Ann Thorac Surg 1997;63:689-696
© 1997 The Society of Thoracic Surgeons
Original Article: Cardiovascular
Assessment of Continuous Cold Blood Cardioplegia in Coronary Artery Bypass Grafting
Yves A. G. Louagie, MD,
Emmanuel Gonzalez, MD,
Jacques Jamart, MD,
Brigitte Malhomme, MSc,
Serge Broka, MD,
Michel Buche, MD,
Philippe M. Eucher, MD,
Jean-Claude Schoevaerdts, MD
Units of Cardiovascular and Thoracic Surgery, Intensive Care, Biostatistics, and Anesthesiology, University Hospital of Mont-Godinne (Catholic University of Louvain), Mont-Yvoir, Belgium
Accepted for publication October 7, 1996.
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Abstract
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Background. A method of cold blood cardioplegia (CBCP) delivered continuously and in a retrograde manner was compared with methods differing only by their rate (intermittent) or way (antegrade) of administration.
Methods. This study comprises 298 consecutive patients undergoing isolated coronary artery bypass grafting procedures performed by the same surgeon from 1992 to 1995. Three-vessel disease characterized 58.8% of the cases, and the left ventricular ejection fraction was less than 0.40 in 22.8%. In group I (n = 100), CBCP was administered in an antegrade and intermittent fashion; in group II (n = 87), CBCP was given in a retrograde and intermittent manner; in group III (n = 111), CBCP delivery was retrograde and continuous.
Results. The incidence of major cardiac adverse outcome (death or need for intraaortic balloon counterpul-sation) was 7.0% in group I, 8.0% in group II, and 0.9% in group III (p = 0.040). Repeated-measures analysis of hemodynamic indices showed a marked superiority of continuous retrograde compared with antegrade intermittent blood cardioplegia regarding left ventricular stroke work index (p < 10-4) and compared with both methods of intermittent CBCP regarding right ventricular stroke work index (p < 10-5).
Conclusions. The use of continuous CBCP resulted in a significant reduction in major cardiac events, better left ventricular performance, and a marked improvement of right ventricular function in comparison with similar solutions of blood cardioplegia administered intermittently, independent of their way of delivery.
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Introduction
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Continuous cold blood cardioplegia (CBCP) has been rarely studied in coronary artery bypass grafting (CABG). Johnson and associates [1] demonstrated in an experimental study using pigs that continuous retrograde coronary sinus perfusion can reduce myocardial acidosis during ischemia. Bomfim and co-workers [2] showed in two groups of patients undergoing aortic valve replacement that the myocardial protection afforded by continuous 15°C blood cardioplegia administered into the coronary ostia was superior to that of the single-dose group. Later, Khuri and associates [3] showed by intraoperative monitoring of myocardial pH in patients undergoing valve replacement that continuous CBCP administered through the left main ostium and through the completed coronary bypass grafts provided better metabolic protection of the hypertrophied human heart than either intermittent crystalloid or intermittent blood cardioplegia.
Conversely, much attention has been given to the use of continuous warm blood cardioplegia. Because warm cardioplegia must be administered at a minimum rate of 80 mL/min [4], it is not administered in a continuous manner, but is interrupted when coronary visualization is inadequate. That frequent interruptions of warm cardioplegia during long aortic cross-clamp periods are not detrimental to the human heart awaits further demonstration. Moreover, there is experimental evidence that interrupting warm blood cardioplegia diminishes its effectiveness and results in increased ischemic damage [5]. On the other hand, cold blood cardioplegia requires a much slower rate of delivery and can be administered uninterrupted, as the coronary backflow can be managed easily by recent technical means.
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Patients and Methods
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Patient Population
This study comprises 298 patients who underwent isolated CABG procedures between January 20, 1992 and March 29, 1995. All of the patients underwent isolated coronary artery operations under the care of the same surgeon (Y.L.). Three consecutive groups of patients undergoing CABG with three different techniques of administration of CBCP were compared. In the first group (n = 100), cardioplegia was administered intermittently and in an antegrade fashion; in the second group (n = 87), cardioplegia was given intermittently and in a retrograde manner; in the third group (n = 111), cardioplegia was administered continuously and in a retrograde manner. The patients did not differ significantly regarding age, sex distribution, and the principal risk factors as described in Table 1
. The only significant difference was a larger proportion of patients with three-vessel disease in the first group. This factor is taken into account in the analyses. There was a trend toward a higher frequency of urgent cases in the third group.
Surgical Technique
The conduct of the operation, apart from the technique of cardioplegia, did not differ markedly among the groups. The left internal thoracic artery (ITA) was used liberally; 97.4% of the patients had at least one ITA implantation and 23.5% had bilateral ITA implantation. The median number of anastomoses was three. The mean aortic cross-clamp time was 78.0 ± 1.2 minutes, and the mean pump time was 123.6 ± 1.8 minutes. The minimal esophageal temperature was 26.5° ± 0.1°C, and the minimal rectal temperature was 28.1° ± 0.1°C. Intraoperative assessment of coronary artery bypass grafts using a pulsed Doppler flowmeter was done systematically. The technique of flow measurement and its validation were described previously [6]. The flow in the ITA and saphenous vein grafts was measured on bypass immediately after completion of the proximal anastomoses while the patient was rewarmed to 36°C rectal temperature. Flow measurements were done in 91.4%, 88.6%, and 90.9% of the grafts in groups I, II, and III, respectively (not significant).
An intraaortic balloon pump was inserted if the patient could not be weaned from cardiopulmonary bypass (CPB) despite the administration of dopamine or dobutamine at doses greater than 5 µg·kg-1·min-1 or adrenaline at any dosage.
Cardioplegic Groups and Protocol for Delivery of Cardioplegic Solution
GROUP I.
Group I included 100 patients operated on between January 20, 1992 and December 29, 1992. Immediately after aortic cross-clamping, rapid initial arrest was obtained by instillation of 500 mL of 4°C crystalloid cardioplegia solution while the blood cardioplegia system was primed. The blood cardioplegia solution was then infused through a roller pump into the aortic root at a flow rate of 250 mL/min over 2 minutes. The cardioplegic delivery system consisted of disposable tubing to deliver a 4:1 blood/crystalloid cardioplegia ratio (HE 100 heat exchanger; American Bentley Hospital Supply Corp, Irvine, CA). The composition of the blood cardioplegic solution was as follows: Na, 138.9 ± 0.9 mEq/L; K, 8.5 ± 0.5 mEq/L; Ca, 7.0 ± 0.2 mEq/L; HCO3, 19.3 ± 0.3 mEq/L; osmolarity, 305.2 ± 2.0 mOsm/L; pH, 7.34 ± 0.01; hemoglobin, 6.1 ± 0.4 g/100 mL; hematocrit, 0.17 ± 0.01; partial pressure of oxygen, 248.3 ± 31.6 mm Hg; and partial pressure of carbon dioxide, 33.1 ± 1.0 mm Hg. The temperature of the perfusate was 8.0° ± 0.3°C and the temperature of the septum was 11.1° ± 0.7°C. The tubing was attached to a coronary cardioplegic adapter containing four limbs that allows simultaneous cardioplegic distribution into the aorta and into the vein grafts (CDS-004; Research Medical, Inc, Midvale, UT). Reinfusion into the vein grafts and the aortic root was done after each distal anastomosis at a flow rate of 250 mL/min for 2 minutes. Early progressive reperfusion through the vein grafts was started by connecting one limb of the cardioplegic connector to the arterial cannula before the aorta was unclamped.
GROUP II.
Group 2 comprised 87 patients operated on between December 31, 1992, and January 20, 1994. The blood cardioplegic solution and rate of administration were similar to those in group I, but the solution was delivered in a retrograde fashion through a catheter inserted into the coronary sinus (94115ST Gundry RCSP Cannula; DLP, Inc, Grand Rapids, MI). The initial 500-mL bolus of crystalloid cardioplegia used to obtain immediate diastolic arrest was maintained.
GROUP III.
Group III included 111 patients operated on between February 10, 1994, and March 29, 1995. Cardiac arrest was obtained in the same way by an initial bolus of 500 mL of antegrade 4°C crystalloid cardioplegia followed by a bolus of 500 mL of retrograde 8°C blood cardioplegia. Thereafter, cold blood cardioplegia was administered in a retrograde and continuous fashion at a rate of 50 mL/min. We used a microblower (Visuflo; Research Medical, Inc) delivering 6 L/min of compressed air passing through a 20-µm filter to blow blood away while completing the distal anastomoses. This has proved most effective.
The temperature of infusate was set at 18°C, but it was reduced to 8°C if complete cardiac arrest was not obtained, using a heater-cooler (Bentley HE-30 Gold Heat Exchanger; Baxter Healthcare Corporation, Bentley Division, Irvine, CA). To avoid hemodilution due to larger amounts of cardioplegia infused, we used a cardioplegia delivery system consisting of a disposable tubing with an 8:1 blood/cardioplegia ratio (Bentley Custompac Cardioplegic Set; Bentley Laboratories Europe, Ad Uden, Holland) in the last 43 patients. The potassium concentration of the crystalloid solution was adapted to obtain a final kalemia in the cardioplegic solution of 10 to 12 mEq/L. The composition of the perfusate, particularly kalemia and hemoglobinemia, remained very stable throughout the period of aortic cross-clamping. The total amount of crystalloids used in combination with blood was 858.9 ± 31.0 mL for the 68 patients having the 4:1 blood/cardioplegia delivery tubing and 338.9 ± 19.4 mL for the 43 patients having the 8:1 blood/cardioplegia delivery tubing. After each completed distal anastomosis, a bolus of retrograde blood cardioplegia was administered at a rate of 250 mL/min during 2 minutes. While the last anastomosis was completed, the temperature of the perfusate was gradually increased to 37°C. Before the aorta was unclamped, a final "hot shot" of 37°C noncardioplegic blood was administered in a retrograde manner for 4 minutes. The principal steps of continuous cardioplegia delivery are depicted in Figure 1; the composition and precise conditions of administration are presented in Table 2.
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Fig 1. . Our technique of administration of continuous cold blood cardioplegia. The initial bolus of St. Thomas' cardioplegia is delivered in an antegrade fashion, whereas the following cardioplegia solutions are given in a retrograde manner.
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Enzymatic Determinations
Venous blood samples were taken for determination of total creatine kinase (CK), creatine kinase myocardial isoenzyme (CK-MB), and lactate dehydrogenase isoenzyme (LDH) at 0, 4, 12, 24, and 48 hours after admission to the intensive care unit. Patients having perioperative myocardial infarction obviously related to malfunction of a bypass graft were excluded from the analysis. In addition, patients having delayed (>21 hours) CK-MB elevation were excluded from the analysis because it was demonstrated [7] that the later enzymatic elevation is caused by myocardial infarction rather than by inadequate myocardial protection. Thus, a total of 10 patients (3.4%) were excluded from the analysis for the aforementioned reasons.
Hemodynamic Measurements
The following hemodynamic data were obtained: mean arterial pressure, mean pulmonary arterial pressure, pulmonary capillary wedge pressure, right atrial pressure, and heart rate. Thermodilution cardiac output was measured in triplicate using a Hellige CO computer (Freiburg Im Breisgau, Germany). From these data, we calculated cardiac index, systemic and pulmonary vascular resistance, and right and left ventricular stroke work index (RVSWI, LVSWI) using standard formulas. The hemodynamic measurements were repeated before aortic cannulation (pericardial incision), at the end of the operation after reversal of heparin, and 2, 6, 8, and 20 hours after CPB. The relation between the left and right ventricular stroke work indices and the corresponding preload determinations was evaluated.
Data Analysis
Perioperative data were collected and entered prospectively into the cardiovascular surgery clinical research database by the surgeon. Postoperative data were collected by a data manager (B.M.). Values are presented as mean ± standard error of the mean. Clinical data were compared by one-way analysis of variance, 
2 test, or Fisher's exact test when appropriate. Data obtained repeatedly, such as hemodynamic and enzymatic determinations, were compared by regression analysis of repeated measures using generalized estimating equations, as described by Liang and Zeger [8]. The latter analysis allows one to take into account simultaneously the influence of the initial value, time, and between-subject categoric variable(s). Paired sets of the stroke work and the corresponding filling pressure were compared between groups by Hotelling's T2 test, a multivariate generalization of the univariate t value. Logistic regression analysis was done with forward selection of variables using the Wald test at 0.05 entry and 0.10 exclusion levels to identify factors that independently influenced the occurrence of supraventricular arrhythmias. All statistical analyses were performed using the SPSS (SPSS Inc, Chicago, IL) software package except for the repeated-measures regression analysis, for which the RMGEE program was used [9].
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Results
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Influence of Method of Cardioplegia on Operative Technique
Grafts were considered dysfunctional if flow determined by intraoperative Doppler measurement was less than 10 mL/min. This was the case for 3.1% of the anastomoses in group I, 3.9% in group II, and 1.4% in group III (not significant). An additional saphenous vein graft had to be implanted distal to a dysfunctional ITA graft in 1 case in group II (0.4%) and in 2 cases in group III (0.6%) (not significant). Finally, a distal anastomosis had to be reconstructed on two occasions (0.6%) in group I, in 1 case (0.4%) in group II, and in 1 case (0.3%) in group III (not significant). Hence, there is no evidence that the uninterrupted delivery of cardioplegia altered the quality of the operative anastomoses. In addition, the use of a microblower did not seem to favor the continuous-cardioplegia group by improving vision.
Aortic cross-clamping time was 78.1 ± 1.9 minutes for continuous CBCP and 77.9 ± 1.5 minutes for the two groups of intermittent CBCP (not significant). Finally, pump time was shorter in the continuous CBCP group (116.5 ± 2.7 versus 127.8 ± 2.4 minutes; p = 0.002).
Early Outcome
Early outcome was characterized by the absence of hospital death and a significantly reduced incidence of major adverse cardiac events (combination of hospital death and CPB and post-CPB intraaortic balloon pump implantation) in the continuous CBCP group (Table 3). The incidence of relevant complications did not differ among the groups except for a higher rate of supraventricular arrhythmias in the continuous-cardioplegia group. Because cardioplegia was administered in that group at either 8° or 18°C, the effect of temperature was tested independently. The patients undergoing blood cardioplegia at 8°C had an incidence of supraventricular arrhythmias of 19.6% (43/219), versus 34.2% (27/79) in the 18°C continuous-cardioplegia group (p = 0.009). A logistic regression analysis was performed using the end point of postoperative supraventricular arrhythmia. Besides the type of cardioplegia, the following covariates were investigated: age, sex, cardioplegia temperature, hypertension, diabetes, smoking habits, dyslipidemia, renal insufficiency, obesity, chronic pulmonary obstruction, history of previous infarction (recent, old), New York Heart Association functional class, need for preoperative intravenous nitrates, urgency of operation, number of vessels diseased, left ventricular dysfunction, number of ITAs used, number of anastomoses performed, esophageal temperature during CPB, and aortic cross-clamping time. The analysis identified two independent variables: temperature of cardioplegia and diabetes. These results suggest that cardioplegia temperature, rather than administration rate (continuous or intermittent), influences the occurrence of supraventricular arrhythmias.
Inotropic drug support did not differ among the groups except for a lower incidence of dobutamine administration in the continuous-cardioplegia group on the day of admission in the intensive care unit (Table 4).
Enzymatic Determinations
The independent influence of techniques of blood cardioplegia administration on myocardial enzyme release was assessed by comparing the enzymatic trends obtained after using antegrade, retrograde, and continuous cardioplegia at 8°C, with continuous blood cardioplegia at 18°C taken as reference. Furthermore, time interval, number of diseased vessels, number of ITAs used, and volume of autotransfusion were included as covariates (Table 5).
Among the techniques of blood cardioplegia delivery, only intermittent retrograde cardioplegia was associated with an increased release of CK-MB enzymes by comparison with continuous cardioplegia given at 18°C. The percentage of CK-MB isoenzymes, however, was not influenced by any technique of blood cardioplegia delivery. On the other hand, as time elapsed after CPB, total CK release tended to increase, whereas CK-MB concentrations tended to diminish (Fig 2). Bilateral ITA grafting increased the release of total CK and CK-MB isoenzymes, and the amount of autotransfusion increased the release of lactate dehydrogenase, total CK, and CK-MB isoenzymes.
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Fig 2. . Myocardial enzyme release from admission in the intensive care unit. Data are shown as mean ± standard error. ( CK = total creatine kinase; CK MB = creatine kinase myocardial isoenzyme.)
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Hemodynamic Measurements
Determinations of LVSWI and RVSWI made at different intervals and expressed as a percentage of values before CPB are shown in Figure 3. The results of the two continuous-cardioplegia groups were superior for all time periods with regard to LVSWI. Likewise, the results of RVSWI were markedly higher in the continuous-cardioplegia groups.
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Fig 3. . Left ( LVSWI) and right (RVSWI) ventricular stroke work index expressed as percentage of the pre–cardiopulmonary bypass (CPB) value. Data are mean ± standard error of the mean.
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Nevertheless, a simple intergroup comparison of the repeated measurements not taking into account indices such as the pre-CPB value of the variable, aortic cross-clamping duration, inotropic drug administration, and intraaortic balloon pump use would be meaningless. Therefore, the outcomes of the hemodynamic indices for the three techniques of blood cardioplegia were compared with 18°C continuous cardioplegia chosen as a reference, using the generalized estimating equation approach (Table 6), and relevant covariates were included. Besides the type of cardioplegia, predetermined variables considered were preoperative intraaortic balloon pump insertion, preoperative value of the hemodynamic index assessed, and aortic cross-clamp time. Time-related covariates were postoperative interval, influence of intra- or postoperatively inserted intraaortic balloon pump, and inotropic drug support. Regarding LVSWI, only antegrade cardioplegia showed inferior results in comparison with continuous 18°C cardioplegia. The RVSWI was negatively influenced by intermittent cardioplegia (antegrade and retrograde). Aortic cross-clamping duration negatively influenced both LVSWI and RVSWI, but principally LVSWI. The postoperative outcome of every variable was determined in terms of its pre-CPB value. Preoperative insertion of an intraaortic balloon pump reduced significantly the calculated systemic and pulmonary vascular resistance, whereas its later implantation had no influence on these indices. Inotropic drug support was associated with a significant reduction of LVSWI and an increase of pulmonary vascular resistance, highlighting the left ventricular dysfunction that required the drug administration. In contrast, inotropic drug support was associated with an increase in RVSWI.
The relation between LVSWI and pulmonary capillary wedge pressure after CPB is depicted in Figure 4. Stroke work was significantly greater with continuous 8°C retrograde cardioplegia 2 hours after CPB. Because the wedge pressure was lower, the shift of the left ventricular performance curve upward and to the left after continuous 8°C cardioplegia was unlikely to have resulted from an increase in preload. The relation between RVSWI and right atrial pressure is depicted in Figure 5. The right ventricular stroke work indices were superior after continuous cardioplegia (8° or 18°C) compared with intermittent cardioplegia, with similar right atrial pressures 2, 6, 8, and 20 hours after CPB.
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Fig 4. . Relation between the left ventricular stroke work index ( LVSWI) and the pulmonary capillary wedge pressure (PCWP) 2, 6, 8, and 20 hours after cardiopulmonary bypass. (ns = not significant.)
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Fig 5. . Relation between the right ventricular stroke work index ( RVSWI) and the central venous pressure (CVP) 2, 6, 8, and 20 hours after cardiopulmonary bypass.
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Comment
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The present study demonstrates a significant reduction of major adverse cardiac events associated with the use of continuous retrograde blood cardioplegia. Indeed, the incidence declined from 7.0% and 8.0%, respectively, after intermittent antegrade and retrograde cardioplegia, to 0.9% after continuous cardioplegia. The patient population was homogeneous regarding most relevant risk factors. The only exception was a higher incidence of three-vessel disease observed in the group of patients undergoing antegrade cardioplegia. Nevertheless, the marked difference in the incidence of major adverse outcome was maintained between the intermittent and continuous retrograde cardioplegia groups despite a similar frequency of three-vessel disease.
The same continuous monitoring was used throughout the study to detect supraventricular arrhythmias, and only arrhythmias requiring pharmacologic treatment were considered in the analysis. The higher rate of supraventricular arrhythmias observed after CABG with continuous cardioplegia was related to the temperature of the perfusate, as demonstrated by univariate and multivariate analyses. Nevertheless, the latter incidence compares with an average rate of 32% of supraventricular arrhythmias after isolated CABG as noted in large study groups [10]. The hypothesis of the independent influence of cardioplegic perfusate temperature is in accordance with early clinical studies designating inadequate atrial preservation as a cause of early supraventricular arrhythmia [11, 12]. Moreover, normothermic cardioplegia did not reduce the rate of postoperative supraventricular arrhythmias in comparison with cold blood cardioplegia (40.0% with warm versus 42.4% with cold) [13]. The same conclusions were reached after a clinical study comparing cold potassium cardioplegia with intermittent aortic cross-clamping at a systemic temperature of 32°C [14].
Myocardial enzyme data showed a significant influence of intermittent retrograde cardioplegia on CK-MB isoenzyme release in comparison with continuous 18°C cardioplegia administration. In addition, myocardial enzyme release was influenced by the volume of autotransfusion, the number of diseased vessels, and bilateral ITA grafting. It was shown that autotransfusion after CABG increased circulating levels of CK and lactate dehydrogenase [15]. We demonstrated in the present series that autotransfusion affected simultaneously lactate dehydrogenase, CK, and CK-MB levels. The influence of bilateral ITA grafting is not surprising given the greater muscular insult associated with the harvesting of these arteries. Hence, the influence of the type of cardioplegia on myocardial enzyme release was overshadowed by other variables.
The rate of administration of cardioplegia (continuous or intermittent) seemed to matter more than the way of administration (antegrade or retrograde). A significant superiority of continuous retrograde cardioplegia over intermittent antegrade cardioplegia was evident for LVSWI. Moreover, hearts protected by continuous cardioplegia infused at 8° or 18°C had a better RVSWI postoperatively, and this was indirectly corroborated by a reduced need for dobutamine support on the day of admission to the intensive care unit. These differences did not result from an increase in preload, as demonstrated by assessing the relation between stroke work indices and atrial filling pressures. Moreover, systemic vascular resistance after CPB was not affected by the technique of cardioplegia.
Protection of the right ventricle has been a concern with retrograde cardioplegia given the limited retrograde perfusion of the right ventricle and posterior septum, as demonstrated in human explanted hearts [16, 17] and by contrast echocardiography [18]. Moreover, Mullen and associates [19] demonstrated that blood cardioplegia provided excellent protection for the left ventricle, but that crystalloid cardioplegia produced colder right ventricular temperatures and better postoperative right ventricular function. This major drawback of intermittent retrograde cardioplegia was overcome by a continuous perfusion through the same route. The present method, by allowing a larger volume of blood to reach the right ventricle, probably compensates for the amount of cardioplegia shunted by thebesian veins into the ventricles.
Our results should be interpreted cautiously. Indeed, three study groups represented by three different time periods were considered. We attempted to compensate for differences in treatment by using multifactorial analyses applied to patients operated on by the same surgeon. Nevertheless, we can conclude from the present pilot study that continuous retrograde cardioplegia is a reliable method of myocardial protection. Within the limits of the presently described conditions of administration, the latter technique allows the realization of precise coronary anastomoses. In this nonrandomized study, continuous retrograde cardioplegia was associated with a significant reduction in major postoperative cardiac adverse events, a trend toward better left ventricular performance, and a marked improvement of right ventricular function. Yet, a prospective randomized study comparing intermittent and continuous retrograde blood cardioplegia and investigating perioperative ventricular performance is needed to confirm these early observations.
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Footnotes
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Address reprint requests to Dr Louagie, Cardiovascular and Thoracic Surgery, University Clinics of Mont-Godinne, 1 av Therasse, B-5530 Mont-Yvoir, Belgium.
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References
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Abstract
Introduction
