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Eur J Cardiothorac Surg 2000;17:63-70
© 2000 Elsevier Science NL

Myocardial protection with high-dose ß-blockade in acute myocardial ischemia

Hans J. Geisslera, Karen L. Davisa, Glen A. Laineb, Edwin J. Ostrina, Uwe Mehlhornc, Khosro Hekmatc, R. David Wartersa, Steven J. Allena

a Department of Anesthesiology, University of Texas-Houston Medical School, 6431 Fannin, MSMB 5.020, Houston, TX 77030, USA
b Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA
c Department of Cardiothoracic Surgery, University of Cologne, Cologne, Germany

Corresponding author. Tel.: +1-713-500-6200; fax: +1-713-500-6201
e-mail: sallen{at}anes1.med.uth.tmc.edu


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objective: The risk of postoperative cardiac dysfunction is markedly increased by emergency coronary artery bypass grafting in the presence of acute myocardial ischemia. High dose ß-blockade during continuous coronary perfusion has been suggested as an alternative to conventional cardioplegia and this technique has been applied successfully in high risk patients for coronary artery bypass grafting (CABG) surgery. This study compared high dose ß-blockade with esmolol to continuous warm blood cardioplegia in a clinically oriented model of acute left ventricular (LV) ischemia and reperfusion. Methods: Twelve dogs were subjected to 60 min of regional LV ischemia by left anterior descending branch (LAD) ligation. Cardiopulmonary bypass (CPB) and aortic crossclamp were applied after 45 min of ischemia. Thereafter, high dose ß-blockade during continuous coronary perfusion (ESMO, n=6) or antegrade continuous warm blood cardioplegia (WBC, n=6) were maintained for 60 min. Myocardial water content (measured from endomyocardial biopsies using a microgravimetric technique), global LV function (preload recruitable stroke work: PRSW), and regional LV function (echocardiographic wall motion score) were determined at baseline and after weaning from CPB. Results: During aortic crossclamp interstitial edema formation was significantly higher in the WBC group with an average water gain of 2.2±0.49 vs. 0.76±0.12% in the ESMO group. Thereafter, edema resolved in both groups, but myocardial water gain remained significantly higher in the WBC group at 60 and 120 min post CPB (0.98±0.19 and 1.13±0.32% vs. 0.07±0.25 and 0.04±0.08%). Global LV function was significantly higher in the ESMO group at 60 and 120 min post CPB (PRSW 103±6 and 94.7±4.6% of baseline vs. 85.3±4.9 and 74.7±7.6% of baseline). However, regional LV function showed no significant difference between groups. Conclusions: High-dose ß-blockade during continuous coronary perfusion may allow the surgeon to utilize the advantages of warm heart surgery, while avoiding the interstitial edema formation and temporary cardiac dysfunction associated with continuous warm blood cardioplegia. In high risk patients such as patients with unstable angina or after failed PTCA, high-dose ß-blockade may be an applicable alternative to cardioplegic arrest.

Key Words: Myocardial ischemia • Myocardial edema • ß-Blocker • Esmolol • Warm blood cardioplegia • Myocardial contractility


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Emergency coronary artery bypass grafting (CABG) in the presence of acute myocardial ischemia is associated with increased risk for postoperative cardiac dysfunction and low cardiac output syndrome [1]. Well-established myocardial protection techniques, which yield excellent results in the majority of patients may fail in this situation. The short acting ß-blocker esmolol has been shown to reduce infarct size [2] and myocardial edema after myocardial ischemia [3].

As an alternative to cardioplegic arrest, myocardial protection can be achieved with high doses of the ß-blocker esmolol [4]. Similar to warm blood cardioplegia, the coronary arteries are continuously perfused with oxygenated blood, but instead of a cardioplegic solution, which induces complete cardiac arrest, high doses of the ß-blocker esmolol are added to the coronary perfusate. The esmolol dose is adjusted to reduce heart rate and myocardial contractility to an extent that convenient surgical conditions are achieved, thus maintaining minimal myocardial contraction and avoiding a complete cardioplegic arrest. It has been shown that this minimal mechanical activity of the heart during high-dose ß-blockade is sufficient to maintain myocardial lymph flow, whereas during cardioplegic arrest myocardial lymph flow ceases due to the lack of myocardial contraction [5]. Therefore, cardioplegic arrest predisposes to the development of myocardial edema and subsequent temporary myocardial dysfunction. Due to the short half-life of esmolol, which is approximately 9 min, myocardial inotropy and chronotropy recover quickly after discontinuation of the esmolol infusion and weaning from cardiopulmonary bypass can be performed briefly after the release of aortic crossclamp.

It was the purpose of this study to compare the impact of myocardial protection by either high dose ß-blockade or continuous warm blood cardioplegia on interstitial myocardial edema and left ventricular (LV) function in a clinically relevant model of regional myocardial ischemia and reperfusion.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1. Animal preparation
All procedures were approved by The University of Texas Animal Welfare Committee and were consistent with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals [6]. Twelve mongrel dogs (31.4±0.9 kg) of either sex were anesthetized by intravenous administration of thiopental sodium (25 mg/kg body weight [BW]), endotracheally intubated, and mechanically ventilated with 100% oxygen using a volume-cycled respirator (Siemens–Elema AB, Sundbyberg, Sweden). Anesthesia was maintained with intravenous infusion of 1% thiopental sodium in Ringer's solution. Fluid-filled catheters were placed into the left femoral artery and vein for arterial pressure monitoring, arterial blood sampling, and fluid administration, respectively. We placed a 7 Fr thermodilution catheter via the left jugular vein into the pulmonary artery for pressure and cardiac output measurements. The pressure monitoring catheters were connected to calibrated pressure transducers (Isotec, Healthdyne Cardiovascular, Irvine, CA), and data were recorded on a computer (MacLab, WorldPrecision Instruments, Sarasota, FL). A 7 Fr catheter was introduced via the right jugular vein into the coronary sinus for coronary sinus blood sampling. The right femoral artery was exposed for subsequent cardiopulmonary bypass (CPB) cannulation. Following a median sternotomy and pericardiotomy we placed sonomicrometry crystals (10 MHz, Sonometrics, London, Ontario, Canada) in the subendocardium at midventricular level across the septum/free wall axis of the left ventricle (LV). A micromanometer tipped pressure transducer (Millar Instruments Inc, Houston, TX) was introduced in the LV cavity through the apex. For cardiac preload manipulation, we placed a snare around the inferior vena cava. Distally from the sonomicrometry crystals, vascular loop snares were placed around the distal third of the left anterior descending branch (LAD) of the left coronary artery, and any distal diagonal branch of the LAD.

2.2. Left ventricular function parameters
During 12 s of inferior vena cava occlusion we recorded LV pressure measured with the micromanometer and LV septum/free wall diameter obtained with the sonomicrometer at a frequency of 200 Hz. (Sonolab/Sonoview software package, Sonometrics, London, Ontario, Canada). From these measurements, pressure–volume loops were derived and we calculated preload recruitable stroke work (PRSW) as the slope of the relation between LV end-diastolic volume and LV stroke work.

As a parameter of diastolic LV function, the time constant of isovolumic relaxation, {tau}, was calculated based on a monoexponential pressure decay model [7]

((1))
where t=time, P0=pressure at t=0, Pasym=asymptotic pressure (as t->{infty}), and A=-1/{tau}. To solve the equation, A and Pasym were varied using a non-linear optimization algorithm (Microsoft Excel Solver, Frontline Systems, Inc., Incline Village, NV) until the best fit line was obtained by minimizing the residual sum of squares [8]. Measurements for PRSW and {tau} calculation were taken at baseline, and at 30, 60, and 120 min after weaning from CPB.

Epicardial two-dimensional echocardiograms were obtained with a 5 MHz ultrasound transducer (Aloka, Corometrics Medical Systems, Wallingfort, CT) in ten dogs (ESMO n=5; WBC n=5). For the assessment of regional LV function we used a semiquantitative wall motion score. The LV was divided into eight anatomical areas and wall motion was analyzed by a numerical score in which 4=normal, 3=mild hypokinesis, 2=moderate hypokinesis, 1=severe hypokinesis, 0=akinesis, and -1=dyskinesis [9]. Echocardiograms were taken at baseline, 20 min of ischemia and 120 min after CPB.

2.3. Interstitial myocardial edema
Myocardial water content was measured from endomyocardial biopsies using a microgravimetric technique as previously described [5]. Briefly, a linear density gradient was prepared in a gradient former from two different mixtures of kerosene and bromobenzene, which were adjusted to a specific gravity of 0.990 and 1.080, respectively. Calibration of the gradient was performed using various K2SO4 solutions with known specific gravities and by recording the equilibration depth of 10 µl drops of the various solutions. Linearity of the gradient was confirmed by linear least-square regression analysis after plotting the equilibration depths vs. specific gravity. The mean correlation coefficient was 0.991±0.00084 (n=12). To determine the specific gravity of myocardium we introduced an endoluminal biopsy forceps (Cordis® Corporation, Miami, FL) transapically into the LV and collected myocardial samples. These samples were placed into the density column and the equilibration depth was recorded after 1 min. Myocardial water content (MWC) can be calculated using the equation

((2))
where SGmyo and SGdry are the specific gravities of the myocardial tissue and of dry myocardium, respectively. Upon conclusion of the experiment, the dog was euthanized with an i.v. overdose of pentothal and saturated potassium chloride. After a last myocardial tissue density measurement, the heart was rapidly excised. Right and left ventricle were then weighed and dried at 60°C in an oven to a constant weight. SGdry was calculated using the following equation

((3))
where W and D are the wet and dry weights of both ventricles, respectively. We assumed that SGdry did not change over the experimental period. The biopsies were taken from the non-ischemic LV posterior wall, assuming that in the absence of ischemia, changes in myocardial water content would be almost completely due to changes in interstitial myocardial fluid. Measurements were performed in triplicate and taken at baseline, 50 min of aortic crossclamp, and at 30, 60, and 120 min after CPB.

2.4. Cardiopulmonary bypass
For systemic anticoagulation heparin was administered intravenously (250 IU/kg body wt.) followed by additional doses of 100 IU/kg body wt. given every 60 min throughout the experiment. Perfusion was performed using a 14 Fr arterial perfusion cannula placed into the prepared right femoral artery and a two-stage venous cannula (36x46 Fr) placed into the right atrium and inferior vena cava. The LV was vented with a 12 Fr catheter inserted via the left atrium. The extracorporeal circuit and the hollow fiber oxygenator (PlexusTM, Sorin Biomedical, Irvine, CA) were primed with 1200 ml of Ringer's solution with 2% hetastarch (McGaw® Inc., Irvine, CA) and 1000 IU heparin. We used four roller pumps (Mod. 7000, Sarns® Inc. Ann Arbor, MI) for extracorporeal circulation, cardiotomy suction, LV drainage and aortic root perfusion, respectively. For the warm blood cardioplegia group (WBC), blood cardioplegia was prepared as previously described [10] (Table 1) and applied at a blood:cardioplegia ratio of 4:1 using a commercially available system (Cobe Cardiovascular Inc., Arvada, CO). Arterial, coronary sinus, and, where applicable, blood cardioplegia plasma samples were frozen at -20°C for lactate quantification using an enzymatic test (Sigma Diagnostics, St. Louis, MO).


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  		Table 1. Crystalloid component of blood cardioplegia

 
During aortic crossclamp coronary vascular resistance was calculated using the equation

((4))
where R=coronary vascular resistance, Pao. root=aortic root perfusion pressure, Pcs=coronary sinus pressure, and Qao. root=aortic root perfusion flow.

2.5. Experimental protocol
Fig. 1 shows the time course of the experiment. Following instrumentation we recorded baseline measurements of all parameters. LV ischemia was induced by tightening the vascular loops around the LAD and the diagonal branch. To avoid ventricular fibrillation and clotting in the snared coronary vessels we administered intravenously lidocaine 1 mg/kg body wt. and 1000 IU heparin before the onset of ischemia. CPB was started after insertion of the arterial and venous perfusion cannulas at 30 min of ischemia. After 45 min of ischemia we crossclamped the aorta and started antegrade aortic root perfusion at 70 mmHg with either continuous normothermic (warm) blood cardioplegia (group WBC, n=6) or with oxygenated normothermic CPB blood and esmolol (group ESMO, n=6). Warm blood cardioplegia was delivered only in an antegrade fashion to have identical conditions to the ESMO group. Esmolol (Brevibloc®, Ohmeda Pharmaceutical Products Division Inc., Liberty Corner, NJ) was administered at an average dose of 1.4 mg/min. In the ESMO group minimal myocardial contraction was induced immediately after crossclamp with a bolus injection of 25 mg esmolol into the aortic root and thereafter esmolol was directly infused into the aortic root perfusion line by a syringe pump. Dosage for the continuous esmolol infusion was adjusted to reduce heart rate and myocardial contractility to an extent that convenient surgical conditions were achieved. After 1 h of regional ischemia, reperfusion was started by releasing the coronary snares. Aortic crossclamp was maintained for a total of 60 min. Thereafter, circulatory support was continued for another 30 min, before weaning from CPB. After weaning from CPB, we took endomyocardial biopsies, measurements of hemodynamic parameters, arterial and coronary sinus blood samples at 30, 60, and 120 min post CPB.



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  		Fig. 1. Time course of experimental model. CPB, cardiopulmonary bypass; ischemia, after LAD occlusion; reperfusion, after release of LAD occlusion.

 
2.6. Statistical analysis
All data are presented as mean±SE. Data from WBC and ESMO were compared using two-way analysis of variance for repeated measures. Post hoc comparisons were performed using paired Student's t-test with Bonferroni correction for three or four comparisons, respectively. An unpaired Student's t-test or Mann–Whitney U-test were applied where appropriate. A P-value of <0.05 was considered significant. Statistical analysis was performed using the Statistica 4.0 software package.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
Data from six dogs, which received warm blood cardioplegia (WBC) during aortic crossclamp, are compared to six dogs, which received warm blood and esmolol (ESMO). CPB characteristics are presented in Table 2 and showed no relevant difference between the two groups. During aortic crossclamp coronary artery resistance was significantly lower in the ESMO group as compared to the WBC group. Accordingly, at a constant perfusion pressure of approximately 70 mmHg aortic root perfusion was significantly higher in the ESMO group (Table 2). However, there was no evidence, in neither group, of hypoperfusion during aortic crossclamp. The lactate concentration difference between aortic root and coronary sinus blood during aortic crossclamp remained positive in both groups. In addition, the coronary sinus oxygen saturation during aortic crossclamp was significantly higher than at baseline in both groups (Table 2).


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  		Table 2. CPB related dataa

 
3.1. Hemodynamics
Measurements of mean arterial, mean pulmonary artery, and central venous pressure, and cardiac index were not significantly different between groups. Hemodynamic measurements are shown in Table 3.


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  		Table 3. Hemodynamic parameters, hematocrit and plasma protein concentrationa

 
3.2. Interstitial myocardial edema
At baseline there was no difference in myocardial water content between groups (ESMO 77.03±0.33%, WBC 76.92±0.55%). During aortic crossclamp interstitial edema formation was significantly higher in the WBC group with an average water gain of 2.2±0.49% vs. 0.76±0.12 in the ESMO group. Thereafter, myocardial edema resolved partially in both groups, but myocardial water gain at 60 and 120 min post CPB remained significantly higher in the WBC group (Fig. 2).



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  		Fig. 2. Myocardial water gain in (%). Interstitial edema formation in non-ischemic myocardium was significantly lower in the esmolol and warm blood group (ESMO, {circ}, n=6) than in the warm blood cardioplegia group (WBC, •, n=6). Two hours after weaning from CPB myocardial water content is almost normal in the ESMO group, whereas in the WBC group there is still substantial interstitial edema. 50' ACX, 50 min of aortic crossclamp; 'pCPB, minutes post cardiopulmonary bypass; # P<0.05 ESMO vs. WBC (ANOVA P<0.0089).

 
3.3. Left ventricular function
At baseline all animals had normal LV wall motion scores with no regional deficits. Scores decreased significantly in both groups at 20 min of ischemia, primarily due to severe hypokinesis or akinesis of the anterior and apical wall segments. One hundred and twenty minutes post CPB LV wall motion scores were still significantly lower than at baseline, although we observed substantial recovery compared to 20 min of ischemia. The ESMO group had higher post CPB scores in comparison to the WBC group, but the difference did not reach statistical significance (Fig. 3).



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  		Fig. 3. Regional LV function. Echocardiographic LV wall motion scores. {square}, esmolol and warm blood group (ESMO, n=5); {blacksquare},warm blood cardioplegia group (WBC, n=5); ', minutes; pCPB, post cardiopulmonary bypass; *, P<0.05 vs. baseline, Mann–Whitney U-test.

 
PRSW and {tau}, as parameters of global LV and diastolic function, respectively, showed no difference between groups at baseline. At 60 and 120 min post CPB PRSW was significantly higher in the ESMO group compared to WBC (Fig. 4). For post CPB values of {tau}, neither the differences among groups, nor the difference from baseline were statistically significant (Table 3).



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  		Fig. 4. Global LV function. Preload recruitable strokework (PRSW) after cardiopulmonary bypass. {circ}, esmolol and warm blood group (ESMO, n=6); •, warm blood cardioplegia group (WBC, n=6); 'pCPB, minutes post cardiopulmonary bypass; #, P<0.05 ESMO vs. WBC (ANOVA P<0.034).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
In patients with compromised LV function or acute myocardial ischemia, continuous warm blood cardioplegia has been advocated as superior myocardial protection in comparison to cold crystalloid cardioplegia [11]. However, warm blood cardioplegia has been found to be associated with interstitial myocardial edema formation and temporary cardiac dysfunction [5,12]. This study compared myocardial protection by high-dose ß-blockade with esmolol to continuous warm blood cardioplegia in a clinically oriented model of acute myocardial ischemia and reperfusion. High-dose ß-blockade (group ESMO) resulted in less interstitial myocardial edema and improved global LV function than continuous warm blood cardioplegia (group WBC). As the negative inotropic effect of even small increases in interstitial myocardial water has been shown in various studies [13,14], we believe that the better global LV function in the ESMO group was primarily due to decreased interstitial edema. Possible mechanisms by which interstitial edema depresses cardiac function include decreased contractility [13,14], decreased cardiac compliance [15] and increased myocardial stiffness [16]. Furthermore, interstitial edema may aggravate reperfusion injury by increasing oxygen diffusion distance [13] or compromising regional blood flow [17]. Reduction of interstitial edema by hyperosmotic reperfusion after ischemia has been shown to reduce infarct size [18] and improve post ischemic cardiac function [19].

Interstitial myocardial edema develops because of an imbalance between fluid influx from the myocardial microvasculature into the interstitium and its subsequent removal via myocardial lymphatics. Microvascular filtration, i.e. fluid influx, is increased during CPB due to several factors such as hemodilution, increased microvascular permeability, and increased filtration coefficient. In the presence of increased microvascular filtration, removal of interstitial fluid via myocardial lymphatics is the main defense mechanism against edema formation in the heart. However, during cardioplegic arrest, myocardial lymph flow decreases substantially, due to the lack of organized ventricular contraction, which is the main driving force of myocardial lymph flow [5]. Therefore, interstitial fluid accumulates during cardioplegic arrest not only due to increased filtration, but also due to impairment of myocardial lymphatic function. The minimal mechanical activity of the heart, which is sustained during high dose ß-blockade has been shown to be sufficient to maintain myocardial lymphatic function and limit edema formation [5]. Another mechanism for lower edema accumulation in the ESMO group compared to the WBC group may be a lower microvascular filtration rate due to a lower plasma colloid osmotic pressure in the latter. As per standard clinical practice, blood cardioplegia in the WBC animals was prepared at a blood: cardioplegia ratio of 4:1, while no such dilution was necessary in the ESMO group. Thus, compared to the ESMO group, the plasma colloid osmotic pressure of the aortic perfusate during crossclamp was lower in the WBC group's cardioplegia solution, which may have contributed to a higher microvascular filtration rate. Although we measured systemic plasma protein concentration (CP), which was not different between groups, we did not measure CP in the aortic root perfusion solutions. In addition, in our experiments esmolol caused a pronounced coronary vasodilation resulting in a significantly lower coronary vascular resistance in the ESMO group. This vasodilation may have caused a lower hydrostatic pressure in the coronary microvasculature, which would also result in reduced microvascular filtration. Therefore, we believe that the lower edema accumulation in the ESMO compared to the WBC group was due to maintained myocardial lymphatic function and reduced microvascular filtration.

Factors other than lower interstitial edema may have contributed to the better global LV function in the ESMO group. In myocardial ischemia the ß-blocker esmolol has been shown to decrease lactate production [20], reduce infarct size [2,3], and modulate free-radical-mediated reactions [21]. On the cellular level ß-blockers have been shown to reduce mitochondrial respiration [22] and inhibit calcium uptake by sarcoplasmatic reticulum [23].

There was no difference for regional LV function between groups. However, functional recovery of stunned myocardium has been observed as late as 48 h after the end of ischemia [24]. Therefore, the investigated time period of 2 h post CPB may have been too short to detect differences in functional recovery of the ischemic area.

Myocardial protection with high dose ß-blockade has been clinically applied during elective and emergency CABG [25–27]. In comparison to cold crystalloid cardioplegia high dose ß-blockade was associated with better clinical outcome after emergency CABG surgery and reduced need for inotropic support after elective CABG surgery [25,27]. Following elective CABG, expression of intracellular adhesion-molecule (ICAM-I) was significantly lower with high-dose ß-blockade than in comparison to intermittent cold blood cardioplegia [26]. However, it remains unclear whether these observed effects can be attributed to avoidance of ischemia by continuous coronary perfusion or the application of esmolol, as these clinical investigations compared intermittent delivery of cold cardioplegia to high-dose ß-blockade during continuous coronary perfusion with warm blood.

One technical challenge associated with continuous coronary perfusion, either during high-dose ß-blockade or warm blood cardioplegia, is impairment of the surgical field by bleeding from the incised coronary artery during CABG. Application of intracoronary shunt tubes, which are inserted into the incised coronary artery prevents bleeding out of the vessel and maintains blood flow through the shunt to the peripheral myocardium [24]. In addition, tip suckers and filtered room air blowers may improve surgical exposure by removing blood from the anastomosis.

High-dose ß-blockade during continuous coronary perfusion may provide the advantages of warm heart surgery while avoiding the interstitial edema formation associated with continuous warm blood cardioplegia. Compared to continuous warm blood cardioplegia, high-dose ß-blockade resulted in less interstitial edema formation and better global LV function in this model of acute myocardial ischemia and reperfusion. Regional LV function however, showed no difference between groups in this model. High dose ß-blockade during continuous coronary perfusion may be a useful application of warm heart surgery and an applicable alternative to cardioplegic arrest in some patients at risk for myocardial infarction, such as those with unstable angina or after failed PTCA.


   Acknowledgments
 
The authors thank Mr Michael Brennan for his excellent technical assistance. The authors express their appreciation to Cobe Cardiovascular Inc., Arvada, CO, and Sorin Biomedical, Irvine CA for their generous donation of cardiopulmonary bypass equipment.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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Received September 6, 1999; received in revised form November 29, 1999; accepted December 6, 1999.




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