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J Thorac Cardiovasc Surg 2000;120:528-537
© 2000 The American Association for Thoracic Surgery
Cardiopulmonary Support and Physiology |
From Cardiac Surgical Research/Cardiothoracic Surgery, The Rayne Institute, Guy's and St Thomas' Hospital NHS Trust, St Thomas' Hospital, London, United Kingdom.
Address for reprints: David J. Chambers, PhD, Cardiac Surgical Research/Cardiothoracic Surgery, The Rayne Institute, Guy's and St Thomas' Hospital NHS Trust, St Thomas' Hospital, London SE1 7EH, United Kingdom (E-mail: david.chambers{at}kcl.ac.uk ).
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Abstract |
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 Top Abstract IntroductionMaterial and methods Results Discussion Limitations of the study...Conclusion References |
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Introduction |
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TopAbstractIntroductionMaterial and methods Results Discussion Limitations of the study...Conclusion References |
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1,2 However, for isolated myocardial revascularization (coronary artery bypass surgery), the technique of intermittent ventricular fibrillation (VF), either with continued coronary perfusion 3 or, more commonly, with aortic crossclamping, 1,4 has been favored by a minority of surgeons.
Recently, the use of intermittent crossclamping with VF for myocardial protection has been re-evaluated because of its simplicity and because of interest in a potential connection between intermittent crossclamping with VF and myocardial protection induced by ischemic preconditioning. Randomized clinical trials have shown that myocardial preservation by means of intermittent crossclamping with VF is equal to or better than that obtained with cold cardioplegia, 5-11 assessed by clinical outcome, 5,8,11 cardiac specific markers of injury (such as creatine kinase MB isoform or troponin T assays), 6,7,11 free radical activity (such as lipid peroxidation and plasma antioxidant status), 9 and from preoperative and postoperative electrocardiographic changes. 6,9,11 Invariably, the cumulative ischemic period for intermittent crossclamping with VF during coronary surgery was relatively short (30-40 minutes) and was generally significantly shorter than the ischemic period when cardioplegic protection was used. 5,7-11 Thus, from these clinical studies, it remains unclear whether intermittent crossclamping with VF is associated with an intrinsic myocardial protective effect or whether the shorter ischemic duration results in less severe myocardial injury.
We therefore conducted an experimental study to investigate whether intermittent crossclamping with VF has intrinsic myocardial protection and to compare any protective effect of this technique with those of other methods of elective cardiac arrest used during cardiac surgery procedures.
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Material and methods |
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TopAbstractIntroductionMaterial and methods Results Discussion Limitations of the study...Conclusion References |
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Heart isolation and perfusion
Hearts were rapidly excised from the anesthetized rat and immersed in cold (4°C) Krebs-Henseleit buffer. The aorta was then cannulated and the heart perfused in the Langendorff mode with Krebs-Henseleit buffer at a constant pressure (75 mm Hg) and temperature (37°C) within 30 seconds of excision. The pulmonary artery was incised to allow free drainage of coronary effluent.
An ultrathin intraventricular balloon, constructed from cling film (Saran Wrap; S. C. Johnson, Racine, Wis) over a 20-gauge cannula and made to match the internal dimensions of the left ventricle, was then introduced through the mitral valve into the left ventricle. The balloon, attached to a pressure transducer that in turn was connected to a chart recorder system (Gould Instruments, Oxnard, Calif), was gradually inflated with water to give a stable left ventricular end-diastolic pressure (LVEDP) of 3.0 to 8.0 mm Hg. This isovolumic state was maintained throughout the protocol.
All hearts were subjected to an equilibration period of aerobic perfusion for 20 minutes, and baseline readings of left ventricular systolic pressure (millimeters of mercury), LVEDP (millimeters of mercury), heart rate (beats per minute), and coronary flow rate (milliliters per minute) were then taken. Left ventricular developed pressure (LVDP) was calculated as the left ventricular systolic pressure minus LVEDP. Coronary flow rate was measured by timed collections of the coronary effluent. The development of contracture during ischemia was recorded by means of the intraventricular balloon.
Exclusion criteria
Hearts not satisfying preassigned exclusion criteria at the time of the baseline readings (after 20 minutes of aerobic perfusion) were excluded from the study. The acceptable ranges for LVDP, heart rate, and coronary flow rate were more than 100 mm Hg, 220 beats/min, and 8 to 16 mL/min, respectively.
Perfusion medium
The perfusion medium was a modified Krebs-Henseleit bicarbonate buffer with the following composition (in millimoles per liter): NaCl, 118.5; NaHCO3, 25.0; KCl, 4.8; MgSO4, 1.2; CaCl2, 1.4; and glucose, 11.0. The buffer was prepared daily, filtered through a 5-µm pore-size cellulose nitrate membrane filter before use, and continuously gassed with a mixture of 95% oxygen and 5% carbon dioxide to give a pH of 7.4 at 37°C.
Preparation and administration of cardioplegic solution
In studies involving cardioplegia, the St Thomas' Hospital cardioplegic solution No. 2 (STH2), with the following composition (in millimoles per liter), was used: NaCl, 110.0; MgCl2 · 6 H2O, 16.0; KCl, 16.0; CaCl2 · 2 H2O, 1.2; and NaHCO3, 10.0. STH2 was prepared daily; pH was adjusted to 7.8 at 37°C and then filtered through a 5-µm filter before use. The solution was delivered at 37°C and at a pressure of 45 mm Hg for 2 minutes every infusion.
Induction and termination of VF
VF was induced by an electrical fibrillator (model G570, Department of Bioengineering, St Thomas' Hospital) by passing alternating current through two electrodes. The silver electrodes were coated with silicone; one was attached to the apex of the ventricle and the other to the aortic cannula for grounding. 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 G434, Department of Bioengineering, St Thomas' Hospital).
Experimental design
The perfusion protocols are shown in Fig 1. After equilibration, hearts were randomly assigned to 1 of 9 groups. All hearts (n = at least 6 per group) were subjected to one of the following protocols: (1) continuous global ischemia for 40 minutes (C-GI; n = 9); (2) a single-dose infusion of STH2 before 40 minutes of continuous global ischemia (S-CP; n = 9); (3) multidose infusion of STH2 (before and every 10 minutes) throughout 40 minutes of continuous global ischemia (M-CP; n = 6); (4) 40 minutes of continuous global ischemia with electrically induced VF throughout (C-GI+VF; n = 6); (5) 4 intermittent episodes of 10 minutes of global ischemia and 10 minutes of reperfusion (I-GI; n = 6); (6) 4 intermittent episodes of 10 minutes of global ischemia preceded by 2-minute infusions of STH2 and followed by 8 minutes of reperfusion (I-CP; n = 6); (7) 4 intermittent episodes of 10 minutes of global ischemia with electrically induced VF followed by 10 minutes of reperfusion in sinus rhythm (I-GI+VF; n = 6); (8) continuous electrically induced VF for 40 minutes with coronary perfusion (C-VF; n = 6); and (9) 4 intermittent episodes of 10 minutes of electrically induced VF with coronary perfusion followed by 10 minutes of coronary perfusion in sinus rhythm (I-VF; n = 6). LVEDP (intracavity pressure) was measured throughout these protocols.
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Expression of results
Postischemic recovery of LVDP was expressed as a percentage of baseline values at the end of 20 minutes of aerobic perfusion; LVEDP was expressed as absolute values (millimeters of mercury). The following measurements related to contracture during ischemia were also noted: (1) time to onset of contracture (minutes), (2) time to peak contracture (minutes), and (3) magnitude of peak contracture (millimeters of mercury).
Statistics
Statistical analysis was performed with StatView and SuperANOVA software (Abacus Concepts, Inc, Berkeley, Calif) on an Apple Macintosh computer (Apple Computer, Cupertino, Calif).
All data are reported as mean ± SEM. Comparisons between groups were assessed for significance by 1-way analysis of variance with post hoc analysis by means of the Fisher test, which allowed for multiple comparisons. A value of P < .05 (probability of < 5% that a difference between groups occurred by chance) was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterial and methods Results Discussion Limitations of the study...Conclusion References |
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, the rate of recovery was also significantly more rapid. When compared with hearts subjected to continuous (40 minutes) global ischemia (group 1; control), all but one group had a significantly better degree of recovery; the exception was group 4, hearts in which VF was imposed on global ischemia, which showed a tendency for a lower degree of recovery (although this difference did not reach significance). The significance of between-group post hoc analysis for LVDP is shown in Table II.
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, similar contracture measurements were obtained in hearts subjected to global ischemia alone (either continuous or intermittent), but the degree of recovery of LVDP was significantly higher with intermittent ischemia (Fig 3). Cardioplegic protection, however, prolonged the ischemic duration before contracture occurred and the extent was reduced, although the recovery of LVDP was similar to that of intermittent ischemia. In contrast, VF associated with either continuous or intermittent global ischemia significantly shortened the ischemic duration before the occurrence of contracture and significantly increased the extent of contracture. Although the contracture characteristics with VF were very similar, the extent of recovery of LVDP was different; recovery after continuous ischemia and VF was poor whereas it was good after intermittent ischemia and VF.
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Discussion |
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TopAbstractIntroductionMaterial and methods Results Discussion Limitations of the study...Conclusion References |
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In the 1970s, numerous experimental studies into the myocardial protective effect of VF were undertaken. 12-16 Studies from Buckberg's group 12,15 demonstrated that electrically maintained VF caused subendocardial ischemia, shown by acidosis, potassium loss, and a fall in lactate extraction, all of which contributed to subendocardial injury and impaired post-VF function despite apparently normal coronary perfusion. In further studies, Hottenrott and Buckberg 13 presented evidence that ventricular distention secondary to VF added to the occurrence of subendocardial underperfusion. The suggested mechanism by which flow was shunted away from the subendocardium during VF was the compressive force exerted on subendocardial vessels, either by the strength of VF or from elevated intracavity pressure caused by malfunction of the ventricular vent, leading to the evolution of myocardial edema as ischemia was prolonged. 14 Moreover, Hearse, Stewart, and Chain 16 demonstrated that, in hearts subjected to electrically induced VF during coronary perfusion, the recovery of cardiac function was reduced and myocardial adenosine triphosphate and creatine phosphate levels were considerably depleted, indicating increased myocardial energy consumption.
In our study, intraventricular pressure (LVEDP) increased in hearts subjected to VF with coronary perfusion (groups 8 and 9) to approximately 40 mm Hg (range 34-56 mm Hg). In these hearts, coronary flow was maintained close to (or higher than) baseline values, which suggests that adequate coronary perfusion was maintained. From our data, however, it was not possible to determine whether underperfusion occurred in the subendocardium 13; it is possible that the maintained coronary flow reflects an increased flow in the other regions (coronary steal). This theory may be supported by our observation that continuous or intermittent VF, in combination with continuous perfusion during VF (groups 8 and 9, respectively), produced a significant reduction in recovery of function when compared with either multidose cardioplegia or intermittent crossclamping with VF (groups 3 and 7, respectively).
The role of left ventricular distention on myocardial injury has been evaluated in isolated cat hearts perfused with crystalloid solution and subjected to cardioplegic ischemic arrest or VF with maintained coronary perfusion. 17 Increased LVEDP (induced by inflating an intraventricular balloon) during ischemia did not influence myocardial gas tension, left ventricular function, coronary blood flow, endocardial/epicardial blood flow ratio, or myocardial water content. In contrast, fibrillating hearts with maintained perfusion exhibited decreased function, impaired subendocardial blood flow, and elevated carbon dioxide tension, confirming previous results 12-15 of the detrimental effects of VF. Thus, left ventricular distention does not appear to be detrimental during periods of ischemia (no coronary flow), but distention with VF and maintained coronary perfusion is harmful. Our data support this theory; hearts in groups 8 and 9, which were subjected to VF with maintained perfusion (in which LVEDP was around 40 mm Hg) recovered to a significantly lesser degree than hearts subjected to intermittent ischemia with VF (group 7), in which contracture-generated LVEDPs rose to around 90 mm Hg. In addition, our results indicate that application of VF during crossclamp ischemia (group 7), which is applied to induce a still, nonbeating heart during surgery, does not exacerbate any ischemic injury (group 5). These results confirm the relative safety of using intermittent crossclamping with VF during coronary artery bypass surgery.
In this study, the lowest degree of recovery of LVDP was observed in hearts in which VF was induced throughout continuous (40 minutes) global ischemia (group 4); in contrast, intermittent global ischemia with the same total cumulative ischemic duration (40 minutes), either with or without induction of VF (groups 7 and 5, respectively), recovered to a significantly higher level. Similar results have previously been shown by Engelman and colleagues 18 in nonhypertrophic pig hearts. When normothermic ischemic arrest with VF was induced for 15 minutes, no maldistribution of coronary flow or loss of the hyperemic response was observed, even if this protocol was repeated 6 times with only 5 minutes of reperfusion separating the ischemic intervals each time. In contrast, prolonging the duration of ischemia with VF to 30 minutes (again with only 5 minutes of reperfusion between intervals) led to a maldistribution of flow away from the endocardium, as well as the loss of the hyperemic response. Thus, the addition of VF to ischemia had no significant detrimental effect when the ischemic durations were short (even up to 15 minutes) but, with prolonged ischemia and VF, severe myocardial damage occurred.
Our results showed that intermittent global ischemia (with or without VF) preserved postischemic recovery of LVDP to a level similar to that of multidose cardioplegia. It is tempting to speculate that intermittent ischemia may be protecting the myocardium in a manner similar to that of ischemic preconditioning 19; however, there are a number of differences between intermittent ischemia and classic preconditioning. The ischemic period is longer than those usually used to induce a preconditioning protection, although some studies 20 have used similar durations (2 episodes of 8 minutes of ischemia and 8 minutes of reperfusion) and obtained excellent preconditioning protection in pig hearts. The most obvious difference is the absence of the prolonged ischemic period after the preconditioning stimulus, but it is possible that the initial ischemia-reperfusion episode protects the subsequent episodes. In fact, this was the question addressed in a study of cardiopulmonary bypass in dogs by Abd-Elfattah, Ding, and Wechsler 21; they used a protocol similar to that of the present study, comparing 60 minutes of normothermic global ischemia to 6 episodes of 10 minutes of normothermic global ischemia and 10 minutes of reperfusion. Interestingly, adenosine triphosphate levels were maintained after the second episode of ischemia and reperfusion and were significantly higher at the end of the intermittent protocol than after sustained ischemia. In addition, purine release was limited and cardiac function was significantly better than that obtained with the sustained ischemia group. It was suggested that the intermittent ischemia and reperfusion augmented the endogenous protective mechanism or mechanisms of "preconditioning." However, the present study was not intended to examine whether intermittent global ischemia (either with or without VF) exerted any protective effect by a preconditioning mechanism, although further studies appear warranted.
Marked differences exist between the present study, the more recent clinical studies, 5-11 and previous experimental and clinical investigations, 22-25 in which a loss of cardiac protection was demonstrated when intermittent crossclamping (global ischemia) was used. These differences involve the relative durations of ischemia and reperfusion that were used; when repeated episodes of ischemia of around 10 to 20 minutes in duration were interspersed with reperfusion durations of only 3 to 5 minutes, poor cardiac protection was observed. Thus, in these studies, the ischemic duration was 3 to 6 times longer than the reperfusion interval. In contrast, in those studies in which a cardioprotective effect of intermittent crossclamping has been demonstrated, 5-11,26 a protocol was used in which repeated episodes of 10 minutes of ischemia were followed by 10 to 15 minutes of reperfusion; thus, the reperfusion duration was at least as long as the preceding duration. These results were similar to those achieved in the present study, in which intermittent ischemic durations of 10 minutes, followed by reperfusion for 10 minutes, resulted in a high level of recovery of function, regardless of whether VF was induced during ischemia. It has previously been shown 27 in the pig heart that myocardial injury associated with intermittent ischemia and reperfusion can be exacerbated by coincident VF, by shortening the period of reperfusion, extending the periods of ischemia, or by using high perfusion pressure. Of these factors, the most critical determinant to sustain adequate subendocardial perfusion was the duration of reperfusion. Benzing and coworkers 22 concluded that the longer the individual ischemic intervals or the shorter the periods of reperfusion, the greater is the likelihood of tissue injury. Thus, the time ratio of ischemic duration to reperfusion duration appears to be the important factor in determining how well the myocardium will recover. Ischemic preconditioning is induced by a short period (2-5 minutes) of ischemia followed by a period of reperfusion (5-10 minutes) before the sustained period of ischemia. A growing body of evidence suggests that the duration and number of cycles of ischemia and reperfusion necessary to confer protection may vary between species and between the end points assessed. 28 In studies in which the time ratio of ischemia to reperfusion is high (such as was the case in previous studies 22-25), any potential benefit that might have occurred as a result of ischemic preconditioning was not seen. In fact, this high ratio, together with the longer total ischemic time, caused severe myocardial injury.
In fairness to these earlier studies, the protocols of ischemia and reperfusion used in basic experimental studies were influenced by the clinical techniques of myocardial protection at that time. In the 1970s, intermittent crossclamping was used not only during coronary artery bypass surgery but also during other types of cardiac operations, such as valve replacement for valve disease or intracardiac repair for congenital heart disease. During cardiac operations, it is not possible to continue the operation during reperfusion periods; consequently, the duration of ischemia had to be much longer than the duration of reperfusion. Coronary artery bypass surgery, however, is the exception because the proximal ends of grafts can be sutured during reperfusion. Considering the circumstances mentioned above, we would suggest that intermittent ischemia with VF is suitable for myocardial preservation during coronary artery surgery but is not a good technique to protect the myocardium during other cardiac operations.
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Limitations of the study |
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TopAbstractIntroductionMaterial and methods Results Discussion Limitations of the study...Conclusion References |
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14,21 Another possible limitation of the present study may be the use of an isolated heart preparation that does not possess a collateral circulation (a notable difference from the clinical situation). In these studies, VF was maintained by continuous alternating current stimulation. This was necessary because the rat heart is too small (has insufficient mass of ventricular tissue) for VF to be maintained from a short stimulus (the "critical mass" theory). We appreciate that either a short VF stimulus or spontaneous VF is sufficient for VF to be maintained in the clinical setting and that these differences may influence the outcome of the results, since spontaneous VF has been shown to be less damaging. 12 |
Conclusion |
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TopAbstractIntroductionMaterial and methods Results Discussion Limitations of the study...Conclusion References |
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Footnotes |
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References |
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TopAbstractIntroductionMaterial and methods Results Discussion Limitations of the study...Conclusion References |
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This article has been cited by other articles:
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  D. J. Chambers and M. Fujii Reply to Mishra Eur. J. Cardiothorac. Surg., May 1, 2006; 29(5): 861 - 861. [Full Text] [PDF]
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M. Fujii and D. J. Chambers Myocardial protection with intermittent cross-clamp fibrillation: does preconditioning play a role? Eur. J. Cardiothorac. Surg., December 1, 2005; 28(6): 821 - 831. [Abstract] [Full Text] [PDF]
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 M. Fujii, M. Avkiran, and D. J Chambers Experimental studies on myocardial protection with intermittent cross-clamp fibrillation: additive effect of the sodium-hydrogen exchanger inhibitor, cariporide Ann. Thorac. Surg., April 1, 2004; 77(4): 1398 - 1407. [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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