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J Thorac Cardiovasc Surg 2001;122:993-1003
© 2001 The American Association for Thoracic Surgery
Cardiopulmonary Support and Physiology (CSP) |
From the Cardiac Surgical Research/ Cardiothoracic Surgery, The Rayne Institute, Guy's and St Thomas' NHS Trust, St Thomas' Hospital, London, United Kingdom.
Received for publication Oct 10, 2000. Revisions requested Nov 30, 2000; revisions received March 12, 2001. Accepted for publication March 19, 2001. Address for reprints: David J. Chambers, PhD, Cardiac Surgical Research/Cardiothoracic Surgery, The Rayne Institute, Guy's and St Thomas' NHS Trust, St Thomas' Hospital, London SE1 7EH, United Kingdom (E-mail: david.chambers{at}kcl.ac.uk).
Abstract
Objective: During myocardial revascularization, some surgeons (particularly in the United Kingdom) use intermittent crossclamping with fibrillation as an alternative to cardioplegia. We recently showed that intermittent crossclamping with fibrillation has an intrinsic protection equivalent to that of cardioplegia. In this study we hypothesized that arrest, rather than fibrillation, during intermittent crossclamping may be beneficial. Because esmolol, an ultra-short-acting ß-blocker, is known to attenuate myocardial ischemia-reperfusion injury, we compared the protective effect of esmolol arrest with that of intermittent crossclamping with fibrillation and conventional cardioplegia (St Thomas' Hospital solution).
Methods: Isolated rat hearts were Langendorff perfused at either constant flow (14 mL/min) or constant pressure (75 mm Hg) with oxygenated Krebs-Henseleit bicarbonate buffer (37°C), and left ventricular developed pressure was assessed. In study 1 (constant flow perfusion) 8 groups (n = 6 hearts per group) were studied: (1) 40 minutes of global ischemia; (2) 2 minutes of St Thomas' Hospital infusion and 40 minutes of ischemia; (3) multidose (every 10 minutes) infusions of St Thomas' Hospital solution during 40 minutes of ischemia; (4) 2 minutes of esmolol infusion and 40 minutes of ischemia; (5) multidose (every 10 minutes) esmolol infusions during 40 minutes of ischemia; (6) continuous infusion of esmolol for 40 minutes during coronary perfusion; (7) intermittent (4 x 10 minutes) ischemia with ventricular fibrillation; and (8) intermittent (4 x 10 minutes) ischemia preceded by intermittent esmolol administration. All protocols were followed by 60 minutes of reperfusion. Further experiments (study 2) examined the esmolol administration method in hearts perfused by constant pressure.
Results: An optimal arresting dose of 1.0 mmol/L esmolol was established. In study 1 recovery of left ventricular developed pressure (expressed as percentage of preischemic value) was 7% ± 4%, 28% ± 8%, 70% ± 5%, 8% ± 1%, 90% ± 4%, 65% ± 3%, 71% ± 5%, and 76% ± 5% in groups 1 to 8, respectively. Intermittent esmolol arrest with global ischemia provided equivalent myocardial protection to intermittent crossclamping with fibrillation, continuous esmolol perfusion, and multidose St Thomas' Hospital solution. Surprisingly, multidose esmolol infusion was more protective than all other treatments. In further experiments (study 2) optimal recovery was obtained with multiple esmolol infusions (by constant flow or constant pressure), but continuous esmolol infusion (at constant flow) was less effective than constant pressure infusion.
Conclusions: Intermittent arrest with esmolol did not enhance protection of intermittent crossclamping with fibrillation; however, multiple esmolol infusions during global ischemia provided improved protection. Administration (constant flow or constant pressure) of arresting solutions influenced outcome only during continuous infusion. Multidose esmolol arrest may be a beneficial alternative to intermittent crossclamping with fibrillation or conventional cardioplegia.
Myocardial protection during cardiac operations is most commonly achieved by hyperkalemic cardioplegic arrest
1,2; however, a minority of surgeons, particularly in the United Kingdom, continue to favor the technique of intermittent ventricular fibrillation (VF), either with 3 or without 4 aortic crossclamping. Recent clinical studies 5,6 have shown that intermittent crossclamp (ventricular) fibrillation (ICCF) provides equivalent myocardial protection to cold cardioplegia. In these studies, however, the cumulative ischemic duration during ICCF was invariably shorter than that of the comparative ischemia associated with cardioplegic arrest; hence, it was unclear whether this shorter ischemic duration was associated with reduced injury. We 7 have recently demonstrated, in an experimental study, that intermittent global ischemia either alone or with VF does provide an intrinsic protection. In addition, VF did not appear to exacerbate any ischemic injury. This suggested the possibility that rapid arrest with a cardioplegic agent, rather than ischemic arrest or VF (ICCF), might further improve myocardial protection.
It is known that ß-adrenergic antagonists (ß-blockers) attenuate the extent of myocardial injury during ischemia and reperfusion. 8,9 The negative inotropic and chronotropic effects of these drugs is thought to concomitantly reduce myocardial oxygen consumption, decrease sympathetic tone, reduce myocardial substrate use, and stabilize cell membranes, 10,11 thereby exerting a beneficial effect on ischemic myocardium. Most ß-blockers, however, have prolonged negative inotropic properties, 12 with a half-life of many hours, which limits their use during cardiac operations. In contrast, the ultra-short-acting and cardioselective ß-blocker esmolol has a half-life of a few minutes, 13 which allows its negative inotropic effects to be abolished rapidly after reduction or cessation of infusion. This short half-life of esmolol led Sweeney and Frazier 14 to use high-dose esmolol infusion in hearts of patients with compromised left ventricular (LV) function who were supported by an LV assist device to suppress cardiac inotropy and chronotropy during myocardial revascularization. Subsequently, experimental 15,16 and clinical 17-20 studies have shown that esmolol can be used to obtain minimal myocardial contraction during cardiac operations while maintaining continuous normothermic coronary perfusion to avoid ischemia. With this technique, myocardial protection was equivalent to or better than that obtained with cold crystalloid or blood cardioplegia.
Therefore, we hypothesized that a combination of esmolol arrest with intermittent global ischemia would enhance the protection observed with ICCF, and we conducted a study to examine the protective effect of intermittent esmolol arrest and to compare this effect with ICCF and conventional cardioplegic solutions. As a consequence of this, a further study was conducted to examine the optimal method for infusion of the protective solutions.
Materials and methods
Animals
Adult male Wistar rats (240-300 g body weight) were used (Bantin and Kingman, Hull, United Kingdom). All animals received humane care in accordance with the "Guidance on the Operation of the Animals (Scientific Procedures) Act of 1986" published by Her Majesty's Stationery Office (London, England). Rats were anesthetized with 95% oxygen/5% carbon dioxide bubbled through diethyl ether and were then anticoagulated with heparin (1000 IU/kg body weight) administered intravenously.
Heart isolation and perfusion
Hearts were rapidly excised from the anesthetized rats and immersed in cold (4°C) Krebs-Henseleit buffer (KHB). The aorta was then cannulated, and the heart was perfused at 37°C in the Langendorff mode, as previously described. 7 Hearts were perfused at either constant pressure (75 mm Hg) or constant flow (14 mL/min) by means of a peristaltic pump (Gilson Minipuls 3; Gilson Company, Inc, Lewis Center, Ohio). A unipolar electrocardiogram (ECG) was obtained through a silver electrode inserted into the free wall of the left ventricle and a reference electrode connected to the aortic cannula; the ECG was continuously recorded throughout the protocol. All hearts were subjected to an equilibration period (20 minutes) of aerobic perfusion, and baseline readings of LV systolic pressure (in millimeters of mercury), LV end-diastolic pressure (LVEDP; in millimeters of mercury), heart rate (in beats per minute), and coronary flow (in milliliters per minute) were taken. LV developed pressure (LVDP) was calculated as the LV systolic pressure minus LVEDP. Coronary flow was measured by timed collections of the coronary effluent. The development of contracture during ischemia (when of sufficient duration) was recorded. Infusion volume of cardioplegic solution was measured by collecting coronary effluent during infusion of cardioplegic solution.
Exclusion criteria
Hearts not satisfying preassigned exclusion criteria at the time of the baseline readings were excluded from the study. The acceptable ranges for LVDP, heart rate, and coronary flow were as follows: greater than 100 mm Hg, greater than 220 beats/min, and 8 to 16 mL/min, respectively.
Perfusion Medium
This was a modified KHB with the following composition: NaCl, 118.5 mmol/L; NaHCO3, 25.0 mmol/L; KCl, 4.8 mmol/L; MgSO4, 1.2 mmol/L; CaCl2, 1.4 mmol/L; and glucose, 11.0 mmol/L. The buffer was prepared daily, filtered through a 5-µm pore size cellulose nitrate membrane filter before use, and continuously gassed with 95% oxygen/5% carbon dioxide mixture to give a pH of 7.4 at 37°C.
Preparation and administration of esmolol and cardioplegic solution
Esmolol (Brevibloc; Baxter Pharmaceuticals, Crowthorne, Berkshire, United Kingdom) was provided in vials containing 10 mL of a 250 mg/mL solution. Preliminary studies were carried out to determine a dose-response curve for esmolol; 5 dilutions of the original esmolol solution (1:3, 1:10, 1:30, 1:100, and 1:300 diluted in oxygenated KHB) were infused with an electronic syringe pump (Razel Scientific Instruments Inc, Stamford, Conn) attached to a multiway aortic cannula at an infusion rate of 0.215 mL/min. Hearts were perfused at a constant flow rate of 14 mL/min; consequently, the final concentrations of esmolol reaching the heart were approximately 3.0, 1.0, 0.3, 0.1, and 0.03 mmol/L, respectively. As a result of these dose-response studies, subsequent esmolol cardioplegic solution was prepared by diluting 1.5 mL of esmolol (250 mg/mL) in 1000 mL of oxygenated KHB, giving a final esmolol concentration of 1.0 mmol/L.
The St Thomas' Hospital cardioplegic solution No. 2 (STH2) was prepared daily with the following composition: NaCl, 110.0 mmol/L; MgCl2· 6H2O, 16.0 mmol/L; KCl, 16.0 mmol/L; CaCl2· 2H2O, 1.2 mmol/L; and NaHCO3, 10.0 mmol/L. The pH was adjusted to 7.8 at 37°C, and the solution was filtered through a 5-µm cellulose nitrate filter before use.
Each solution was delivered at 37°C and at either a constant pressure of 45 mm Hg or a constant flow rate of 14 mL/min for 2 minutes each infusion.
Induction and termination of VF
VF was induced with an electrical fibrillator (model G570, Department of Bioengineering, St Thomas' Hospital) by passing alternating current through 2 silicone-coated silver electrodes, one attached to the apex of the ventricle and the other grounded on the aortic cannula. The minimum voltage necessary to achieve an alternating current that maintained VF was used. If VF occurred during reperfusion or did not terminate spontaneously after the fibrillator was turned off, it was terminated by the use of a defibrillator (model G 434, Department of Bioengineering, St Thomas' Hospital).
Preliminary Study: Determination of dose-response curve for esmolol
Before starting the following protocols, we determined the dose-response curve for esmolol. Hearts were randomly assigned to one of 5 esmolol concentration groups (ie, 0.03, 0.1, 0.3, 1.0, and 3.0 mmol/L; n = 6 hearts per group). Each concentration of esmolol was continuously delivered to the heart for 10 minutes, and function (LVDP) and ECG characteristics (atrial and ventricular rate) were measured and compared with initial values (expressed as percentage of aerobic function).
Perfusion protocol
After 20 minutes of aerobic equilibration perfusion, hearts were subjected to 1 of 2 perfusion protocols, as shown in Figure 1. During the ischemic periods, hearts were immersed in KHB at 37°C with the use of a temperature-controlled, water-jacketed heart chamber.
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(n = 6 hearts per group). All protocols were followed by a further 60 minutes of reperfusion, when recovery of myocardial function was measured.
Study 2: Does the method of cardioplegic infusion (constant flow vs constant pressure) influence protection?
In study 1 (above) all hearts were perfused throughout by means of constant flow, which is a relatively nonphysiologic perfusion technique and may have affected recovery of function. Consequently, it was decided to perfuse hearts at constant pressure during aerobic perfusion and reperfusion and to determine whether constant flow or constant pressure infusion influenced protection.
Thus, all hearts were perfused at a constant perfusion pressure equivalent to 75 mm Hg both before and after global ischemia and randomized to 1 of 8 groups as listed inTable 2 (n = 6 hearts per group). All protocols were followed by a further 60 minutes of reperfusion, when recovery of myocardial function was measured.
Expression of results
Postischemic recovery of LVDP, heart rate, and coronary flow were expressed as a percentage of the baseline values; LVEDP was expressed as an absolute value (in millimeters of mercury). The following measurements related to contracture during ischemia were also noted: (1) time to onset of contracture (in minutes); (2) time to peak contracture (in minutes); and (3) magnitude of peak contracture (in millimeters of mercury). In addition, we measured the time to the cessation of mechanical activity (in seconds).
Statistics
Statistical analysis was performed with StatView and SuperANOVA programs (Abacus Concepts Inc, Berkeley, Calif) on an Apple Macintosh computer (Apple Computer, Cupertino, Calif). All data are reported as means ± standard error of the mean. Comparison between groups was assessed with 1-way analysis of variance with post hoc analysis by the Fisher protected least significant difference test, which allowed for multiple comparisons. The Student t test (or the Mann-Whitney test when appropriate) was used to compare 2 means.
Results
Preliminary Study: Determination of dose-response curve for esmolol
The esmolol dose-response curve for LVDP, ventricular rate, and atrial rate (expressed as percentage of initial values) is shown inFigure 2. Each index demonstrated a negative sigmoidal curve with increasing concentrations of esmolol. LVDP and ventricular rate were zero at an esmolol concentration of 1 mmol/L, whereas atrial rate did not reach zero until a concentration of 3 mmol/L.
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LVEDP
Changes in postischemic LVEDP during 60 minutes of reperfusion are shown in Figure 4. At the onset of reperfusion, LVEDP values were moderately elevated, although continuous coronary perfusion (at 14 mL/min) of esmolol cardioplegic solution caused an LVEDP of 109 mm Hg. Interestingly, poor LVDP recovery (groups 1, 2, and 4) was associated with rapid and maintained increases in LVEDP on reperfusion. In contrast, in groups 3 and 5 to 8, LVEDP declined to relatively normal levels, mirroring the good recovery in LVDP(Figure 3).
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for each group. Hearts subjected to global ischemia alone (group 1) had significantly prolonged mechanical activity compared with all other groups; mechanical quiescence was most rapid in the STH2 groups. In addition, the mean total volumes of cardioplegic solution delivered to the heart in the single-dose, multidose, and continuous groups are shown inTable 4.
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, B). In particular, hearts subjected to multiple infusions of STH2 exhibited a hyperemic peak (to 40%) at 5 minutes, with subsequent decline. In contrast, coronary flow in hearts subjected to multiple infusions of esmolol (infused either by means of constant pressure or constant flow) recovered to supranormal levels, which increased throughout the 60 minutes of reperfusion, reaching significantly higher levels than all other groups. The percentage recovery of heart rate was similar in all groups, reaching approximately 100% of baseline values (data not shown).
LVEDP
Changes in postischemic LVEDP during 60 minutes of reperfusion are shown in Figure 6; these changes were similar to those seen in study 1. In general, LVEDP values mirrored those of LVDP, in which those hearts that recovered well showed a relatively low value of LVEDP during reperfusion, whereas hearts that recovered poorly (with a low LVDP) had a higher LVEDP (groups 1, 2, and 4).
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Discussion
The present study has demonstrated the following: (1) the ultra-short-acting ß-blocker esmolol induces complete mechanical and ventricular arrest at a concentration of 1 mmol/L; (2) intermittent esmolol arrest did not enhance the protection achieved with ICCF; (3) our previous findings that ICCF was equally as protective as multidose cardioplegia can be supported; (4) multidose esmolol arrest was significantly more protective than that with other solutions (at least when hearts were perfused at constant flow); (5) the method of infusion (constant flow or constant pressure) was not an influence on recovery for multidose esmolol infusion (at this ischemic duration) but had a significant effect on continuous esmolol infusion; and (6) constant flow during perfusion-reperfusion had a generally detrimental effect.
In the United Kingdom a significant number of surgeons use ICCF to induce cardiac surgical conditions that allow coronary revascularization during coronary artery bypass operations 3; this technique was shown to produce good myocardial protection in recent clinical trials. 5,6 However, because it was unclear from these studies whether ICCF was itself protective or whether the similar protection to that achieved with cardioplegia was due to the shorter ischemic durations (and hence less ischemic injury) associated with ICCF, our previous study 7 was the first (to our knowledge) to demonstrate that ICCF exerted an intrinsic protection that was equivalent to that of multidose cardioplegia when the total ischemic duration was the same. For the present study, we hypothesized that arrest, rather than VF, during the intermittent crossclamp periods might further enhance the protective effect of this technique, and we therefore examined whether the ultra-short-acting ß-blocker esmolol might have a role in this situation.
ß-blockers and myocardial protection
The mechanism of action of ß-blockers is widely known 21; they antagonize the binding of catecholamines to the ß-adrenergic receptors of the cell membrane complex, indirectly reducing the number of activated calcium channels and hence cellular calcium influx. This results in a decrease in heart rate and myocardial contractility. Although ß-blockers have been demonstrated to exert a protective effect in the setting of ischemia in both clinical and experimental studies, the mechanism by which this is achieved is incompletely understood. Catecholamine depletion has been shown to improve recovery of isolated hearts after ischemia, 22 and part of the cardioprotective effect of ß-blockers probably derives from their antagonism to the unfavorable effects of catecholamines in ischemia; however, several other theories have been suggested. 23,24
Most ß-blockers have prolonged negative inotropic effects that last for hours, 12 which renders them unsuitable for use during acute situations, such as cardiac operations. However, esmolol, a cardioselective ß-adrenergic blocker, has an extremely short duration of action (half-life of about 9 minutes), 13 which is attributable to rapid enzymatic hydrolysis by blood and tissue esterases, 25 making esmolol a potential candidate for myocardial protection during operations. Indeed, esmolol was first used to improve myocardial protection during cardiac operations in 1992. 14 Subsequently, a number of experimental 15,16,26 and clinical 17,19,20,27 studies have demonstrated the efficacy of using esmolol-enriched blood to induce minimal myocardial contraction with a flaccid heart, thereby generating conditions suitable for coronary artery operations while maintaining coronary perfusion. This use of esmolol was shown to reduce myocardial edema formation and result in either equivalent or improved myocardial protection when compared with intermittent cold crystalloid cardioplegia, 16,19,27 intermittent cold blood cardioplegia, 20 or warm continuous blood cardioplegia. 15,26
Esmolol has previously been shown to induce ventricular arrest when used at high concentrations. Ede and colleagues 28 arrested rat hearts at a dose of 1.36 mmol/L. Pirk and coworkers 29 demonstrated that 250 mg/L esmolol (approximately 0.7 mmol/L) was an optimal concentration for arrest of the rat heart, whereas 500 mg/L (approximately 1.4 mmol/L) resulted in reduced recovery of cardiac function (when washed out). In the present study we observed similar effects, with an optimal arrest dose of 1.0 mmol/L; a higher dose (3.0 mmol/L) was required for atrial arrest but led to ventricular dysfunction on washout.
Cardioplegic infusion regimen: Effects of single-dose, multidose, or continuous infusion
Multidose cardioplegic infusion enhances protection compared with single-dose infusion, 30,31 and this was confirmed in the present study with both STH2 and esmolol arrest. This additional benefit has been related to many factors, including washout of metabolites (eg, lactate, protons, and inorganic phosphate) that inhibit anaerobic metabolism, replacement of substrate (particularly oxygen with blood cardioplegia or the oxygenated KHB with esmolol in the present study), and limits an evolving edema. Accumulation of metabolic intermediates cause further disturbances of energy metabolism, ionic homeostasis, and intracellular pH regulation 32 and eventually leads to loss of cellular viability. Recently, 33 multiple STH2 infusions were shown to maintain intracellular sodium (Na+i) concentrations during ischemia and reperfusion in rat hearts, whereas a single STH infusion only delayed (and slightly reduced) the rise in Nai in unprotected hearts. Interestingly, Nai levels correlated with recovery of function, which were of a similar order to those observed in the present study. It is tempting to speculate that similar effects on ionic homeostasis may be occurring in our study with the multiple infusions of esmolol cardioplegic solution, particularly in view of the suggested lidocaine-like activity (sodium-channel blocking effect) of esmolol at high doses. 28 The efficacy of myocardial protection with ß-blockers may require multiple infusion. It has been demonstrated 34 that acute ß-blockade was only effective during relatively short ischemic periods, and this would be supported by the present data. The short biologic half-life of esmolol 25 would also implicate the importance of multiple reinfusions.
There is increasing use of continuous (blood) cardioplegia, which avoids additional ischemia and is particularly useful for patients with severe ischemic disease for which further ischemic trauma is likely to be detrimental. Logically, avoidance of ischemia should provide optimal myocardial protection. However, previous experimental studies 15,16 with continuous esmolol infusion demonstrated that full protection was only provided for a finite duration, and extended infusions resulted in depressed function. This is supported by the present study: hearts receiving continuous esmolol had a lower recovery than hearts subjected to global ischemia with multidose esmolol infusions. It is feasible that total esmolol dose may influence outcome 16 and that the relatively high dose may exert an adverse effect when infused over long periods. 29 Our preliminary dose-response studies also showed adverse effects with a higher esmolol dose (3.0 mmol/L), and it is possible that continuous infusion with the lower dose (1.0 mmol/L) may have had similar effects. It is also known that esmolol increases coronary vascular resistance, with high doses inducing vasoconstriction. We confirmed this in the present study with our observation that coronary vascular resistance increased during continuous esmolol infusion at constant flow, and infusion volume decreased throughout continuous esmolol infusion at constant pressure (data not shown).
Effect of constant flow or constant pressure perfusion-infusion
In study 1 all hearts were perfused and reperfused at constant flow, and all cardioplegic solutions were infused at the same constant flow. It has previously been shown 35-37 that postischemic perfusion pressure (or flow rate) plays an important role in myocardial protection, particularly during the initial reperfusion period, during which reduced flow rate (compared with the preischemia period) was shown 37 to enhance postischemic recovery of function. Hearts in study 2 were perfused and reperfused by the more physiologic method of constant pressure, and effects of administering cardioplegic solutions by constant flow or constant pressure were investigated. The results supported the previous findings 35-37 that reperfusion pressure is an important component of protection. Equivalent groups of hearts had higher recovery than that in study 1. Also of interest was our finding that continuous infusion of esmolol cardioplegic solution at constant flow resulted in depressed recovery of function(Figure 5), an effect that is likely to be related to increased coronary vascular resistance (see above).
Limitations of the Study
We concede that the present studies were conducted in rat hearts perfused with a crystalloid solution rather than blood and that this is a relatively unphysiologic situation. We are aware that esmolol is metabolized by esterases, 25 and consequently, this study would fail to reveal any interaction between the metabolism of esmolol and the cardioprotective efficacy of esmolol.
It is also possible that esmolol may have adverse systemic effects that would not be revealed in our study; this would require investigation in the intact animal. Previous studies 14,19,20,27 have used esmolol clinically during relatively long-term continuous infusion (albeit at lower concentrations) with no report of any systemic adverse effects. Hence, we would speculate that use of short, multiple, high-dose infusions is unlikely to have major systemic effects, although this would need verification.
Myocardial ischemic disease is a multifactorial process; there is a spectrum of injury that affects the method of myocardial protection. Hearts used in this study were taken from normal rats, and it is likely that any protective effect of esmolol would be different in jeopardized hearts with ischemic injury or disease. In addition, any such hearts are likely to require prolonged periods of ischemia to correct the lesion, and the ischemic duration described in this study is relatively short. Further studies are warranted to investigate these aspects of myocardial protection with esmolol cardioplegic solution.
Conclusion
Esmolol arrest, rather than VF, during intermittent crossclamping did not enhance the myocardial protection of this technique. Interestingly, however, we observed that multidose esmolol infusions during global ischemia provided complete protection, and this protection was not influenced by the method of administration. The method of administration of esmolol cardioplegic solution was important, however, during continuous esmolol infusion. The use of esmolol as a cardioplegic agent may be a beneficial alternative to conventional cardioplegia or ICCF and would be applicable to all types of cardiac operations.
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Footnotes
Dr Ryuzo Bessho was a visiting research fellow from the Division of Cardiovascular Surgery, the Department of Surgery II, Nippon Medical School, Tokyo, Japan. 
References
This article has been cited by other articles:
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  M. Fujii and D. J. Chambers Cardioprotection with esmolol cardioplegia: efficacy as a blood-based solution Eur J Cardiothorac Surg, March 1, 2013; 43(3): 619 - 627. [Abstract] [Full Text] [PDF]
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 H. B. Fallouh, S. C. Bardswell, L. M. McLatchie, M. J. Shattock, D. J. Chambers, and J. C. Kentish Esmolol cardioplegia: the cellular mechanism of diastolic arrest Cardiovasc Res, August 1, 2010; 87(3): 552 - 560. [Abstract] [Full Text] [PDF]
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 M. Kambe, R. Bessho, M. Fujii, M. Ochi, and K. Shimizu Sivelestat reduces myocardial ischemia and reperfusion injury in rat hearts even when administered after onset of myocardial ischemia Interact CardioVasc Thorac Surg, June 1, 2009; 8(6): 629 - 634. [Abstract] [Full Text] [PDF]
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 M. Scorsin, A. Mebazaa, N. A. Attar, B. Medini, J. Callebert, R. Raffoul, R. Ramadan, J. M. Maillet, A. Ruffenach, F. Simoneau, et al. Efficacy of esmolol as a myocardial protective agent during continuous retrograde blood cardioplegia J. Thorac. Cardiovasc. Surg., May 1, 2003; 125(5): 1022 - 1029. [Abstract] [Full Text] [PDF]
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 D. J. Chambers Mechanisms and alternative methods of achieving cardiac arrest Ann. Thorac. Surg., February 1, 2003; 75(2): S661 - S666. [Abstract] [Full Text] [PDF]
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R. Bessho and D. J. Chambers Myocardial protection with oxygenated esmolol cardioplegia during prolonged normothermic ischemia in the rat J. Thorac. Cardiovasc. Surg., August 1, 2002; 124(2): 340 - 351. [Abstract] [Full Text] [PDF]
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P= .011 and P= .026 versus groups 3 and 5, respectively. Symbols and abbreviations are as inFigure 5