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Ann Thorac Surg 1995;59:398-402
© 1995 The Society of Thoracic Surgeons

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Orginal Articles

Intermittent Antegrade Warm Blood Cardioplegia

Departments of Cardiac Surgery, Medical Pathophysiology, and Anesthesia, ``G. D'Annunzio'' Chieti University, Chieti, Italy

Accepted for publication September 23, 1994.

Abstract

Intermittent antegrade warm blood cardioplegia has been used routinely at our institution over the last 3 years. We report here a comparison between the first 250 consecutive patients undergoing elective coronary artery bypass grafting in which intermittent antegrade warm blood cardioplegia was used (group A) and the last 250 consecutive patients who received intermittent antegrade cold blood cardioplegia, during bypass grafting (group B). There were no differences in sex, age, number of grafts, and functional status between the two groups; left ventricular ejection fraction was lower in group A. The overall mortality rate in group A was 0.8% versus 3.6% in group B (p < 0.05). There was no in-hospital mortality among high-risk patients (ejection fraction 0.35) in group A (0/53) versus two deaths in group B (2/28) (p < 0.05). No patient in group A needed circulatory assistance; 4 patients in group B received intraaortic balloon pumping. Only 1 patient in group A required inotropic support versus 20 patients in group B (p < 0.0005), and 5 patients in group A received lidocaine hydrochloride for ventricular arrhythmias versus 18 in group B (p < 0.01). The rates of myocardial infarction and stroke were not different between the two groups. The peak concentration of the myocardial-specific isoenzyme of creatine kinase were higher in group B in absolute value (51 ± 30 IU/L) than in group A (38 ± 38 IU/L) (p < 0.0005) and in percent of total creatine kinase (8.2% ± 4.1% versus 6.2% ± 2.9%, respectively). Group A patients awoke earlier (2.7 ± 1.5 hours versus 3.9 ± 2.8 hours; p < 0.0005) and had a shorter stay in the intensive care unit (28 ± 7 hours versus 43 ± 10 hours; p < 0.0005) than group B patients. We conclude that intermittent antegrade warm blood cardioplegia is a safe, reliable, and effective technique of myocardial protection that deserves further assessment.

Continuous normothermic blood cardioplegia, so-called warm heart surgery, was developed as a means of preventing ischemia during the period of aortic clamping [1, 2]. However, most surgeons discontinue cardioplegic flow for a few minutes during construction of the distal anastomoses. This is not a recommended practice, as the heart is subjected to normothermic ischemia, and other means to achieve visualization of the operative field are available [3].

We report here our experience with a different method of myocardial protection, namely, intermittent antegrade warm blood cardioplegia (IAWBC). It uses the principles established for warm heart surgery but eliminates the problem of blood in the operative field.

Material and Methods

A consecutive series of 250 patients underwent elective or urgent coronary artery bypass grafting with IAWBC from May 1992 to December 31, 1993 (group A). This group was compared with the last 250 consecutive patients who had elective or urgent bypass grafting with intermittent antegrade cold blood cardioplegia (IACBC) from January 1991 to April 28, 1992 (group B). All procedures were performed by one surgeon (A.M.C.).

The demographic data are shown in Table 1. There were no differences between the two groups except that the left ventricular ejection fraction was lower in group A patients. In all patients in both groups, anesthesia was induced with fentanyl and sodium thiopental and maintained with fentanyl and droperidol. Muscular relaxation was obtained with pancuronium bromide. The chest was opened through a median sternotomy, and the aorta and the right atrium were cannulated for arterial inflow and venous drainage, respectively. An aortic needle was inserted for infusion of cardioplegia and aortic venting.

View larger version (23K): [in this window] [in a new window]   Fig 1. . Blood is taken from the oxygenator and is injected, by means of a roller pump, into the aortic root or the coronary ostia. A syringe pump delivers K+ to the blood.

Definitions
A perioperative myocardial infarction (MI) was identified by electrocardiographic or enzymatic criteria or both. Enzyme samples, like other blood samples, were collected at admission to the intensive care unit, at 6 PM on the operative day, at 8 AM and 6 PM on the first postoperative day, and at 8 AM on the second postoperative day. Electrocardiograms were made at the same hours the blood samples were taken. A diagnosis of postoperative MI was made according to the following criteria: new Q waves in two or more contiguous electrocardiographic leads, poor R-wave progression, new left bundle-branch block, and unstable ventricular rhythm. Values of the myocardial-specific isoenzyme of creatine kinase were considered significant only if there were electrocardiographic or hemodynamic abnormalities. In our laboratory, the MB fraction is considered normal at less than 6% of the total creatine kinase, but higher levels may reflect muscular dissection for arterial conduit harvesting and not necessarily myocardial necrosis.

Operative deaths were defined as deaths occurring before discharge or within 30 days after operation. Circulatory assistance was represented by the necessity to prolong cardiopulmonary bypass to wean the patient, intraaortic balloon pumping, or both. Cerebrovascular accidents were defined as any central neurologic impairment including focal neurologic deficits suggestive of cerebral infarction and global confusion or incoherence suggestive of diffuse encephalopathy. Awaking time was defined as the interval between admission to the intensive care unit and the return of complete consciousness.

Statistical Analysis
The ² analysis was used to compare nonparametric data. Unpaired Student's t test was used to compare intergroup means. Parametric data are presented as the group mean ± the standard deviation. A p value equal to or less than 0.05 is considered significant.

Results

Results are summarized in Table 3. Preoperatively, there were no differences between the two groups except that patients in group A had a lower left ventricular ejection fraction and that group had a larger number of patients with a left ventricular ejection fraction of 0.35 or less (see Table 1).

The overall mortality was lower in group A (0.8%, 2 patients) than in group B (3.6%, 9 patients) (p < 0.05). There were no deaths among patients with poor left ventricular function (0/53) in group A versus two deaths in group B (2/28) (p < 0.05). The cause of the two deaths in group A was pneumonia. In group B, the causes of death were pneumonia (1 patient), stroke (1 patient), MI (5 patients), sepsis (1 patient), and pancreatic shock (1 patient). The mortality from cardiac-related causes was significantly different (p < 0.025).

The serum potassium peak level during cardiopulmonary bypass was lower in the group A patients (4.7 ± 0.5 mEq/L) than in the group B patients (5.3 ± 0.5 mEq/L) (p < 0.005). Blood loss was similar in the two groups (556 ± 423 mL/12 h in group A and 502 ± 338 mL/12 hours in group B). Also, the number of patients given blood transfusions was similar (62 patients in group A and 60 patients in group B). Patients in group A awoke earlier (2.7 ± 1.5 hours) than those in group B (3.9 ± 2.8 hours) (p < 0.005) because of normothermic perfusion. The intensive care unit stay was significantly shorter in group A (28 ± 7 hours) than in group B (43 ± 10 hours) (p < 0.0005) as was the postoperative in-hospital stay (see Table 3). Eleven patients had a cerebrovascular accident. The difference between the two groups was not significant. One of these patients who was in group B died; the others had permanent deficit.

The peak levels in the myocardial-specific isoenzyme of creatine kinase are shown in Table 3. To better evaluate its release, we chose 20 patients from both groups with the following characteristics: three or four grafts (one internal mammary artery and two or three saphenous vein grafts), similar aortic cross-clamp times (42.1 ± 12.1 minutes versus 41.7 ± 8 minutes), no drugs, no lidocaine, no hemodynamic or electrocardiographic signs of myocardial ischemia or MI, and no transfusion. The results, in absolute values, are shown in Figure 2. The values were significantly lower in group A until the last measurement.

View larger version (20K): [in this window] [in a new window]   Fig 2. . Release in absolute values of the myocardial-specific isoenzyme of creatine kinase (CK-MB) in selected patients (see Results). (ICU = intensive care unit; n.s. = not significant; od = operative day; pod = postoperative day.)

The introduction of normothermic blood cardioplegia into clinical practice [1, 2, 4] represented a radical change from conventional approaches to myocardial protection, and its benefits and risks have been reported [5–8]. Early work by Bigelow and colleagues [9] demonstrated that hypothermia was essential in preserving the heart and body during open heart procedures. With small differences (reintroduction of cold crystalloid cardioplegia and subsequently cold blood cardioplegia), the role of hypothermia maintained its validity even though studies of cardiac metabolism showed detrimental effects of hypothermia [10–13]. The sodium potassium and calcium adenosine triphosphatase enzyme systems of the sarcoplasmic reticulum are inactivated by hypothermia. All adenosine triphosphatase–dependent reactions are therefore impaired, with a resulting negative influence on membrane stability, energy production, enzyme function (eg, cytochrome oxidase system and coenzyme Q of the respiratory chain), aerobic glucose utilization, adenosine triphosphate generation and utilization, cyclic adenosine monophosphate production, and osmotic homeostasis. Moreover, blood, if cold, fails to deliver normal amounts of oxygen to the tissues; with hypoxia, lactic acidosis develops from Embdem-Meyerhof pathway glucose utilization, and intracellular and, secondarily, extracellular pH fall, further impairing a large variety of pH-dependent enzymatic processes. Nevertheless, these data failed to have an impact on surgical practice.

The basic concept of warm heart surgery has been known for many years [14–16]: oxygen consumption of the heart arrested by potassium-enriched normothermic blood cardioplegia falls to 10% of baseline values. A slight further reduction in the oxygen requirement can be obtained by lowering the temperature by 11°C or less [17–19].

This consideration has led us to the use of IAWBC [20, 21] with the standardized delivery protocol shown in Table 2. The length of the maximum ischemic interval was not determined on a scientific basis; 15 minutes was chosen because during this time, we could perform even a difficult distal anastomosis.

To assess the effectiveness of IAWBC, we compared this group of patients (group A) with a group previously operated on using IACBC (group B). Bypass time was longer in the latter group because of hypothermic perfusion, but aortic cross-clamp and ischemic times were similar. In-hospital mortality was lower in group A, and there were no cardiac-related deaths in this group compared with six such deaths in group B (cause of death = MI) (p < 0.025). The most striking difference between the two groups was morbidity. Five patients in group B needed circulatory assistance to be weaned from bypass, and 20 had a low-output syndrome. No patient in group A needed circulatory assistance, and only 1 patient had a low-output syndrome. Lidocaine infusion was higher in group B. The incidence of postoperative MI was lower in group A, but the difference was not significant.

Two major criticisms might be made of this study. First, it is not a randomized but a retrospective study. When we started to use IAWBC, the low morbidity associated with the technique was immediately evident; because of the superior benefit to patients, a randomized study was not scheduled. We then decided to compare the first 250 patients treated with IAWBC with the last 250 patients for whom IACBC was used, because we thought that this comparison and the large number of patients would overcome that problem.

Second, the composition of the blood cardioplegic solutions and the delivery protocol are not perfectly similar because of the different goals of the two techniques. In the cold group (group B), the first dose is both cardioplegic and hypothermic; this means that because it must lower the temperature of the heart, a longer time is necessary to reach a uniform distribution, 3 minutes in our protocol. In the warm group (group A), the first dose is cardioplegic only; as the majority of hearts stop in less than 30 seconds, we could arrest the flow then, but we prefer 2 minutes to allow a uniform distribution of K⁺. For the subsequent doses in the cold group, we reinfused a smaller dose (200 mL) with every distal anastomosis to maintain a cold environment instead of waiting a longer time (20 or 30 minutes) and delivering a larger amount of cardioplegia. In the warm group, on the other hand, the doses following the first are, in reality, warm reperfusions with blood and K⁺. The cardiac metabolism is restored and the heart is prepared for the following ischemic period. For this reason we used only blood and K⁺, as normothermic blood has physiologically every component necessary to counteract damage from ischemia and reperfusion.

Our group [22] demonstrated that after about 1 hour of ischemia in hearts protected with IAWBC, blood samples taken simultaneously from the radial artery and coronary sinus did not show release of creatine kinase and reduced glutathione 1 minute and 20 minutes after aortic declamping. Lipid peroxidation products were also absent. On the other hand, under similar conditions in hearts protected with IACBC, creatine kinase and reduced glutathione were released, and lipid peroxidation products were detected. There was evidence of lactate washout in both groups 1 minute after aortic declamping. Whereas lactate production was present 20 minutes after reperfusion in group B, there was evidence of normal lactate extraction, representing rapid restoration of a normal metabolism, in group A. Others [23] have demonstrated that after 90 minutes of ischemia, pig hearts protected from ischemia with IAWBC showed adenosine triphosphate and creatine phosphate levels equal to baseline values. Therefore, ischemic periods do not seem to be cumulative.

These data clearly show that excellent clinical results in patients protected with IAWBC are due to a well-preserved myocardial metabolism. This provides a superior clinical outcome, especially for patients with poor left ventricular function. The technique we propose is simple and reliable, and allows adjustment of the duration of cardioplegic doses according to surgical requirements.

In conclusion, IAWBC provides lower morbidity and mortality than IACBC in elective and urgent coronary bypass procedures, especially for patients with poor left ventricular function. The technique, together with normothermic perfusion, also reduces the awaking period, the intensive care unit stay, and the postoperative in-hospital stay.

Footnotes

Address reprint requests to Dr Calafiore, Department of Cardiac Surgery, c/o ``San Camillo De Lellis'' Hospital, Via Forlanini, 50, 66100 Chieti, Italy.

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				A. M. Calafiore, S. Gallina, M. Di Mauro, F. Gaeta, A. L. Iaco, S. D'Alessandro, V. Mazzei, and G. Di Giammarco Mitral valve procedure in dilated cardiomyopathy: repair or replacement? Ann. Thorac. Surg., April 1, 2001; 71(4): 1146 - 1152. [Abstract] [Full Text] [PDF]

				M. Yeatman, M. Caputo, R. Ascione, F. Ciulli, and G. D. Angelini Off-pump coronary artery bypass surgery for critical left main stem disease: safety, efficacy and outcome Eur. J. Cardiothorac. Surg., March 1, 2001; 19(3): 239 - 244. [Abstract] [Full Text] [PDF]

				A. Kramer, M. Mastsa, Y. Paz, C. Locker, D. Pevni, J. Gurevitch, I. Shapira, O. Lev-Ran, and R. Mohr Bilateral skeletonized internal thoracic artery grafting in 303 patients seventy years and older J. Thorac. Cardiovasc. Surg., August 1, 2000; 120(2): 290 - 297. [Abstract] [Full Text] [PDF]

				R. Dion, D. Glineur, D. Derouck, R. Verhelst, P. Noirhomme, G. El Khoury, E. Degrave, and C. Hanet Long-term clinical and angiographic follow-up of sequential internal thoracic artery grafting Eur. J. Cardiothorac. Surg., April 1, 2000; 17(4): 407 - 414. [Abstract] [Full Text] [PDF]

				C. Locker, I. Shapira, Y. Paz, A. Kramer, J. Gurevitch, M. Matsa, D. Pevni, and R. Mohr Emergency myocardial revascularization for acute myocardial infarction: survival benefits of avoiding cardiopulmonary bypass Eur. J. Cardiothorac. Surg., March 1, 2000; 17(3): 234 - 238. [Abstract] [Full Text] [PDF]

				S. Chocron, D. Kaili, Y. Yan, G. Toubin, L. Latini, F. Clement, J.-F. Viel, and J.-P. Etievent INTERMEDIATE LUKEWARM (20{degrees}C) ANTEGRADE INTERMITTENT BLOOD CARDIOPLEGIA COMPARED WITH COLD AND WARM BLOOD CARDIOPLEGIA J. Thorac. Cardiovasc. Surg., March 1, 2000; 119(3): 610 - 616. [Abstract] [Full Text] [PDF]

K. Minatoya, H. Okabayashi, I. Shimada, A. Tanabe, T. Nishina, K. Nandate, and M. Kunihiro Intermittent antegrade warm blood cardioplegia for CABG: extended interval of cardioplegia Ann. Thorac. Surg., January 1, 2000; 69(1): 74 - 76. [Abstract] [F