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Ann Thorac Surg 2001;71:565-570
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

Myocardial preservation during coronary surgery with and without cardiopulmonary bypass

^a Department of Anesthesiology, Oulu University Hospital, Oulu, Finland
^b Department of Thoracic Surgery, Oulu University Hospital, Oulu, Finland
^c Department of Medical Biochemistry, Oulu University, Oulu, Finland
^d Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland

Accepted for publication June 5, 2000.

Address reprint requests to Dr Penttilä, Department of Anesthesiology, Oulu University Hospital, Kajaanintie 50, 90220 Oulu, Finland
e-mail: hannu.penttila{at}oulu.fi

	Abstract

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Background. There is increased interest in coronary artery bypass grafting (CABG) without cardiopulmonary bypass (CPB), although the preservation of the myocardium under such circumstances has not been properly investigated. The aim of this randomized study was to compare the changes in myocardial metabolism during CABG with and without CPB.

Methods. Myocardial energy metabolism and tissue injury during CABG was monitored in a series of 22 patients (11 with and 11 without CPB).

Results. The maximum myocardial lactate production was significantly higher (p = 0.02) in the group operated with CPB (0.56 mmol/L) than without it (0.17 mmol/L). A similar phenomenon was seen in the transcardiac pH differences (0.085 and 0.034 with and without CPB, p = 0.007). The postoperative peak values of creatine kinase-MB mass (15.1 vs 6.3 µg/L) and troponin I (13.8 vs 5.2 µg/L) were significantly higher (p < 0.001 and p = 0.008) with than without CPB.

Conclusions. CABG on a beating heart is associated with better myocardial energy preservation and less myocardial damage compared with conventional CABG with CPB and intermittent antegrade mild hypothermic blood cardioplegia.

	Introduction

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The number of cardiac operations has increased because of the development of cardiopulmonary bypass (CPB) and the delivery of cardioplegia. Although widely used and relatively safe, CPB has some well-known adverse effects, such as neuropsychologic deficits, whole-body inflammatory response, and impaired platelet function and hemostasis. Myocardial protection during the aortic cross-clamping period ultimately depends on adequate distribution of cardioplegia to all parts of the myocardium [1, 2]. Abnormal septal motion [3], a decline in left ventricular systolic function [4–6], and deleterious effects on diastolic function [7–9] have been documented after cardioplegia. The ideal routes, temperature, composition, and need for continuity of cardioplegia delivery are still under dispute [10, 11]. Renewed interest in coronary artery bypass grafting (CABG) without CPB has arisen lately, and several nonrandomized series of CABG operations without CPB have been reported. The coronary artery to be bypassed is usually occluded during the suturing of the distal anastomosis on a beating heart, which may lead to regional ischemia. In our pilot study, we were able to demonstrate that CABG without CPB seems to be well tolerated in selected cases [12]. To clarify the issue, we performed a trial where changes in myocardial energy metabolism and tissue preservation during CABG with and without CPB were studied in a prospective, randomized manner.

	Material and methods

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Patients
The study was approved by the Ethical Committee of Oulu University Hospital. Twenty-two patients with coronary artery disease suitable for CABG without CPB were included in the study after written informed consent had been obtained. The exclusion criteria were ongoing ischemia, acute myocardial infarction less than 1 month previously, poorly controlled diabetes, a serum creatinine level higher than 150 µmol/L, chronic atrial fibrillation, and aortic or mitral valvular diseases. The patients were randomized into two groups: CABG with CPB (11 patients) and CABG without CPB (11 patients).

Anesthesia and CPB
All the patients were anesthetized and CPB was performed by one experienced cardiac anesthesiologist (H.J.P.). All medication except salicylates were allowed without interruption until the day of operation. Salicylates were withdrawn 1 to 2 weeks before the operation, except in 1 patient in each group. Premedication consisted of intramuscular morphine (6 to 15 mg), oral diazepam (10 to 15 mg), and oral dipyridamole (200 mg). Radial artery was cannulated and a pulmonary artery catheter for continuous monitoring of cardiac output and mixed venous oxygen saturation (Baxter Swan-Ganz Combo; Baxter Healthcare Corporation, Edwards Critical Care Division, Irvine, CA) was introduced. Anesthesia was induced with propofol (1.0 to 2.8 mg/kg) and fentanyl (4.0 to 7.2 µg/kg). Muscle relaxation was achieved with pancuronium (0.08 to 0.12 mg/kg). The patients were ventilated with 30% to 50% oxygen in air, and anesthesia was maintained with propofol (1.4 to 5.2 mg/kg/h), alfentanil (24 to 43 µg/kg/h), and sevoflurane (0.7 to 1.9 MAC). All the patients received 20 mg of dipyridamole intravenously before the start of the operation.

The patients in the group without CPB were anticoagulated with an initial heparin dose of 1 mg/kg, and additional heparin was given when needed. The activated clotting time (ACT) was maintained above 300 seconds and heparinization was reversed with protamine sulphate (50 to 100 mg). Intraoperative myocardial ischemia was evaluated by continuous monitoring of the ST-segment in the modified leads V5 and II and by observing the appearance of a V-wave in the pulmonary artery wedge pressure curve. Ischemia, if present, was treated with intravenous nitroglycerin. If the patient did not respond to nitroglycerin, an intracoronary flow-through catheter (CTS Flo Coil Shunt; Cardiothoracic Systems Inc., Cupertino, CA) was used during the suturing of the distal anastomoses. The mean arterial blood pressure was maintained above 50 mm Hg with phenylephrine hydrochloride and enhanced fluid infusion. After the harvesting of vein grafts, the patients were actively heated with a thermoblanket on their lower body to raise the core temperature above 36°C.

The patients in the CPB group were anticoagulated with an initial heparin dose of 3 mg/kg, and ACT was maintained above 480 seconds with additional heparin. Heparinization was reversed with protamine sulphate (3 mg/kg). CPB was performed with a roller pump (Stöckert Caps; Stöckert Instrument, Munich, Germany) by maintaining the flow rate above 2.3 L/m², and a membrane oxygenator (Compactflow; Dideco, Mirandola, Italy) was used. Forty percent to 60% oxygen in air was used to keep the arterial line blood oxygen tension at 20 to 25 kPa. Perfusion pressure was maintained above 50 mm Hg with phenylephrine hydrochloride. The patients were cooled to 33°C and rewarmed to 37°C before CPB was discontinued.

Surgical technique
All the operations were performed by the same experienced cardiac surgeon (M.V.K.L.). A conventional midline sternum splitting incision was made, and a coronary sinus catheter (Pediatric Cannula; RCSP, Grand Rapids, MI) was introduced through the right atrial wall before suturing the first anastomosis or before the start of CPB.

In the group without CPB, pericardial traction sutures and elevating gauze pads were used to facilitate visibility and access to either the left or the right side of the heart. A commercial mechanical suction stabilizer (Octopus Medtronic; Medtronic Inc, Minneapolis, MN), and a moist air blower were used to facilitate the construction of the distal anastomoses, and coronary artery probes were used to diminish the bleeding of the target artery. The proximal anastomoses of vein grafts were finished with the aid of a partially occluding aortic side clamp.

CPB was established with a single two-stage right atrial cannula and an ascending aortic cannula. A cardioplegic cannula with additional venting and pressure-monitoring channels (DLP Inc, Grand Rapids, MI) was used for intermittent antegrade delivery of aspartate-glutamate-enriched blood cardioplegia. A commercial cardioplegia set (CE 008; Dideco, Mirandola, Italy) was used to mix the cardioplegic solution and blood in a proportion of 1:9. The pressure of the aortic root during infusion was maintained at 40 to 50 mm Hg and the temperature of blood cardioplegia at 33°C, with the exception of normothermic initial arresting and terminal infusions. Mild hypothermic antegrade blood cardioplegia was chosen, because this in our hands has provided the best myocardial protection. During the construction of the anastomoses, cardioplegia was interrupted for short periods to improve visibility. Both the distal and the proximal anastomoses were accomplished during a single period of aortic cross-clamping.

Laboratory data and electrocardiograms (ECGs)
Intraoperative blood samples were withdrawn simultaneously from the arterial line and the coronary sinus catheter (T₀–T₄ in Fig 1). Lactate was assayed using an electrode-based lactate analyzer (YSI model 1500; Yellow Springs Instrument Co, Inc, Yellow Springs, OH), pH was determined with a 288 blood gas system (Ciba-Corning, Medfield, MA), and transcardiac differences were calculated. To measure the plasma levels of adenosine triphosphate (ATP) degradation products (adenosine, inosine, hypoxanthine, and xanthine), blood samples were withdrawn simultaneously into a syringe containing dipyridamole solution, processed as described earlier, and analyzed with high-pressure liquid chromatography [12, 13]. Transcardiac concentration differences of ATP degradation products were then calculated.

View larger version (24K): [in this window] [in a new window]   Fig 1. Study design and blood sampling schedule. T0= before bypass grafting; T1–T2= immediately after the first two distal anastomoses; T3–T4= 5 and 15 minutes after the suturing of the last anastomosis; T5–T6= 2 and 8 hours after the suturing of the last anastomosis; T7–T10= On the first to fourth postoperative day.

Statistics
The statistical analyses were performed using the Statistica package software, version 5.1 (StatSoft, Tulsa, OH). A t test for independent changes was used for single measurements to test the differences between the groups. Analysis of variance with contrast analysis was used to analyze the variance within each group and to test the differences between the groups, when repeated measures were made. The data are presented as means and 95% confidence intervals (CIs). Significance was assumed when the p value was less than 0.05.

	Results

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Preoperative characteristics and perioperative course
The two study groups had similar preoperative characteristics and perioperative courses, with the exception of a longer total grafting time in the group without CPB in comparison with the aortic occlusion time in the CPB group and the lower core temperature in the CPB group (Table 1). The mean ischemia times for the first two distal anastomoses were 15.2 minutes (CI 12.5 to 17.9 minutes) without CPB and 6.9 minutes (CI 5.2 to 8.6 minutes) with CPB (p < 0.001). The CPB patients received higher doses of heparin (4.3 vs 1.8 mg/kg, p < 0.001), resulting in significantly longer ACTs (505 to 758 seconds vs 261 to 345 seconds, p < 0.001), and, consequently, higher doses of protamine sulphate (3.3 vs 0.7 mg/kg, p < 0.001).

Myocardial energy metabolism
Transmyocardial differences of xanthine, inosine, and the sum of ATP degradation products increased significantly during the suturing of the first two distal anastomoses in the CPB group (p = 0.04, p = 0.006 and p = 0.02, respectively). In the case of a beating heart, the corresponding changes were statistically significant for inosine (p = 0.01) and the sum of ATP degradation products (p = 0.04). There were no statistically significant differences between the groups, however (Table 2).

View larger version (23K): [in this window] [in a new window]   Fig 2. Myocardial lactate production (A) and transcardiac pH difference (B) (median, 25% and 75% percentiles, and nonoutlier range) before bypass (T0), after the completition of the first (T1) and second (T2) distal anastomoses, and 5 (T3) and 15 (T4) minutes after the suturing of the last anastomosis. The increases in myocardial lactate production (p = 0.002 with CPB, and p = 0.04 without CPB) and the transcardiac pH difference (p < 0.001) were significant in both groups. The letters a, b, c, and d indicate the differences between the groups (p = 0.02, p = 0.01, p = 0.007, and p < 0.001, respectively).

View larger version (25K): [in this window] [in a new window]   Fig 3. Plasma levels of CK-MB mass (A) and Troponin I (B) (median, 25% and 75% percentiles, and nonoutlier range) before the construction of the anastomoses (T0), at 2 (T5) and 8 (T6) hours after the suturing of the last anastomosis, and on the next 4 days (T7–T10). The increases in both myocardial markers were statistically significant in both groups (p 0.001). The letters a, b, c, d, and e indicate significant differences between the groups (p < 0.001, p = 0.002, p = 0.04, p = 0.002, and p = 0.008, respectively).

One patient in the group without CPB and 3 patients in the CPB group developed atrial fibrillation after the operation, and they were converted to sinus rhythm with ß-blocking agents, amiodarone hydrochloride, or ibutilide fumarate. Two patients in the group without CPB and 6 patients in the CPB group received dopamine for 1 to 44 hours at infusion rates of 4.2 to 15.3 µg/kg/min. However, only 1 patient with CPB had cardiac a index below 2.2 L/m², and dopamine was used mainly for the treatment of hypotension, which was modest in every case. Tracheal extubation took place 5.5 hours (CI 3.4 to 7.5 hours) and 4.1 hours (CI 3.3 to 4.9 hours) after the operation with and without CPB, respectively. Apart from two perioperative myocardial infarctions, there were no major complications during the 1-week in-hospital period.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The importance of optimal myocardial protection during CABG cannot be overemphasized. Our pilot study of myocardial energy metabolism during CABG without CPB [12] suggested less perturbations in myocardial energy metabolism compared with historical controls on CABG with CPB [13, 15]. The purpose of this trial was to compare the changes in myocardial energy metabolism and the development of tissue injury during CABG with and without CPB in a prospective, randomized fashion. Intermittent antegrade mild hypothermic blood cardioplegia with normothermic arresting and terminal infusions was chosen for the CPB group [10, 11, 16–18], because this mode of cardioplegia, in our hands, has provided the best myocardial protection during CPB [15, 19].

The changes in myocardial metabolism were assessed by measuring the myocardial net production of acid, lactate, and ATP degradation products during and immediately after the operation. The extent of tissue damage was evaluated by following the release of myocardial CK-MBM and TnI. A significant release of lactate occurred in both groups during the suturing of the anastomoses. Lactate production was significantly greater, however, in the CPB group. Myocardial lactate production returned to the basal levels in the beating heart group and near to the basal levels in the CPB group within 15 minutes after the construction of the anastomoses, indicating rapid recovery of metabolism in both groups. Lactate production without CPB equaled that observed in our pilot study [12] on the beating heart, and in the patients with CPB, it equaled that observed in the mild hypothermic cardioplegia group by Raatikainen and associates [15]. The transcardiac pH differences also increased in both groups, indicating deterioration of anaerobic energy metabolism. During CPB, the net acid release was more prominent, resembling that observed previously by Raatikainen and associates [15].

The changes in the transcardiac differences of adenosine and its metabolites have been used as an estimate of the changes in the average cellular energy state [11–13, 15]. Adenosine is rapidly metabolized or taken up by red blood cells, its half-life in human plasma being around 0.6 to 1.5 seconds [20]. Therefore, dipyridamole was used in the stopping solution to prevent adenosine metabolism in vitro in the sampling syringes [12]. To minimize adenosine catabolism in blood, the patients also received dipyridamole before the operation. There was a significant increase in the net release of inosine and the sum of ATP degradation products in both groups, whereas the net release of xanthine was only significant in the CPB group. There were no statistically significant differences between the groups, despite the clear tendency towards a higher net release with CPB. The ischemia periods for the first two bypasses in the CPB group were shorter than in the beating heart group, but the ischemia in the CPB group was global in nature. This is important, because the average myocardial energy state seems to be better maintained during CABG on the beating heart than with CPB and blood cardioplegia.

Postoperatively, CK-MBM and TnI levels increased in both groups, but the increases were significantly higher in the CPB group, indicating more prominent myocardial injury. Wan and associates monitored the serum levels of TnI in patients undergoing multivessel CABG with or without CPB, and their results are in accordance with ours [21].

A large number of patients in the group without CPB had nonspecific changes in their postoperative ECGs, suggesting pericardial irritation, but fewer patients had atrial fibrillation, and the need for dopamine was also lower in this group. There were two perioperative myocardial infarctions, one in each group, diagnosed on the basis of postoperative changes in ECGs and high levels of CK-MBM and TnI. Those 2 patients were excluded from the analyses of these markers. This was considered justified, as the purpose of this study was to compare two different operation techniques for their capacity of tissue protection in patients with a normal perioperative course. Hemodynamically, both patients with perioperative infarctions recovered well and were discharged normally from hospital. There were no other major complications during the 1-week in-hospital period.

We conclude that the changes in myocardial energy metabolism in general remain relatively small during CABG without CPB, but also during CPB with mild hypothermic intermittent antegrade blood cardioplegia delivery. However, myocardial derangements are clearly more prominent during CPB than during surgery on a beating heart. This may be important when choosing the best strategy for myocardial protection during CABG, at least in selected cases. Larger randomized trials are needed to investigate the true differences in morbidity after CABG with and without CPB.

	Acknowledgments

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This study was supported by a grant from the Inari and Reijo Holopainen Foundation. We are grateful to Marja-Leena Lehtonen for her assistance in analyzing the ATP degradation products, and the staff of the operative and postoperative intensive care units of Oulu University Hospital.

	References

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