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Ann Thorac Surg 2002;74:2156-2160
© 2002 The Society of Thoracic Surgeons


Original article: cardiovascular

Warm and tepid cardioplegia

Do they provide equal myocardial protection?

Pierre-Emmanuel Falcoz, MDa*, Djamel Kaili, MDa, Sidney Chocron, MD, PhDa, Gérard Toubin, MDb, Marc Puyraveau, PhDc, Jean-François Viel, MD, PhDd, Joseph-Philippe Etievent, MDa

a Department of Thoracic and Cardiovascular Surgery, Besançon, France
b Department of Pharmacology, Hôpital Jean-Minjoz, Besançon, France
c Department of Biostatistics and Epidemiology, Faculté de Médecine et de Pharmacie, Besançon, France
d Department of Public Health, Hôpital Saint-Jacques, Besançon, France

Accepted for publication June 30, 2002.

* Address reprint requests to Dr Falcoz, Department of Thoracic and Cardiovascular Surgery, Hôpital Jean-Minjoz, Boulevard Fleming, 25000 Besançon, France
e-mail: pierre-emmanuel.falcoz{at}wanadoo.fr


    Abstract
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Cardiac troponin I (CTnI) has been shown to be a marker of myocardial injury. The aim of this prospective, randomized study was to compare intermittent antegrade warm cardioplegia with tepid blood cardioplegia in patients undergoing first elective coronary artery bypass graft, using CTnI release as the criterion for evaluating the adequacy of myocardial protection.

METHODS: Seventy patients were randomly assigned to one of two cardioplegia groups. CTnI concentrations were measured in serial venous blood samples drawn immediately before cardiopulmonary bypass and after aortic unclamping at 6, 9, 12, and 24 hours. Analysis of covariance with repeated measures was performed to test the effect of the type of cardioplegia and time on CTnI concentration.

RESULTS: The total amount of CTnI released (8.23 ± 20.5 µg in the warm group and 3.19 ± 2.4 µg in the tepid group) was not statistically different (p = 0.23). The CTnI concentration did not differ for any sample in either of the two groups when adjusted on ejection fraction and the number of preoperative myocardial infarctions (p = 0.06). No patient in the tepid group versus 4 patients in the warm group showed CTnI evidence of perioperative myocardial infarction (p = 0.12).

CONCLUSIONS: Our study showed no preference for warm or tepid cardioplegia in terms of myocardial protection, either for clinical or biological data.


    Introduction
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
The cardioprotective strategies available for intraoperative management are numerous. In the field of blood cardioplegia, we previously demonstrated that warm cardioplegia provides better myocardial protection than cold or intermediate lukewarm cardioplegia [1]. Hayashida and colleagues [2] showed that tepid cardioplegia provides better myocardial protection than cold or warm combination cardioplegia.

Cardiac troponin I (CTnI) has been shown to be a sensitive and specific marker of myocardial injury during open-heart operations [3]. We have already used CTnI to compare different methods of myocardial protection [46].

It appeared worthwhile to design a study to compare two temperatures of blood cardioplegia: (1) tepid (29°C) and (2) warm (37°C). To the best of our knowledge, to date, no study has compared the quality of myocardial protection provided by these two cardioplegia in terms of CTnI release. The aim of this prospective, randomized study was to compare the use of intermittent antegrade warm blood cardioplegia (WBC) with intermittent antegrade tepid blood cardioplegia (TBC) in patients undergoing first elective coronary artery bypass graft, with CTnI release as the criterion for evaluating the adequacy of myocardial protection.


    Material and methods
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Patient selection
After approval by our Institutional Review Board, informed consent was obtained from all eligible patients. Seventy patients (54 men and 16 women; mean age, 65 ± 9 years) scheduled for first elective coronary artery bypass graft were enrolled in a prospective randomized trial comparing tepid (29°C) and warm (37°C) blood cardioplegia.

Patients not included in this study were those who suffered from aortic incompetence, required only one distal anastomosis, presented an ejection fraction less than 0.30, underwent reoperation, or suffered from concomitant heart valve disease or unstable angina.

Coronary artery stenoses causing a loss of 70% or more of the cross-sectional area were considered to be significant lesions. For the left main coronary artery, a loss of 50% was considered significant.

The study took place over a 7-month period. An independent data manager supervised patient registration. Shortly before incision the surgical team was told to which group a patient had been randomized.

Operative technique
Cannulation for cardiopulmonary bypass was carried out in the usual fashion with a single-stage venous cannulation technique. Cardiopulmonary bypass was performed with active normothermia (37°C) in the warm group. In the tepid group, blood was injected at 29°C, which obviated the need for the heat exchanger. Therefore the systemic temperature of the patients drifted to 32° ± 1°C. These patients were rewarmed after the onset of the last distal anastomosis. The left ventricle was vented by a catheter introduced through the right superior pulmonary vein. The route of delivery was exclusively antegrade in both groups. High-potassium cardioplegia was injected into the aortic root immediately after aortic cross-clamping and until cardiac arrest was achieved with a minimal amount of 800 mL [K+] = 20 meq/L). A dose of 400 mL ([K+] = 10 meq/L) was reinjected into the aortic root after each distal anastomosis except the last. Proximal graft anastomoses to the aorta were performed during aortic cross clamping.

Cardioplegia groups
Patients were randomly assigned to one of two cardioplegia groups by a computer-generated randomization table. Cardioplegia was administered with the Medtronic Cardioplegia Safety System CSS 990 delivery set (Medtronic Inc, Eden Prairie, MN), which mixes the patient’s oxygenated blood with potassium. The temperature of cardioplegia depended on the group. In the warm group, cardioplegia was administered at 37°C using the technique described by Calafiore and colleagues [7]. In the tepid group, cardioplegia was administered at 29°C as proposed by Hayashida and colleagues [2]. A two-minute hot shot composed exclusively of 37°C oxygenated blood with a constant flow rate of 200 mL per minute was performed in both groups immediately after the last distal anastomosis, after the mammary arteries were unclamped.

Measurements of cardiac marker proteins
Serial venous blood samples were drawn just before cardiopulmonary bypass and after aortic unclamping at 6, 9, 12, and 24 hours. CTnI concentrations were measured by a specific immunoenzymometric assay developed by ERIA Diagnostics Pasteur (Marne-la-Coquette, France). Each standard CTnI or test sample was incubated with monoclonal antibody 8E1 for 15 minutes. After washing, enzyme activity was measured subsequent to the addition of a substrate (tetramethylbenzydine). The reaction was stopped by adding H2SO4 and the absorbance was read at 450 nm on the status spectrophotometer.

Electrocardiogram
A 12-lead electrocardiogram was recorded before the operation, at 2 hours, and then daily after the operation. Electrocardiogram diagnosis criteria for perioperative myocardial infarction (PMI) were new Q-waves of > 0.04 ms and a reduction in R-waves of > 25% in at least two leads. CTnI diagnosis criteria for PMI were CTnI peak concentrations of > 3.7 µg/L, and CTnI concentration of > 3.1 µg/L at 12 hours or > 2.5 µg/L at 24 hours, as determined by Mair and colleagues [8]. Acquired conduction defects were considered.

Statistical analysis
Sample sizes were calculated for a two-sided significance level of {alpha} = 0.05 and power of 1 - ß = 0.8 to detect a difference of 0.5 µg/L in CTnI concentration between groups. The standard deviation of CTnI measurements had been determined in a previous study standard deviation = 0.75) [3]. The number of subjects required was 35 per group.

Statistical analysis was performed with SAS software, version 8.02 (SAS Institute Inc, Cary, NC). One-way analysis of covariance with repeated measures was performed to test the effect of the type of cardioplegia and time on CTnI concentration. Two-way analysis of covariance with repeated measures was performed to test the effect of the ejection fraction and the number of preoperative myocardial infarction on CTnI concentration.

Categorical data were compared with the {chi}2 test or Fisher’s exact test, and quantitative variables were compared with the two-group t test. Values are expressed as mean ± standard deviation. A value of p <= 0.05 was considered statistically significant.


    Results
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Preoperative data
No patient suffered from aortic incompetence or renal dysfunction. Preoperative and operative data are shown in Table 1. Ejection fraction was significantly lower in the TBC group than in the WBC group (p = 0.01). The number of preoperative myocardial infarctions was significantly higher in the TBC group than in the WBC group (p = 0.001). The repartition of coronary angiographic data did not differ from one group to the other (Table 2).


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Table 1. Patient Profile by Group

 

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Table 2. Angiographic Data

 
Operative data
With the operative data, randomization produced two equivalent groups. At least one mammary artery was used in all patients. The number of distal anastomoses, cross-clamp time and cardiopulmonary bypass time did not differ significantly between groups. Sequential grafts were performed in 10 patients in the TBC group, and 12 patients in the WBC group [p = not significant (ns)]. Defibrillation was not required after aortic unclamping for 30 patients in the TBC group and 33 in the WBC group (p = ns).

Postoperative data
Two patients from the TBC group were excluded from analysis. One of the patients died from PMI at hour 4 because of a thrombus on a preoperative angioplasty site on the right coronary artery, which was assessed by a control coronary angiography (no CTnI samples were available). Blood samples were not drawn for the other patient, whose postoperative course was uneventful. Hence, blood samples were drawn for 33 patients in the TBC group and 35 in the WBC group.

One patient from the TBC group died of multiorgan failure within 30 days. There were no cases of acquired left bundle branch block in either the TBC or the WBC group (p = ns). There was 1 patient with right bundle branch block in each group (p = ns). Acquired atrial fibrillation occurred in 5 TBC patients and 7 WBC patients (p = ns) during the first 10 postoperative days.

Four TBC and 2 WBC patients had electrocardiographic evidence of PMI (p = ns). No patient in the TBC group and 4 patients in the WBC group showed CTnI evidence of PMI (p = ns). The CTnI level of 1 of these patients was >25 µg for the samples drawn at hours 6, 9, and 12 after aortic unclamping. All WBC patients with electrocardiographic evidence of PMI had CTnI evidence of PMI.

Twenty-eight TBC patients and 27 WBC patients required no inotropic support (p = ns). Five patients in each group (p = ns) received either dopamine hydrochloride (3 to 5µgkg-1min-1) or dobutamine (3 to 5µgkg-1min-1). One TBC patient and 2 WBC patients (p = ns) received epinephrine (0.2 to 0.5 µg kg-1min-1); 1 of these patients in each group required an intraaortic balloon pump (p = ns). The total amount of CTnI released was higher in patients who required inotropic support (15.02 ± 31.3 µg) than those patients who did not require inotropic support (3.34 ± 2.8 µg; p = 0.01).

Cardiac troponin I features
Figure 1 shows the time course of cardiac troponin I concentration according to the type of cardioplegia. The curves do not differ significantly. The total amount of CTnI released was not statistically different (8.23 ± 20.5 µg in the WBC group and 3.19 ± 2.4 µg in the TBC group [p = 0.23]). The CTnI concentration did not differ for any sample in either of the two groups.



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Fig 1. Time course of cardiac troponin I concentration according to type of cardioplegia. The curves do not differ significantly (p= not significant). The cardiac troponin I (CTnI) concentration did not differ significantly for any sample in either of the two groups. Values are expressed as mean ± standard error. (TBC= tepid blood cardioplegia;WBC= warm blood cardioplegia.)

 
As the randomization was unbalanced because of the ejection fraction and the number of preoperative myocardial infarctions, we performed a two-way analysis of covariance with repeated measures, adjusted on these 2 factors. The adjustment showed a tendency in favor of TBC cardioplegia (p = 0.06).


    Comment
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Buckberg and colleagues [9], looking at oxygen consumption in canine hearts, suggested that cardioplegia did not need to be cold to be effective. Most of the advantages of blood cardioplegia [10] are temperature-dependent; they occur at 37°C and are probably less effective when the temperature goes down. On the other hand, myocardial requirements increase with higher temperatures. Many studies have demonstrated the interest of using WBC [11, 12] or TBC [2, 13]. What is the best compromise? In a previous study, we showed that warm cardioplegia provided better protection than cold (8°C) or lukewarm (20°C) cardioplegia [1]. The next step was to compare warm and tepid cardioplegia.

Based on results in the literature, WBC and TBC cardioplegia were likely to provide similar myocardial protection. First, Buckberg and colleague’s results [9], suggest that the difference in oxygen consumption should be very slight when the temperature falls from 37°C to 29°C. This was confirmed by Hayashida and colleagues [14] who showed that there was no difference in oxygen extraction, lactate or acid production between warm and tepid antegrade cardioplegia. Second, because of the proximity of the temperatures, mitochondrial respiration preservation should be equivalent with both techniques, as confirmed by Hayashida and colleagues [2].

The aim of our prospective randomized study was to test the quality of myocardial protection provided by two different temperatures of blood cardioplegia (tepid and warm) using CTnI as the criteria for evaluating the adequacy of myocardial protection. To answer this question we designed a study including two temperatures of blood cardioplegia delivery (1) tepid (29°C) and (2) warm (37°C). The following parameters were identical in both groups: (1) the route of delivery was exclusively antegrade, (2) delivery was intermittent, and (3) a hot shot was performed before aortic unclamping. Cardiopulmonary bypass was conducted in active normothermia (37°C) in the warm group and moderate hypothermia (temperature drift) in the tepid group.

The standard deviation of measurements of CTnI (20.5 µg in the WBC group versus 2.4 µg in the TBC group) is somewhat disturbing, but understandable. In fact, it is due to 1 patient who had a very high CTnI release (blood samples were double-checked in our laboratory). If we had excluded this patient from analysis, the standard deviation between the two groups would have been closer (7.46 µg in the WBC group versus 2.4 µg in the TBC group). Even if this patient did not present electrocardiogram diagnosis criteria for PMI, he did require inotropic support for what we thought to be a spontaneously resolved case of myocardial protection failure.

Randomization provided two equivalent groups for all of the preoperative and operative variables studied (Table 1), save the number of preoperative myocardial infarction and the level of ejection fraction. Therefore an analysis of covariance with repeated measures was adjusted on these two parameters.

CTnI release indicated no preference for TBC or WBC in term of myocardial protection (p = ns) in a group of patients undergoing an elective first cardiac operation.

Regarding the clinical results, the number of PMIs (4 in the WBC group and none in the TBC group) was not statistically different (p = ns) according to the CTnI concentration criteria determined by Mair and colleagues [8] (see Material and Methods).

In conclusion, the findings of the current study show no preference for TBC or WBC in terms of myocardial protection, either for clinical or biological data.


    Acknowledgments
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
The authors thank Nancy Richardson-Peuteuil for her editorial assistance.


    References
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Chocron S., Kaili D., Yan Y., et al. Intermediate lukewarm (20°C) antegrade intermittent blood cardioplegia compared with cold and warm blood cardioplegia. J Thorac Cardiovasc Surg 2000;119(3):610-616.[Abstract/Free Full Text]
  2. Hayashida N., Weisel R.D., Shirai T., et al. Tepid antegrade and retrograde cardioplegia. Ann Thorac Surg 1995;59:723-729.[Abstract/Free Full Text]
  3. Etievent J.P.H., 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]
  4. 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]
  5. Pichon H., Chocron S., Alwan K., et al. Crystalloid versus cold blood cardioplegia and cardiac troponin I release. Circulation 1997;96:316-320.
  6. Chocron S., Alwan K., Yan Y., et al. Warm reperfusion and myocardial protection. Ann Thorac Surg 1998;66:2003-2007.[Abstract/Free Full Text]
  7. Calafiore A., Teodori G., Mezzetti A., et al. Intermittent antegrade warm blood cardioplegia. Ann Thorac Surg 1995;59:398-402.[Abstract/Free Full Text]
  8. Mair J., Larue C., Mair P., Balogh D., Calzolari C., Puschendorf B. Use of cardiac troponin I to diagnose perioperative myocardial infarction in coronary artery bypass grafting. Clin Chem 1994;40:2066-2070.[Abstract]
  9. Buckberg G.D., Brazier J.R., Nelson R.L., Goldstein S.M., McConnell D.H., Cooper N. Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. The adequately perfused beating, fibrillating and arrested heart. J Thorac Cardiovasc Surg 1977;73(1):87-94.[Abstract]
  10. Barner H.B. Blood cardioplegia: a review and comparison with crystalloid cardioplegia. Ann Thorac Surg 1991;52:1354-1367.[Abstract]
  11. Yasuda T., Kawasuji M., Sakakibara N., Takemura H., Tomita S., Watababe Y. Ultrastructural assessment of the myocardium receiving intermittent antegrade warm blood cardioplegia. Cardiovasc Surg 1998;6(3):282-287.[Medline]
  12. Lichtenstein S.V., Naylor C.D., Feidel C.M., et al. Intermittent antegrade warm blood cardioplegia. Warm heart investigators. Circulation 1995;92(Suppl 9):1341-1346.
  13. Fiore A.C., Swartz M.T., Nevett R., et al. Intermittent antegrade tepid versus cold blood cardioplegia in elective myocardial revascularization. Ann Thorac Surg 1998;65:1559-1564.[Abstract/Free Full Text]
  14. Hayashida N., Ikonomidis J.S., Weisel R.D., et al. The optimal cardioplegic temperature. Ann Thorac Surg 1994;58:961-971.[Abstract]



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