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Asian Cardiovasc Thorac Ann 2004;12:115-120
© 2004 Asia Publishing EXchange Ltd

ORIGINAL CONTRIBUTION

Hyperkalemic Blood versus Crystalloid Cardioplegia in Longer Clamping Times

Alexander A Albert, MD, Bert Arnrich, MS1, Jörg A Walter, MD1, Wael M Hassanein, MD, Ulrich P Rosendahl, MD, Petra Gehle, MD, Frank Schön2, Jürgen Ennker, PhD

Clinic for Cardiothoracic Surgery
2 Department of Perfusion, Heart Institute Lahr/Baden, Germany
1 Institute of Neuroinformatics, University of Bielefeld, Germany

For reprint information contact: Alexander A Albert, MD Tel: 49 7821 925 226 Fax: 49 7821 925 253 Email: alexander.albert{at}heart-lahr.com Heart Institute Lahr/Baden, Hohbergweg 2, 77933 Lahr, Germany.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
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 1Go).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 colleagues10 was used, but the blood was cooled to 8°C–10°C (Table 2Go). 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.


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  		Table 1. Composition of Kirsch Solution for Induction and Hamburg Solution for Reperfusion8,9
 

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  		Table 2. Technique of Delivery of Blood Cardioplegia10
 
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
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
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 3Go & 4Go). 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 5Go). 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 1Go). 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 2Go 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.


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  		Table 3. Preoperative Patient Profiles
 

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  		Table 4. Intraoperative Parameters
 

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  		Table 5. Outcome
 


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  		Figure 1. After changing from crystalloid to blood cardioplegia, the mean postoperative creatine kinase-MB levels decreased in the patients of 7 of the 8 surgeons.

 


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  		Figure 2. 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.

 
All preoperative and intraoperative variables were fed into the multivariate regression analysis (Tables 3Go & 4Go) 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 6Go shows all variables that significantly affected post-bypass CK-MB release. It was found that the previous CK-MB versus ACT trend difference (Figure 2Go) was confirmed, since both the offset (isBCP) as well as the slope difference (isBCP x 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 x ACT) was an independent predictor of CK-MB release 90 min after bypass.


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  		Table 6. Factors Affecting Post-Bypass CK-MB Release With p < 0.05*
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
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 colleagues13 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 1Go). 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.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Robinson LA, Schwarz GD, Goddard DB, Fleming WH, Galbraith TA. Myocardial protection for acquired heart disease surgery: results of a national survey. Ann Thorac Surg 1995;59:361–72.[Abstract/Free Full Text]

  2. Barner HB. Blood cardioplegia: a review and comparison with crystalloid cardioplegia. Ann Thorac Surg 1991;52:1354–67.[Abstract]

  3. Codd JE, Barner HB, Pennington DG, Merjavy JP, Kaiser GC, Devine JE, et al. Intraoperative myocardial protection: a comparison of blood and asanguineous cardioplegia. Ann Thorac Surg 1985;39:125–31.[Abstract]

  4. Engelman RM, Rousou JA, Flack JE, Deaton DW, Liu X, Das D. A prospective randomized analysis of cold crystalloid, cold blood and warm blood cardioplegia for coronary revascularization. In: Engelman RM, Levitsky S, editors. A textbook of cardioplegia for difficult clinical problems. Mt Kisco, NY: Futura, 1992:159–71.

  5. Fremes SE, Christakis GT, Weisel RD, Mickle DAG, Madonik MM, Ivanov J, et al. A clinical trial of blood and crystalloid cardioplegia. J Thorac Cardiovasc Surg 1984;88:726–41.[Abstract]

  6. Lapenna D, Mezzetti A, de Gioia S, Pierdomenico SD, Verna AM, Daniele F, et al. Blood cardioplegia reduces oxidant burden in the ischemic and reperfused human myocardium. Ann Thorac Surg 1994;57:1522–5.[Abstract]

  7. Rinne T, Pehkonen E, Kaukinen S, Tarkka M. Comparison of cardioprotection with crystalloid and blood cardioplegia in CABG patients. J Cardiothorac Vasc Anesth 1993;7:679–83.[Medline]

  8. Kirsch U, Rodewald G, Kalmár P. Induced ischemic arrest. Clinical experience with cardioplegia in open-heart surgery. J Thorac Cardiovasc Surg 1972;63:121–30.[Medline]

  9. Schaper J, Scheld HH, Schmidt U, Hehrlein F. Ultrastructural study comparing the efficacy of five different methods of intraoperative myocardial protection in the human heart. J Thorac Cardiovasc Surg 1986;92:47–55.[Abstract]

  10. Calafiore AM, Teodori G, Mezzetti A, Bosco G, Verna AM, Di Giammarco G, et al. Intermittent antegrade warm blood cardioplegia. Ann Thorac Surg 1995;59:398–402.[Abstract/Free Full Text]

  11. Farah SY, Moss DW, Ribeiro P, Oakley CM, Sapsford RN. Interpretation of changes in the activity of creatine kinase MB isoenzyme in serum after coronary artery bypass grafting. Clin Chim Acta 1984;141:219–25.[Medline]

  12. Wandschneider W, Winter S, Thalmann M, Howanietz N, Deutsch M. Crystalloid versus blood cardioplegia in coronary bypass surgery. A prospective, randomized, controlled study in 100 consecutive adults. J Cardiovasc Surg (Torino) 1994;25(Suppl 1):85–9.

  13. Flack JE 3rd, Cook JR, May SJ, Lemeshow S, Engelman RM, Rousou JA, et al. Does cardioplegia type affect outcome and survival in patients with advanced left ventricular dysfunction? Results from the CABG Patch Trial. Circulation 2000;102(Suppl III):84–9.

  14. Roberts AJ, Moran JM, Sanders JH, Spies SM, Lichtenthal PR, Kaplan KJ, et al. Clinical evaluation of the relative effectiveness of multidose crystalloid and cold blood potassium cardioplegia in coronary artery bypass graft surgery: a non-randomized matched-pair analysis. Ann Thorac Surg 1982;33:421–33.[Abstract]

  15. Loop FD, Higgins TL, Panda R, Pearce G, Estafanous FG. Myocardial protection during cardiac operations. J Thorac Cardiovasc Surg 1992;104:608–18.[Abstract]

  16. Shapira N, Kirsh M, Jochim K, Behrendt DM. Comparison of the effect of blood cardioplegia to crystalloid cardioplegia on myocardial contractility in man. J Thorac Cardiovasc Surg 1980;80:647–53.[Abstract]

  17. Buttner EE, Karp RB, Reves JG, Oparil S, Brummett C, McDaniel HG, et al. A randomized comparison of cold blood and cold crystalloid and blood-containing cardioplegic solutions in 60 patients. Circulation 1994;69:973–8.

  18. Nicolini F, Beghi C, Muscari C, Agostinelli A, Maria Budillon A, Spaggiari I, et al. Myocardial protection in adult cardiac surgery: current options and future challenges. Eur J Cardiothorac Surg 2003;24:986–93.[Abstract/Free Full Text]

  19. Tait GA, Booker PD, Wilson GJ, Coles JG, Steward DJ, MacGregor DC. Effect of multidose cardioplegia and cardioplegic solution buffering on myocardial tissue acidosis. J Thorac Cardiovasc Surg 1982;83:824–9.[Abstract]

  20. Buckberg G. Overview: procedure versus protection: an impossible separation. Semin Thorac Cardiovasc Surg 2001;13:29–32.[Medline]





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