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Is repeated administration of blood-cardioplegia really necessary?

Department of Cardiac Surgery, Dresden Heart Center, Dresden Technical University, Germany

Received 2 September 2008; received in revised form 19 December 2008; accepted 23 December 2008

Presented at the 22nd Annual Meeting of the European Association for Cardio-thoracic Surgery, Lisbon, Portugal, September 14–17, 2008.

*Corresponding author. Herzzentrum Dresden GmbH, Universitätsklinik, Fetscherstrasse 76, 01307 Dresden, Germany. Tel.: +49-351-4501511; fax: +49-351-4501511.

E-mail address: tamer_ghazy{at}hotmail.com (T. Ghazy).

	Abstract

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Conclusion Conference discussion References

 
The aim of this work was to question the necessity of repeated administration of warm blood cardioplegia in modern cardiac surgery. A consecutive series of 4014 patients underwent cardiosurgical procedures in the period from January 2001 to December 2006 in our centre, where modified Calafiore warm blood-cardioplegic solution was used. 1708 patients received a single shot of cardioplegia instead of repeated blood cardioplegia (every 20 min). A multivariate analysis was performed using logistic regression models to reveal the statistical significance of the effect of single-shot cardioplegia on the occurrence of: death, intraoperative need of inotropics, intraoperative intra-aortic balloon pump (IABP), postoperative infarction, arrhythmia, postoperative need for inotropics and postoperative IABP. The results showed statistical insignificance concerning mortality (P=0.704), intraoperative IABP (P=0.247), postoperative inotropics (P=0.273), postoperative IABP (P=0.678), postoperative arrhythmia (P=0.661). Single-shot cardioplegia showed a positive effect concerning postoperative myocardial infarction (P=0.003). However, it showed an unfavourable effect concerning intraoperative inotropics (P=0.038) and postoperative dialysis (P=0.015). The clinical safety of the first shot of warm blood cardioplegia might be exceeding 20 min. In the light of increasingly short cross-clamping time, the safety of the first shot might be long enough to cover the whole cross-clamping time.

Key Words: Blood cardioplegia; Myocardial protection; Cardiopulmonary bypass

	1. Introduction

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Conclusion Conference discussion References

 
Since Dr John Gibbon performed the first cardiopulmonary bypass in 1953 [1, 2], prolonged interruption of normal circulation has become possible, providing a non-contracting heart and a field without blood in which surgeons could work.

As the procedure demands the administration of a cardioplegic solution, more than one form of cardioplegic solution was presented, from which the warm blood cardioplegia was proved to be a safe, effective cardioplegic solution that is capable of achieving adequate myocardial protection [3–5, 10].

The goal of myocardial protection is minimising the negative effect of myocardial ischaemia, enabling the heart to resume its function adequately after weaning from CPB. Failure of myocardial protection will result in extensive myocardial injury, which will subsequently result in poor myocardial performance and a need of medical or mechanical support [6].

The standard in literature until now is the repeated administration of the blood-cardioplegic solution every 15 min [7, 8], and that is to maintain the state of asystole and to improve myocardial protection. In our analysis we intend to put that standard into test, to find out if a single administration of the blood-cardioplegic solution is at least comparable to the repeated administration of the blood-cardioplegic solution.

In this analysis we try to reveal the significance of the ‘single-shot cardioplegia’ effect on the clinical outcome, namely the occurrence of: death, intraoperative need of inotropics, intraoperative intra-aortic balloon pump (IABP), postoperative infarction, arrhythmia, postoperative need of inotropics and postoperative IABP.

	2. Patients and methods

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Conclusion Conference discussion References

 
From 14,023 patients operated in our department in the period from January 2001 to December 2006, modified Calafiore warm blood-cardioplegic solution was used for cardioplegia in 4014 patients. From these, 1708 patients received a single shot of cardioplegia instead of the classic intermittent blood cardioplegia (i.e. every 20 min). The rest of the 4014 patients received the classic intermittent blood cardioplegia. The data were collected retrospectively. All patients receiving warm-blood cardioplegia in this period (i.e. 4014 patients) were included in the analysis. No patients were excluded. The use of a single-shot or multi-shot cardioplegia was solely based on surgeons' preferences.

2.1. Operative technique

2.2. Cardioplegia

The stepwise regression is an approach to select a subset of regressors (i.e. variables) for a regression model. The stepwise feature computes not only the significance probability of each variable in the model, but also the significance probability of the variables that are still not included in the model but considered ‘regressor candidates’. The variable with the significance probability lower than a given value of significance (e.g. 0.05) will then enter the model and the regressors that are already inside the model but have a significance probability above a given value (e.g. 0.05) will leave the model. The process is repeated until all the variables in the model have a significance probability lower than the given value (i.e. 0.05) and the variables outside the model above the given value (i.e. 0.05). This way, all the statistically significant variables will be included in the model and all the non-significant variables will be excluded.

All statistics were carried out using JMP^® (version 6.0.0) software (SAS Institute Inc, Cary, NC, USA). In the JMP^® software there is an extra feature to the stepwise feature. That is the ability to intentionally lock any variable outside or inside the model. Using this feature, the ‘single-shot cardioplegia’ was locked inside the model and kept within. This way, we were able to force the single-shot cardioplegia into the model to test it as an independent risk factor.

	3. Results

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Conclusion Conference discussion References

 
3.1. Distribution analysis

3.2.3. Intraoperative need of inotropics
The logistic regression model (with R²=0.230) showed a weak statistical significance of cardioplegia in favour of repeated administration of cardioplegia (P=0.038). The other independent risk factors included arterial hypertension (P=0.014), pulmonary hypertension (P<0.001), history of smoking (P<0.019), renal insufficiency (P<0.001), history of dialysis (P=0.038), preoperative inotropics (P=0.007), preoperative anticoagulation (P<0.006), preoperative myocardial infarction (P<0.001), unstable angina pectoris (P=0.0049), perioperative cardiogenic shock (P<0.001), coronary heart disease (P=0.006), emergency procedure (P<0.001), operative time (P<0.001), combined procedure (P=0.010) and redo-procedures (P=0.043).

3.2.4. Intraoperative IABP
The logistic regression model built (with R²=0.314) showed no significant effect of single-shot cardioplegia on the intraoperative need of IABP (P=0.247). The model also showed that the significant risk factors were: preoperative inotropics (P<0.001), poor EF (P=0.003), preoperative myocardial infarction (P<0.001), emergency procedure (P<0.001), operative time (P<0.001), CPB time (P=0.030), aortic cross-clamping time (P<0.001) and combined procedures (P=0.007).

3.2.5. Postoperative infarction
The model (with R²=0.174) revealed a significant effect of cardioplegia on postoperative infarction in favour of single-shot cardioplegia (P=0.002). The other significant risk factors were: age (P=0.009), female gender (P=0.013), logistic EuroSCORE (P=0.007), operative time (P=0.004), combined procedures (P=0.22), redo-procedures (P=0.23) and intraoperative low cardiac output (P<0.001).

3.2.6. Arrhythmia
The logistic regression model (with R²=0.169) showed no significant effect of single-shot cardioplegia on arrhythmia (P=0.661). The model showed significant effects of preoperative infarction (P=0.043), pulmonary hypertension (P<0.001), CPB-time (P=0.031), intraoperative low cardiac output (P=0.001), prolonged mechanical ventilation (P=0.005), reintubation (P=0.046), postoperative infarction (P=0.001), new onset of dialysis (P<0.001) and postoperative IABP.

3.2.7. Postoperative inotropics
There was no significant effect of type of cardioplegia on the postoperative need of inotropics (P=0.273). The regression model (with R²=0.439) showed significant effects of preoperative infarction (P<0.001), perioperative cardiogenic shock (P<0.001), emergency procedures (P<0.001), operative time (P<0.001), combined procedures (P=0.006) and prolonged mechanical ventilation (P<0.001).

3.2.8. Postoperative IABP
The single-shot cardioplegia had no significant effect on the need of postoperative IABP (P=0.678). The significant risk factors revealed by the statistical analysis (with R²=0.622) included: preoperative inotropics (P=0.027), preoperative anticoagulation (P=0.030), preoperative infarction (P=0.042), perioperative cardiogenic shock (P=0.037), logistic EuroSCORE (P<0.001), emergency procedures (P<0.001), operative time (P<0.001), intraoperative inotropics (P<0.001), prolonged mechanical ventilation (P<0.001) and postoperative infarction (P<0.001).

3.2.9. Postoperative dialysis
The logistic regression model for postoperative dialysis (with R²=0.302) showed that single-shot cardioplegia had a statistically significant negative effect (P=0.015). The other significant factors were: age (P<0.001), renal insufficiency (P<0.001), diabetes mellitus (P=0.010), combined procedures (P=0.038), intraoperative low cardiac output (P<0.001) and rethoracotomy (P=0.0017).

	4. Discussion

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Conclusion Conference discussion References

 
Medical research has been active putting blood cardioplegia in general and warm-blood cardioplegia in particular into test, exploring its capabilities [9, 10]. In our centre, the use of one-shot warm-blood cardioplegia has been expanding, but based solely on surgeons' preferences. Our clinical experience has been quite satisfying, making us re-question the necessity of repeated administration of cardioplegic solution in the light of the increasingly short cross-clamp time in modern surgery. Taking it one step further was performing this analysis putting the hypothesis into test.

The analysis of our data (as summarized in Table 6) proved that the single-shot cardioplegia did not have a significant influence on mortality, the need of intraoperative IABP, postoperative inotropics, postoperative need of IABP and arrhythmias.

The analysis of postoperative dialysis was in favour of repeated administration of blood cardioplegia. We could not find an explanation for this result, because the possible explanation for that would have been a low cardiac output as a pre-renal cause of renal failure, but the analysis of postoperative inotropics and IABP failed to prove a significant effect of the single-shot cardioplegia.

On the other side, the analysis showed that single-shot cardioplegia had a positive effect concerning the post- operative infarction. This might be an indicator that the myocardial protection performed by the single-shot cardioplegia might be satisfactory and the second shot might not be a necessity in all procedures.

The above data collectively indicate that single-shot cardioplegia does not add a clinical risk to patients undergoing a cardiosurgical procedure. That should be understood together with the fact that adult cardiac surgery has gone far in the last decade and the operative time in general, and cross-clamping time in particular, is markedly shorter.

	5. Conclusion

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Conclusion Conference discussion References

 
The clinical safety of the first shot of warm-blood cardioplegia might be exceeding 20 min. In the light of increasingly short cross-clamping time, the safety of the first shot might be long enough to cover the whole cross-clamping time. Within limits, the single-shot warm-blood cardioplegia can be used safely without major clinical drawbacks. Further studies are still needed to reveal the limit of single-shot cardioplegia and the cross-clamping time within which the single-shot cardioplegia is safe.

	Conference discussion

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Conclusion Conference discussion References

 
Dr. J. Vaage (Oslo, Norway): When warm blood cardioplegia emerged, it was like a continuous infusion, but the surgeons had to stop it now and then in order to get a clear field, and this is when intermittent warm blood cardioplegia emerged. However, when the so-called ‘warm heart surgery’ group published some of their results in the early 1990s in Circulation, they found that if the surgeon stopped for a longer period than 13 min, there was an increase in adverse cardiac effects. I think that a major limitation of your study is your patient population. This is obviously a selected population from your total, I mean, it is 25%, and you have short cross-clamp times, <40 min. Of course, this also shows that you have very good surgeons. But I always felt when we were discussing myocardial protection and cardioplegia, if you had a clamp time of <60 min, you could actually use whatever cardioplegia or myocardial protection you wanted. You could always get to the shore, so to say. However, as is written in John Kirklin's textbook, if you use the right cardioplegia or myocardial protection, clamp time doesn't really matter.

I think that it is quite dangerous to give a message that a single infusion of warm blood cardioplegia is safe unless you actually have also looked at this in patients with much longer cross-clamp times. I see that in your presentation your conclusions are a bit weaker than in your manuscript, and maybe you should also change that when you get the revised manuscript.

I have a few questions for you. Did you only use antegrade cardioplegia or was also retrograde used? And there is one thing I wonder. Why was the single-shot warm blood cardioplegia selected? Who did it? Was there a difference between the different surgeons? Was this a surgeon's preference? Was it that the more experienced did it and the less experienced used maybe the more safer way? And there is another thing. When you look retrospectively into a study, there are always things that you cannot really detect, and even if your patient population varies between the two groups, maybe you should cut out some of the patients and in the smaller part of this actually do a case-controlled study.

Dr. Ghazy: First of all, I would like to make a statement, our target is not to say we know the answer. Actually my target today was to pop the question, is single-shot cardioplegia really a necessity? That has been asked. The consensus is that cross-clamp time is in most of the time quite short. I am not saying that a single shot will be enough for two hours' clamp time. I personally don't think so. That is why you will see in the manuscript I say we have to do more studies to see the limit of that. How long is too long? 20 min? 30 min? 40 min? when? So I am not saying that a single shot will suffice whoever the patient is, whatever the operation is.

To answer your first question about antegrade, yes, we did antegrade for all patients. We did not use retrograde.

And the second question, who did that and why? Actually, it increased with time. I am proud to say we are, more or less, fast operators in Dresden. It started this way: we can say as operators to the perfusionist ‘give me 20 min’, after 20 min the perfusionist says, okay, we have been now 20 min on cross-clamp. Sometimes we are in the middle of the anastomosis, so we tell him to give 2 min to finish the anastomosis and then we will give the second shot. But the 2 min became 4 min, and the 4 min became 8 min, and then 10 min, and then 15 min, and more. In our surgical experience we didn't see a major effect, and that is why we did this retrospective analysis. Because actually personally I don't think that will be enough to say: ‘yes, we have done it, it is okay.’, ‘We have seen it, it works.’. No, it is not that easy. We have to prove it. It is not about believing. Four hundred years ago Galileo said something and nobody believed it. He was right and they were wrong. Before that, Icarus believed he could fly to the sun with wings of feather and wax but he died. So it is not about belief; it is about proof.

And the last question was?

Dr. Vaage: A possible case-controlled study.

Dr. Ghazy: Yes, that is a good idea. I thought about it and we want to do a matched case-controlled study actually, and then after discussion with our department for biometry, we thought it would be better to use multivariate analysis to use the collective number of patients, which will have a major impact on the study.

	References

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion 5. Conclusion Conference discussion References

 

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