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Right arrow Myocardial protection

J Thorac Cardiovasc Surg 2003;125:711-720
© 2003 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

The short-term and long-term effects of warm or tepid cardioplegia

Hari R. Mallidi, MD*, Jeri Sever, Miguel Tamariz, MD, Steve Singh, BSc, Naoji Hanayama, MD, George T. Christakis, MD, Gopal Bhatnagar, MD, Charles A. Cutrara, MD, Bernard S. Goldman, MD, Stephen E. Fremes, MD

From the Division of Cardiovascular Surgery of Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada.

*Supported in part by a partnership fellowship grant from the Medical Research Council and the Heart and Stroke Foundation of Ontario.

Presented in part at the Seventy-third Annual Meeting of the American Heart Association, New Orleans, La, Nov 13-15, 2000.

Received for publication Aug 15, 2001. Revisions requested Jan 3, 2002; revisions received May 20, 2002. Accepted for publication Aug 15, 2002. Address for reprints: Stephen E. Fremes MD, Head, Division of Cardiovascular Surgery, Sunnybrook and Women's College HSC, H405B2075 Bayview Ave, Toronto, Ontario, Canada, M4N 3M5 (E-mail: stephen.fremes{at}swchsc.on.ca).


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Background: Clinical studies of myocardial protection rarely identify differences in hard clinical outcomes after surgery, either early or late, because most trials lack sufficient statistical power to deal with low-frequency events.
Methods: Prospectively collected data concerning all isolated coronary bypass operations from November 1989 to February 2000 were analyzed to determine the effects of cold blood cardioplegia and warm or tepid blood cardioplegia on early and late outcomes after surgery. Warm blood cardioplegia was used in 4532 patients, whereas cold blood cardioplegia was used in 1532. The allocation of patients to receive warm blood cardioplegia and cold blood cardioplegia was random in 749 cases and according to surgeon preference in the remainder. Most patients in the cold blood cardioplegia group had surgery earlier in the time course of the study, and most in the warm blood cardioplegia group underwent surgery later.
Results: Perioperative death, myocardial infarction, and death or myocardial infarction were all more common in the cold blood cardioplegia group than in the warm blood cardioplegia group (death 2.5% vs 1.6%, P = .027, adjusted odds ratio 1.45, 95% confidence interval 0.95-2.22, P = .09; myocardial infarction 5.4% vs 2.4%, P < .0001, adjusted odds ratio 1.86, 95% confidence interval 1.36-2.53, P < .0001; death or myocardial infarction 7.3% vs. 3.8%, P < .0001, adjusted odds ratio 1.70, 95% confidence interval 1.30-2.21, P < .0001). Actuarial survival at 60 months was 91.1% ± 1.4% in the warm blood cardioplegia group and 89.9% ± 1.3% in the cold blood cardioplegia group (P = .09), whereas freedom from death or myocardial infarction was 84.7% ± 1.8% and 83.2% ± 1.6%, respectively (P = .16). In multivariate models, cold blood cardioplegia was associated with poorer survival (risk ratio 1.30, 95% confidence interval 0.96-1.75, P = .09) and freedom from any death or late myocardial infarction (risk ratio 1.93, 95% confidence interval 1.56-2.39, P = .0001).
Conclusions: In 6064 patients undergoing isolated coronary artery bypass grafting, warm or tepid blood cardioplegia may be associated with better early and late event-free survivals than is cold cardioplegia.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The Warm Heart Trial (WHT) was a randomized trial of 1732 patients comparing cold versus warm cardioplegia that demonstrated that although there were significant decreases in low-output syndrome (9.3% vs 6.1%, P = .01) and enzymatically identified myocardial infarction (MI, 17.3% vs 12.3%, P < .01), there was only a nonsignificant improvement in early mortality (2.5% vs 1.4%, P = 0.12).Go 1 The early benefits of improved myocardial protection may not be observed in gross measures of such outcomes after cardiac surgery as mortality or MI. By lengthening the time of observation and changing the time horizon from a short-term perioperative period to a long-term or late follow-up period, it may be possible to distinguish differences in mortality and morbidity resulting from subtle improvements in perioperative myocardial protection conferred by the use of warm cardioplegia. In particular, with a subpopulation of the WHT we have shown that patients who survive perioperative events have poorer long-term survival than do patients in whom there are no perioperative complications.Go 2 It is often the case that clinical trials of cardioplegia fail to demonstrate differences in important but uncommon outcomes, such as mortality. Retrospective cohort studies may be useful in these situations because of the larger sample size and statistical power that increased size confers. The objective of this study was to determine differences in early and late outcomes after isolated coronary artery bypass surgery, comparing cold and warm cardioplegia.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Patient population and data collection
All patients undergoing isolated coronary artery bypass grafting at Sunnybrook and Women's College Health Sciences Centre between November 1989 and February 2000 were identified from a hospital based research database and included in the study. A total of 6064 patients were included; 4532 of these patients received warm or tepid cardioplegia and 1532 patients received cold cardioplegia. Of these 6064 patients, 762 were enrolled in the WHT,Go 1 and their cardioplegia regimens were determined by random allocation (warm or tepid blood cardioplegia n = 378, cold blood cardioplegia n = 384). The cardioplegia received in the remaining cases was according to surgeon preference.

Data on more than 200 demographic, anatomic, preoperative, perioperative, and postoperative variables were collected prospectively on all patients undergoing surgery at Sunnybrook and Women's College Health Sciences Centre by chart review during the hospital stay and completed shortly after discharge from hospital. Follow-up data were collected during routine follow-up care. All patients were seen at 3 months and 1 year and were requested to return on a voluntary basis at 3, 5, 7.5, and 10 years after surgery. This information is supplemented with information from referring physicians' offices.

Surgical management
The surgical procedure has been described in detail elsewhere.Go Go 1,3 In brief, cardiopulmonary bypass was established with a single 2-staged right atrial cannula and ascending aortic perfusion cannula and ascending aortic cardioplegia cannula and vent line. Cardiopulmonary bypass included membrane oxygenators, arterial line filters, nonpulsatile flows of 2.4 L · min-1 · m2, mean arterial pressure of 50 to 80 mm Hg, moderate hemodilution with a hematocrit value greater than 20%, and alpha-stat acid-base balance. In the warm or tepid blood cardioplegia group, the systemic temperature was maintained at 33°C to 37°C, and the blood cardioplegia was delivered at a temperature of 37°C. In the tepid cardioplegia group, the systemic temperature was permitted to drift passively during the operation to 32°C to 34°C. The temperature of the cardioplegia was 28° to 30°C. In the cold cardioplegia group, the systemic temperature was actively cooled to 25°C to 32°C, and the blood cardioplegia was actively cooled to a temperature of 5°C to 8°C. The blood cardioplegia was prepared by mixing oxygenated blood with a crystalloid additive (Fremes solution) in a 4:1 ratioGo 4 or an 8:1 ratioGo 5 and was administered in an intermittent, antegrade manner. Retrograde cardioplegia was used in 8.5% of cases. The warm strategy was used exclusively in the study patients. The tepid strategy was gradually adopted after the completion of the WHT on December 31, 1992.

Study end points
Study outcomes are reported for the early and the late phases of postoperative recovery. The primary early outcome measure of this study was the combined end point of perioperative death or MI. Other outcomes were early mortality and MI considered separately, postoperative stroke, postoperative intra-aortic balloon pump (IABP) insertion, low-output syndrome, and blood transfusion. MI was defined as the emergence of new Q waves after the operation, or a peak creatine kinase isoenzyme MB level greater than 50 IU/L that represented more than 7% of total creatine kinase. Low output syndrome was defined as the requirement of inotropic or IABP support for a period longer than 60 minutes after surgery to maintain a cardiac index greater than 2.2 L · min-1 · m-2 and a systolic blood pressure greater than 90 mm Hg in association with a wedge pressure greater than 18 mm Hg. Blood transfusion was considered to be the transfusion of any blood product.

The primary late outcome measures of this study were late survival and freedom from death or MI determined late after operation. Perioperative deaths contributed toward estimates of late survival and event-free status. However, perioperative MI did not contribute toward estimates of late event-free status.

Statistical analysis
Continuous data are expressed as mean SD, and categoric data are given as frequency or percentage. Baseline comparisons were made with a 2-tailed Student t tests for continuous variables and the Fisher exact test for categoric variables. Early outcomes were compared by stepwise logistic regression. The area under the receiver operating characteristic curve was used to evaluate model discrimination, and the calibration was assessed with the Hosmer-Lemeshow goodness-of-fit test.Go 6 Late events were compared by survival analysis methods, with covariate adjustment performed by Cox proportional hazards model. All statistical analyses were performed with the SAS statistical package for the personal computer (version 8; SAS Institute, Inc, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The clinical characteristics of the cardioplegia groups are shown in Table 1. Patients in the warm or tepid blood cardioplegia group were generally at higher predicted preoperative risk than were patients in the cold blood cardioplegia group because of a greater number of female patients and higher prevalences of diabetes, hypertension, peripheral or cerebral vascular disease, severe angina, and depressed ventricular function. Patients in the warm or tepid blood cardioplegia group were more likely to undergo urgent operation for unstable angina, and a greater percentage had recent MI. In contrast, reoperation was more common in the cold blood cardioplegia group. There were similar prevalences in the two groups of older patients, patients with renal disease, and patients with left main disease.


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  		Table 1. Patient characteristics
 
In total, there were 6 patients who had both initial and repeated isolated coronary bypass operations in this study. All 6 patients had warm blood cardioplegia at the time of the initial operation, and 2 of these patients had cold blood cardioplegia at the reoperation. However, all these patients were treated as part of the warm or tepid blood cardioplegia group for the purpose of analysis.

The early results, unadjusted for other covariates, are presented in Table 2. There was a decreased incidence of the primary early outcome of death or MI (P < .0001) with warm or tepid blood cardioplegia as compared with cold blood cardioplegia. In addition, the incidence of death (P = .027) and MI (P < .0001) considered separately and of IABP insertion (P < .0001), low-output syndrome (P < .0001), and blood transfusion (P < .0001) was decreased in the warm or tepid blood cardioplegia group. The incidence of stroke was similar in the two groups.


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  		Table 2. Early results
 
The multivariate predictors of early death or MI are presented in Figure 1. The main predictors of death or MI after surgery were older age, hypertension, worse New York Heart Association status, poorer left ventricular function, reoperation, preoperative IABP, and use of endarterectomy. The use of any internal thoracic artery graft was protective against early death or MI. This analysis also showed that cold blood cardioplegia was associated with a greater adjusted risk of death or MI relative to warm or tepid blood cardioplegia, with an odds ratio of 1.70 (95% confidence interval [CI] 1.3-2.2, P < .0001). Separate logistic regression analyses were also performed for the outcomes of death or MI considered separately and for stroke, IABP insertion, and low-output syndrome (Table 3). Cold blood cardioplegia cardioplegia was associated with greater adjusted risks of death (P = .09), MI (P < .0001), IABP insertion (P = .0002), and low-output syndrome (P = .0006) but not of stroke.



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  		Fig. 1. Predictors of early death or MI. Bar lengths represent odds ratios, and error bars represent 95% CI. Use of internal thoracic artery (ITA) was protective of perioperative events, whereas all other factors were predictive of worse outcome. Adjusted odds ratio for cold cardioplegia was 1.724. REDO, Reoperation; PREIABP, preoperative IABP; ENDART, endarterectomy; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association functional class.

 

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  		Table 3. Logistic regression: Early results
 
An important potential confounder of the effect of cardioplegia temperature was the date of surgery. Figure 2 depicts the use of warm or tepid blood cardioplegia and cold cardioplegia during the study period. This figure shows a steady decrease with time in the number of patients in whom cold cardioplegia was used, from a high of 529 cases (67.6%) in 1989 through 1991 to the recent low of 116 cases (6.3%) in 1997 through 2000. The logistic regression analyses were therefore repeated for the end point of death or MI with date included as an additional covariate expressed as a dichotomous variable, before versus after January 1, 1995. The magnitude of the effect of cold blood cardioplegia cardioplegia when controlled for era was not significantly different from that shown in Table 3Go. Late outcomes after surgery were also investigated. Actuarial survival is shown in Figure 3, and freedom from death or MI is shown in Figure 4. Neither the actuarial survival (P = .09) nor the event-free survival (P = .16) was significantly greater in the warm or tepid blood cardioplegia cohort in unadjusted analyses. Results of the Cox regression analyses of late death and of death or MI are shown in Tables 4 and 5, respectively. Figure 5 shows the results of Cox regression analysis on late death or MI. Cold blood cardioplegia was not a significant predictor of late mortality (P = .09) but was a significant predictor of late death or MI. These analyses were repeated with the confounder of era of operation. Cold cardioplegia remained a significant predictor of death or MI in Cox regression analyses after controlling for date of operation.



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  		Fig. 2. Cardioplegia use with time. Bars represent number of cases performed in indicated period. Use of cold cardioplegia decreased from a high of 67% in early years to 6% in late years.

 


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  		Fig. 3. Late survival. Percentages alive at 0, 1, 2, 3, 4, 5, and 6 years are plotted according to cardioplegia temperature used. Numbers across bottom are numbers of patients at risk for event at different periods. There was no significant difference between cold and warm or tepid cardioplegia with respect to late survival according to univariate analysis (P = .09).

 


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  		Fig. 4. Freedom from death or MI. Percentages alive at 0, 1, 2, 3, 4, 5, and 6 years are plotted according to cardioplegia temperature used. Numbers across bottom are numbers of patients at risk for event at different periods. There was no significant difference between cold and warm or tepid cardioplegia with respect to death or MI according to univariate analysis (P = .16).

 

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  		Table 4. Late mortality: Cox regression
 

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  		Table 5. Late mortality or MI: Cox regression
 


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  		Fig. 5. Predictors of late death or MI. Bar lengths represent odds ratios, and error bars represent 95% CI. Hazard ratios of statistically significant risk factors are shown. Greatest predictor of late death or MI was presence of renal disease (RENAL), followed by cold blood cardioplegia (COLD, hazard ratio 1.93, 95% CI 1.56-2.39). Internal thoracic artery (ITA) use was protective against late adverse outcome. VASCULAR, Cerebrovascular or peripheral vascular disease; ENDART, endarterectomy; LVEF, left ventricular ejection fraction.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Buckberg and colleaguesGo 7 introduced warm blood cardioplegia in 1977. It was used as a method to decrease the reperfusion injury that occurred after crossclamp removal and was delivered as a terminal hot shot given approximately 3 to 5 minutes before aortic crossclamp removal.Go 8 The concept of warm blood cardioplegia induction was introduced in 1983 with the realization that the initial dose of cardioplegia to a chronically ischemic and substrate depleted heart represented the first phase of reperfusion. It was shown that warm blood induction resulted in active resuscitation and improved tolerance of the myocardium to the subsequent ischemic period.Go 9 Subsequently, multidose warm cardioplegia has been used throughout the induction, maintenance, and reperfusion phase of the ischemic period. Warm blood cardioplegia has been shown to result in improved metabolic and functional recovery of the myocardium in many experimental models. There have been many randomized control trials of warm blood cardioplegia.Go Go Go Go 1,3,10-20 Investigators at the universities of Toronto and Emory conducted the two largest clinical trials of warm versus cold cardioplegia. The Emory University trial enrolled 1001 patients and was stopped prematurely as a result of increased incidence of adverse neurologic events in the warm cardioplegia group. It was reported that 4.5% of patients in the warm group had adverse neurologic events (defined as either a new stroke or encephalopathy), versus 1.4% in the cold cardioplegia group. Other important findings were that there were no significant differences in mortality (1.0% with warm or tepid blood cardioplegia vs 1.6% with cold blood cardioplegia), Q-wave MI (1.4% for warm or tepid blood cardioplegia vs 0.8% for cold blood cardioplegia), or need for IABP (1.4% for warm or tepid blood cardioplegia vs 2.0% for cold blood cardioplegia). The WHT was published in 1994 and was one of the largest cardiac surgical randomized control trials ever performed. There were no significant differences in the primary end points of death or Q-wave MI. However, there were significantly fewer cases of enzymatically defined MI (12.3% vs 17.3%, P < .01) and low-output syndrome (6.1% vs 9.3%, P = .01) with warm or tepid blood cardioplegia, and perioperative mortality was nonsignificantly reduced (1.4% vs 2.5%, P = .12). This study was undertaken to investigate the effect of warm cardioplegia on early and late death and MI.

The effect of cold cardioplegia on late survival is shown in Table 4Go. The significant predictors of late mortality were reoperation (hazard ratio 3.36, 95% CI 2.07-5.48), renal disease (hazard ratio 2.55, 95% CI 1.59-4.08), vascular disease (hazard ratio 2.29, 95% CI 1.66-3.13), left ventricular ejection fraction less than 40% (hazard ratio 2.28, 95% CI 1.67-3.12), and age older than 70 years (hazard ratio 1.70, 95% CI 1.26-2.30). The use of cold cardioplegia was not significantly associated with poorer long-term survival (hazard ratio 1.30, 95% CI 0.96-1.75). The use of an internal thoracic artery graft was associated with improved late survival (hazard ratio 0.74, 95% CI 0.48-0.94). Thus it would appear that the use of warm/tepid cardioplegia, although tending toward improved late survival, did not exert a statistically significant effect.

The main findings of this study were that cold cardioplegia is associated with poor short-term freedom from death or MI and poorer long-term freedom from death or MI. In the short-term, cold cardioplegia was associated with death or MI in both univariate and multivariate analyses. There was an absolute risk increase of 3.5% with the use of cold cardioplegia (P < .0001). The factor-adjusted odds ratio was 1.70 for the composite end point of death or MI (95% CI 1.30-2.21, P < .0001). This also translated into worse values for freedom from death or MI with cold cardioplegia. A hazard ratio of 1.93 (95% CI 1.56-2.39, P < .0001) was observed with cold cardioplegia when perioperative MIs were excluded from the analysis. A more robust measure of coronary artery bypass grafting outcomes is any death or MI. Indeed, when perioperative deaths from MI were included in the analysis of late outcomes, cold cardioplegia remained a significant predictor of late morbidity. Cold cardioplegia was associated with a hazard ratio of 1.65 (95% CI 1.31-2.07, P < .0001). After controlling for era of procedure and retrograde cardioplegia delivery, it remained a significant predictor of poor outcome (hazard ratio 1.64, 95% CI 1.31-2.05, P < .0001).

The use of retrograde cardioplegia has been shown to be of particular benefit in the setting of warm or tepid cardioplegia.Go Go 21-24 It has been suggested that the use of normothermic cardioplegic solutions necessitates the use of retrograde cardioplegia as a means of attaining continuous myocardial perfusion.Go 25 The use of retrograde cardioplegia in our study was generally limited to patients perceived to be at higher risk from surgery. These included more patients undergoing urgent surgery with recent MI or increased incidence of preoperative IABP insertion, patients with severely depressed ventricular function or active congestive heart failure, or patients undergoing reoperation. There was no difference in the use of retrograde cardioplegia between cold and warm or tepid strategies. In multivariate analyses, retrograde administration was associated with worse long-term outcomes even after controlling for the effects other risk factors (hazard ratio 1.74, 95% CI 1.20-2.53). The risk of retrograde cardioplegia is probably overestimated by the presence of significant selection bias. Despite inclusion of retrograde cardioplegia in the models for short-term and long-term outcomes, cold cardioplegia remained an important predictor of poorer result.

Since the advent of warm heart surgery, there has been great concern regarding the potential increased incidence of adverse perioperative neurologic outcomes with warm cardioplegia. Stroke is one of the most devastating complications of cardiac surgery. Multivariate statistical analyses of stroke after coronary artery bypass grafting have identified several important risk factors, including older age, female gender, renal insufficiency, the presence of cerebrovascular or peripheral vascular disease, higher New York Heart Association functional class, perioperative MI, and intraoperative detection of atheromatous debris in the aorta.Go Go 26-36 Warm heart surgery, or the administration of warm cardioplegia with the maintenance of normothermia during cardiopulmonary bypass, has also been suggested as another risk factor for stroke.Go Go Go 10,37,38 Despite the finding of the Emory University trial investigators demonstrating an increased incidence of stroke with warm cardioplegia, however, the WHT did not corroborate this finding. A substudy of the trial examined neuropsychologic outcomes in these patients and concluded that cognitive changes were similar in the warm and cold cardioplegia groups.Go 39 This new study included more than 6000 patients undergoing coronary artery bypass grafting, and there were no differences in stroke rate between the hypothermic and tepid or normothermic strategies of cardiopulmonary bypass maintenance. The differences between the rates of stroke in the warm cardioplegia groups from the Emory and University of Toronto trials may be due to the strict adherence to systemic normothermia in the Atlanta study and the use of mild systemic hypothermia and avoidance of hyperthermia during rewarming.Go 38

This study includes patients who were operated on over the period of a decade. During this period there have been great changes in the management of patients with cardiovascular disease, from both surgical and medical points of view, that have had a large impact on the survival of these patients. The positive interpretation of the results of the WHT at our institution led to the increased acceptance of warm or tepid blood cardioplegia as a strategy for myocardial protection and may in large part explain the shift in cardioplegia use from predominately cold blood cardioplegia in the earliest period to warm or tepid blood cardioplegia in the most recent period (Figure 2Go). In the recent era, patients being evaluated for operation have had higher burdens of illness and greater risk profiles than in earlier periods.Go Go 40-42 Earlier studies from this institution also suggested that adjusted perioperative event rates had declined. We were therefore concerned that our conclusions regarding warm cardioplegia were confounded by the year of surgery. Cardioplegia temperature remained a significant variable with minimal change in the odds or hazard ratios in multivariate analyses of early and long-term results after controlling for the year of surgery.

Randomized controlled trials are the criterion standard of evidence in clinical research. A well-designed study should eliminate problems of bias that can occur with other types of studies.Go Go 43,44 However, randomized controlled trials often have strict entry and exclusion criteria that limit their applicability to the general practice of coronary bypass surgery. In addition, they often fail to demonstrate differences in uncommon but important clinical events because of insufficient power of the study design.Go 43 To circumvent the power problem of a randomized control trial, retrospective cohort studies may be used. If the information to conduct these studies is retrieved from administrative or research databases, generally there are enough subjects to provide sufficient statistical power to be able to demonstrate small differences in important clinical variables.

Cohort studies are prone, however, to unmeasured bias. An important systematic bias may exist in this study with respect to the late attrition in warm or tepid blood cardioplegia and cold blood cardioplegia groups. Most patients in the cold blood cardioplegia group underwent surgery in the earlier period, and this may have resulted in either better or poorer attrition rates than in the warm or tepid blood cardioplegia group. During the time course of the study, the quality of follow-up care may have changed, and this would systematically affect the two groups differently because the distribution of patients into the treatment groups was not constant with time. Despite the previously listed advantages of performing a cohort study, the possibility of unmeasured bias influencing the results of this analysis is not precluded.

In conclusion, this large retrospective cohort analysis of cold cardioplegia versus warm or tepid cardioplegia demonstrates two facts. First, warm cardioplegia is safe for patients undergoing coronary artery bypass grafting. In particular, it is not associated with an increased incidence of adverse neurologic outcomes. Second, this study demonstrates that warm or tepid cardioplegia may be associated with better short-term and long-term freedoms from cardiac morbidity and mortality.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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