a heat exchanger until the aorta was unclamped.

Myocardial protection
The cardioplegic solution was infused through a 14F double-lumen needle (Medtronic Inc, Grand Rapids, MI) in the ascending aorta. The cardioplegia infusion set (CardioMed Supplies Inc, Gormley, ON, Canada) consisted of two inflow lines for mixing of the crystalloid solution with blood from the arterial circuit at a ratio of 4:1. Ringer’s lactate solution, 1 L, containing either 80 mmol (high K) or 40 mmol (low K) of potassium, 20 g of mannitol, 80 mg of lidocaine hydrochloride, and 1.9 mL of 8.4% sodium bicarbonate solution to obtain a pH of 7.4 was used as the crystalloid cardioplegic solution. In 9 patients in each group, the cardioplegic solution was administered simultaneously through a catheter in the coronary sinus.

After cross-clamping the ascending aorta, cardioplegic arrest was induced in all patients by antegrade infusion of 300 mL of high-potassium solution (80 mmol/L) over a period of 2 to 3 minutes at a perfusion pressure not exceeding 250 mm Hg in the infusion line. Diastolic arrest was usually obtained before termination of the initial infusion. Thereafter and throughout the remainder of the procedure, repeated intermittent infusions of 200 to 300 mL of high-potassium (80 mmol/L) or low-potassium solution (40 mmol/L) were administered after each distal anastomosis. In both groups, the initial bag of 500 mL of high potassium solution (80 mmol/L) was first used, followed by the low potassium (40 mmol/L) solution thereafter if needed.

The cardioplegic mixture was administered warm (74% of patients) at 33°C, or the solution was cooled (26% of patients) by immersing the heat exchanger of the infusion line in ice to decrease the solution temperature to below 20°C (cold cardioplegia), according to the surgeon’s preference.

L-arginine, 7.5 g, was diluted in the 500 mL high-potassium cardioplegic solution in patients randomized to the treatment group, and a standard high-potassium solution was injected in control patients. The cardioplegic solutions were prepared by our hospital’s pharmacists, and both perfusionists and surgeons were blinded to the presence of L-arginine in the cardioplegic solution.

Markers of myocardial ischemia and diagnosis of perioperative myocardial infarction
Blood samples for the determination of cardiac troponin T were taken at the beginning of the operation, and at 12, 24, and 48 hours after chest closure. Blood samples for determination of serum levels of total creatine kinase (CK) and of the catalytic activity of its MB isoenzyme were taken 12, 24 and 48 hours after surgery. Total CK serum level (normal range 24 to 195 IU/L) and, after inhibition of the monomer with a monoclonal antibody, CK-MB isoenzyme serum catalytic activity was measured by standard methods using a Hitachi 917 analyzer and reagents from Roche/Boehringer-Mannheim (Mannheim, Germany). The cardiac troponin T serum concentration was determined with an ELECSYS 1010 electrochemiluminescence instrument (Roche), which uses two monoclonal antibodies and human recombinant cardiac troponin T as a calibrator (third generation).

Electrocardiographic tracings were obtained the day before operation, on arrival in the intensive care unit (ICU), and on postoperative days 1, 2, and 3. The diagnosis of perioperative myocardial infarction was based on the presence of the following criteria: 1) a new Q wave or the disappearance of the R wave persisting on two consecutive postoperative electrographic tracings, or 2) a peak CK-MB serum activity level greater than 100 IU/L or evidence of perioperative myocardial necrosis at autopsy.

Data analysis
Analysis of continuous variables was performed with the Student’s t test and the multivariate analysis of variance test. The ² test or Fisher’s exact test were used for comparison of discontinuous data. A two-way analysis of variance was performed to study the interaction between the temperature of administration of the cardioplegic solution and the effect of L-arginine on the release of troponin T 12, 24, and 48 hours after surgery. The level of statistical significance was established at 95%. Data are expressed as mean ± standard deviation.

	Results

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Preoperative profiles of patients
The two groups of patients had similar preoperative characteristics (Table 1). The majority of patients had a three-vessel coronary artery disease and 40% of patients had significant stenoses of the left main coronary artery. Of the patients, 40% were treated with intravenous nitroglycerin or heparin for unstable angina at the time of surgery.

Postoperative morbidity and mortality
Three patients (2 patients in the L-arginine group and 1 in the control group) died of perioperative myocardial infarction. Another patient in the control group died of respiratory failure (Table 3). There were no deaths among patients receiving warm blood cardioplegia in the two groups of patients. Among the 9 patients who showed evidence of perioperative myocardial infarction, 6 were treated with intravenous nitroglycerin or heparin for unstable angina before surgery.

Release of troponin T
In the 190 patients without perioperative myocardial infarction, serum cardiac troponin T levels were lower in patients with L-arginine-enriched cardioplegia (n = 94), averaging 0.28 ± 0.22 µg/L, 0.24 ± 0.18 µg/L, and 0.27 ± 0.24 µg/L 12, 24, and 48 hours after surgery, compared with 0.40 ± 0.43 µg/L, 0.38 ± 0.42 µg/L, and 0.39 ± 0.50 µg/L among control patients (n = 96), a statistically significant difference (Fig 1). The differences remained significant in patients who received warm blood L-arginine-enriched cardioplegic solution (Fig 2). Overall, and irrespective of L-arginine supplementation, patients who received warm blood cardioplegia (n = 141) averaged 0.34 ± 0.36 µg/L, 0.32 ± 0.36 µg/L, and 0.34 ± 0.44 µg/L of troponin T serum level compared with 0.35 ± 0.30 µg/L, 0.28 ± 0.21 µg/L, and 0.32 ± 0.29 µg/L in patients with cold blood cardioplegia, (n = 49) respectively, 12, 24, and 48 hours after surgery (p = 0.9, p = 0.5, and p = 0.8, a nonsignificant difference).

View larger version (23K): [in this window] [in a new window]   Fig 1. Serum cardiac troponin T levels were lower in patients with L-arginine-enriched cardioplegia compared with control patients (n = 96 patients in control group and n = 94 patients in L-arginine group), including both warm and cold blood cardioplegic solution in the two groups. The 10 patients with perioperative myocardial infarction were excluded.

View larger version (24K): [in this window] [in a new window]   Fig 2. Serum cardiac troponin T levels in patients with warm blood cardioplegia (n = 65 patients in control group and n = 73 patients in L-arginine group). Patients with perioperative myocardial infarction were excluded.

	Comment

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
The present study shows that patients who received L-arginine-enriched blood cardioplegic solution had lower levels of serum cardiac troponin T after surgery, suggesting an overall improvement in myocardial protection. Although our previous experience with administration of L-arginine at a lower concentration did not affect the release of cardiac troponin after coronary artery bypass grafting, the present study especially design to test this hypothesis, recruiting more patients and giving a larger amount of the amino acid L-arginine was effective in decreasing the release of cardiac troponin T after surgery. Of interest, there were no deaths among patients who received warm blood cardioplegia, and the release of cardiac troponin T was also decreased among the these patients. The lower release of cardiac troponin T observed in patients receiving warm blood cardioplegia and L-arginine comes as no surprise, as two randomized trials have already shown a decrease in the incidence of postoperative myocardial infarction and as well as better myocardial protection with warm blood cardioplegia [8, 9]. The present study suggests that L-arginine was beneficial, especially in patients who received cardioplegia at a degree close to normothermia (33°C). A larger group of patients would be necessary to document the effect of L-arginine in cold blood solutions.

The effect of L-arginine on patients with endothelial dysfunction has been well characterized. Patients with peripheral arterial occlusive disease [10], hypercholesterolemia [11–13], and angina [14, 15] have been treated with L-arginine, resulting in improvement of endothelial function and of symptoms. The release of nitric oxide appears to be the mechanism responsible for the physiologic effect of L-arginine supplementation. Mizuno and colleagues [16] showed that supplementation of a blood cardioplegic solution with L-arginine enhanced the release of nitric oxide in an animal model. The exact mode of action of L-arginine to enhance nitric oxide release, besides an increased availability of the substrate for nitric oxide synthase, remains undefined. Nitric oxide causes coronary vasodilatation in preserving endothelial cell function and reduced neutrophil accumulation in the ischemic myocardium [16].

The clinical experience in cardiac surgery with L-arginine is limited, albeit of great interest. Wallace and colleagues [17], in a small randomized trial, administered 30 g of L-arginine to patients immediately after coronary artery bypass grafting. They documented a significant decrease of 20% in coronary vascular resistance, an increase in blood flow through saphenous vein grafts, and an increase in the serum level of L-citrulline, suggesting an increase in the production of nitric oxide after the administration of L-arginine. Schulze-Neick and colleagues [18] administered L-arginine to young patients after repair of ventricular septal defects, and showed that maximal stimulation of nitric oxide release caused a significant decrease in the pulmonary vascular resistance index.

Nitric oxide is a gas that is highly soluble, diffuses readily across cell membranes, and gains access to the intraluminal as well as the vascular smooth muscle cells of arteries with a half-life of 10 to 20 seconds. Whereas L-arginine increases nitric oxide release and causes coronary vasodilation, the beneficial effect may also result from inhibition of platelets and leukocytes function. Side effects may occur because of the diffuse action of L-arginine and nitric oxide. No significant detrimental effect was observed with the use of L-arginine-supplemented blood cardioplegic solution in patients recruited in the two studies using L-arginine-enriched cardioplegia in our institution [7]. Specifically, blood losses were identical and hemodynamic stability was similar among patients with and without L-arginine.

In conclusion, L-arginine-supplemented blood cardioplegic solution is associated with a lower release of cardiac troponin T, a highly sensitive biochemical marker of myocardial damage, suggesting improvement in myocardial protection. The effect of L-arginine was also significant in the subgroup of patients with the warm blood cardioplegic solution. A larger group of patients will allow testing of this hypothesis in patients with cold blood cadioplegia.

	Acknowledgments

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
This study was supported by a grant from the Canadian and Quebec Heart and Stroke Foundation.

	References

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Michel Carrier Michel Pellerin Louis P. Perrault Denis Bouchard Pierre Pagé Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Carrier, M. Articles by Lavoie, J. Search for Related Content PubMed PubMed Citation Articles by Carrier, M. Articles by Lavoie, J. Related Collections Related Article