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Eur J Cardiothorac Surg 1999;15:67-74
© 1999 Elsevier Science NL
a Department of Cardiothoracic Surgery, University of Cologne; Joseph Stelzmannstr. 9, 50924 Cologne, Germany
b Department of Cardiology, University of Cologne; Joseph Stelzmannstr. 9, 50924 Cologne, Germany
c Department of Anesthesiology, University of Cologne; Joseph Stelzmannstr. 9, 50924 Cologne, Germany
d Department of Pharmacology, University of Cologne; Joseph Stelzmannstr. 9, 50924 Cologne, Germany
Received 22 September 1998; received in revised form 10 November 1998; accepted 25 November 1998.
Corresponding author. Tel.: +49-221-478-6043; fax:+49-221-478-5906; e-mail: ferdinand.kuhn-regnier@medizin.uni-koeln.de
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Abstract |
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 Top Abstract Introduction
Materials and methodsResults
Discussion
Conclusions
Appendix A. Conference...References |
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Key Words: Beta-blocker • Esmolol • Myocardial protection • Blood cardioplegia • Coronary surgery • Intercellular adhesion molecule • Cardiopulmonary bypass
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Introduction |
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TopAbstractIntroduction
Materials and methodsResults
Discussion
Conclusions
Appendix A. Conference...References |
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Crystalloid cardioplegia has been shown to be associated with anaerobic myocardial metabolism and edema formation which leads to impaired cardiac function and prolonged myocardial recovery after cardiac surgery [2] [3] [4] [5] [6] [7]. Even blood cardioplegia has been shown to result in impaired left ventricular (LV) function [8] [9] [10] [11] [12].
Considering the changing profile of CABG patients with an increased perioperative risk [13] [14] [15] the major goal of myocardial protection during CABG should be a further reduction of ischemic periods.
The insight that both above mentioned broadly applied protection techniques show important disadvantages brought us to the technique of continuous perfusion of the coronary arteries with normothermic ß-blocker-enriched blood, herewith inducing a hypocontractile, slow beating heart and avoiding ischemia.
This technique was first described by Sweeney and Frazier who applied the ultrashort acting ß-blocker esmolol (half-life: 7–9 min) systemically to create surgical conditions on a continuously oxygenated and substrate provided beating heart [16]. The ß-blocker technique combines avoidance of ischemia by continuous perfusion with the application of a cardioprotective agent, herewith reducing oxygen demand [17]. In addition, experimental work demonstrated that the persistence of minimal cardiac contraction supports myocardial lymphatic function resulting in reduced myocardial edema formation [17].
One problem associated with this technique is bleeding from the incised coronary artery resulting in impaired anastomosis vision. To overcome this drawback we used intracoronary shunt tubes which ensure a bloodless surgical field with optimal anastomosis vision and simultaneously maintain blood flow to the peripheral myocardium beyond the anastomosis [18].
In a recent prospective randomized clinical study we demonstrated the superiority of the ß-blocker technique in CABG patients compared to Bretschneider's crystalloid cardioplegia [18]. The purpose of our present study was to compare the impact of the ß-blocker technique versus Buckberg's blood cardioplegia on myocardial protection and postoperative LV function in routine CABG patients.
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Materials and methods |
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TopAbstractIntroduction
Materials and methodsResults
Discussion
Conclusions
Appendix A. Conference...References |
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Hemodynamic monitoring
Catheters were placed into the radial artery, the central and at least one peripheral vein as well as into the pulmonary artery (Swan–Ganz thermodilution catheter) after endotracheal intubation. Patients were ventilated (Servo 900 C, Siemens) with 50% oxygen in room air in a volume controlled modus: 10–12 respirations/min, 100–150 ml/kg body weight per min. Ventilation was modified in accordance to arterial blood gas analyses. Thereafter, a 5 MHz transesophageal echocardiography (TEE) probe (Vingmed CFM 800®, Sonotron, Horten, Norway) was positioned into the esophagus. For coronary sinus blood sampling a 5F catheter was introduced into the coronary sinus via the right atrium. To ease coronary sinus blood withdrawal, we cut several holes at the tip of this catheter prior to placement in the coronary sinus.
Operative procedures
All 60 patients were operated by the same surgeon. Following standard surgical preparation a median sternotomy, preparation of the internal mammary artery and the saphenous vein was performed. Heparin (300 IU/kg body weight) was injected followed by cannulation of the ascending aorta (aortic cannula 6.5 mm, Stöckert Instruments, Munich, Germany) and venous cannulation by a 36/51F two stage cannula (Jostra Medizintechnik, Hirrlingen, Germany) into the right atrium and vena cava inferior. A vent was placed into the left ventricle via the right upper pulmonary vein and left atrium.
Cardiopulmonary bypass (CPB) circuit (HLM-CAPS®, Stöckert Instruments, Munich, Germany) and the membrane oxygenator (Maxima®, Medtronic, Düsseldorf, Germany) were primed with 1500 ml Ringer's solution, 500 ml oxypolygelatine (Gelifudol®, Biotest Pharma, Dreieich, Germany), 100 mEquiv. sodium bicarbonate, and 2000 IU heparin. During CPB we maintained a systemic flow of 2.2–2.6 l/min per m2. Mean arterial pressure was kept between 50 and 70 mmHg and norfenefrine (Novadral®, Gödecke, Berlin, Germany) was administered as required. Normothermia was kept in both groups.
The aorta was then cross-clamped. After institution of surgical conditions i.e.: hypocontractile bradycardia in the ES group and cardiac arrest in the BC group (for details see below) distal coronary artery anastomoses were performed. Proximal bypass anastomoses were completed after aortic cross-clamp removal. For weaning off CPB in all patients dopamine at 3 µg/kg per min was started and titrated as required to maintain stable hemodynamics. Following decannulation and sternal closure the intubated patients were transferred to the intensive care unit (ICU).
Myocardial protection in the ß-blocker, esmolol-group (ES)
After aortic cross-clamp in 30 patients the coronary arteries were perfused with oxygenated normothermic CPB blood via an aortic root cannula (Medtronic DLP, Grand Rapids, MI) with a pressure monitoring line. Perfusion pressure was kept at 50–70 mmHg. Initially, a bolus of 100 mg esmolol (Brevibloc®, Gensia Europe, UK) was added to the blood followed by continuous esmolol infusion at 10–15 mg/min dependent on the degree of contractility and heart rate. By this method a flaccid and hypocontractile heart, beating at a rate of about 40/min was obtained. Different methods were applied to remove blood from the operating field.
Dependent on the diameter of the coronary arteries which must be greater than 1.5 mm, intravascular shunts (Intravascular arteriotomy cannula®, Medtronic, Grand Rapids, MI) were inserted into the incised coronary arteries to prevent bleeding out of the vessel and to maintain blood flow through the shunt to the peripheral myocardium.
In case of smaller coronary arteries and sufficient retrograde blood flow through the coronary arteries vessel occluders were applied.
In addition, tip suckers, saline rinse, or filtered room air blowers were used to remove blood out of the operating field.
After accomplishment of the peripheral anastomoses the aortic cross-clamp was released and the aortic root perfusion discontinued. Hearts returned rapidly to normal heart rate. Patients were then weaned off CPB.
Myocardial protection in the blood-cardioplegia group (BC)
In accordance with the propositions of Buckberg
[19]
[20]
[21] hearts of the other 30 patients were protected by an antegrade cold blood cardioplegia. After aortic cross-clamp we started with a antegrade high potassium cold induction (Dr. F. Köhler Chemie, Alsbach-Hähnlein, Germany), continued with antegrade cold low potassium reperfusion every 20 min, and gave an antegrade warm low potassium reperfusion (hot-shot) prior to reopening of the aortic cross-clamp. Except three hearts which went into ventricular fibrillation, all remaining hearts resumed spontaneous sinus rhythm. Patients were then weaned off CPB.
Measurements
After median sternotomy and pericardiotomy and prior to aortic cannulation baseline measurements of hemodynamics and left ventricular (LV) contractility as well as metabolic parameters were recorded. Five milliliters of arterial and coronary sinus blood were taken for blood gas analysis and determination of the arterio-coronary sinus lactate difference. A transmural biopsy from a fat free region of the LV anterior wall was collected using a 14G biopsy needle (Tru-Cut®, Baxter Healthcare Corp., Deerfield, IL). Thereafter, CPB and myocardial protection were established as described above. In the ß-blocker group, simultaneous arterial and coronary sinus blood collections were performed after each distal anastomosis except the last one. In the blood cardioplegia group simultaneous arterial and coronary sinus blood samples were drawn during each reperfusion period. Following the last distal anastomosis, a second LV needle biopsy was taken. The aortic cross-clamp was removed, and arterial and coronary sinus blood samples were simultaneously drawn at 2 and 5 min, respectively. Prior to weaning off CPB and prior to application of catecholamines a third LV needle biopsy was taken. After separation from CPB and 10–15 min following decannulation hemodynamic and functional parameters as described above were measured, and the last simultaneous arterial and coronary sinus blood samples were collected. The coronary sinus catheter was then removed. Four hours postoperatively the last hemodynamic and functional measurements were performed in the ICU.
Hemodynamic and left ventricular (LV) contractility parameters
Beside standard hemodynamics including arterial, pulmonary artery, and central venous pressures as well as cardiac output, we determined LV contractility using transesophageal echocardiography (TEE). LV short-axis images at the mid-papillary level were recorded for 1 min. The fractional area of contraction (FAC, in %) was derived as average of ten consecutive beats using the following equation
[22]
[23]:
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End-diastolic area was defined as the endocardial area corresponding to the ECG R wave peak, end-systolic area as the smallest systolic endocardial area [22] [23].
LV biopsies
LV biopsies were used to quantify structural myocardial alterations by determination of inducible heat shock protein-70 (HSP-70), intercellular adhesion molecule-I (ICAM-I) expression, and myocardial actin pattern using immuno-histochemical methods.
After cryopreservation with liquid nitrogen, the biopsies were cut into 5 µm slices at -20°C, air-dried, and immunostained [24]. Specimens were then fixed in methanol at -20°C followed by incubation with 0.1% Triton X-100 and 0.01 mol phosphate buffered saline (PBS; pH 7.4) +1 mg/ml bovine serum albumin (BSA). Sections were then incubated with the primary antibody against the inducible HSP-70 (anti-HSP 70 i; dilution 1:200; monoclonal mouse antibody C 92 F 3 A-5, Stress Gen, Victoria, Canada) and against ICAM-I (CD 54; dilution: 1:200; monoclonal mouse antibody clone 15.2, Leico Technologies, Manchester, UK). Thereafter, sections were rinsed with 0.01 mol/l PBS, followed by incubation in 0.01 mol/l PBS and 1 mg/ml BSA. Subsequently, the secondary antibody (FITC-labelled goat anti-mouse IgG antibody; dilution 1:1000; Fc specific, Sigma, St. Louis, MO) was applied and rinsed off using 0.01 mol/l PBS. Finally, the specimens were incubated in 0.01 mol/l PBS.
Actin-pattern was visualized using a FITC-labelled Phalloidin technique [25]. Specimens were cut at 5 µm in a cryostat, mounted, fixed in 3.7% formaldehyde at room temperature, and incubated in 0.01 mol/l PBS (pH: 7.4). Subsequently, 5x10-5% FITC-labelled Phalloidin (Sigma, St. Louis, MO) was applied. Finally, sections were rinsed with 0.01 mol/l PBS and incubated in 0.01 mol/l PBS. Then image analyses were performed: photographs were taken from each specimen at 400x and 1000x magnification and processed using a computerized image analysis system (JAVA®, Jandel Scientific, Erkrath, Germany). After digitalization, the number of cells exhibiting positive fluorescence for ICAM-I was counted and divided by the total number of cells counted per view field. The number of HSP-70 positive fluorescence spots was counted per viewfield and expressed as HSP-70 spots per 174 µm2. The actin band length was measured in micrometers. Each measurement was repeated by an independent investigator not involved in the study.
Statistical analysis
Data are presented as mean±standard error of mean (SEM). Data analyses were performed by use of two-way analysis of variance (ANOVA) followed by two-tailed Student's t-test for comparisons between dependent and independent samples with Bonferroni correction for multiple comparisons, where appropriate. Statistical significance was assumed for P<0.05.
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Results |
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TopAbstractIntroduction
Materials and methodsResults
Discussion
Conclusions
Appendix A. Conference...References |
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Postoperatively, patients of both groups needed inotropic drugs but no difference between groups was noticed. Duration of ventilation, frequency of arrhythmias, time of ICU stay, and mortality did not differ (Table 4).
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Discussion |
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TopAbstractIntroduction
Materials and methodsResults
Discussion
Conclusions
Appendix A. Conference...References |
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The ß-blocker technique combines continuous coronary perfusion with the application of a cardioprotective agent. In comparison to intermittent blood cardioplegia avoidance of ischemia might be a significant advantage of the ß-blocker technique. Continuous oxygen supply is demonstrated by the data for arterial-coronary sinus lactate concentration differences. High oxygen saturation values in the ES group can be explained by markedly reduced oxygen demand of the myocardium owing to ß-blockade, and thus, oxygen supply exceeding demand [17].
Despite hypothermia and complete mechanical inactivity blood cardioplegia did not prevent significant lactate production during aortic cross-clamp time. Although a rapid decrease of lactate production after aortic cross-clamp release was noticed myocardial ischemia and subsequent reperfusion resulting in myocardial stunning is likely. This is supported by the fact that during reperfusion the number of ICAM-I positive myocytes increased in the BC-group, whereas in the ES group ICAM-I expression did not further increase between cross-clamp removal and weaning off CPB. This suggests that ischemia minimization in the ES group minimizes reperfusion injury and subsequent myocardial stunning. In contrast, myocardial ischemia during intermittent blood cardioplegia and subsequent reperfusion results in myocardial stunning which corresponds to the LV functional data measured at 4 h post CPB. These data suggest that aerobic myocardial metabolism during continuous coronary perfusion with warm blood is the major advantage of the ß-blocker technique as compared to intermittent cold blood cardioplegia which is in agreement to other studies demonstrating slightly better myocardial protection by use of continuos warm blood cardioplegia in comparison to intermittent cold cardioplegia techniques [7] [8] [9] [12] [17] [18] [19].
However, even in the ES-group structural changes demonstrated by elevated postoperative HSP-70 expression and actin band length indicate some degree of myocardial injury. Manipulation of the heart, especially for circumflex artery grafting with even short ischemic periods could explain these data. This is supported by studies showing that brief ischemia periods result in increased HSP-70, ICAM-I and actin-pattern values [26] [27] [28]. However, myocardial CK release was similar for both techniques suggesting that structural changes in the BC group were only temporary, and thus reversible, because myocardial stunning is known to recover with time [1].
Continuous ß-blocker application for myocardial contractility reduction without arresting the heart is particularly dependent on an ultra-short acting agent such as esmolol with a half-life of 7–9 min [29]. The rapid onset of ß-blockade following cross-clamping and esmolol administration allows the surgeon to immediately start anastomoses construction. In addition, the fast elimination of negative inotropy and chronotropy following esmolol cessation and cross-clamp removal allows rapid weaning off CPB.
Despite technical refinements such as intracoronary shunt insertion, room air blower, suction, or saline rinse we still observed some limitations of the esmolol technique. First, revascularization of the circumflex artery and their branches usually requires luxation of the heart which sometimes results in aortic insufficiency. As a consequence, myocardial perfusion is impaired which may cause ischemia and subsequent myocardial damage. This is easily detected by a pressure drop in the aortic root and has to be corrected by repositioning the heart [18].
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Conclusions |
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TopAbstractIntroduction
Materials and methodsResults
Discussion
Conclusions
Appendix A. Conference...References |
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Acknowledgments |
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Footnotes |
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Appendix A. Conference discussion |
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TopAbstractIntroduction
Materials and methodsResults
Discussion
Conclusions
Appendix A. Conference...References |
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Dr Kuhn-Régnier: Yes.
Dr von Segesser: What are the blood flows you use for the esmolol group for the coronaries?
Dr Kuhn-Régnier: Well, the coronary blood flow rates varied between 150 and 300 milliliters, at a pressure of about 60 mmHg.
Dr A. Royse (Melbourne, Australia): I put it to you that your study has shown no more than that continuous blood cardioplegia, compared to intermittent blood cardioplegia has less ischemia. Now, most of us use intermittent cardioplegia because we like to see during the anastomosis unobscured by blood. Can you tell us if your technique can be adjusted for an intermittent cardioplegic technique rather than a continuous one?
Dr Kuhn-Régnier: You mean, if I understand it correctly, why didn't we use continuous blood cardioplegia?
Dr Royse: Well, your conclusion is that the beta blocker group has less myocardial ischemia. That has got nothing to do with the beta blocker. That has got to do with the fact that you gave continuous blood. Now, we would like to have an intermittent technique so that we could have no blood coming out of the coronary artery whilst doing the anastomosis; but instead of using potassium, are you able to use a beta blocker instead to achieve the same thing?
Dr Kuhn-Régnier: Well, we know from publications in the past that continuous blood cardioplegia, for example, is associated with edema formation and reduced cardiac function postoperatively. This was published in Circulation in 1995. And to induce cardiac arrest is, in our opinion, not ideal because we know that by the contraction of the heart, lymphatic function, and thus, lymphatic flow in the heart is present. So by this way, by slow contracting hearts, we could reduce edema formation.
Dr Royse: If I may, Mr. Chairman, a cross-clamp on the lymphatics would probably stop them working?
Dr Kuhn-Régnier: I did not understand. Sorry.
Dr Royse: Your lymphatics go up the aorta. If you put a cross-clamp on there, you have effectively stopped your lymphatics, surely.
Dr Kuhn-Régnier: The myocardial lymphatics do not go to the aorta; they run through the connective tissue between aorta and superior vena cava. So, if you clamp the aorta, you don't stop myocardial lymph flow, as we have previously demonstrated. In addition, myocardial lymphatics have connections to the pulmonary lymph system.
Mr H. Gama (Glasgow, UK): I just want to know if you looked into the incidence of atrial fibrillation post-op in your esmolol hearts, if it was lower?
Dr Kuhn-Régnier: No, there was no difference of atrial fibrillation between the groups.
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References |
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TopAbstractIntroduction
Materials and methodsResults
Discussion
Conclusions
Appendix A. Conference...References |
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