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Ann Thorac Surg 1998;66:108-112
© 1998 The Society of Thoracic Surgeons

Original articles: cardiovascular

Can L-arginine improve myocardial protection during cardioplegic arrest? Results of a phase I pilot study

Michel Carrier, MDa, Michel Pellerin, MDa, Pierre L. Pagé, MDa, Norman R. Searle, MDa, Raymond Martineau, MDa, Claire Caron, Perfa, B. Charles Solymoss, MDa, L. Conrad Pelletier, MDa

a Departments of Surgery, Anesthesia, and Laboratory Medicine, Montreal Heart Institute, Montreal, Quebec, Canada

Accepted for publication February 21, 1998.

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


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Comment
 References
 
Background. L-Arginine appears to improve myocardial protection during cardioplegic arrest in animal models.

Methods. To study the clinical effect and safety of L-arginine in humans, a phase I pilot study was performed with 50 patients who underwent coronary artery bypass grafting. We randomly assigned half to a treatment group, which received 1 g of L-arginine administered during the first 30 minutes of cardioplegic arrest induced by either warm or cold blood cardioplegia, and half to a control group, which did not receive L-arginine supplementation.

Results. Age, sex, and preoperative clinical status were similar in both groups. Seventeen patients of each group were administered intermittent warm antegrade blood cardioplegia, whereas the solution needed to be cooled to obtain complete standstill of the remaining eight hearts in each group. An internal thoracic artery graft to the left anterior descending coronary artery was performed in all patients. There was no death and no myocardial infarction in the treatment group, but there were one death and two infarctions in the control group. The amount of serial release of troponin I during the first 72 hours after the operation was similar between the L-arginine group and the control group (p > 0.05). Peak serum troponin levels averaged 4.9 ± 1.0 µg/L in the arginine group and 3.9 ± 1.0 µg/L in the control group (p > 0.05). A multivariate analysis of variance showed no effect of L-arginine (p > 0.05) but a significant effect of the temperature of the cardioplegic solution on the release of troponin I (p < 0.05). Serum troponin I levels averaged 2.2 ± 0.4 µg/L, 4.5 ± 0.4 µg/L, and 6.9 ± 0.4 µg/L in the patients with cold cardioplegia and 1.4 ± 0.3 µg/L, 2.4 ± 0.3 µg/L, and 3.3 ± 0.3 µg/L in the patients with warm cardioplegia 1, 2, and 6 hours, respectively, postoperatively.

Conclusions. The administration of 1 g of L-arginine during the first 30 minutes of blood cardioplegic arrest did not result in a decrease in the postoperative release of cardiac enzyme; however, cold cardioplegic arrest significantly increased the release of cardiac troponin I postoperatively. There was no significant side effect related to the addition of L-arginine to the cardioplegic solution.


   Introduction
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 Abstract
 Introduction
Patients and methods
 Results
 Comment
 References
 
The addition of L-arginine to the cardioplegic solution appears to improve myocardial protection by stimulating the release of nitric oxide [1], which is known to increase coronary vasodilation and to decrease platelet and leukocyte adhesion to the endothelial surface [2]. Moreover, in animal studies the release of nitric oxide is reduced throughout periods of coronary occlusion [3–6]. Several laboratory experiments suggest that L-arginine might have a beneficial effect in enhancing myocardial protection during episodes of cardioplegic arrest.

The objective of the present study was to determine the safety and feasibility of a clinical study to evaluate the potential benefit of adding L-arginine to cardioplegic solutions during cardiac operations. Because of the lack of clinical experience with L-arginine, we undertook a feasibility phase I study to determine potential benefits and side effects related to the addition of L-arginine to a standard cardioplegic solution.


   Patients and methods
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 Abstract
 Introduction
 Patients and methods
Results
 Comment
 References
 
Study population
Between June and October 1996, 50 patients who underwent 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 had given their written informed consent, they were randomly assigned to a group just before the beginning of the operation, by blocks of four for equal sample size in the two groups. The study sample size was arbitrarily set at 50 patients in this pilot study. Design of the study was evaluated and approved by our institution’s review board.

Exclusion criteria were (1) operation within 7 days of an acute myocardial infarction, (2) urgent operation for acute coronary occlusion at angioplasty, (3) emergency surgical procedures performed outside of normal working hours, (4) reoperation for myocardial revascularization, or (5) coronary operations associated with any other cardiac surgical procedures.

Surgical technique
The operation was performed according to standard surgical techniques. Internal mammary artery grafts and saphenous vein grafts were used in all patients. Proximal anastomoses to the aorta were performed with partial occlusion of the ascending aorta after completion of the distal coronary anastomosis. Cardiopulmonary bypass was performed using moderate hemodilution, with a hematocrit level between 20% and 25%. Mild systemic hypothermia was attained by permitting body temperature to drift down progressively to 33°C, the core temperature being thereafter maintained 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) consisted of two inflow catheters for mixing of the crystalloid solution with blood from the arterial circuit at a ratio of 4:1. A liter of Ringer’s lactate containing either 80 mmol/L or 40 mmol/L 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 [1, 2].

After the ascending aorta was cross-clamped, cardioplegic arrest was induced in all patients by antegrade infusion of 300 mL of high-potassium solution over a period of 3 to 5 minutes, at a perfusion pressure not exceeding 250 mm Hg in the infusion catheter, and at a core temperature of 33°C. Diastolic arrest was usually obtained before termination of the initial infusion. Thereafter and throughout the remainder of the procedure, repeat intermittent infusions of 200 to 300 mL of low-potassium solution were administered after each distal anastomosis. In 16 patients (36%), some electromechanical activity of the heart persisted after the infusion of 300 to 400 mL of high-potassium solution. The cardioplegic mixture was then cooled by immersing the heat exchanger of the infusion catheter in ice to decrease the solution temperature to lower than 20°C (cold cardioplegia).

One gram of L-arginine diluted in 50 mL of saline or a control injection of saline alone was injected directly in the cardioplegic mixture of crystalloid solution and blood through a side-port in the infusion catheter, during the initial 30 minutes of cardioplegic arrest. Both perfusionists and surgeons were blinded to the content of the injected solutions. The dosage of L-arginine was based on the result of our animal study [1].

Markers of myocardial ischemia and diagnosis of perioperative myocardial infarction
To determine the dosage of cardiac troponin I, blood samples were taken at the beginning of the operation, and at 1, 3, 6, 12, 24, and 48 hours after chest closure. To determine serum levels of total creatine kinase (CK) and of the catalytic activity of its MB isoenzyme, blood samples were taken 1 and 24 hours postoperatively. 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 were measured by standard methods using a Hitachi (Tokyo, Japan) 717 analyzer and reagents from Boehringer-Mannheim (Mannheim, Germany). The cardiac troponin I serum concentration was determined by the immunoassay method with the Baxter (Deerfield, IL) Stratus analyzer, which uses two monoclonal antibodies specific for cardiac troponin I [7].

Electrocardiographic tracings were obtained the day before operation, upon arrival in the intensive care unit, 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) peak CK-MB serum activity level higher than 100 IU/L.

Data analysis
Analysis of continuous variables was performed with the Student’s t test and the multivariate analysis of variance test. The {chi}2 test or the Fisher’s exact test were used for comparison of discontinuous data. The level of statistical significance was established at 0.05 or less. Data are expressed as mean ± standard deviation.


   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Comment
 References
 
Preoperative profile of patients
The two groups of patients had similar preoperative characteristics (Table 1). Most patients had a previous myocardial infarction and three-vessel coronary disease. The left ventricular ejection fraction was normal in all patients of both groups.


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  		Table 1. Preoperative Clinical and Angiographic Characteristics of the Two Groups of Patientsa

 
Surgical procedures and cardioplegic infusion
There was no difference between groups with regard to the number of bypassed vessels, aortic cross-clamp time, and lowest body temperature (Table 2). For 8 patients in each group, the cardioplegic mixture was cooled to between 10°C and 20°C because we were unable to achieve or maintain complete cardiac arrest with the warm infusion (33°C). The total volume of crystalloid solution infused and the duration of infusion of the cardioplegic solution were similar in the two groups.


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  		Table 2. Comparison of Operative Data Between the Two Groupsa

 
Systemic perfusion pressure during cardiopulmonary bypass averaged 75 ± 1 mm Hg in the L-arginine group and 72 ± 1 mm Hg in the control group (p > 0.05). Phenylephrine injections were used to maintain systemic pressure during bypass in 16 (64%) of 25 L-arginine patients and in 17 (68%) of 25 control patients. Cardiac index measured by thermodilution averaged 2.6 ± 0.1 L · min-1 · m-2 before and 3.0 ± 0.1 L · min-1 · m-2 after cardiopulmonary bypass in the treatment group (p = 0.047) compared with 2.5 ± 0.1 L · min-1 · m-2 and 2.8 L · min-1 · m-2 in the control group (p = 0.02); there was no difference between the two groups. Inotropic support was used in 3 patients (12%) in the L-arginine group and in 2 patients (8%) in the control group to wean them from bypass.

Postoperative morbidity and mortality
One patient in the control group died of a perioperative myocardial infarction (Table 3). Upon arrival in the operating room, this patient had continuous chest pain and electrocardiographic changes consistent with ischemia before the induction of anesthesia. Two other patients in the control group had a perioperative myocardial infarction. Saphenous vein graft thrombosis secondary to heparin-induced thrombocytopenia occurred in 1, and the other had an asymptomatic but significant increase in serum CK-MB levels to 200 IU/L 24 hours postoperatively. There was no infarction and no death in the treatment group. The difference between groups was not significant.


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  		Table 3. Comparison of Postoperative Morbidity and Mortalitya

 
Release of troponin i
In the 47 patients without perioperative myocardial infarction, the release curve of troponin I was similar in the two groups (Fig 1). In the control and L-arginine groups serum CK-MB activity levels averaged 30 ± 8 IU/L and 27 ± 6 IU/L at 1 hour, 15 ± 6 IU/L and 12 ± 7 IU/L at 24 hours, and 10 ± 9 IU/L and 9 ± 4 IU/L at 48 hours postoperatively (p > 0.05).



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  		Fig 1. Postoperative Troponin I serum levels were similar between the two groups.

 
In patients with cold blood cardioplegia, troponin I serum levels at 1, 3, and 6 hours postoperatively were significantly higher (p < 0.05) than in those to whom warm cardioplegia was given (Fig 2).



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  		Fig 2. Troponin I serum levels were higher among patients who were administered cold blood cardioplegia compared with those given warm blood cardioplegia (p < 0.05).

 

   Comment
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
References
 
Results of the present phase I pilot study suggest that L-arginine can be safely added to a cardioplegic solution; however, we did not show any improvement in myocardial protection when administered during cardioplegic arrest in the human heart. Several experimental studies have shown that L-arginine improves myocardial metabolism [1], functional recovery of the myocardium [8–12], and coronary endothelial function [8, 11, 12] after regional and global ischemia, but the timing for nitric oxide supplementation to obtain beneficial effects remains controversial.

Morita and associates [13] studied hypoxic and reoxygenation injury in hypoxemic immature piglet hearts and found that the L-arginine nitric oxide pathway is involved in the pathogenesis of myocardial reoxygenation injury and that there may be a nitric oxide paradox causing injury at reperfusion. Engelman and associates [14] determined in isolated working rat hearts that L-arginine is most beneficial for the recovery of myocardial function when given before cardioplegic arrest, is still effective when given during cardioplegic arrest, but is detrimental if infused during reperfusion. These authors clearly documented that L-arginine can reduce myocardial damage associated with ischemia and reperfusion, if it is administered before the ischemic insult. In the present study, L-arginine was given during the first 30 minutes of cardioplegic infusion. Whereas injecting L-arginine during cardioplegia resulted in a modest but significant improvement in myocardial protection in animal experiments [1], we found no changes in postoperative release of cardiac troponin I in these patients.

Cardiac troponin I is a highly sensitive and specific marker of myocardial ischemia in acute coronary syndromes [15] and in the perioperative period [16, 17]. This protein is not present in skeletal muscles and it is not detectable in the blood of healthy volunteers. Thus, it is a useful prognostic factor in unstable angina and following non–Q-wave myocardial infarction [14]. In the present study, the postoperative release of troponin I was similar in the two groups, when patients with perioperative myocardial infarction were excluded (Fig 1). A subgroup analysis of the effect of the temperature of the cardioplegic mixture showed that patients who were administered cold-blood cardioplegia had a significantly higher serum level of troponin I at 1, 3, and 6 hours postoperatively compared to those who had warm-blood cardioplegia (Fig 2). Previous studies have found that the latter approach is associated with lower postoperative release of CK-MB and troponin T [18, 19].

There was no effect of L-arginine on hemodynamic stability perioperatively. The average systemic perfusion pressure and the use of phenylephrine to maintain perfusion pressure during cardiopulmonary bypass were similar in the two groups. Thus, adding L-arginine to a cardioplegic solution appears safe, but its efficacy remains to be proved. Furthermore, the dose of L-arginine administered in the cardioplegic solution was based empirically on our animal experience [1]. A study evaluating blood levels of L-arginine and monitoring nitric oxide level in blood samples from the coronary sinus at different dosages of L-arginine administration will likely help determine its efficacy [20].

In conclusion, adding L-arginine to a blood cardioplegic solution had no related side effect. Postoperative release of cardiac troponin I was similar in the two groups, but patients who were administered cold-blood cardioplegia released higher serum levels of this cardiac-specific protein immediately postoperatively compared with those who were given only warm-blood cardioplegia. This finding may result from a reversible increase of cell membrane permeability by the cold temperature of myocardial cells or from poorer protection in this subgroup of patients who were unresponsive to the warm injection of the cardioplegic solution. Although L-arginine did not cause any significant clinical side effects or any significant benefits when administered during cardioplegia, we cannot exclude that a different timing, perhaps L-arginine administered before cardioplegic arrest, could improve myocardial protection during cardiac operations. A larger and well-designed trial should test this hypothesis.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 References
 

  1. Carrier M., Khalil A., Tourigny A., et al. Effects of L-arginine on metabolic recovery of the myocardium. Ann Thorac Surg 1996;61:1651-1657.[Abstract/Free Full Text]
  2. Provost P., Lam J.Y.T., Lacoste L., et al. Endothelium-derived nitric oxide attenuates neutrophil adhesion to endothelium under arterial flow condition. Arterioscler Thromb 1994;14:331-335.[Abstract/Free Full Text]
  3. Pearson P.J., Pyng J.L., Schaff H.V. Global myocardial ischemia and reperfusion impair endothelium-dependent relaxation to aggregating platelets in the canine artery. J Thorac Cardiovasc Surg 1992;103:1147-1154.[Abstract]
  4. Evora P.R.B., Pearson P.J., Schaff H.V. Impaired endothelium-dependent relaxation after coronary reperfusion injury: evidence for G-protein dysfunction. Ann Thorac Surg 1994;57:1550-1556.[Abstract]
  5. Pearson P.J., Schaff H.V., Vanhoutte P.M. Acute impairment of endothelium-dependent relaxations to aggregating platelets following reperfusion injury in canine coronary arteries. Circ Res 1990;67:385-393.[Abstract/Free Full Text]
  6. Pearson P.J., Schaff H.V., Vanhoutte P.M. Long-term impairment of endothelium-dependent relaxations to aggregating platelets after reperfusion injury in canine coronary arteries. Circulation 1990;81:1921-1927.[Abstract/Free Full Text]
  7. Adams J.E., Sicard G.A., Allen B.T., et al. Diagnosis of perioperative myocardial infarction with measurement of cardiac troponin I. N Engl J Med 1994;330:670-674.[Abstract/Free Full Text]
  8. Hiramatsu T., Forbess J.M., Miura T., et al. Effect of L-arginine cardioplegia on recovery of neonatal lamb heart after 2 hours of cold ischemia. Ann Thorac Surg 1995;60:187-192.
  9. Engelman D.T., Watanabe M., Engelman R.M., et al. Constitutive nitric oxide release is impaired after ischemia and reperfusion. J Thorac Cardiovasc Surg 1995;110:1047-1053.[Abstract/Free Full Text]
  10. Engelman D.T., Watanabe M., Maulik N., et al. L-Arginine reduces endothelial inflammation and myocardial stunning during ischemia/reperfusion. Ann Thorac Surg 1995;60:1275-1281.[Abstract/Free Full Text]
  11. Sato H., Zhao Z.Q., McGee D.S., et al. Supplemental L-arginine during cardioplegic arrest and reperfusion avoids regional postischemic injury. J Thorac Cardiovasc Surg 1995;110:302-314.[Abstract/Free Full Text]
  12. Nakanishi K., Vinten-Johansen J., Lefer D.J., et al. Intracoronary L-arginine during reperfusion improves endothelial function and reduces infarct size. Am J Physiol 1992;263:H1650-H1658.
  13. Morita K., Sherman M.P., Buckberg G.D., et al. Role of the L-arginine-nitric oxide pathway: the nitric oxide paradox. J Thorac Cardiovasc Surg 1995;110:1200-1211.
  14. Engelman D.T., Watanabe M., Maulik N., et al. Critical timing of nitric oxide supplementation in cardioplegic arrest and reperfusion. Circulation 1996;94(Suppl 2):407-411.[Abstract/Free Full Text]
  15. Antman E.M., Tanasijevic M., Thompson B., et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335:1342-1349.[Abstract/Free Full Text]
  16. Etievent J.P., Chocron S., Toubin G., et al. Use of cardiac troponin I as a marker of perioperative myocardial ischemia. Ann Thorac Surg 1995;59:1192-1194.[Abstract/Free Full Text]
  17. Chocron S., Alwan K., Toubin G., et al. Crystalloid cardioplegia route of delivery and cardiac troponin I release. Ann Thorac Surg 1996;62:481-485.[Abstract/Free Full Text]
  18. Pelletier L.C., Carrier M., Leclerc Y., et al. Intermittent antegrade warm versus cold blood cardioplegia: a prospective, randomized study. Ann Thorac Surg 1994;58:41-49.[Abstract]
  19. The Warm Heart Investigators. Randomized trial of normothermic versus hypothermic coronary bypass surgery. Lancet 1994;343:559-563.[Medline]
  20. Amrani M., Chester A., Jayakumar L., et al. L-Arginine reverses low reflow and enhances post-ischaemic recovery of cardiac mechanical function. Cardiovasc Res 1995;30:200-204.[Medline]



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