Does warm antegrade intermittent blood cardioplegia really protect the heart during coronary surgery?

Cardiovascular Surgery, Vol. 9, No. 2, pp. 188–193, 2001  2001 The International Society for Cardiovascular Surgery. Published by Elsevier Science Ltd All rights reserved. Printed in Great Britain 0967–2109/01 $20.00

PII: S0967-2109(00)00087-9

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Does warm antegrade intermittent blood cardioplegia really protect the heart during coronary surgery? O.M. Bical*, Y. Fromes*, D. Paumier†, D. Gaillard*, J.C. Foiret* and F. Trivin† *Department of Cardiac Surgery, Foundation Hoˆpital Saint Joseph, 185 rue Raymond Losserand 75674 Paris cedex, France and †Department of Clinical Biochemistry, Fondation Hoˆpital Saint Joseph 185 rue Raymond Losserand 75674 Paris cedex, France Objective: Intermittent antegrade blood cardioplegia (IABC) has been standardized as a routine technique for myocardial protection in coronary surgery. However, if the myocardium is known to tolerate short periods of ischemia during hypothermic arrest, it may be less tolerant of warm ischemia, so the optimal cardioplegic temperature of intermittent antegrade blood cardioplegia is still controversial. The aim of this study was to compare the effects of warm intermittent antegrade blood cardioplegia and cold intermittent antegrade blood cardioplegia on myocardial pH and different parameters of the myocardial metabolism. Methods: Thirty patients undergoing first-time isolated coronary surgery were randomly allocated into two groups: group 1 (15 patients) received warm (37°C) intermittent antegrade blood cardioplegia and group 2 (15 patients) received cold (4°C) intermittent antegrade blood cardioplegia. The two randomization groups had similar demographic and angiographic characteristics. Total duration of cardiopulmonary bypass (108 ⫾ 17 and 98 ⫾ 21 min) and of aortic cross-clamping (70 ⫾ 13 and 65 ⫾ 15 min) were similar. The cardioplegic solutions were prepared by mixing blood with potassium and infused at a flow rate of 250 ml/min for a concentration of 20 mEq/l during 2 min after each anastomosis or after 15 min of ischemia. Intramyocardial pH was continuously measured during cardioplegic arrest by a miniature glass electrode and values were corrected by temperature. Myocardial metabolism was assessed before aortic clamping (pre-XCL), 1 min after removal of the clamp (XCL off) and 15 min after reperfusion (Rep) by collecting coronary sinus blood samples. All samples were analyzed for lactate, creatine kinase (MB fraction), myoglobin and troponin I. Creatine kinase and troponin I were also daily evaluated in peripheral blood during 6 days post-operatively. Results: The clinical outcomes and the haemodynamic parameters between the two groups were identical. In group 1, XCL off and Rep were associated with higher coronary sinus release of lactate (5.5 ⫾ 1.8 and 2.2 ⫾ 0.5 mmol/l) than in group 2 (2.0 ⫾ 0.7 and 1.6 ⫾ 0.3 mmol/l, P ⬍ 0.05). Mean intramyocardial pH was lower in group 1 (7.23 ⫾ 0.08) than in group 2 (7.65 ⫾ 0.30, P ⬍ 0.05). There were no significant differences between the two groups with respect of creatine kinase (MB fraction) either after Rep or during the post-operative period. Lower coronary sinus release of myoglobin was detected at Rep in group 1 (170 ⫾ 53 ␮g/l) than in group 2 (240 ⫾ 95 ␮g/l, P ⬍ 0.05). At day 1, a lower release of troponin I was found in group 1 (0.11 ⫾ 0.07 g/ml) compared to group 2 (0.17 ⫾ 0.07 ng/ml, P ⬍ 0.05).

Correspondence to: Oliver M. Bical M.D. Tel.: ⫹ 33-1-44-123376; fax: ⫹ 33-1-44-123383

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Warm antegrade intermittent blood cardioplegia: O.M. Bical et al.

Conclusion: With regards to similar clinical and haemodynamic results, myocardial protection induced by warm IAEX is associated with more acidic conditions (intramyocardial pH and lactate release) and less myocardial injury (myoglobin and troponin I release) than cold intermittent antegrade blood cardioplegia during coronary surgery.  2001 The International Society for Cardiovascular Surgery. Published by Elsevier Science Ltd. All rights reserved Keywords: Myocardial protection, intermittent blood cardioplegia, intramyocardial pH, troponin I

Introduction Warm heart surgery has been proposed as an alternative to conventional methods of myocardial protection [1]. The concept of warm heart protection is attractive because the continuous infusion of warm hyperkaliemic blood not only maintains cardiac arrest but supports aerobic metabolism [1]. However, for coronary bypass surgery, interruption of either global or regional cardioplegia delivery enhances visualization during construction of the distal coronary anastomosis. As a result, warm blood cardioplegia is usually administrated in an intermittent rather than a continuous manner [2, 3]. As currently practiced, antegrade warm blood cardioplegia is therefore associated with periods of normothermia ischemia. If the myocardium is known to tolerate short periods of ischemia during hypothermic arrest, it may be less tolerant of warm ischemia and successive short periods of warm ischemia may predispose to ischemic myocardial injury. The tolerance to these successive short periods of warm ischemia is still controversial; some authors [4, 5] report absence of functional impairment and absence of myocardial damage, however other authors [6, 7] report detrimental effects of short periods of warm ischemia during coronary revascularization. As others [2–5], we employ warm intermittent antegrade blood cardioplegia (intermittent antegrade blood cardoplegia) in coronary surgery with good clinical and biochemical results [8] but we ignore the real effects of the short periods of warm ischemia on myocardial pH and myocardial metabolism. The aim of our study was in patients undergoing myocardial revascularization to compare warm and blood cardioplegia using hemodynamic parameters, specific myocardial metabolism parameters and myocardial pH values.

Methods Patient population Our study was performed in 30 patients scheduled for first-time isolated coronary bypass surgery. The patients were operated on by the same surgeon (OB). They were randomly allocated into two groups: group 1 (15 patients) received warm (37°C) intermittent antegrade blood cardioplegia CARDIOVASCULAR SURGERY

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(intermittent antegrade blood cardoplegia) and group 2 (15 patients) received cold (4°C) intermittent antegrade blood cardoplegia. The two randomization groups had similar demographic and angiographic characteristics Table 1. All subjects gave informed consent to the study and the protocol was received and approved by the Ethics Committee of our Institution. Operative techniques Cardiopulmonary bypass was established between the ascending aorta and a single two-staged right atria1 cannulation. The cardiopulmonary bypass circuit was primed with 1.5 l of macromolecules (Haemacel)*. Total hemodilution (hematocrit 0.22– 0.24) was used during bypass. The systemic temperature was allowed to drift to 33°C. The cardioplegic solutions were prepared by mixing blood with potassium and infused in the ascending aorta at a flow rate of 250 ml/min for a concentration of 20 mEq/l during 2 min after aortic cross-clamping and after the completion of each graft anastomosis. The mixed solution was circulated through a heat exchanger immersed in water at 37°C (group 1) or in slush-ice at 4°C (group 2). In the two groups the cardioplegia was delivered during 2 min after each anastomosis with a maximal interval of 15–18 min. Cardioplegia was therefore delivered during 15–25% of total duration of aortic cross-clamping. No topical cooling was used. All distal and proximal anastomosis were performed with total aortic cross-clamping. The patients were weaned from cardiopulmonary bypass when the systemic temperature reached 37°C. Hemodynamic measurements Hemodynamic data were obtained by a radial arterial catheter and a thermistor-tipped pulmonary arterial catheter (Swan-Ganz model 93A-83 1H-7.5Fr.)†. Pulmonary capillary wedge pressure, radial artery pressure and cardiac output were recorded. The cardiac index and the left ventricular stroke work index

*Hoechst laboratory 1 terrasse Bellini 92080 Paris La De´fense France. †Baxter Heathcare Corp., Edwards Division Santa Ana, CA, USA.

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Warm antegrade intermittent blood cardioplegia: O.M. Bical et al. Table 1 Clinical information

No of patients Age (yr) Main vessels involved Ejection fraction (%) Number of CABG Bypass time (min) Cross-clamp time (min)

Group 1 warm intermittent antegrade blood cardoplegia

Group 2 cold intermittent antegrade blood cardoplegia

15 59 ⫾ 9 2.8 ⫾ 0.4 51 ⫾ 9 3.1 ⫾ 0.7 108 ⫾ 17 70 ⫾ 13

15 62 ⫾ 11 2.9 ⫾ 0.3 48 ⫾ 10 3.2 ⫾ 0.7 98 ⫾ 21 65 ⫾ 15

IABC:intermittent antegrade blood cardoplegia; CABG: coronary artery bypass graft

(LVSWI) were calculated. The hemodynamic parameters were measured before initiation of cardiopulmonary bypass (pre-CPB) after weaning of cardiopulmonary bypass (post-CPB) and in the intensive care unit at 3 (H3), and 12 (H12) h postoperatively. Biochemical blood measurements The coronary sinus catheter* was positioned in the coronary sinus through the right atrial wall and, coronary sinus blood samples was collected before aortic cross-clamping, just after removal of the clamp and 15 minutes after removal of the clamp. Lactate, MB isoenzyme of creatine kinase, myoglobin and Troponin I were measured in the coronary sinus blood samples. The quantitative determination of myoglobin was realized by a Turbitimer Behring TT 30†, MB isoenzyme of creatine kinase and lactate were measured with reflectance spectrophotometry on a Kodak Ektakem apparatus‡. Cardiac troponin I was measured by immunoenzymatic method by ERIA Diagnostic Pasteur§. MB isozyme of creatine kinase and troponin I were also daily evaluated in peripheral blood during 6 days post-operatively. Measurements of myocardial pH Intramyocardial pH was measured by a miniature glass electrode¶ as previously described [9]. All the myocardial pH values were corrected by temperature according to the formula: pH corrected ⫽ pH ⫺ (␪ ⫺ 20) ⫻ 0.0198 where pH was the myocardial pH value and ␪ the myocardial temperature at the same time [10]. The electrode was inserted in the anteroseptal wall of the left ventricle after aortic crossclamping. The output of both the temperature probe and the pH electrode was recorded every minute

*Research Medical Inc. Midvale, UT, USA †Behringwerke, Marburg, Germany. ‡Johnson and Johnson, Rochester, New York, USA. § ERIA diagnostic Pasteur, Marnes, la Coquette, France. ¶ Heito laboratory, 5 me Gramme, 75015 Paris.

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during the aortic cross-clamping period. A temperature-corrected pH curve was obtained. Statistical analysis Data were presented as the mean ⫾ SD. Comparisons were performed using an analysis of variance (ANOVA). Analysis was performed using STATVIEW statistical software.

Results There was no death or perioperative myocardial infarction. Table 2 depicts the hemodynamic results: cardiac index, pulmonary capillary wedge pressure and LVSWI were similar in the two groups preoperatively, postoperatively in the operating room and postoperatively at 3 and 12 h. The biochemical results are presented in Table 3. No statistical differences of CPK-MB and troponin I coronary sinus concentrations appeared between the two groups, before cross-clamp, after cross-clamp removal and 15 min after reperfusion. Lactate production in coronary sinus was greater after cross-clamp removal and 15 min after reperfusion in warm group than in cold group Table 3. In contrast, coronary sinus myoglobin release was lower 15 min after reperfusion in warm group than in cold group Table 3. At day 1, a lower release of peripheral blood troponin I was found in warm group (0.11 ⫾ 0.07 ng/ml) compared to cold group (0.17 ⫾ 0.07 ng/ml, P ⬍ 0.05) Figure 1. No statistical differences of CPK-MB peripheral blood concentrations appeared between group comparisons during 6 days postoperatively Figure 1. The curves of intramyocardial pH variations during ischemia are presented in Figure 2 as a function of time (min). The median values of intramyocardial pH were 7.23 ⫾ 0.08 in warm group and 7.65 ⫾ 0.30 (P ⬍ 0.05) in cold group. In addition, the profiles evolve in distinct ways in the two groups. During warm cardioplegia, myocardial pH remains more stable in an acidic range. However during cold cardioplegia, pH values display marked variations with a sharp increase of CARDIOVASCULAR SURGERY

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Warm antegrade intermittent blood cardioplegia: O.M. Bical et al. Table 2 Preoperative and postoperative hemodynamic data Pre-op Groups

Post-op

1

Cardiac index 2.0 ⫾ 0.6 (l/min/m2) Pulmonary 10.3 ⫾ 4.0 capillary wedge pressure (mmHg) Left ventricular 32.3 ⫾ 7.7 stroke work (g/m/m2)

at 3 h post-op

at 12 h post-op

2

1

2

1

2

1

1

1.7 ⫾ 0.6

3.6 ⫾ 1.0

3.6 ⫾ 0.5

3.1 ⫾ 0.6

2.9 ⫾ 0.7

3.4 ⫾ 0.5

3.1 ⫾ 1.0

8.3 ⫾ 4.2

10.9 ⫾ 5.1

10.6 ⫾ 4.0

10.4 ⫾ 3.8

12.3 ⫾ 2.9

10.7 ⫾ 3.4

11.5 ⫾ 30.

32.8 ⫾ 12.3

37.7 ⫾ 12.2

40.3 ⫾ 9.5

34.3 ⫾ 9.6

36.0 ⫾ 8.8

37.2 ⫾ 7.0

37.3 ⫾ 11.6

Group 1: warm intermittent antegrade blood cardioplegia; Group 2: cold intermittent antegrade blood cardioplegia

Table 3 Biochemical results in coronary sinus (CS) before cross-clamp (pre-XCL), after cross-clampremoval (XCL off) and 15 min after reperfusion (reperf) pre XCL

XCL off

reperf

Groups

1

2

1

2

1

2

Lactate (mmol/l) Myoglobin (␮g/l) CPK-MB (UI/l) Troponin I (ng/ml) 10−2

0.9 ⫾ 0.2 51 ⫾ 15 1.8 ⫾ 1.5 2.4 ⫾ 2.5

0.910.1 48 ⫾ 11 1.7 ⫾ 1.5 2.2 ⫾ 2.8

5.2 ⫾ 1.6* 178 ⫾ 62 6.5 ⫾ 2.7 3.7 ⫾ 2.3

2.0 ⫾ 0.6 227 ⫾ 105 8.3 ⫾ 4.2 3.7 ⫾ 3.4

2.1 ⫾ 0.5* 170 ⫾ 53* 6.5 ⫾ 2.8 4.8 ⫾ 3.4

1.7 ⫾ 0.3 240 ⫾ 95 6.7 ⫾ 4.1 5.5 ⫾ 5.0

Group 1: warm intermittent antegrade blood cardioplegia; Group 2: cold intermittent antegrade blood cardioplegia; *P ⬍ 0.05

Figure 1 Time course of two biochemical markers for myocardial injury, as determined in peripheral blood during 6 days post-operatively

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Warm antegrade intermittent blood cardioplegia: O.M. Bical et al.

Figure 2 Average curves of temperature-corrected intramyocardial pH during ischemia in the two groups (ordinate: pH units, abscissa: minutes)

pH following each cardioplegic infusion and a quick progressive drop of pH as described previously [9].

Discussion Warm heart surgery has been proposed as an alternative to conventional methods of myocardial protection [1]. The concept of warm heart protection is attractive because the continuous infusion of warm hyperkakiemic blood not only maintains cardiac arrest but supports aerobic metabolism [1]. However for coronary bypass grafting, delivery of either global or regional cardioplegia should sometimes be discontinued to obtain a clear operative field. As a result, for coronary bypass grafting warm blood cardioplegia is usually administrated in an intermittent rather than a continuous manner [4, 5]. Matsuura et al. [6] revealed that interrupting warm blood cardioplegia during coronary revascularization diminished the effect of warm blood cardioplegia. Successive short periods of warm ischemia may predispose to ischemic myocardial injury. As other reports [3–5], we found no significant difference in clinical and hemodynamic results between warm and cold cardiac protection with intermittent antegrade administration. No patient had difficulty in being weaned form extracorporeal circulation with little inotropic support in either groups. The release of CPK-MB form remains controversial after warm intermittent antegrade blood cardoplegia. Pelletier et al. [4] found a lower CPK-MB mass concentration after warm intermittent antegrade blood cardioplegia than after cold intermittent antegrade blood cardoplegia, but Isomura et al. [5] found no significant CPK-MB release after warm intermittent antegrade blood car192

doplegia. In our study the CPK-MB release representing a wash-out phenomenon was identical with warm and cold intermittent antegrade blood cardioplegia. In contrast, the lactate release in the coronary sinus was greater after cross clamp removal in the warm group than in the cold group. This higher lactate release with warm cardioplegia indicated that ischemic anaerobic metabolism became more profound [5]. The short lactic acidosis observed with warm cardioplegia was confirmed in our study by the lower myocardial pH observed in this group. The negative myocardial pH change form baseline values observed with warm cardioplegia was not identified in previous studies and could indicated a more severe and durable ischemia with warm cardioplegia than with cold cardioplegia. However, we did not observe an intramyocardial drop to a low level (6.6) which could indicate poor myocardial preservation and possible irreversible myocardial damage [11]. Despite this midly acidic environment the post ischemic functional recovery after warm cardioplegia is equally effective as with cold cardioplegia and we have no explanation for this phenomenon. The biochemical markers of myocardial damage used in our study (myoglobin and Troponin I) were more sensitive [12] than those used in other reports [4–6]. However these sensitive biochemical markers of myocardial damage confirmed that the myocardial protection was better with warm cardioplegia than with cold cardioplegia. The myoglobin release was higher with cold cardioplegia than with warm cardioplegia and the Troponin I release at day 1 was higher with cold cardioplegia than with warm cardioplegia. Finally, our study suggested that warm ischemia during cardioplegic arrest resulted in higher CARDIOVASCULAR SURGERY

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lactate production in a midly acidic myocardium without any functional impairment and without any significant release of sensitive myocardial damage markers. How can we explain this paradoxal phenomenon in normothermic intermittent antegrade blood cardoplegia with a better myocardial protection associated with an acidic condition ? As suggested by Landymore et al. [13], absence of functional and myocardial impairment, and absence of myocardial damage with intermittent warm ischemia during multidose warm blood cardioplegia may have been related to a variant of the ischemic preconditioning concept. The term of ischemic preconditioning has been used classically to describe an increased tolerance of the myocardium to prolonged ischemia when the ischemic insult is preceded by repetitive episodes of ischemia of short duration. Repetitive sequences of short reperfusion/long ischemia in warm intermittent antegrade blood cardioplegia did not correspond exactly to the ischemic preconditioning concept. But we clearly showed in our study that repetitive episodes of warm ischemia in intermittent antegrade blood cardoplegia have not a cumulative effect on myocardial metabolism and recovery in spite of a midly acidic condition. An other mechanism of explaination could be the prevention of oxidative stress by warm cardioplegia as described by Mezzetti et al. [14]. Normothermia seemed to facilitate tissue oxygen delivery and increase the cell’s ability to produce adenosine triphosphate. In contrast, crucial metabolic pathways such as glycodysis or free radical detoxification could be inhibited by low tissue temperatures.

Conclusion Warm intermittent antegrade blood cardioplegia provides equally effective post ischemic functional recovery and a better metabolic recovery than does cold intermittent antegrade blood cardioplegia. This effect is obtained in spite of a midly acidic myocardial condition.

Acknowledgements We gratefully acknowledge the assistance of our perfusionists: T. Duffet and M. Szliwowski and the assistance of O. Normand in preparing the manuscript.

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