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Ann Thorac Surg 1998;66:462-465
© 1998 The Society of Thoracic Surgeons

Original articles: cardiovascular

Cold blood cardioplegia or intermittent cross-clamping in coronary artery bypass grafting?1

Zhiyong Liu, MDa, Oswaldo Valencia, MDa, Tom Treasure, FRCSa, Andrew J. Murday, FRCSa

a Cardiothoracic Unit, St. George’s Hospital, London, England, United Kingdom

Accepted for publication March 19, 1998.

Address reprint requests to Dr Treasure, Cardiothoracic Unit, St. George’s Hospital, Blackshaw Rd, London SW17 0QT, England


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. We determined that cold blood cardioplegia and intermittent ventricular fibrillation with ischemia were associated with similar enzyme and myocardial protein leakage in a randomized, prospective study of 40 patients. We have continued to use both methods in our unit, according to surgeons’ preference.

Methods. In our database we have reviewed 1,923 patients who have undergone first-time elective or urgent coronary artery bypass grafting from January 1992 to May 1997.

Results. Five hundred seventy-eight patients underwent coronary artery bypass grafting with cold blood cardioplegia and 1,345 had ventricular fibrillation and aortic cross-clamping. The preoperative factors were virtually identical. Intraoperative differences were only those inherent to the two techniques: temperature and cross-clamp time. Mortality was 2.5% for ventricular fibrillation and aortic cross-clamping arrest and 2.1% for cardioplegia (p = 0.55 by {chi}2 test). There was a higher use of the intraaortic balloon pump in the ventricular fibrillation and aortic cross-clamping group (2.4% versus 1.0%; p = 0.04), but no other differences in outcome were detected.

Conclusions. A truly randomized trial to demonstrate which technique is superior is impractical at this level of difference because it would require 37,000 patients to avoid a beta error. We have to base our practice on the retrospective data available. Each technique has its merits in practice, which are discussed.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
For routine coronary artery bypass grafting, performed on cardiopulmonary bypass in the conventional way, it is customary to suture the distal coronary anastomoses with the heart relatively still and the coronary arteries empty. Cold blood cardioplegia is probably the worldwide standard used by the majority of surgeons. Some surgeons are using warm blood cardioplegia, whereas a minority use intermittent ischemia and induced ventricular fibrillation [1, 2].

A few years ago we reported in The Annals a prospective, randomized, controlled trial comparing intermittent aortic cross-clamping and a cold blood cardioplegia technique, with myocardial enzyme and structural protein leakage as the outcome measure [3]. Two surgeons, practiced in both techniques, randomized their cases, with minimization for patient’s age, sex, left ventricular function, expected number of grafts, and operator. Within the limits of the study, which was confined to elective coronary artery bypass grafting for stable angina, we found that the two techniques are equally safe and effective in the hands of two experienced consultant surgeons.

Therefore, our group has continued to use both techniques, at the discretion of individual surgeons who, on the basis of our previous experiment, are entitled to exercise subjective preference. Of four consultant surgeons, one has used exclusively cold blood cardioplegia and one has used exclusively intermittent cross-clamping, both before and since the study. A third prefers intermittent cross-clamping for most patients, and does a small proportion of cases without bypass. The fourth changed to intermittent cross-clamping as a result of the study by Anderson and colleagues [3], but has recently reverted to cold blood cardioplegia for all patients in his practice, largely in the interests of teaching junior surgeons, itself a judgment based on preference rather than scientific evidence.

Although we were satisfied on the basis of our randomized, controlled trial that the two techniques are similarly safe within the limitations of the trial, there remained some doubt as to whether these results are generalizable to the full case mix of coronary artery bypass grafting. Also there remains an uncertainty about extrapolating from the enzyme and structural protein data to clinical outcome. These were biochemical surrogate end points, but do they reflect the risk of perioperative death, for which all small studies are underpowered?

We have kept a complete database since January 1992, including all the elements required to construct a Parsonnet risk stratification [4]. We have developed a technique of data display derived from de Leval’s application of cumulative sum technique [5–8]. Our variable life-adjusted display takes into account the risk ascribed to all patients, those who died and survivors, and they are plotted sequentially [9]. We report here the outcome for all 1,923 nonemergency, first-time coronary operations from January 1992 to May 1997, categorized according to the method of myocardial management, cold blood cardioplegia (BC) or intermittent cross-clamping with ventricular fibrillation (VF).


   Material and methods
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
We retrieved data on all patients who underwent nonemergency, isolated coronary artery bypass grafting in the unit from January 1992 to May 1997. We have excluded emergency cases, which are only those brought to the operation room directly from the catheterization laboratory with either evolving infarction, deteriorating hemodynamic status, or being massaged. Patients receiving nitrate infusions, or otherwise with unstable angina, are categorized as urgent, not as emergencies, and are included in the data set. We have also excluded repeat operations.

The preoperative data on all patients are entered at the time of operation along with perfusion data and operative details into a database from a PC keyboard in each of our three operating rooms. The data were subsequently checked for completeness and validated, and follow-up data were entered by one of us (O.V.).

There were no differences in premedication, induction, maintenance, or reversal of anesthesia, none of which is determined directly by the choice of myocardial management. There may have been differences in anesthetic management subsequent to the surgeon’s choice of cardioplegic temperature.

Cardiopulmonary bypass was established between the right atrium (with either a Ross basket or a two-stage venous cannula) and arterial return to the ascending aorta. In the BC group, myocardial protection was achieved with antegrade cold blood cardioplegia, including 20 mL of St. Thomas’ formula (Manor Park Pharmaceutical, Bristol, UK) made up to 1 L with 400 mL of Ringer’s solution and 600 mL of oxygenated blood from the pump, infused into the aortic root at 12°C at an initial volume of 500 mL/m2 body surface area. Moderate systemic hypothermia (28°C) and topical iced slush were also used. After the completion of each distal anastomosis, an additional 100 to 200 mL of cold blood cardioplegia was infused into the aortic root. Small variations in the detail of the protocol may have existed between surgeons and over time. Systemic rewarming was started during the final distal anastomosis.

In the VF group, moderate systemic hypothermia (32°C) was used. Ventricular fibrillation was induced electrically and the aorta was cross-clamped. Some grafts were made without the need to apply the cross-clamp, and an occasional vessel, usually the right coronary, was operated on without induced VF. During the period of ischemia, the distal anastomosis was performed. The myocardium was reperfused and the heart defibrillated and allowed to beat during the construction of the proximal anastomosis. This process was repeated for each graft with systemic rewarming commenced during the final distal anastomosis.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
There were 2,013 patients undergoing nonemergency coronary artery bypass grafting in the data set; 596 patients had cold blood cardioplegia (BC group) and 1,417 patients had hypothermic ventricular fibrillation (VF group). We found an uneven distribution of redo cases with 18 of 596 (3%) in the BC group and 72 of 1,417 (5%) in the VF group, a significant difference (p = 0.04). There were no differences in any of the other preoperative factors that approached significance, and most were very similar (Table 1 ). Therefore, we decided to exclude redo cases from further analysis (total 1,923 operations). Parsonnet scores were similar, with a median of 3 in both groups (range, 0 to 25 for BC and 0 to 27 for VF).


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  		Table 1. Preoperative Patient Data

 
The operative details differed significantly for temperature and cumulative cross-clamp time, which are inherent differences between the methods. Total bypass time was significantly shorter (mean, 78 minutes versus 86 minutes) with VF (p < 0.001 by t test). The number of distal anastomoses was similar, with a median of 3, and mammary artery use was similar, with an average of 1.04 for BC and 1.10 for VF (Table 2 ).


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  		Table 2. Intraoperative Patient Data

 
In-hospital mortality was 2.1% for the BC group and 2.5% for the VF group (p = 0.55 by {chi}2 test). Balloon pump use was 1.0% for the BC group and 2.4% for the VF group (p = 0.04 by {chi}2 test). There were no significant differences for intensive care unit stay, hemofiltration, and the incidence of cerebrovascular accident (Table 3 ).


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  		Table 3. Postoperative Patient Data

 
All patients in each group are displayed sequentially in the variable life-adjusted display plot (Fig 1 ; see legend for details of its construction).



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  		Fig 1. Variable life-adjusted display of myocardial protection in coronary artery bypass grafting. For each patient the plot moves by one unit, from left to right along the horizontal axis. On the vertical axis, the plot goes up for each survivor and down for each death, adjusted by the preoperative risk. Thus, if the Parsonnet scores were 0, 5, and 10 for three consecutive survivors, the plot would ascend by 0, 0.05, or 0.1 (giving the surgeon the credit for survival in the face of those risks). Conversely, for deaths, the plot would go down by 1.0, 0.95, and 0.9. To illustrate the point, note that at about 1,000 patients the plot is at about plus 20, the number of deaths fewer than Parsonnet would have predicted, equivalent to the difference between the observed mortality of 2.4% compared with a prediction of 4.3% [9]. (BC = cold blood cardioplegia group; XCF = ventricular fibrillation and aortic cross-clamp group.)

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
The gold standard in comparing treatments is the randomized, controlled trial. Our previous study, a randomized, controlled trial with the surrogate end points of area under the curve of enzyme and troponin T release, suggested that these two techniques were similar [3]. In the present analysis of retrospective data on nearly 2,000 patients we have found a mortality rate of 2.5% with the technique of intermittent cross-clamping and of 2.1% with cold blood cardioplegia, and a significant difference in balloon pump use. If we were to design a randomized, controlled trial using these as pilot study data, our power calculation indicates that we would need substantially more than 36,000 patients to show a reduction of mortality from 2.5% to 2.1%. Such a trial would probably be impractical; in fact, our experience of trying to set up multicenter surgical trials deems it impossible. Virtually all the coronary operations performed in a 2-year period in the United Kingdom would have to be randomized. There are times when data other than those from randomized trials must be used [10].

We have excluded any systematic difference in case mix in that the patients in the two groups are very similar in all respects including Parsonnet scoring, and differences in other parameters that fall outside are attributable to the technique. It is possible that Parsonnet risk adjustment conceals real differences, but we believe that in spite of its shortcomings [11] it provides a robust means of indicating similarities and differences in case mix in groups of this size [12, 13]. Can we conclude that the results are equivalent? In the absence of a prospective, randomized trial we cannot be sure because there are a number of known and unknown confounding effects.

One confounding effect is that the different techniques were used by different surgeons. That could move the result in either direction: a very good surgeon may get good results with an inferior technique, and a less good surgeon may have poorer results even with the better technique. For the surgeon who used a mixture of techniques there was a deliberate selection, preferring one technique to the other under particular circumstances, not necessarily reflected in Parsonnet scoring, but for training purposes. We have not used a multivariate analysis because the known association between technique and surgeon’s overall preference in the majority of the cases, and the surgeon’s decision to use a specific technique in the remainder, would have invalidated the result, whatever the analysis showed. Therefore, we decided it was inappropriate to use a technique if we knew ahead of time that we might want to reject its findings.

The variable life-adjusted display plot (Fig 1) helps us explore trends over time for each policy, but as the accrual rates are different, it does not permit contemporaneous comparison by eye from the graph. It is clear from the irregularities in the plot that difference over time within a series is greater than any differences between the two techniques. The combined series of 1,923 patients has a mortality of 2.4% (46 of 1,923) compared with an average Parsonnet risk of 4.3%. The data do not allow us to go beyond the conclusion that either technique is acceptable.

Therefore, on what basis should surgeons choose one technique rather than another? We believe that evidence, whether gathered by prospective, controlled trials or more qualitative data, should be used to guide practice but must be interpreted intelligently and appropriately, and the conclusion may be tempered by other knowledge, practicalities, and experience. Surgeons comfortable with both techniques readily attest to the simplicity of the VF technique and believe it has merits for that reason [2]. Interestingly our anesthetists agree with that subjective impression, and welcome the announcement that the consultant surgeon is going to use the speedier technique. They believe (in the absence of proof) that there are advantages in the postoperative course and that this technique may shorten time on the ventilator. It also allows the surgeon to restore promptly flow to the most ischemic territories and progressively improve the state of the heart, which some believe is an advantage.

On the other hand, beginners may need 15 or more minutes to complete safely an anastomosis. Three or more ischemic episodes of that length of time become increasingly worrisome and fall well outside the times that were used by the consultants in the prospective study by Anderson and colleagues [3], making it inappropriate to invoke those results as evidence under these different circumstances. Our perfusionists vote for cold blood cardioplegia if the operation is to be performed by a trainee, because of anxiety about the longer individual and cumulative ischemic periods, but again without objective evidence.

We believe that advocates of either technique may find support for their policy in these data.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
We thank John Smith and John Parker for allowing us to use data from their clinical practice.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
1 This article has been selected for the open discussion forum on the STS Web site: http://www.sts.org/annals Back


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Warm heart surgery. Lancet 1992;339:841-842.[Medline]
  2. Bonchek L.I., Burlingame M.W., Vazales B.E., Lundy E.F., Gassmann C.J. Applicability of noncardioplegic coronary bypass to high-risk patients. Selection of patients, techniques, and clinical experience in 3000 patients. J Thorac Cardiovasc Surg 1992;103:230-237.[Abstract]
  3. Anderson J.R., Hossein-Nia M., Kallis P., Pye M., Holt D.W., Murday A.J., Treasure T. Comparison of two strategies of myocardial management during coronary operations. Ann Thorac Surg 1994;58:768-773.[Abstract]
  4. Parsonnet V., Dean D., Bernstein A.D. A method of uniform stratification of risk for evaluating the results of surgery in acquired adult heart disease. Circulation 1989;779(Suppl 1):3-12.
  5. Williams S.M., Parry B.R., Schlup M.M.T. Quality control: an application of the cusum. BMJ 1992;304:1359-1361.
  6. De Leval M.R., Francois K., Bull C., Brawn W., Spiegelhalter D. Analysis of a cluster of surgical failures. Application to a series of neonatal arterial switch operations. J Thorac Cardiovasc Surg 1994;107:914-924.[Abstract/Free Full Text]
  7. Treasure T. Where did I go wrong?. Lancet 1994;344:419-420.[Medline]
  8. De Leval M.R. Human factors and surgical outcomes: a Cartesian dream. Lancet 1997;349:723-725.[Medline]
  9. Lovegrove J., Valencia O., Treasure T., Gallivan S., Sherlaw-Johnson C., Gallivan S. Monitoring the results of cardiac surgery by variable life-adjusted display. Lancet 1997;350:1128-1130.[Medline]
  10. Black N. Why we need observational studies to evaluate the effectiveness of health care. BMJ 1996;312:1215-1218.[Free Full Text]
  11. Spiegelhalter D.J. Risk stratification of open heart surgery. BMJ 1992;305:1500.
  12. Nashef S.A.M., Carey F., Silcock M.M., Oommen P.K., Levy R.D., Jones M.T. Risk stratification for open heart surgery: trial of the Parsonnet system in a British hospital. BMJ 1992;305:1066-1067.
  13. Treasure T. Risks and results of surgery. Br Heart J 1995;74:11-12.[Free Full Text]



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