Abstract
The 715 patients who had crystalloid cardioplegia were compared with 5419 who had cold hyperkalemic blood cardioplegia for isolated coronary artery grafting from 1996 through 2001. Creatine kinase-MB was measured preoperatively, at 90 min, and 7 hours after the end of extracorporeal circulation. Correlation of post-bypass creatine kinase-MB release with aortic crossclamp time and other variables in the two cardioplegia groups was made using dichotomous encoding of cardioplegia in a multivariate linear regression model. Creatine kinase-MB levels 90 min after bypass were higher in patients who had crystalloid cardioplegia than in those who had blood cardioplegia. There was a linear relationship between aortic crossclamp time and post-bypass creatine kinase-MB release in both cardioplegia groups. Post-bypass creatine kinase-MB release increased with aortic crossclamp time independently of other factors and significantly more with crystalloid cardioplegia than with blood cardioplegia (the slope of the regression line was 0.230 versus 0.106). Intraaortic balloon pumping was used less frequently in the blood cardioplegia group. There was an advantage with blood cardioplegia for myocardial protection in longer aortic crossclamp times for isolated coronary bypass grafting.
Introduction
Varieties of both crystalloid and blood cardioplegic solutions are used clinically worldwide to achieve elective cardiac arrest and a bloodless surgical field. Crystalloid cardioplegic solutions were widely used until the 1980s when blood-based potassium solutions were advocated. The physiologic attributes of blood cardioplegia, including better buffering capacity, endogenous oxygen free-radical scavengers, detoxifying substances, and greater oxygen-transport capacity have established this approach as the superior strategy. A recent survey in the United States revealed that 28% of surgeons used crystalloid solutions and 72% used blood cardioplegia. 1 However, many cardiac surgeons still prefer crystalloid cardioplegia for its ease of use and better visibility. Proponents of each method emphasize comparable clinical results although reduced rates of infarction and release of creatine kinase-MB (CK-MB) and troponin I have been demonstrated for blood-based cardioplegia in small cohorts. 2 –7 Encouraged by these findings, we progressively used cold hyperkalemic blood since 1997 and abandoned the use of Kirsch/Hamburg cardioplegia shortly thereafter. 8,9 A potential advantage of blood cardioplegia over crystalloid solutions should become clear with increasing crossclamp time but, to our knowledge, the role of cardioplegia type on aortic crossclamp-dependent CK-MB release has not been studied. Our large computer database of patients who had elective coronary artery bypass grafting (CABG) enabled us to study the effect of the type of cardioplegia on CK-MB release and correlate this with the duration of aortic crossclamp time as well as to compare other possible determinants of postoperative CK-MB release (e.g. use of internal mammary artery, preoperative hematocrit, and leukocytes).
Patients and Methods
From January 1996 to December 2001, 6900 adults underwent isolated CABG in the Heart Institute Lahr/Baden. Patients who had off-pump CABG, redo CABG, emergency operations, or elevated preoperative CK-MB were excluded from the study. There were 6134 patients included in this study: 715 had Kirsch/Hamburg cardioplegia from 1996 to 1998, and 5419 had cold hyperkalemic blood cardioplegia between 1997 and 2001. Data were collected prospectively on all patients as part of a national quality assessment trial of cardiothoracic surgery and cardioanesthesia (Quadra: Quality Assurance Data Review Analysis) using standardized protocols of the German Society of Thoracic and Cardiovascular Surgery and Intensive Care Medicine. A technical assistant for data collection and medical documentation controlled the data collection and tested inter-operator reliability. Variables such as preoperative medications and data concerning the operating team (e.g. individual surgeon) were recorded. The data were stored perioperatively in our institutional databases and extracted together with laboratory data by our dedicated project-orientated data warehouse (data-mart). They were transformed, consolidated, and subjected to several plausibility checks. In this study, 24 variables were analyzed from more than 200 attributes collected for each patient.
Plasma CK and CK-MB were measured preoperatively, at 90 min, and 7 hours after bypass. The activity of CK-MB was assayed at 25°C and calculated for 37°C (Roche UV-test, Roche Diagnostics, Mannheim, Germany). The total CK and CK-MB were measured with a Hitachi 917 analyzer (Boehringer Mannheim, Mannheim, Germany). The normal CK-MB range was 2–10 U·L−1. Yearly controls of blood cell measurements were performed by the Institute for Standardization and Documentation in Medical Laboratories, according to the instructions of the German Medical Association. Comprehensive results were obtained for the entire period 1996–2001.
The patients were operated upon by 8 different surgeons. Five minutes before aortic cannulation, heparin 375 IU·kg−1 was given to obtain an activated clotting time in excess of 400 seconds. A Jostra HL 20 (Medizintechnik, Hierlingen, Germany) heart-lung machine with membrane oxygenators and arterial filters (pore size 40 μm) was used. Roller pumps generated non-pulsatile flow. Target bypass flow was 90%–120% of the calculated value (2.5 L·m−2), and the pressure was 60 mmHg and up to 80 mmHg in patients with known carotid stenosis, maintained with noradrenaline if necessary. Moderate hemodilution (hematocrit 24%–30%, age-dependent) and moderate systemic hypothermia (32°C–35°C) were used. Heparin was neutralized with protamine. Aprotinin (2.5–5 million KIE) was used in nearly all patients. Those with low cardiac output or needing adrenaline > 0.2 μg·kg−1·min−1 were given an intraaortic balloon pump (IABP).
For crystalloid cardioplegia (CCP), non-oxygenated Kirsch and Hamburg solutions were used, with Kirsch solution for induction and Hamburg solution for intermittent delivery (Table 1). 8,9 The first dose of 50–300 mL Kirsch solution was administered directly into the aortic root until cardiac arrest was achieved, followed by 600mL Hamburg solution. Subsequent doses were given at 30 min intervals. The cooled (icebox) crystalloid solution was administered by a roller pump and filtered with a 0.2 μm filter. For blood cardioplegia (BCP), the technique described by Calafiore and colleagues 10 was used, but the blood was cooled to 8°C–10°C (Table 2). Oxygenated blood was pumped by an occlusive roller pump from the cardioplegia outlet of the oxygenator into the aorta. A heat exchanger (Jostra HEC 44; Medizintechnik, Hierlingen, Germany) was positioned distal to the roller pump and contained a temperature port. The outlet of the bubble trap over the cardioplegia delivery system was connected to the line of the potassium perfusor (2 mol·mL−1 potassium) and there was a port for pressure monitoring. The cardioplegic solution was replenished at 20–30 min intervals. No topical cooling, retrograde perfusion, warm induction, or controlled reperfusion was used in either group.
Fresenius AG, Bad Homburg, Germany; unlike original Hamburg solution, no gentamicin, sodium bicarbonate, or oxygen was added. †Molecular weight 450 000.
Technique of Delivery of Blood Cardioplegia 10
Osmolarity of blood Cardioplegia: 290–310 mOsm·L−1
Univariate comparisons between groups were performed using the chi-squared test and Fisher's exact test for categorical data. Continuous variables were evaluated by the unpaired Student t-test or analysis of variance. Forward stepwise multivariate linear regression methods were used to determine predictors of postoperative CK-MB release. To study differences in the type of cardioplegia, a binary (dichotomous) encoding “isBPC” = 1 for BPC and 0 for CCP was employed. The expression “isBCP” follows the name convention of Boolean variables. By additionally feeding “isBCP” and its products with other variables to the stepwise regression analysis, knowledge was gained of significant response differences for all the independent variables with respect to cardioplegia type. The SPSS version 10.0 (SPSS, Inc., Chicago, IL, USA) package was used for the statistical tests.
Results
There was a higher percentage of patients with a low ejection fraction and more who received perioperative beta blockers in the BCP group. There was a higher incidence of renal dysfunction, unstable angina, peripheral arterial disease, and perioperative medication with calcium channel blockers in the CCP group. In the CCP group, the number of distal anastomoses was higher and the crossclamp times were longer (Tables 3 & 4). Because the two study groups differed in some preoperative and intraoperative variables, multivariate analysis was used to neutralize the effect of differences in patient profile on outcome variables. In addition, the impact of every individual variable on the crossclamp time-dependent CK-MB release in the CCP and BCP groups was assessed. There were no significant differences between the two groups in perioperative mortality, resuscitation, and postoperative arrhythmias. However, there was a trend towards less use of an IABP in the BCP group (Table 5). While CK-MB release was higher 90 min after bypass in the CCP group (18.3 ± 4.9 U·L−1 versus 15.7 ± 0.15 U·L−1; p < 0.05), no significant differences between the two groups were observed at 7 hours after bypass. After changing from CCP to BCP, the mean postoperative CK-MB levels decreased in the patients of 7 of the 8 surgeons (Figure 1). There was a linear correlation between aortic crossclamp time (ACT) and postoperative CK-MB release in both groups (p < 0.01 on analysis of variance). Figure 2 shows the significantly different trend lines together with the scatter plots for CK-MB versus crossclamp time. The linear regression lines cross close to 40 min. Beyond that time, BCP provided better myocardial protection than CCP.
After changing from crystalloid to blood cardioplegia, the mean postoperative creatine kinase-MB levels decreased in the patients of 7 of the 8 surgeons.
The significantly different trend lines together with the scatter plots of creatine kinase-MB (CK-MB) versus aortic crossclamp time. The linear regression lines cross close to 40 min. Beyond that time, blood cardioplegia provides greater myocardial protection than crystalloid cardioplegia.
Preoperative Patient Profiles
Last dose taken on the day of operation. ACE = angiotensin-converting enzyme; BCP = blood cardioplegia; CCP = crystalloid cardioplegia.
Intraoperative Parameters
BCP = blood cardioplegia;
CCP = crystalloid cardioplegia.
Outcome
BCP = blood cardioplegia;
CCP = crystalloid cardioplegia.
All preoperative and intraoperative variables were fed into the multivariate regression analysis (Tables 3 & 4) to determine which factors influenced postoperative CK-MB Release. To investigate the difference due to the type of cardioplegia, a stepwise regression process was undertaken with the dichotomous cardioplegia type encoding isBCP” and its products with all the input variables described above. Stepwise multivariate linear regression analysis identified several factors that correlated with postoperative CK-MB. Table 6 shows all variables that significantly affected post-bypass CK-MB release. It was found that the previous CK-MB versus ACT trend difference (Figure 2) was confirmed, since both the offset (isBCP) as well as the slope difference (isBCP × ACT) are included with p ≤ 0.01; crossclamp time was the only variable that correlated with the influence of cardioplegia type on CK-MB release. Furthermore, the slope difference (isBCP × ACT) was an independent predictor of CK-MB release 90 min after bypass.
Factors Affecting Post-Bypass CK-MB Release With p < 0.05 *
Result from stepwise forward linear regression analysis. Pearson regression coefficient (R) = 0.215; B = weighting in the multivariate regression analysis; CI = confidence intervals of B.
isBCP encodes the trend offset (isBCP = 1 for blood cardioplegia, 0 for crystalloid cardioplegia).
isBCP × ACT encodes the slope difference with respect to aortic crossclamp time between crystalloid and blood cardioplegia.
Discussion
The goal of this study was to demonstrate the increasing importance of the type of cardioplegia in longer aortic crossclamp times. There are various studies showing that postoperative CK-MB release was reduced when BCP was used instead of CCP. 2 –7 However, these studies did not consider important variables possibly influencing postoperative CK-MB release, such as creatinine clearance, hematocrit, leukocyte count, or perioperative use of calcium channel antagonists. Furthermore, they did not investigate the correlation of postoperative CK-MB release with aortic crossclamp time. A potential advantage of BCP over CCP for myocardial protection should become evident with increasing crossclamp time. The observation that cardioplegia type influenced differences in CK-MB release, developing only in correlation with aortic crossclamp time but with no other variable, confirms the hypothesis that the type of cardioplegia determines its protective effect on myocardium jeopardized by a longer clamping time. It has been shown that CK-MB release is a good marker of myocardial protection. 11 In contrast, outcome measurements are less valuable indicators of the protective effect of cardioplegia. 2,4 This is due to the fact that cases with a very long crossclamp time, where the impact of cardioplegia type becomes more important, are rare, and their outcome is influenced by numerous intraoperative and postoperative factors.
In this study, the postoperative use of an IABP was less frequent in the BCP group. Although this difference did not reach statistical significance, it should not be ignored, especially in view of the rarity of IABP use and the better preoperative ejection fraction in the CCP group. Apart from IABP use, there were no important differences in clinical outcome. There are some studies demonstrating a better outcome in patients receiving BCP, in terms of clinical parameters: significantly reduced inotropic support in the BCP group and higher mortality with CCP. 2,3,12 Blood cardioplegia was found to be particularly beneficial in patients with a low ejection fraction, and intensive care unit stay was shorter. 13 –15 Spontaneous resumption of cardiac rhythm after declamping the aorta was significantly higher in patients receiving BCP. 7 According to one report, the incidences of intraventricular conduction disturbances and atrial arrhythmias were significantly lower in the BCP group. 4 However, in another series, atrial fibrillation was higher in patients given BCP than in those given CCP. 12
Some studies have not addressed the clear advantage of BCP regarding clinical outcome; one group evaluated intraoperative left ventricular function and found no difference between BCP and CCP. 16 Another demonstrated that blood and crystalloid cardioplegia were similar regarding lactate metabolism after reperfusion, CK-MB release, and ventricular function. 17 The type of CCP used in these studies varied, making comparison of results difficult. Flack and colleagues 13 comparing CCP and BCP in a multicenter study, did not even differentiate subtypes of CCP. The principle of our CCP is that membrane stabilizers such as anesthetics and large amounts of magnesium slow down the decay of organic phosphates. Experimental studies showed satisfactory myocardial protection, comparable to Bretschneider and St. Thomas' Hospital cardioplegia solutions. 9 For BCP, most studies used hemodiluted blood in the ratio 4:1 or 2:1, enriched with citrate, phosphate, dextrose and/or Tris. 5,12 Because variables such as the composition of the cardioplegic solution, temperature, and parameters of infusion were not studied independently, the differences between CCP and BCP may not depend solely on the presence of red blood cells. 2 However, it is generally accepted that the increased capability of blood for oxygen delivery, buffering capacity, oncotic pressure, capillary flow distribution, and protection from free radicals are the cause of the observed differences between BCP and CCP. 2,6
We used pure blood without hemodilution and no adjuncts other than potassium. In cold BCP, the capability of oxygen delivery to the myocardium is still a matter of discussion. At lower temperatures, oxygen delivery to the myocardium is severely reduced due to a shift to the left of the hemoglobin dissociation curve. Thus, warm blood in continuous infusion or intermittent delivery seems to be gaining popularity. 10,18 However, there is little doubt that some myocardial uptake occurs during hypothermic BCP. The mild myocardial acidosis that develops during ischemic arrest favors the release of hemoglobin-bound oxygen. 19 On the basis of our results, it was concluded that intermittent delivery of cold hyperkalemic blood is safe, cost-effective, and very simple to handle. This reconfirms the importance of BCP as a basic step towards an integrated system of myocardial protection. 18,20 Beyond this, using data obtained from daily practice, the advantage of blood over crystalloid cardioplegia rises as the clamping time increases.
A limitation of this study was the fact that the two groups were operated on during two different periods of time. However, there were no differences in pharmacological management or surgical technique, apart from an increasing tendency to perform the proximal anastomosis with the aorta clamped. The decline of CK-MB was consistent for all surgeons (Figure 1). Considering that most had already had long experience before the area of BCP, the impact of a learning curve on myocardial protection from 1998 to 2001 is a remote possibility. We have had good experience with BCP since 1997 (more than 10000 patients), including some with severely hypertrophied myocardium and dilated ventricles. We observed similar slope differences of ACT-dependent CK-MB release. However, exact and fair comparisons to CCP in groups other than isolated CABG (valve replacements, reoperations) were not possible because we routinely use retrograde BCP in these cases.