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Ann Thorac Surg 1995;60:805-814
© 1995 The Society of Thoracic Surgeons
Department of Surgery, University of California, Los Angeles, School of Medicine, Los Angeles, California
Abstract
The spectrum of strategies for myocardial protection has led to the artificial creation of adversarial positions in regard to warm versus cold blood cardioplegia, antegrade versus retrograde delivery, and intermittent versus continuous perfusion. This report reviews the background for the aforementioned methods, that has led to the evolution of an integrated myocardial management technique that combines the advantages of the aforementioned methods to compensate for their individual shortcomings. This approach coordinates the myocardial protective strategies with the continuity of the operation so that the surgical procedure is never interrupted. It provides unimpaired vision, avoids unnecessary ischemia and cardioplegic overdose, allows aortic clamping as soon as cardiopulmonary bypass is started, permits aortic unclamping and discontinuation of bypass shortly after the technical procedure is completed, and minimizes the ration of ischemia and cardiopulmonary bypass. The preliminary results in 1,474 patients from four centers with surgeons participating in the infrastructure of this method are presented.
The objectives of every cardiac operation must be a technically perfect anatomic result, and avoidance or limitation of intraoperative damage in pursuit of this goal. Two prerequisites to accomplish these objectives are adequate visualization of the operative field to allow for surgical precision, and use of cardioprotective techniques that exclude intraoperative damage that can nullify the immediate and long-term benefits of surgical correction. Cardiac damage from inadequate myocardial protection leading to low output syndrome can prolong hospital stay and cost, and may result in delayed myocardial fibrosis. Efforts to avoid this problem have led to the development of numerous methods of intraoperative myocardial management.
The spectrum of cardioprotective strategies available for intraoperative management has led to the artificial creation of adversarial positions in regard to use of warm versus cold blood cardioplegia, antegrade versus retrograde delivery, and intermittent versus continuous perfusion. Consequently, confusion has arisen due to the self-imposed restrictions resulting when these strategies are pitted one against the other. Alignment on one side or another of this imaginary dividing line deprives the patient from deriving the benefits from each of the aforementioned methods if any are discarded because of the perception that fidelity to one technique is mandatory, and blending them into a comprehensive approach signifies either indecision or disloyalty to the ``warm versus cold'' or ``antegrade versus retrograde'' or ``continuous versus intermittent'' schools of myocardial protection.
Cardioprotective strategies, like cardiac operations, have evolved to the point that it is essential to understand and use various techniques to obtain the desired result of limitation of intraoperative damage during completion of a technically perfect operation that offers the best long-term benefit. We must refrain from using simplistic solutions for the very reason that simplicity and safety are not synonymous. For example, arterial conduits (ie, internal mammary artery or gastroepiploic artery) and mitral valve repair are evolving to be superior to the simple use of all saphenous vein grafts or routine mitral valve replacement. The test of time provides insight into the advantages and limitations of various operations, and a similar situation exists with methods of intraoperative myocardial management.
Our views of myocardial management for cardioprotection have evolved as a consequence of our experimental studies and their subsequent clinical application over the past several years, starting with the introduction of multidose crystalloid cardioplegia in 1976 [1], cold blood cardioplegia in 1978 [2, 3], warm blood cardioplegic reperfusion and warm induction in 1977 [4, 5] and 1983 [6–8], alternating between antegrade and retrograde delivery in 1989 [9], and most recently in 1994, the techniques of simultaneous antegrade/retrograde perfusion [10] and continuous cold noncardioplegic blood perfusion [11]. These experimental/clinical investigations have evolved into the method that we term ``integrated myocardial management.'' This approach to be described herein combines the advantages of various techniques to compensate for their individual shortcomings. The overriding principle is marriage of the cardioprotective strategy to the conduct of the operation so that the surgeon can work continuously (ie, without interruption of the continuity of the operation) and simultaneously (1) have unimpaired vision, (2) avoid unnecessary ischemia and cardioplegic overdose, (3) place the aortic clamp on as soon as cardiopulmonary bypass is begun, and (4) unclamp the aorta and discontinue bypass very shortly after the technical aspects of the operation are completed, while (5) minimizing the duration of ischemia and cardiopulmonary bypass and (6) maximizing the positive attributes of the strategies available currently.
This report contains a brief review of the experimental infrastructure upon which the integrated myocardial management method is based, as it combines warm/cold blood cardioplegia, antegrade/retrograde delivery, and continuous/intermittent perfusion of blood/blood cardioplegia during a single interval of aortic clamping. It includes a description of the simple and efficient way that this method is applied, together with the clinical rationale for each step. Finally, the preliminary clinical results in a consecutive series of patients in which it was undertaken are presented.
Background
The emergence of blood cardioplegia as the preferred cardioprotective strategy in the United States is based on a recent survey of more than 1,400 surgeons [12] and is attributed to its versatility, because a blood vehicle for cardioplegic delivery blends onconicity, buffering, rheology, and the antioxidant benefits [13] with its capacity to augment oxygen delivery and its ability to ``resuscitate'' the heart [8], ``prevent ischemic injury'' [14] and ``limit reperfusion damage'' [5, 15], and ``reverse ischemic/reperfusion injury [16–18].
Cold Blood Cardioplegia
The original introduction of cold blood cardioplegia underscores its capacity to ``prevent ischemic damage'' by providing data that complete recovery of function follows up to 4 hours of aortic clamping when cold multidose blood cardioplegia (at 20- to 30-minute intervals) is delivered to normal hearts [2, 14]. Unfortunately, the normal myocardium is becoming a surgical rarity, and subsequent studies [6, 8, 19, 20] show that retention of the capacity to prevent further damage in the energy- and substrate-depleted heart is an insufficient end point, and that impaired function may persist despite avoidance of further injury with primary reliance on hypothermic blood cardioplegic techniques (Fig 1
). The primary advantage of cold blood cardioplegia is that it couples the provision of myocardial nourishment [21] with the capacity, through perfusion hypothermia, to lower myocardial oxygen demands and the rate and development of ischemic damage when blood supply must be interrupted to provide the technical advantages of a quiet dry operative field, or becomes maldistributed due to coronary obstruction or retrograde routes of administration (right ventricular ischemia).
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Warm blood cardioplegia was introduced initially in 1977 to ``limit reperfusion damage'' [4, 5]. This management method was based on the knowledge that ischemia increases the vulnerability to myocardial damage if normal (unmodified) blood is used as the initial reperfusate and that this damage may, in large part, be limited by delivery of a brief (ie, 3 to 5 minutes) period of warm blood cardioplegic reperfusion before aortic unclamping, provided the formulation limits calcium influx and buffers acidosis while keeping the heart arrested to lower its demands; normothermia maximizes the rate of metabolic repair by channeling aerobic adenosine triphosphate production to reparative processes [8, 18, 22]. The subsequent clinical metabolic studies by Teoh and associates [23] confirm these experimental findings, and the reports by Kirklin [24, 25] demonstrates that warm controlled reperfusion provides a powerful tool to limit reperfusion damage and nullify the adverse effects of prolonged aortic clamping.
The concept of warm cardioplegic induction was introduced in 1983, based on the realization that induction of cardioplegia in the ischemically damaged, energy- and substrate-depleted heart is really the first phase of reperfusion [8]. This approach attempts to maximize the kinetics of repair, and minimize O2 demands by maintaining arrest. Experimental and subsequent clinical data showed that warm induction could ``actively resuscitate'' the heart and improve its tolerance to the subsequent interval of cold ischemia imposed for technical reasons [7]. Subsequent studies in damaged hearts show that the benefits of warm induction are amplified by enriching the cardioplegic solution with the amino acids glutamate and aspartate to replenish key Krebs cycle intermediates that are depleted during ischemia by enhancing aerobic metabolism and reparative processes [8].
Multidose Cardioplegia
The rationale for multidose blood cardioplegia [1] derives from the occurrence of noncoronary collateral flow in all in situ hearts [26]. This noncoronary collateral flow rewarms the hearts by replacing any carefully formulated cardioplegic solution with systemic (noncardioplegic) blood at the temperature prevailing in the extracorporeal circuit. It enters the heart via open mediastinal connections and becomes evident as blood fills coronary arteries or the coronary ostia while the aorta is clamped and the heart is decompressed. Rewarming can be circumvented by topical hypothermia, but this cumbersome adjunct may cause pulmonary complications without supplementing the cardioprotective effect of multidose cold blood cardioplegia with warm induction and reperfusion. Consequently, we have stopped routine use of topical cooling. An added benefit of multidose cardioplegia is that formulations that include buffering and hypocalcemia may limit reperfusion damage during subsequent doses between intermittent ischemic intervals [5].
Antegrade/Retrograde Perfusion: Alternating or Simultaneous
The benefits conferred by either warm or cold blood cardioplegia (of any specific formulation) are effective only if the solutions are delivered to all myocardial regions in sufficient amounts to exert their desired effects. Maldistribution of flow is commonplace in patients with coronary artery disease if principal reliance is placed on antegrade perfusion, especially when arterial conduits are used, and precludes delivery that can otherwise be achieved via newly constructed vein grafts. Retrograde cardioplegia has overcome this limitation, as good left ventricular protection follows coronary sinus or right atrial perfusion [9].
The development of transatrial coronary sinus cannulation techniques has made simple, safe, and rapid access to the coronary sinus feasible [27, 28], and the antegrade/retrograde technique is used by at least 60% of surgeons in the United States [12]. Nutritive retrograde flow to the right ventricle via the coronary sinus is, however, reduced markedly in comparison with capillary perfusion of the left ventricle, and only 70% of retrograde flow is nutritive (ie, perfuses capillaries) [29]. Conversely, 90% of antegrade perfusion nourishes the myocardium and ensures right ventricular delivery if the right coronary artery is open [29]. Metabolic studies show that conversion from antegrade to retrograde infusion results in increased O2 uptake and lactate washout (Fig 2), indicating that the different myocardial regions are perfused by the two routes of delivery.
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). Venous hypertension is prevented during simultaneous antegrade/retrograde perfusion because most of coronary sinus retroperfusion drains via thebesian veins. Experimental and clinical studies document the safety of simultaneous arterial and coronary sinus perfusion to offset concerns over causing myocardial edema during this combined perfusion method [10].
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A dry quiet operative field is a prerequisite for a technically precise cardiac surgical procedure, so most surgeons interrupt flow to achieve this goal and thereby create ``intentional ischemia.'' This can be done either by local control (coronary operations) or more commonly by intermittently stopping cardioplegic flow completely. All in situ hearts receive some noncoronary collateral flow (of unpredictable volume) that washes away the cardioplegic solution so that intermittent replenishment is needed to attain the goals of restoring hypothermia, washout of accumulated metabolites, counteraction of acidosis and edema, and provision of a cardioplegic composition to lower perfusion injury before the next period of planned ischemia. Recurrence of unwanted electromechanical activity while the aorta is clamped and cardioplegic flow is stopped is a surgical inconvenience, while simultaneously providing evidence of washout of the cardioplegic solution and signifying the retained capacity to produce sufficient adenosine triphosphate to allow contractility to resume.
Continuous perfusion has been advocated to provide the theoretic advantage of ``avoiding ischemia'' by delivery of flow continually either antegrade or retrograde [30], but this objective has never been achieved in either the beating empty [31], fibrillating [32, 33], or arrested heart [34]. Consequently, ``unintentional ischemia'' occurs during continuous perfusion and vision becomes obscured when blood cardioplegia is used, and adds a technical disadvantage to the false sense of security that continuous perfusion avoids ischemia. Additionally, cardioplegic overdose is potentially problematic if normothermic techniques are used, because electromechanical activity will recur when cardioplegia perfusion is replaced with normal blood perfusion when vision becomes obscured by blood in the operative field. There are, however, many intervals where perfusion can proceed without obscuring the operative field, such as construction of proximal anastomoses, placing sutures from the valve annulus to the valve ring (aortic or mitral), or closing the aorta or atrium.
Blood Cardioplegia, Noncardioplegic Blood Perfusion
Most surgeons stop the heart with high-dose potassium blood cardioplegia (20 mEq/L) and use multidose low-dose potassium (8 to 10 mEq/L) for the remainder of the operation because hypothermia potentiates electromechanical quiescence and more marked hyperkalemia is superfluous. The use of cold normal blood antegrade coronary perfusion was described previously and documented by Bomfim and associates [35] in studies of patients undergoing aortic valve replacement. Recent studies show that cold arrested hearts remain quiescent and both the left and right ventricles recover completely when perfused with cold (4°C to 10°C) retrograde noncardioplegic blood [11], whereas right ventricular recovery is incomplete despite a twofold greater retroperfusion of warm blood cardioplegia (Fig 4). Consequently, the advantages of continuous perfusion and nourishment can be achieved without the drawbacks of excessive hemodilution and cardioplegic overdose or coronary cannulation. These benefits are possible only with cold noncardioplegic blood because electromechanical activity returns when warm noncardioplegic blood is delivered either antegrade or retrograde, and potential right ventricular ischemia will become compounded if continuous perfusion is delivered only via the coronary sinus; oxygen demands rise if electromechanical activity (ie, beating or fibrillating) recurs in the underperfused right ventricle. The use of cold blood, therefore, provides the possibility to change from ``high K+'' to ``low K+'', to ``no K+'' during the same procedure and maintain the arrested state. Figure 5 shows the cardioplegic delivery system used currently to allow the perfusionist to alternate between blood cardioplegia and noncardioplegic blood with minimal effort.
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Coronary artery bypass grafting is the most frequently performed procedure in the United States, and the problem of intraoperative cerebral atheroemboli is increasing as more patients more than 70 years old are undergoing revascularization. The generalized nature of the atherosclerotic process leads to potential cerebral atheroemboli when the aorta is clamped [36], and this potential is amplified if the aorta is clamped tangentially repeatedly to construct proximal anastomoses. A recent report by Loop and colleagues [37], who employed our previously described blood cardioplegic myocardial management method, documents that the single clamping technique limits neurologic complications, and the benefits of clamping the aorta only once were confirmed by Aranki and associates [38]. Adoption of single clamping technique has, until now, been retarded by concern over extending ischemic time, despite evidence that mortality, morbidity, and cost are reduced despite a longer period of aortic clamping [37, 39]. These aforementioned data dispel the previous axiom that ``there is a constant battle against the clock when the aorta is clamped'' by showing that the extent of cardiac damage is related more to how the heart is protected than how long the aortic clamp is in place [37]. The capacity to deliver either blood cardioplegia or noncardioplegic blood (either antegrade or retrograde, alone or in combination) ensures provision of sufficient cardiac nourishment during aortic clamping to contradict the concept that aortic clamping and ischemic time are synonymous. For these reasons, all cardiac operations in our institution are done during a single period of aortic clamping.
Integrated Myocardial Protection
All of these aforementioned individual modalities have been combined recently into a comprehensive cardioplegic strategy, which is termed ``integrated myocardial management.'' This approach provides a flexible and simple method to take maximal advantage of each aforementioned cardioprotective method:
It evolved from concepts tested in our laboratory and incorporates the strategies of warm/cold blood cardioplegia, antegrade/retrograde delivery, continuous/intermittent infusion, and noncardioplegic blood/blood cardioplegia infusions during a single period of aortic cross-clamping (a tangential aortic clamp is not used).
The method is based on the following principles: (1) surgical precision is optimized by a dry bloodless field so that cold intermittent arrest is used to avoid ischemic damage (no perfusion during distal anastomosis or when visualization is needed), (2) ischemia is unnecessary when visualization is not problematic (ie, during construction of proximal anastomosis, placing sutures in a valve annulus or valve sewing ring) so that continuous blood or blood cardioplegia is infused retrograde during this time, (3) continuous blood perfusion of the cold arrested heart does not require cardioplegia to maintain arrest [11], thereby limiting hemodilution and hyperkalemia, (4) simultaneous antegrade and retrograde cardioplegia delivery is safe, (5) the continuity of the operation should not be interrupted to deliver perfusion (blood or cardioplegia) while the aorta is clamped, except during cardioplegic induction when cardiac manipulation may make the aortic valve incompetent, and (6) the aorta is clamped as soon (less than 1 minute) as satisfactory extracorporeal circulation is established (collapsed pulmonary artery) and cardiopulmonary bypass is discontinued within 5 minutes of aortic unclamping, as the last portion of each procedure is performed with continuous warm cardioplegia or blood perfusion.
The following description defines how this technique is used in a typical coronary artery operation. Similar methods are applied to valve operations, where cardioplegic (or noncardioplegic) flow is interrupted only when visualization is needed (eg, valve excision, placing sutures in an annulus and securing prosthesis sutures) and given continuously when visualization is nonproblematic (eg, placing sutures from annulus to valve ring, closing atrium or aorta). Cardioplegic induction is either warm or cold, and the infusion is administered antegrade and retrograde in relatively equal proportions. This is the only time that the operation is interrupted to deliver cardioplegic flow. Systemic temperature is reduced to approximately 34°C to provide a margin of safety if a perfusion accident occurs. Cardioplegic flow is stopped after cold induction so that distal anastomoses can be constructed in a dry operative field required for surgical precision while hypothermia limits the rate of development of ischemic damage. A brief (1 minute) cold blood cardioplegic infusion is delivered retrograde after completion of the distal anastomosis and followed by continuous retrograde cold noncardioplegic blood perfusion as the proximal anastomosis is constructed with the aorta vented. Conversion from cold blood cardioplegia to cold noncardioplegia blood maintains arrest, hypothermia, and cardiac nourishment to both the left and right ventricles [11], while reducing cardioplegia dose and hemodilution. The safety of continuous cold noncardioplegic blood perfusion suggests that cold perfusion of the heart can be used to avoid ischemia during aspects of the operation when the aorta is clamped and visualization is not impeded by continuous coronary perfusion [11]. A brief antegrade cardioplegic infusion is delivered at the conclusion of each proximal anastomosis while the suture line is secured and the graft tip is fashioned for the next anastomosis. This antegrade infusion ensures cardioplegic distribution to the right ventricle, which may be perfused inadequately by retrograde delivery [29, 40, 41], and keeps the heart arrested during the next ischemic interval.
The sequence is repeated for each distal and proximal anastomosis, and the internal mammary anastomosis is performed during rewarming of the patient and cardioplegic solutions. The warm blood cardioplegic reperfusate is delivered first antegrade and then retrograde after the last proximal anastomosis is constructed. This is followed immediately by retrograde perfusion of warm noncardioplegic blood to wash out the cardioplegic solution and allow the heart to begin beating as the proximal anastomosis is completed. This method usually allows discontinuation of bypass within 5 minutes of removing the aortic clamp, as continuous cardioplegic and noncardioplegic blood perfusion reduces ischemic time despite performance of all anastomoses during a single interval of aortic clamping.
Recent reports [37] confirm the concept that myocardial damage is related more to the method of myocardial protection than the duration of aortic cross-clamping, and show also that the incidence of cerebral complications is reduced by avoiding the use of tangential aortic clamps. This avoidance of clamping probably reduces potential dislodgement of intraaortic atheromatous debris [36]. Ischemic duration is also shortened during valve procedures because cold continuous blood or blood cardioplegia can be infused during much of the procedure, and interrupted only when visualization is desired. Table 1 shows results of the integrated myocardial management method in a consecutive series of adult patients undergoing revascularization and valve operations [35].
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Warm Blood Cardioplegia Without Hypothermia
In 1950, Bigelow and associates [42], from the University of Toronto, introduced hypothermia, an important component of myocardial protection that slows cardiac metabolism while limiting ischemic injury during the periods of aortic cross-clamping needed to optimize operative conditions to provide a quiet bloodless field, and Shumway and Lower [43], in 1959, reinforced this cardioprotective strategy. These observations led to the surgical axiom that ``all is well if the heart is made as cold as possible'' and that there is a ``battle against the clock'' when the aorta is clamped. Recent data on the cardioprotective benefits of warm blood cardioplegia suggest that these axioms are outdated, and that intraoperative damage is related more to how the heart is protected than how the aorta is cross-clamped.
Hypothermia may also impose certain adverse consequences, including shifting the oxygen-hemoglobin dissociation curve leftward, retarding sodium potassium adenosine triphosphate to promote edema, reducing membrane stability, increasing blood viscosity, and activating platelets, leukocytes, and complement [30, 44]. These concerns led the surgical team at the University of Toronto (where hypothermia was introduced) to suggest warm blood cardioplegia without hypothermia as a cardioprotective strategy, where the patient and the heart are maintained at 37°C and the cardioplegic flow is delivered continually when feasible. This concept is based on the fact that electromechanical arrest substantially decreases myocardial oxygen requirements to low levels (from 10 mL • 100 g-1 • min-1 to 1 mL • 100 g-1 • min-1), with little further reduction in O2 demands accomplished by adding profound hypothermia. Therefore, they propose that myocardial oxygen demands can be met with continuous warm cardioplegia as long as the heart is kept arrested [44, 45]. This occurs only if there is homogenous and adequate distribution of cardioplegic solutions, and this has yet to be proven.
There is limited current experimental infrastructure for the clinical application of this attractive hypothesis, although preliminary results in patients are encouraging [30, 44, 46]. The continuous warm cardioplegic approach is in contrast to early attempts of 37°C continuous coronary perfusion with normal blood, where the energy requirements remained high when the heart was either kept beating or fibrillated. An added potential advantage of this method is that ischemia is avoided if 37°C blood cardioplegic flow is continuous and postischemic reperfusion injury cannot occur because the heart is maintained in a constant aerobic state. Finally, systemic normothermia may limit the possible detrimental effects of hypothermic cardiopulmonary bypass on coagulation and other organ systems.
Although early results are encouraging, they are not superior to results using techniques with an extensive experimental infrastructure in which warm and cold antegrade and retrograde methods are applied as described above. Subsequent experimental data now show some unforeseen problems of the warm continuous cardioplegic technique, and many questions have arisen and remain unanswered (see below). Experimental studies show the superiority of intermittent cold antegrade and antegrade/retrograde blood cardioplegic techniques over continuous warm antegrade or retrograde cardioplegia, especially in protecting areas of jeopardized myocardium [47, 48]. Intermittent interruption of continuous warm antegrade or retrograde cardioplegia as must be done clinically to optimize visualization during construction of distal anastomoses is particularly deleterious in vulnerable regions, whereas intermittent cold antegrade/retrograde cardioplegia provides superior results under these circumstances [49].
Additional missing data on the role of warm heart surgical techniques include (1) what flow rates are needed to adequately supply the arrested heart, and whether continuous infusion will ensure all areas receive sufficient flow to meet metabolic needs (for example, the normal right ventricle, or when right or left ventricular hypertrophy is present), (2) how long the blood flow can be interrupted safely before ischemic changes take place, and how these changes can be overcome with resumption of cardioplegic flow, (3) what is the ideal cardioplegic composition (ie, is it different from the composition used for intermittent cold blood cardioplegia), (4) whether warm heart operation, with the patient at 37°C, leads to increased bleeding due to the inherently higher flow rates that must be maintained, (5) whether cerebral complications increase if nonpulsatile flows are used with inherently lower perfusion pressure, and (6) whether more fatal ``perfusion accidents'' will occur due to the limited time (3 to 4 minutes) available to the perfusionists to stop extracorporeal circulation and correct the problem before cerebral damage occurs.
Finally, experimental and clinical studies have demonstrated that the normal and ischemically damaged heart can be protected safely for 2 to 4 hours of aortic clamping with intermittent cold blood cardioplegia, especially if bracketed with an interval of warm induction and reperfusion to ``resuscitate'' the heart and ``limited reperfusion injury'' (see earlier sections on Blood Cardioplegia and Warm Induction). These intermittent cardioplegia techniques provide the ideal technical conditions of a bloodless field needed for surgical precision, while simultaneously ensuring metabolic correction of the consequences of ischemia, which are minimized by hypothermic protection. Consequently, abandonment of cold cardioplegic techniques in favor of the warm approach is not recommended until a sufficient infrastructure of data is accumulated to answer the aforementioned questions. Postoperative univentricular or biventricular failure or death after continuous warm retrograde blood cardioplegia reflects a problem that hypothermia and antegrade cardioplegia might avoid, and which is caused directly by an inflexible approach based on the misconception that ``all is well if the heart is perfused continually.'' We suspect that warm blood cardioplegic techniques will become adjunctive to hypothermic techniques, rather an a replacement for them.
Warm Blood Cardioplegia: Starting Points, End Points, and Median Lethal Dose
Cardioplegic research has not, in general, followed established procedures for drug testing. The median lethal dose concept is used routinely in pharmacologic studies, whereby the starting point is an intervention in a model that kills 50% of live organisms; its effectiveness or end point is compared with this starting point. Consequently, an intervention is (1) ineffective if it does not change the starting point, (2) toxic if less than 50% viability results, and (3) defined as effective by how much more than 50% viability it produces. The starting point of most studies of myocardial protection is the normal heart, so that the median lethal dose approach has no relevance to them, inasmuch as any intervention that fails to maintain biochemical and mechanical integrity must be considered ineffective. Consequently, the normal heart model is useful only to test the safety of interventions such as multidose cold blood cardioplegia that allow normal biochemical and mechanical function to recover completely after 4 hours of aortic clamping; the starting point is the same as the end point.
Cardiac surgeons rarely get the chance to operate on normal hearts, so our clinical starting point conforms more closely to the median lethal dose model in pharmacologic studies. Experimental study of the energy- and substrate-depleted heart model has been useful to develop strategies intended to metabolically resuscitate the heart, because cold cardioplegia confers no metabolic benefit other than offsetting further damage. The concepts of warm induction and reperfusion of blood cardioplegia developed from such models, whereby extensive testing of various cardioplegic modifications resulted in a regimen that restored function to ischemically damaged hearts, with the rationale for individual factors described previously. Normothermia is only one element in this regimen and is included to optimize the rate of metabolic recovery, which is retarded by hypothermia.
The objective of adding normothermic blood cardioplegia is to use a cardioprotective strategy in the impaired myocardium that acts in concert with mechanical repair to restore near-normal biochemical and mechanical function (that is, a normal starting point). Conversely, cold cardioplegic techniques alone can only prevent further damage so that total reliance is placed on the mechanical benefits of operative correction to improve cardiac performance. For example, the operative mortality rate for the surgical treatment of cardiogenic shock is approximately 50% with conventional hypothermic cardioprotective techniques because left ventricular power failure progresses unabatedly despite revascularization [50, 51]. In contrast, use of warm blood cardioplegic induction and reperfusion lessens the duration of postoperative circulatory support and improves mortality [52].
Intermittent Warm Blood Cardioplegia
Intermittent warm blood cardioplegia may theoretically prove beneficial without hypothermic supplementation if the formulations result in metabolic resuscitation and limitation of reperfusion damage, as documented previously when normothermic methods were used as an adjunct to intermittent cold ischemia in energy-depleted hearts [14]. Confirmation of this application of intermittent warm ischemia requires testing in globally ischemic hearts that would otherwise develop biochemical or mechanical dysfunction if no intervention was undertaken (for example, aortic unclamping without cardioplegia). The importance of this type of analysis is drawn from our previous studies showing cold intermittent blood cardioplegia that fully protected normal heart muscle for 4 hours, but failed to amplify function in the stressed myocardium [8]. Postischemic dysfunction in hearts protected with 2 hours of intermittent cold blood cardioplegia introduced immediately after 45 minutes of normothermic ischemia (ie, to simulate the time needed for operative repair) was comparable with that when the aorta was unclamped immediately after the 45-minute ischemic insult. The ``end point'' equalled the ``starting point.''
The strategic goal is to make the ``end point'' exceed the ``starting point,'' so intermittent warm cardioplegia would be considered ineffective if an end point equalled a starting point of deranged metabolism and function as observed after simple aortic unclamping after a period of unprotected ischemia. Use of a normal heart to demonstrate that intermittent warm blood cardioplegia restores normal metabolic and contractile function may lead to the misleading conclusion that intermittent warm ischemia is safe in jeopardized muscle. For example, our previous studies showing the limitations of intermittent cold blood cardioplegia as the sole cardioprotective strategy in the stressed myocardium [8] paved the way for use of warm blood cardioplegic induction and reperfusion.
Hopefully, subsequent studies in damaged hearts will be undertaken, because the results may be of fundamental importance in planning cardioprotective strategies devoid of the recognized capacity of hypothermia to delay the rate of development of cell damage. Relatively homogeneous flow distribution via antegrade and retrograde delivery would probably be needed for intermittent normothermic cardioplegia to be effective. Additionally, metabolic interventions that precondition the heart [53] must be evaluated in the aforementioned way to justify their use in allowing exclusion of hypothermic techniques.
Conclusions
The versatility of blood cardioplegia provides the cardiac surgeon with a tool to actively treat the jeopardized myocardium as well as to prevent ischemic damage, provided attention is directed toward ensuring adequate delivering of the cardioplegic solutions. No exogenous blood is needed to deliver blood cardioplegia, as a readily available blood source exists within the extracorporeal circuit during all cardiac operations when the patient's blood volume mixes with the clear priming fluid. The expense of depriving the patient of the potential benefits of blood cardioplegia includes increased perioperative mortality, prolonged intensive care unit stays, and development of late cardiac fibrosis owing to necrosis caused by less adequate protection, and far outweighs the monetary cost of its use.
The aforementioned benefits of enhanced oxygen carrying capacity, active resuscitation, avoidance of reperfusion damage, limitation of hemodilution, provision of onconicity, buffering, rheologic effects, and endogenous oxygen free radical scavengers enumerate only the known benefits of using blood as the vehicle for delivering oxygenated cardioplegia. We are confident that further studies will reveal other naturally occurring blood components (ie, enzymes, cofactors, substrates, electrolytes) that are important and would otherwise need to be added to any artificially constructed solution.
The objective of every cardiac operation must be a technically perfect anatomic result, and avoidance or limitation of intraoperative damage in pursuit of this goal. Two prerequisites to accomplish these objectives are adequate visualization of the operative field to allow for surgical precision, and use of cardioprotective techniques that exclude intraoperative damage that can nullify the immediate and long-term benefits of surgical correction of any acquired or congenital defect. Cardiac damage from inadequate myocardial protection leading to low output syndrome can prolong hospital stay and cost, and may result in delayed myocardial fibrosis. Efforts to avoid this problem have led to the development of numerous methods of intraoperative myocardial management.
Footnotes
Presented at the International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, Sep 25--28, 1994.
Address reprint requests to Dr Buckberg, Department of Surgery, Rm B2-375 CHS, UCLA Medical Center, PO Box 95741, Los Angeles, CA 90095-1741.
References
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 W. B. Gerritsen, W.-J. P. van Boven, D. S. Boss, F. J. Haas, E. P. van Dongen, and L. P. Aarts Malondialdehyde in plasma, a biomarker of global oxidative stress during mini-CABG compared to on- and off-pump CABG surgery: a pilot study Interactive CardioVascular and Thoracic Surgery, February 1, 2006; 5(1): 27 - 31. [Abstract] [Full Text] [PDF]
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B. Ji, M. Liu, F. Lu, J. Liu, G. Wang, Z. Feng, and Q. Hu Warm induction cardioplegia and reperfusion dose influence the occurrence of the post CABG TnI level Interactive CardioVascular and Thoracic Surgery, February 1, 2006; 5(1): 67 - 70. [Abstract] [Full Text] [PDF]
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C. Schlensak Myocardial protection in congenital heart surgery MMCTS, November 29, 2005; 2005(1129): 729. [Abstract] [Full Text] [PDF]
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M. P. Siegenthaler Antegrade administration of cardioplegia MMCTS, June 28, 2005; 2005(0628): 695. [Abstract] [Full Text] [PDF]
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H. Okuyama, K. Hashimoto, H. Kurosawa, K. Tanaka, Y. Sakamoto, and K. Shiratori Midterm results of Manouguian double valve replacement: Comparison with standard double valve replacement J. Thorac. Cardiovasc. Surg., April 1, 2005; 129(4): 869 - 874. [Abstract] [Full Text] [PDF]
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 W.-J. P. van Boven, W. B. M. Gerritsen, P. Zanen, J. C. Grutters, H. P. A. van Dongen, A. Bernard, and L. P. H. J. Aarts Pneumoproteins as a Lung-Specific Biomarker of Alveolar Permeability in Conventional On-pump Coronary Artery Bypass Graft Surgery vs Mini-Extracorporeal Circuit: A Pilot Study Chest, April 1, 2005; 127(4): 1190 - 1195. [Abstract] [Full Text] [PDF]
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P. Modi, M.-S. Suleiman, B. Reeves, A. Pawade, A.J. Parry, G.D. Angelini, and M. Caputo Myocardial metabolic changes during pediatric cardiac surgery: A randomized study of 3 cardioplegic techniques J. Thorac. Cardiovasc. Surg., July 1, 2004; 128(1): 67 - 75. [Abstract] [Full Text] [PDF]
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F. Sayk, S. Kruger, J.F. M. Bechtel, A. C. Feller, H. H. Sievers, and C. Bartels Significant damage of the conduction system during cardioplegic arrest is due to necrosis not apoptosis Eur. J. Cardiothorac. Surg., May 1, 2004; 25(5): 801 - 806. [Abstract] [Full Text] [PDF]
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T. Doenst, C. Schlensak, and F. Beyersdorf Cardioplegia in pediatric cardiac surgery: do we believe in magic? Ann. Thorac. Surg., May 1, 2003; 75(5): 1668 - 1677. [Abstract] [Full Text] [PDF]
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R. Ascione, M. Caputo, and G. D. Angelini Off-pump coronary artery bypass grafting: not a flash in the pan Ann. Thorac. Surg., January 1, 2003; 75(1): 306 - 313. [Abstract] [Full Text] [PDF]
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M. Caputo, P. Modi, H. Imura, A. Pawade, A. J. Parry, M-S. Suleiman, and G. D. Angelini Cold blood versus cold crystalloid cardioplegia for repair of ventricular septal defects in pediatric heart surgery: a randomized controlled trial Ann. Thorac. Surg., August 1, 2002; 74(2): 530 - 535. [Abstract] [Full Text] [PDF]
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R. Ascione, S. Al-Ruzzeh, K. Amer, and G. D Angelini Subsystem organ function during coronary surgery Perfusion, July 1, 2002; 17(4): 295 - 303. [Abstract] [PDF]
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R. Ascione, M. Caputo, W.J. Gomes, A.A. Lotto, A.J. Bryan, G.D. Angelini, and M.-S. Suleiman Myocardial injury in hypertrophic hearts of patients undergoing aortic valve surgery using cold or warm blood cardioplegia Eur. J. Cardiothorac. Surg., March 1, 2002; 21(3): 440 - 446. [Abstract] [Full Text] [PDF]
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M. R. Graham, R. K. Warrian, L. G. Girling, L. Doiron, G. R. Lefevre, M. Cheang, and W. A. C. Mutch Fractal or biologically variable delivery of cardioplegic solution prevents diastolic dysfunction after cardiopulmonary bypass J. Thorac. Cardiovasc. Surg., January 1, 2002; 123(1): 63 - 71. [Abstract] [Full Text] [PDF]
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W.B.M. Gerritsen, W.J.P. van Boven, A.H.G. Driessen, F.J.L.M. Haas, and L.P.H.J. Aarts Off-pump versus on-pump coronary artery bypass grafting: oxidative stress and renal function Eur. J. Cardiothorac. Surg., November 1, 2001; 20(5): 923 - 929. [Abstract] [Full Text] [PDF]
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R. Baretti, A. Mizuno, G. D. Buckberg, H. H. Young, and R. Hetzer Cold continuous antegrade blood cardioplegia: high versus low hematocrit Eur. J. Cardiothorac. Surg., May 1, 2001; 19(5): 640 - 646. [Abstract] [Full Text] [PDF]
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 H. Imura, M. Caputo, A. Parry, A. Pawade, G. D. Angelini, and M.-S. Suleiman Age-Dependent and Hypoxia-Related Differences in Myocardial Protection During Pediatric Open Heart Surgery Circulation, March 20, 2001; 103(11): 1551 - 1556. [Abstract] [Full Text] [PDF]
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T. Yokoyama, F. J. Baumgartner, A. Gheissari, E. R. Capouya, G. P. Panagiotides, and R. J. Declusin Off-pump versus on-pump coronary bypass in high-risk subgroups Ann. Thorac. Surg., November 1, 2000; 70(5): 1546 - 1550. [Abstract] [Full Text] [PDF]
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Z.-K. Wu, M. R. Tarkka, E. Pehkonen, L. Kaukinen, E. L. Honkonen, and S. Kaukinen Beneficial effects of ischemic preconditioning on right ventricular function after coronary artery bypass grafting Ann. Thorac. Surg., November 1, 2000; 70(5): 1551 - 1557. [Abstract] [Full Text] [PDF]
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R. Ascione, M. Caputo, G. Calori, C. T. Lloyd, M. J. Underwood, and G. D. Angelini Predictors of Atrial Fibrillation After Conventional and Beating Heart Coronary Surgery : A Prospective, Randomized Study Circulation, September 26, 2000; 102(13): 1530 - 1535. [Abstract] [Full Text] [PDF]
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S. M. Weman, P. J. Karhunen, A. Penttila, A. A. Jarvinen, and U.-S. Salminen Reperfusion injury associated with one-fourth of deaths after coronary artery bypass grafting Ann. Thorac. Surg., September 1, 2000; 70(3): 807 - 812. [Abstract] [Full Text] [PDF]
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 A. F Elwatidy and A. F Elwatidy Coronary Sinus Injuries Following Retrograde Cardioplegia Asian Cardiovasc Thorac Ann, June 1, 2000; 8(2): 118 - 120. [Abstract] [Full Text] [PDF]
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M. Caputo, R. Ascione, G. D. Angelini, M-S. Suleiman, and A. J. Bryan The end of the cold era: from intermittent cold to intermittent warm blood cardioplegia Eur. J. Cardiothorac. Surg., November 1, 1999; 14(5): 467 - 475. [Abstract] [Full Text] [PDF]
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G. H. Li, S. X. Chen, E. X. Lu, Q. Q. Liu, and Y. J. Li Ischemic Preconditioning Improves Protection with Cold Blood Cardioplegia Asian Cardiovasc Thorac Ann, September 1, 1999; 7(3): 173 - 176. [Abstract] [Full Text] [PDF]
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A. M.F. Elwatidy, M. A. Fadalah, E. A. Bukhari, K. A. Aljubair, A. Syed, A. K. Ashmeg, and M. R. Alfagih Antegrade crystalloid cardioplegia vs antegrade/retrograde cold and tepid blood cardioplegia in CABG Ann. Thorac. Surg., August 1, 1999; 68(2): 447 - 453. [Abstract] [Full Text] [PDF]
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R. Ascione, C. T. Lloyd, M. J. Underwood, W. J. Gomes, and G. D. Angelini On-pump versus off-pump coronary revascularization: evaluation of renal function Ann. Thorac. Surg., August 1, 1999; 68(2): 493 - 498. [Abstract] [Full Text] [PDF]
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M. Caputo, W.C. Dihmis, A.J. Bryan, M.-S. Suleiman, and G.D. Angelini Warm blood hyperkalaemic reperfusion (`hot shot') prevents myocardial substrate derangement in patients undergoing coronary artery bypass surgery Eur. J. Cardiothorac. Surg., May 1, 1999; 13(5): 559 - 564. [Abstract] [Full Text] [PDF]
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G. Li, S. Chen, E. Lu, and Y. Li Ischemic preconditioning improves preservation with cold blood cardioplegia in valve replacement patients Eur. J. Cardiothorac. Surg., May 1, 1999; 15(5): 653 - 657. [Abstract] [Full Text] [PDF]
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R. Ascione, C. T. Lloyd, W. J. Gomes, M. Caputo, A. J. Bryan, and G. D. Angelini Beating versus arrested heart revascularization: evaluation of myocardial function in a prospective randomized study Eur. J. Cardiothorac. Surg., May 1, 1999; 15(5): 685 - 690. [Abstract] [Full Text] [PDF]
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Y. Bar-El, Z. Adler, A. Kophit, V. Kertzman, S. Sawaed, A. Ross, O. Cohen, and S. Milo Myocardial protection in operations requiring more than 2 h of aortic cross-clamping Eur. J. Cardiothorac. Surg., March 1, 1999; 15(3): 271 - 275. [Abstract] [Full Text] [PDF]
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J. S. Lawton, P.-W. Hsia, and R. J. Damiano Jr The adenosine-triphosphate-sensitive potassium-channel opener pinacidil is effective in blood cardioplegia Ann. Thorac. Surg., September 1, 1998; 66(3): 768 - 773. [Abstract] [Full Text] [PDF]
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T. A Abdel Aziz, N. Al Khaja, M. A Ali, A. S Maklad, M. F Bassiouny, M. Turner, and D. G Roberts Antegrade-Retrograde Cardioplegia for Myocardial Protection During Coronary Artery Bypass Graft Surgery Asian Cardiovasc Thorac Ann, September 1, 1998; 6(3): 188 - 194. [Abstract] [Full Text] [PDF]
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J. N. Young, I. O. Choy, N. K. Silva, D. Y. Obayashi, and H. E. Barkan ANTEGRADE COLD BLOOD CARDIOPLEGIA IS NOT DEMONSTRABLY ADVANTAGEOUS OVER COLD CRYSTALLOID CARDIOPLEGIA IN SURGERY FOR CONGENITAL HEART DISEASE J. Thorac. Cardiovasc. Surg., December 1, 1997; 114(6): 1002 - 1009. [Abstract] [Full Text]
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E.-X. Lu, S.-X. Chen, M.-D. Yuan, T.-H. Hu, H.-C. Zhou, W.-J. Luo, G.-H. Li, and L.-M. Xu Preconditioning Improves Myocardial Preservation in Patients Undergoing Open Heart Operations Ann. Thorac. Surg., November 1, 1997; 64(5): 1320 - 1324. [Abstract] [Full Text]
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P. C Mannebach and J. J Sistino Monitoring aortic root effluent during retrograde cardioplegia delivery Perfusion, September 1, 1997; 12(5): 317 - 323. [Abstract] [PDF]
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K. V. Arom, R. W. Emery, R. J. Petersen, and J. W. Bero Evaluation of 7,000+ Patients With Two Different Routes of Cardioplegia Ann. Thorac. Surg., June 1, 1997; 63(6): 1619 - 1624. [Abstract] [Full Text]
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G. E. Cimochowski, M. D. Harostock, and P. J. Foldes MINIMAL OPERATIVE MORTALITY IN PATIENTS UNDERGOING CORONARY ARTERY BYPASS WITH SIGNIFICANT LEFT VENTRICULAR DYSFUNCTION BY MAXIMIZATION OF METABOLIC AND MECHANICAL SUPPORT J. Thorac. Cardiovasc. Surg., April 1, 1997; 113(4): 655 - 666. [Abstract] [Full Text]
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 V. D. Schepkin, I. O. Choy, and T. F. Budinger Sodium alterations in isolated rat heart during cardioplegic arrest J Appl Physiol, December 1, 1996; 81(6): 2696 - 2702. [Abstract] [Full Text] [PDF]
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L. Torracca, E. Pasini, S. Curello, C. Ceconi, G. Coletti, O. Alfieri, R. Solfrini, and R. Ferrari Continuous Versus Intermittent Warm Blood Cardioplegia: Functional and Energetics Changes Ann. Thorac. Surg., October 1, 1996; 62(4): 1172 - 1179. [Abstract] [Full Text]
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I. B. Krukenkamp and S. Levitsky Myocardial Protection: Modern Studies Ann. Thorac. Surg., May 1, 1996; 61(5): 1581 - 1582. [Full Text]
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J. C. Cleveland Jr, D. R. Meldrum, R. T. Rowland, A. Banerjee, and A. H. Harken Optimal Myocardial Preservation: Cooling, Cardioplegia, and Conditioning Ann. Thorac. Surg., February 1, 1996; 61(2): 760 - 768. [Abstract] [Full Text]
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