Does Cardioplegia Type Affect Outcome and Survival in Patients With Advanced Left Ventricular Dysfunction?
Results From the CABG Patch Trial
Background—There is controversy regarding which cardioplegic solution, temperature, and route of administration provides superior protection. The CABG Patch Trial enrolled a high-risk group of coronary artery disease patients with an ejection fraction of <36%. Thus, they constitute an ideal group to benefit most from optimal cardioplegic protection.
Methods and Results—All patients randomized into the trial were compared with respect to the use of blood and crystalloid cardioplegia. In addition, a questionnaire was sent to surgeons requesting blood cardioplegic temperature and route. Patients receiving crystalloid cardioplegia versus those receiving blood cardioplegia were found to have significantly more operative deaths (2% versus 0.3%, P=0.02), postoperative myocardial infarctions (10% versus 2%, P<0.001), shock (13% versus 7%, P=0.013), and postoperative conduction defects (21.6% versus 12.4%, P=0.001). Despite this, early death (6% crystalloid versus 4% blood cardioplegia) and late death (24% crystalloid versus 21% blood cardioplegia) statistics were not significantly different. Patients receiving normothermic blood had less postoperative right ventricular dysfunction (10%) than did patients receiving cold blood (25%) or cold blood with warm reperfusion (30%) (P=0.004). There was no significant difference in early or late death. Finally, patients who received combined antegrade and retrograde cardioplegia had significantly less inotrope use (71% versus 84%, P=0.002), right ventricular dysfunction (23% versus 41%, P=0.001), and postoperative balloon pump use (12% versus 19%, P=0.02) than did those who received antegrade cardioplegia. There was no difference in survival.
Conclusions—Blood cardioplegia and combined antegrade and retrograde cardioplegia are superior to crystalloid and antegrade cardioplegia alone for postoperative morbidity. Despite this, there is no significant difference in early or late survival.
The technique of potassium cardioplegia dates back to 1955. At that time, Melrose et al1 used potassium citrate to arrest the heart. However, this early method was associated with a high incidence of myocardial necrosis.2 Therefore, potassium cardioplegia was abandoned until the middle of the 1970s. Research at that time demonstrated that the injurious effect of this early solution was related to the high potassium concentration and its tonicity.3 This led to crystalloid formulations that made use of potassium at much lower concentrations and at isotonicity.4 These solutions continued in widespread clinical use until the 1980s, when blood-based potassium solutions were advocated to further improve myocardial protection and reduce creatine phosphokinase-MB release.5 6 At the present time, a wide variety of potassium-based cardioplegic solutions are being used by 98% of surgeons.7 8 A recent national survey revealed that 28% of surgeons used crystalloid and that 72% used blood cardioplegia.8 Proponents of each method emphasize comparable clinical results, although many publications demonstrate reduced rates of infarction and creatine phosphokinase-MB release for blood-based cardioplegia.9 10 These clinical results have been criticized because they are limited to patient groups with near normal ejection fractions, which pose relatively low operative risk.9 The CABG Patch Trial (Studying Prophylactic Implantable Cardioverter Defibrillators in Patients Who Are Having Coronary Artery Bypass Graft Surgery and Have Ventricular Dysfunction and a Positive Signal-Averaged ECG) represented a high-risk group of 900 patients with ejection fractions <36% who underwent CABG, with half randomly assigned to cardioverter defibrillator (ICD) implantation. Although not designed to address this issue, the trial collected limited data on cardioplegic type and perioperative events in addition to survival. Although this does not represent an ideal cohort (cardioplegia was not randomized), this group provides data on the effect of blood versus crystalloid cardioplegia on the postoperative outcome in patients with advanced left ventricular (LV) dysfunction, including early and late survival.
To simply answer the question of whether blood cardioplegia is superior to crystalloid cardioplegia in this cohort is not enough. Either cold or warm blood cardioplegia is currently administered, and in some individuals, cold cardioplegia is complemented at the end of the cross-clamp interval by warm reperfusion. Additionally, this solution can be given antegradely, retrogradely, or as a combination of the two. To obtain further information as to what modifications of a blood-based solution may be associated with an improved outcome, a questionnaire was sent to all surgeons who used blood cardioplegia. This information was then combined with the CABG Patch Trial database.
The substudy included all patients randomized in the CABG Patch Trial who had cardioplegic data available (885 patients). The trial itself consisted of 900 randomized patients enrolled between August 14, 1990, and April 30, 1997. Criteria for enrollment in the CABG Patch Trial included the following: age <80 years, LV ejection fraction <36%, and abnormal signal-averaged ECG. Patients were excluded if they had a history of sustained ventricular tachycardia or fibrillation, poorly controlled diabetes mellitus, recurrent infections, previous or concomitant aortic or mitral valve surgery, concomitant cerebrovascular surgery, a serum creatinine concentration >3 mg/dL, emergency operation, or a noncardiovascular condition with expected survival of <2 years. Randomization took place in the operating room after grafting had been completed and was stratified by center and LV ejection fraction. Full details of this process have been described previously.11 Patients considered unstable for ICD implantation at this time were not randomized (88 patients). Although excluded from the trial, cardioplegia and outcome data were available for 87 of these patients.
These procedures were accomplished at 37 centers (see Appendix) by 149 surgeons. The conduct of the operation was not standardized but was left to the discretion of the individual surgeon. The type of cardioplegia used was crystalloid in 22%, given at a temperature of 4°C to 10°C, and blood in 78%, given at a temperature of between 3°C and 37°C.
To obtain further information on blood cardioplegic techniques and their influence on perioperative events and early and late survival, a questionnaire was sent to the 87 surgeons who used blood cardioplegia. The questionnaire included inquiries about the blood temperature, eg, whether cold blood was used and whether warm reperfusion (“hot shot”) was administered. In addition, the surgeons were asked about the route of cardioplegic administration (antegrade, retrograde, or both). They were also queried as to whether their cardioplegic techniques varied over the interval of the study. Surgeons whose techniques varied were excluded from analysis.
The CABG Patch Trial database, which had a mean follow-up of 32 months (median 34 months), was used for preoperative demographics, operative data, and postoperative results, including early (30-day) and long-term outcome. These data were compared for the crystalloid and blood groups by use of information in the database. To examine the blood subgroups, the information acquired from the questionnaires was entered into the database, and then the same preoperative, operative, and postoperative data were obtained for cardioplegic temperature (cold, warm [37°C], and warm reperfusion) and route of administration (antegrade, retrograde, or both).
Data are presented as mean±SE for continuous variables and as proportions for categorical variables. ANOVA and χ2 methods were used as appropriate. To address variables with unequal variances, robust methods were used. Survival curves for each group were estimated by the Kaplan-Meier method.
Blood Versus Crystalloid
Comparison of the 2 groups for baseline demographics (Table 1⇓) revealed them to be quite similar but different in 2 respects. Patients receiving blood cardioplegia were noted to have significantly more diabetes mellitus and hypertension.
Operative data (Table 2⇓) show that patients receiving blood cardioplegia had longer cross-clamp and cardiopulmonary bypass times and received more grafts per patient. However, despite these longer ischemic times, significantly less patients subjected to blood cardioplegia died in the operating room. When the 87 unstable and thus nonrandomized patients in the operating room were examined, it was noted that 42% had received crystalloid cardioplegia versus 22% in the randomized group (P<0.0001). There was only one death in the nonrandomized group, and that patient had received blood cardioplegia. Therefore, if the 2 groups are combined, operative deaths occurred in 1.8% of patients subjected to crystalloid cardioplegia and 0.4% of patients subjected to blood cardioplegia (P=0.05).
Postoperative evaluation (Table 2⇑) revealed that patients receiving blood were significantly less likely to have myocardial infarctions, shock, and new conduction defects. Despite these advantages, there was no significant difference in crystalloid versus blood cardioplegia for either 30-day death (6% versus 4%, respectively) or late death (24% versus 21%, respectively) at a mean follow-up of 32 months (Figure⇓).
Multivariate analysis failed to demonstrate a relation between cardioplegic type and either early or late survival. The only preoperative factors influencing survival were age and a history of congestive heart failure.
Seventy (81%) of the 87 surgeons using blood cardioplegia responded to the survey. This response accounted for 87% of the patients. Of these, 40% of the surgeons used cold blood at a temperature between 3°C and 25°C, 36% used cold blood with a terminal hot shot, and 10% used blood at normothermia. Surgeons were also queried as to the route of cardioplegic administration. Antegrade cardioplegia was always used by 21%, whereas a combination of antegrade and retrograde cardioplegia was used by 54%. A minority of surgeons (6%) used retrograde cardioplegia only. This group consisted of only 13 patients and was excluded from analysis.
Blood Cardioplegic Temperature
The 3 blood groups were compared. There was no significant difference in baseline characteristics (Table 3⇓). In the operating room (Table 4⇓), patients receiving normothermic blood had significantly longer periods of cardiopulmonary bypass and cross-clamp times but a lower incidence of postoperative right ventricular dysfunction, as assessed by visual inspection by the surgeon. There were significantly fewer mammary artery grafts performed in the cold blood group. After surgery, the 3 groups were identical, except that patients who received a hot shot had significantly fewer new conduction defects. Early mortality was 3.5% for cold blood, 2.4% for warm reperfusion, and 6% for warm blood (P=NS). Late mortality was 22% for cold blood, 19% for warm reperfusion, and 16% for warm blood (P=NS).
Route of Cardioplegic Administration
Patients receiving antegrade or mixed antegrade and retrograde cardioplegia had no differences in baseline characteristics (Table 5⇓). In the operating room (Table 6⇓), however, patients receiving mixed cardioplegia had significantly longer cross-clamp and cardiopulmonary bypass times. They also received more grafts per patient but significantly less mammary artery grafts. Despite this, they had significantly less inotrope use and a reduced incidence of postoperative right ventricular dysfunction. They also had a significantly reduced incidence of intra-aortic balloon pump use. After surgery (Table 6⇓), both patient groups did equally well, except that patients receiving mixed cardioplegia had significantly fewer new conduction defects. Early mortality was 5% for antegrade and 3% for mixed cardioplegia. Late mortality was 25% for antegrade and 21% for mixed cardioplegia. This was not significant in either univariate or multivariate analysis.
Blood Versus Crystalloid Cardioplegia
Patients enrolled in the CABG Patch Trial represented a high-risk sample with a 42-month mortality rate of 24%, ≈4-fold the mortality rate of all patients who are subjected to CABG surgery. The CABG Patch Trial demonstrated that prophylactic ICD implantation at the time of elective CABG surgery in patients with an LV ejection fraction of <0.36 and an abnormal signal-averaged ECG did not improve survival.11 Most of the deaths in the ICD and control groups were cardiac-related, as previously described.12 In this high-risk group of patients with LV ejection fraction <36%, 98.3% of the surgeons used either crystalloid or blood cardioplegia. The use of these cardioplegic solutions and the ratios are very similar to those reported in a national survey in 1995.8 In our analysis of the data from the CABG Patch Trial, we found that patients receiving crystalloid cardioplegia were at a significantly increased risk of postoperative myocardial infarction, shock, and development of postoperative conduction defects. Shock as defined by the CABG Patch Trial is a systolic blood pressure of <80 mm Hg associated with a low cardiac output. Barner6 in his review of randomized series comparing crystalloid with blood cardioplegia also noted an increased incidence of myocardial damage, inotrope use, and depression of postoperative ejection fraction in the crystalloid group. We have previously reported on the high incidence of permanent conduction disturbances associated with the administration of crystalloid cardioplegia.10 Patients receiving crystalloid cardioplegia were also found, in our analysis, to have a significantly increased risk of death and dropout from the protocol in the operating room, before the randomization process. This further points toward inferior myocardial protection, despite the fact that crystalloid cardioplegia was associated with significantly shorter cross-clamp times. Christakis et al13 noted similar trends in a group of patients with LV ejection fraction <40%. Despite these findings, our data failed to demonstrate significant differences in either 30-day or late survival by either univariate or multivariate analysis.
The absence of any difference in survival may be related to the larger group of diabetics in the blood group or may reflect the dilution effect of all causes of death on death relating to myocardial protection alone. There were 4 deaths in the operating room in the crystalloid group and 12 deaths at 30 days. In the blood group, there were 2 deaths in the operating room and 23 deaths at 30 days. We can easily see that these late deaths, which occurred for many reasons, can dilute the early operating room deaths. We believe that these early operative deaths relate to myocardial protection.
The late results of The Warm Heart Trial were presented at the 72nd Sessions of the American Heart Association, Atlanta, Ga, November 7–10, 1999, by S.E. Fremes. The data indicated that perioperative infarction and low output syndrome were significant predictors of late survival. In our multivariate analysis, low cardiac output was noted to be a powerful predictor of mortality and was also significantly more likely to occur with crystalloid cardioplegia (results not shown).
We conclude that blood cardioplegia was associated with more operative stability and a reduction in postoperative morbidity. Therefore, we find it superior to crystalloid cardioplegia in patients with an LV ejection fraction of <36%.
Blood Cardioplegic Temperature
This substudy of the CABG Patch Trial as constructed used the questionnaire sent to all surgeons who used blood cardioplegia. It found that 66% of the surgeons used cold blood only between 3°C and 25°C, 25% used cold blood at the same temperatures but coupled it with terminal warm reperfusion, and 9% used normothermic blood cardioplegia. These groups again are quite similar to the national survey conducted by Robinson et al.8
Interestingly, in the postoperative phase, patients receiving normothermic blood cardioplegia had a significantly reduced incidence of postoperative right ventricular dysfunction. This may relate less to temperature and more to route of administration, because 95% of these patients had cardioplegia administered by the combined antegrade retrograde route. In the present study, this route has been demonstrated to be associated with superior right ventricular protection regardless of blood temperature. An experimental study performed by Partington et al14 showed this route to be the best for combined ventricular preservation. Despite this, the patients subjected to normothermic cardioplegia had significantly longer bypass times and a trend toward longer ischemic time and more grafts per patient. Although not significant, there was a trend toward greater balloon pump use in patients subjected to warm cardioplegia. This increased incidence related to the practice of 2 surgeons who routinely placed intra-aortic balloon pumps (IABPs) in patients with low ejection fractions. The significantly lower incidence of conduction defects with warm reperfusion is difficult to explain. We previously published work showing significantly less conduction defects in warm versus cold cardioplegia with the hot shot.15 There were no significant differences in either early or late death.
In conclusion, no clear benefit of any blood subgroup could be found. Perhaps this reflects the wide range of cardioplegic temperatures used for cold cardioplegia, with many surgeons using blood at ≥10°C. McGovern et al16 demonstrated superior myocardial protection with blood at temperatures ≥10°C.
Route of Blood Delivery
Antegrade cardioplegia only was used on 29% of the patients, and combined antegrade and retrograde cardioplegia was used in 69%. When compared, patients who received the combined approach had significantly longer intraoperative ischemic times. Despite this, they left the operating room with less support. They also had less myocardial damage as assessed by new conduction defects. Previous authors have shown the uniform distribution of solutions beyond stenosis obtained by retrograde cardioplegia.17 This uniform distribution is even more important in those patients with impaired LV function because they have no reserve and often have many diseased vessels, making uniform antegrade delivery difficult. These results demonstrate a clear superiority of the combined antegrade and retrograde route in patients with ejection fractions <36%.
The type and administration of cardioplegia was not randomly assigned; thus, imbalances may exist among the various groups analyzed. In addition, because some of the conclusions regarding patients were based on a survey of the surgeons, this may have biased the results of the present study.
Good Samaritan Hospital, Los Angeles, Calif; Sequoia Hospital, Redwood City, Calif; University of Louisville, Louisville, Ky; University of Virginia, Charlottesville; Presbyterian–University of Pennsylvania Medical Center, Philadelphia; Polyclinic Medical Center, Harrisburg, Pa; Presbyterian Hospital in the City of New York, New York, NY; Morristown Memorial Hospital, Morristown, NJ; Sentara Norfolk General Hospital, Norfolk, Va; University of Florida, Gainesville; Washington Hospital Center, Washington, DC; Cleveland Clinic Foundation, Cleveland, Ohio; Kaiser Permanente Medical Center, Los Angeles, Calif; New England Medical Center, Boston, Mass; Jewish Hospital at Washington University Medical Center, St. Louis, Mo; Hermann Hospital, University of Texas Medical School, Houston; Medical College of Virginia, Richmond; Loyola Medical Center, Maywood, Ill; East Carolina University School of Medicine, Greenville, NC; St. Joseph’s Hospital, Atlanta, Ga; Westalische Wilhems–Universität Münster, Münster, Germany; Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany; LDS Hospital, Salt Lake City, Utah; Florida Hospital, Orlando; Northwest Cardiovascular Research Institute, Spokane, Wash; Nebraska Heart Institute, Lincoln; Emory University System of Health Care, Atlanta, Ga; Minneapolis Heart Institute, Minneapolis, Minn; Bowman Gray School of Medicine, Winston-Salem, NC; University of Nebraska Medical Center, Omaha; Brigham and Women’s Hospital, Boston, Mass; Baystate Medical Center, Springfield, Mass; Buffalo General Hospital, Buffalo, NY; Hospital of Saint Raphael, New Haven, Conn; Loma Linda University Medical Center, Loma Linda, Calif; University of Chicago, Chicago, Ill; and Oregon Health Science Centers, Portland.
This study was supported by the CABG Patch Trial, Columbia University; National Institutes of Health grants HL-48120 and HL-48159; and Guidant/CPI, St. Paul, Minn.
- Copyright © 2000 by American Heart Association
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