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  1. 1. II: Surgical Myocardial ProtectionUpdate on Current Techniques of Myocardial ProtectionGerald D. Buckberg, MDDepartment of Surgery, University of California, Los Angeles, School of Medicine, Los Angeles, CaliforniaAbstractThe spectrum of strategies for myocardial protection has led to the artificial creation ofadversarial positions in regard to warm versus cold blood cardioplegia, antegrade versusretrograde delivery, and intermittent versus continuous perfusion. This report reviews thebackground for the aforementioned methods, that has led to the evolution of an integratedmyocardial management technique that combines the advantages of the aforementionedmethods to compensate for their individual shortcomings. This approach coordinates themyocardial protective strategies with the continuity of the operation so that the surgicalprocedure is never interrupted. It provides unimpaired vision, avoids unnecessary ischemiaand cardioplegic overdose, allows aortic clamping as soon as cardiopulmonary bypass isstarted, permits aortic unclamping and discontinuation of bypass shortly after the technicalprocedure is completed, and minimizes the ration of ischemia and cardiopulmonary bypass.The preliminary results in 1,474 patients from four centers with surgeons participating inthe infrastructure of this method are presented.The objectives of every cardiac operation must be a technically perfect anatomic result, andavoidance or limitation of intraoperative damage in pursuit of this goal. Two prerequisitesto accomplish these objectives are adequate visualization of the operative field to allow forsurgical precision, and use of cardioprotective techniques that exclude intraoperativedamage that can nullify the immediate and long-term benefits of surgical correction.Cardiac damage from inadequate myocardial protection leading to low output syndromecan prolong hospital stay and cost, and may result in delayed myocardial fibrosis. Efforts toavoid this problem have led to the development of numerous methods of intraoperativemyocardial management.The spectrum of cardioprotective strategies available for intraoperative management has ledto the artificial creation of adversarial positions in regard to use of warm versus cold bloodcardioplegia, antegrade versus retrograde delivery, and intermittent versus continuousperfusion. Consequently, confusion has arisen due to the self-imposed restrictions resultingwhen these strategies are pitted one against the other. Alignment on one side or another ofthis imaginary dividing line deprives the patient from deriving the benefits from each of theaforementioned methods if any are discarded because of the perception that fidelity to onetechnique is mandatory, and blending them into a comprehensive approach signifies eitherindecision or disloyalty to the ``warm versus cold or ``antegrade versus retrograde or``continuous versus intermittent schools of myocardial protection.
  2. 2. Cardioprotective strategies, like cardiac operations, have evolved to the point that it isessential to understand and use various techniques to obtain the desired result of limitationof intraoperative damage during completion of a technically perfect operation that offers thebest long-term benefit. We must refrain from using simplistic solutions for the very reasonthat simplicity and safety are not synonymous. For example, arterial conduits (ie, internalmammary artery or gastroepiploic artery) and mitral valve repair are evolving to be superiorto the simple use of all saphenous vein grafts or routine mitral valve replacement. The testof time provides insight into the advantages and limitations of various operations, and asimilar situation exists with methods of intraoperative myocardial management.Our views of myocardial management for cardioprotection have evolved as a consequenceof our experimental studies and their subsequent clinical application over the past severalyears, starting with the introduction of multidose crystalloid cardioplegia in 1976 [1], coldblood cardioplegia in 1978 [2, 3], warm blood cardioplegic reperfusion and warm inductionin 1977 [4, 5] and 1983 [6–8], alternating between antegrade and retrograde delivery in1989 [9], and most recently in 1994, the techniques of simultaneous antegrade/retrogradeperfusion [10] and continuous cold noncardioplegic blood perfusion [11]. Theseexperimental/clinical investigations have evolved into the method that we term ``integratedmyocardial management. This approach to be described herein combines the advantages ofvarious techniques to compensate for their individual shortcomings. The overridingprinciple is marriage of the cardioprotective strategy to the conduct of the operation so thatthe surgeon can work continuously (ie, without interruption of the continuity of theoperation) and simultaneously (1) have unimpaired vision, (2) avoid unnecessary ischemiaand cardioplegic overdose, (3) place the aortic clamp on as soon as cardiopulmonarybypass is begun, and (4) unclamp the aorta and discontinue bypass very shortly after thetechnical aspects of the operation are completed, while (5) minimizing the duration ofischemia and cardiopulmonary bypass and (6) maximizing the positive attributes of thestrategies available currently.This report contains a brief review of the experimental infrastructure upon which theintegrated myocardial management method is based, as it combines warm/cold bloodcardioplegia, antegrade/retrograde delivery, and continuous/intermittent perfusion of blood/blood cardioplegia during a single interval of aortic clamping. It includes a description ofthe simple and efficient way that this method is applied, together with the clinical rationalefor each step. Finally, the preliminary clinical results in a consecutive series of patients inwhich it was undertaken are presented.BackgroundThe emergence of blood cardioplegia as the preferred cardioprotective strategy in theUnited States is based on a recent survey of more than 1,400 surgeons [12] and is attributedto its versatility, because a blood vehicle for cardioplegic delivery blends onconicity,buffering, rheology, and the antioxidant benefits [13] with its capacity to augment oxygendelivery 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].
  3. 3. Cold Blood CardioplegiaThe original introduction of cold blood cardioplegia underscores its capacity to ``preventischemic damage by providing data that complete recovery of function follows up to 4hours of aortic clamping when cold multidose blood cardioplegia (at 20- to 30-minuteintervals) is delivered to normal hearts [2, 14]. Unfortunately, the normal myocardium isbecoming a surgical rarity, and subsequent studies [6, 8, 19, 20] show that retention of thecapacity to prevent further damage in the energy- and substrate-depleted heart is aninsufficient end point, and that impaired function may persist despite avoidance of furtherinjury with primary reliance on hypothermic blood cardioplegic techniques (Fig 1 ). Theprimary advantage of cold blood cardioplegia is that it couples the provision of myocardialnourishment [21] with the capacity, through perfusion hypothermia, to lower myocardialoxygen demands and the rate and development of ischemic damage when blood supplymust be interrupted to provide the technical advantages of a quiet dry operative field, orbecomes maldistributed due to coronary obstruction or retrograde routes of administration(right ventricular ischemia). Fig 1. . Left ventricular performance 30 minutes after blood reperfusion. Note (1) normal ventricular performance after warm (37°C) induction of aspartate-enriched glutamate blood cardioplegia, (2) moderate depression in ventricular performance after warm induction with glutamate blood cardioplegia, and (3) severe depression in ventricular failure after cold (4°C) blood cardioplegia. (LAP = left atrial pressure; SWI = stroke work index.) (Reprinted with permission from Rosenkranz ER, Okamoto F, Buckberg GD, Robertson JM, Vinten-Johansen J, View larger version (21K): Bugyi H. Safety of prolonged aortic clamping with [in this window] blood cardioplegia. III. Aspartate enrichment of [in a new window] glutamate-blood cardioplegia in energy-depleted hearts after ischemic and reperfusion injury. J Thorac Cardiovasc Surg 1986;91:428--35.)Warm Blood CardioplegiaWarm blood cardioplegia was introduced initially in 1977 to ``limit reperfusion damage[4, 5]. This management method was based on the knowledge that ischemia increases thevulnerability to myocardial damage if normal (unmodified) blood is used as the initialreperfusate and that this damage may, in large part, be limited by delivery of a brief (ie, 3 to5 minutes) period of warm blood cardioplegic reperfusion before aortic unclamping,provided the formulation limits calcium influx and buffers acidosis while keeping the heartarrested to lower its demands; normothermia maximizes the rate of metabolic repair by
  4. 4. channeling aerobic adenosine triphosphate production to reparative processes [8, 18, 22].The subsequent clinical metabolic studies by Teoh and associates [23] confirm theseexperimental findings, and the reports by Kirklin [24, 25] demonstrates that warmcontrolled reperfusion provides a powerful tool to limit reperfusion damage and nullify theadverse effects of prolonged aortic clamping.The concept of warm cardioplegic induction was introduced in 1983, based on therealization that induction of cardioplegia in the ischemically damaged, energy- andsubstrate-depleted heart is really the first phase of reperfusion [8]. This approach attemptsto maximize the kinetics of repair, and minimize O2 demands by maintaining arrest.Experimental and subsequent clinical data showed that warm induction could ``activelyresuscitate the heart and improve its tolerance to the subsequent interval of cold ischemiaimposed for technical reasons [7]. Subsequent studies in damaged hearts show that thebenefits of warm induction are amplified by enriching the cardioplegic solution with theamino acids glutamate and aspartate to replenish key Krebs cycle intermediates that aredepleted during ischemia by enhancing aerobic metabolism and reparative processes [8].Multidose CardioplegiaThe rationale for multidose blood cardioplegia [1] derives from the occurrence ofnoncoronary collateral flow in all in situ hearts [26]. This noncoronary collateral flowrewarms the hearts by replacing any carefully formulated cardioplegic solution withsystemic (noncardioplegic) blood at the temperature prevailing in the extracorporeal circuit.It enters the heart via open mediastinal connections and becomes evident as blood fillscoronary arteries or the coronary ostia while the aorta is clamped and the heart isdecompressed. Rewarming can be circumvented by topical hypothermia, but thiscumbersome adjunct may cause pulmonary complications without supplementing thecardioprotective effect of multidose cold blood cardioplegia with warm induction andreperfusion. Consequently, we have stopped routine use of topical cooling. An addedbenefit of multidose cardioplegia is that formulations that include buffering andhypocalcemia may limit reperfusion damage during subsequent doses between intermittentischemic intervals [5].Antegrade/Retrograde Perfusion: Alternating or SimultaneousThe benefits conferred by either warm or cold blood cardioplegia (of any specificformulation) are effective only if the solutions are delivered to all myocardial regions insufficient amounts to exert their desired effects. Maldistribution of flow is commonplace inpatients with coronary artery disease if principal reliance is placed on antegrade perfusion,especially when arterial conduits are used, and precludes delivery that can otherwise beachieved via newly constructed vein grafts. Retrograde cardioplegia has overcome thislimitation, as good left ventricular protection follows coronary sinus or right atrialperfusion [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
  5. 5. technique is used by at least 60% of surgeons in the United States [12]. Nutritive retrogradeflow to the right ventricle via the coronary sinus is, however, reduced markedly incomparison with capillary perfusion of the left ventricle, and only 70% of retrograde flow isnutritive (ie, perfuses capillaries) [29]. Conversely, 90% of antegrade perfusion nourishesthe myocardium and ensures right ventricular delivery if the right coronary artery is open[29]. Metabolic studies show that conversion from antegrade to retrograde infusion resultsin increased O2 uptake and lactate washout (Fig 2 ), indicating that the different myocardialregions are perfused by the two routes of delivery. Fig 2. . Metabolic measurements during warm cardioplegic induction at the end of antegrade (solid bar) and at beginning of retrograde (hatched bar) administration in 26 patients. Note (A) myocardial O2 uptake (MVO2) increase when switching from antegrade to retrograde delivery, (B) glucose consumption increases, and (C) lactate consumption switches to production when changing from View larger version (28K): antegrade to retrograde delivery. A similar pattern [in this window] was observed when switching from retrograde to [in a new window] antegrade delivery in separate studies.The majority of retrograde perfusion drains via thebesian veins. Consequently, coronarysinus retroperfusion provides right ventricular hypothermia as the effluent traversesconductance vessels, and therefore confers hypothermic lowering of oxygen demands tocounteract this limited nutritive oxygen supply due to veno-venous shunts. This benefit isachieved only if hypothermia is used in conjunction with retrograde cardioplegic delivery.The aforementioned limitations of antegrade and retrograde delivery were overcomeinitially by cardioprotective methods that alternated between antegrade and retrogradeperfusion [9], and this method is particularly well-suited for high-risk patients receivingarterial conduits. Recent studies show that the combined benefits of antegrade andretrograde perfusion can be achieved by simultaneous antegrade and retrograde delivery viathe coronary sinus and aorta or vein grafts [10], and a manifold has been developed tofacilitate intraoperative delivery (Fig 3 ). Venous hypertension is prevented duringsimultaneous antegrade/retrograde perfusion because most of coronary sinus retroperfusiondrains via thebesian veins. Experimental and clinical studies document the safety ofsimultaneous arterial and coronary sinus perfusion to offset concerns over causingmyocardial edema during this combined perfusion method [10].
  6. 6. Fig 3. . Clinical method of simultaneously delivering antegrade/retrograde cardioplegia to ensure protection of jeopardized myocardium. Please note that this system allows for antegrade or retrograde delivery separately or simultaneous coronary graft and retrograde delivery. Also pressure monitoring is easily accomplished (see text for description). View larger version (119K): [in this window] [in a new window]Intermittent/Continuous InfusionA dry quiet operative field is a prerequisite for a technically precise cardiac surgicalprocedure, so most surgeons interrupt flow to achieve this goal and thereby create``intentional ischemia. This can be done either by local control (coronary operations) ormore commonly by intermittently stopping cardioplegic flow completely. All in situ heartsreceive some noncoronary collateral flow (of unpredictable volume) that washes away thecardioplegic solution so that intermittent replenishment is needed to attain the goals ofrestoring hypothermia, washout of accumulated metabolites, counteraction of acidosis andedema, and provision of a cardioplegic composition to lower perfusion injury before thenext period of planned ischemia. Recurrence of unwanted electromechanical activity whilethe aorta is clamped and cardioplegic flow is stopped is a surgical inconvenience, whilesimultaneously providing evidence of washout of the cardioplegic solution and signifyingthe retained capacity to produce sufficient adenosine triphosphate to allow contractility toresume.Continuous perfusion has been advocated to provide the theoretic advantage of ``avoidingischemia by delivery of flow continually either antegrade or retrograde [30], but thisobjective has never been achieved in either the beating empty [31], fibrillating [32, 33], orarrested heart [34]. Consequently, ``unintentional ischemia occurs during continuousperfusion and vision becomes obscured when blood cardioplegia is used, and adds atechnical disadvantage to the false sense of security that continuous perfusion avoidsischemia. Additionally, cardioplegic overdose is potentially problematic if normothermictechniques are used, because electromechanical activity will recur when cardioplegiaperfusion is replaced with normal blood perfusion when vision becomes obscured by bloodin the operative field. There are, however, many intervals where perfusion can proceedwithout 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 theaorta or atrium.
  7. 7. Blood Cardioplegia, Noncardioplegic Blood PerfusionMost surgeons stop the heart with high-dose potassium blood cardioplegia (20 mEq/L) anduse multidose low-dose potassium (8 to 10 mEq/L) for the remainder of the operationbecause hypothermia potentiates electromechanical quiescence and more markedhyperkalemia is superfluous. The use of cold normal blood antegrade coronary perfusionwas described previously and documented by Bomfim and associates [35] in studies ofpatients undergoing aortic valve replacement. Recent studies show that cold arrested heartsremain quiescent and both the left and right ventricles recover completely when perfusedwith cold (4°C to 10°C) retrograde noncardioplegic blood [11], whereas right ventricularrecovery is incomplete despite a twofold greater retroperfusion of warm blood cardioplegia(Fig 4 ). Consequently, the advantages of continuous perfusion and nourishment can beachieved without the drawbacks of excessive hemodilution and cardioplegic overdose orcoronary cannulation. These benefits are possible only with cold noncardioplegic bloodbecause electromechanical activity returns when warm noncardioplegic blood is deliveredeither antegrade or retrograde, and potential right ventricular ischemia will becomecompounded if continuous perfusion is delivered only via the coronary sinus; oxygendemands rise if electromechanical activity (ie, beating or fibrillating) recurs in theunderperfused right ventricle. The use of cold blood, therefore, provides the possibility tochange from ``high K+ to ``low K+, to ``no K+ during the same procedure andmaintain the arrested state. Figure 5 shows the cardioplegic delivery system usedcurrently to allow the perfusionist to alternate between blood cardioplegia andnoncardioplegic blood with minimal effort. Fig 4. . Right ventricular performance after 30 minutes of continuous retrograde perfusion via the coronary sinus. Note (1) in the cold group, arrest was achieved by a 1-minute infusion of antegrade 4°C blood cardioplegia (30 mEq/L), and noncardioplegia blood was delivered at 100 mL/min thereafter; (2) in the warm group, arrest was achieved by a 1-minute View larger version (16K): infusion of warm blood cardioplegia (30 mEq/L KCl), [in this window] and maintained by retroperfusion of 10 mEq/L KCl [in a new window] blood cardioplegia for 30 minutes; and (3) superior recovery after cold retroperfusion despite 50% reduction of flow rate and no added KCl. ( RAP = right atrial pressure; SWI = stroke work index.)
  8. 8. Fig 5. . Cardioplegic delivery system for alternating between blood cardioplegia and noncardioplegic blood (see text for description). View larger version (47K): [in this window] [in a new window]Single Period of Aortic ClampingCoronary artery bypass grafting is the most frequently performed procedure in the UnitedStates, and the problem of intraoperative cerebral atheroemboli is increasing as morepatients more than 70 years old are undergoing revascularization. The generalized nature ofthe atherosclerotic process leads to potential cerebral atheroemboli when the aorta isclamped [36], and this potential is amplified if the aorta is clamped tangentially repeatedlyto construct proximal anastomoses. A recent report by Loop and colleagues [37], whoemployed our previously described blood cardioplegic myocardial management method,documents that the single clamping technique limits neurologic complications, and thebenefits 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 overextending ischemic time, despite evidence that mortality, morbidity, and cost are reduceddespite a longer period of aortic clamping [37, 39]. These aforementioned data dispel theprevious axiom that ``there is a constant battle against the clock when the aorta is clampedby showing that the extent of cardiac damage is related more to how the heart is protectedthan how long the aortic clamp is in place [37]. The capacity to deliver either bloodcardioplegia or noncardioplegic blood (either antegrade or retrograde, alone or incombination) ensures provision of sufficient cardiac nourishment during aortic clampingto contradict the concept that aortic clamping and ischemic time are synonymous. Forthese reasons, all cardiac operations in our institution are done during a single period ofaortic clamping.Integrated Myocardial ProtectionAll of these aforementioned individual modalities have been combined recently into acomprehensive cardioplegic strategy, which is termed ``integrated myocardialmanagement. This approach provides a flexible and simple method to take maximaladvantage of each aforementioned cardioprotective method:
  9. 9. • Warm/cold blood cardioplegia • Antegrade/retrograde delivery • Intermittent/continuous perfusion • Blood/blood cardioplegia • Limits cardioplegia overdose and hemodilution • Avoids tangential aortic clampingIt evolved from concepts tested in our laboratory and incorporates the strategies ofwarm/cold blood cardioplegia, antegrade/retrograde delivery, continuous/intermittentinfusion, and noncardioplegic blood/blood cardioplegia infusions during a single period ofaortic cross-clamping (a tangential aortic clamp is not used).The method is based on the following principles: (1) surgical precision is optimized by adry bloodless field so that cold intermittent arrest is used to avoid ischemic damage (noperfusion during distal anastomosis or when visualization is needed), (2) ischemia isunnecessary when visualization is not problematic (ie, during construction of proximalanastomosis, placing sutures in a valve annulus or valve sewing ring) so that continuousblood or blood cardioplegia is infused retrograde during this time, (3) continuous bloodperfusion of the cold arrested heart does not require cardioplegia to maintain arrest [11],thereby limiting hemodilution and hyperkalemia, (4) simultaneous antegrade and retrogradecardioplegia delivery is safe, (5) the continuity of the operation should not be interrupted todeliver perfusion (blood or cardioplegia) while the aorta is clamped, except duringcardioplegic induction when cardiac manipulation may make the aortic valve incompetent,and (6) the aorta is clamped as soon (less than 1 minute) as satisfactory extracorporealcirculation is established (collapsed pulmonary artery) and cardiopulmonary bypass isdiscontinued within 5 minutes of aortic unclamping, as the last portion of each procedure isperformed with continuous warm cardioplegia or blood perfusion.The following description defines how this technique is used in a typical coronary arteryoperation. Similar methods are applied to valve operations, where cardioplegic (ornoncardioplegic) flow is interrupted only when visualization is needed (eg, valve excision,placing sutures in an annulus and securing prosthesis sutures) and given continuously whenvisualization is nonproblematic (eg, placing sutures from annulus to valve ring, closingatrium or aorta). Cardioplegic induction is either warm or cold, and the infusion isadministered antegrade and retrograde in relatively equal proportions. This is the only timethat the operation is interrupted to deliver cardioplegic flow. Systemic temperature isreduced 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 beconstructed in a dry operative field required for surgical precision while hypothermia limitsthe rate of development of ischemic damage. A brief (1 minute) cold blood cardioplegicinfusion is delivered retrograde after completion of the distal anastomosis and followed bycontinuous retrograde cold noncardioplegic blood perfusion as the proximal anastomosis isconstructed with the aorta vented. Conversion from cold blood cardioplegia to coldnoncardioplegia blood maintains arrest, hypothermia, and cardiac nourishment to both theleft and right ventricles [11], while reducing cardioplegia dose and hemodilution. Thesafety of continuous cold noncardioplegic blood perfusion suggests that cold perfusion ofthe heart can be used to avoid ischemia during aspects of the operation when the aorta is
  10. 10. clamped and visualization is not impeded by continuous coronary perfusion [11]. A briefantegrade cardioplegic infusion is delivered at the conclusion of each proximal anastomosiswhile the suture line is secured and the graft tip is fashioned for the next anastomosis. Thisantegrade infusion ensures cardioplegic distribution to the right ventricle, which may beperfused inadequately by retrograde delivery [29, 40, 41], and keeps the heart arrestedduring the next ischemic interval.The sequence is repeated for each distal and proximal anastomosis, and the internalmammary anastomosis is performed during rewarming of the patient and cardioplegicsolutions. The warm blood cardioplegic reperfusate is delivered first antegrade and thenretrograde after the last proximal anastomosis is constructed. This is followed immediatelyby retrograde perfusion of warm noncardioplegic blood to wash out the cardioplegicsolution 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 theaortic clamp, as continuous cardioplegic and noncardioplegic blood perfusion reducesischemic time despite performance of all anastomoses during a single interval of aorticclamping.Recent reports [37] confirm the concept that myocardial damage is related more to themethod of myocardial protection than the duration of aortic cross-clamping, and show alsothat the incidence of cerebral complications is reduced by avoiding the use of tangentialaortic clamps. This avoidance of clamping probably reduces potential dislodgement ofintraaortic atheromatous debris [36]. Ischemic duration is also shortened during valveprocedures because cold continuous blood or blood cardioplegia can be infused duringmuch of the procedure, and interrupted only when visualization is desired. Table 1 showsresults of the integrated myocardial management method in a consecutive series of adultpatients undergoing revascularization and valve operations [35]. View this table: Table 1. . Integrated Myocardial Protection [in this window] [in a new window]Proponents of different techniques of intraoperative myocardial protection havetraditionally, and for uncertain reasons, taken adversarial positions (ie, warm versus coldblood cardioplegia, antegrade versus retrograde and intermittent versus continuous delivery,blood versus blood cardioplegic perfusion). The fundamental issue is the development of athoughtful strategy for cardioplegic distribution, and this can be achieved by combining thebenefits of both antegrade and retrograde cardioplegic techniques. We suspect thatapplication of this combined strategy will allow more critically ill patients to undergo safearterial grafting and to experience the same complete immediate recovery of regional andglobal function shown in patients who receive vein grafts.
  11. 11. Warm Blood Cardioplegia Without HypothermiaIn 1950, Bigelow and associates [42], from the University of Toronto, introducedhypothermia, an important component of myocardial protection that slows cardiacmetabolism while limiting ischemic injury during the periods of aortic cross-clampingneeded to optimize operative conditions to provide a quiet bloodless field, and Shumwayand Lower [43], in 1959, reinforced this cardioprotective strategy. These observations ledto the surgical axiom that ``all is well if the heart is made as cold as possible and that thereis a ``battle against the clock when the aorta is clamped. Recent data on thecardioprotective benefits of warm blood cardioplegia suggest that these axioms areoutdated, and that intraoperative damage is related more to how the heart is protected thanhow the aorta is cross-clamped.Hypothermia may also impose certain adverse consequences, including shifting the oxygen-hemoglobin dissociation curve leftward, retarding sodium potassium adenosinetriphosphate to promote edema, reducing membrane stability, increasing blood viscosity,and activating platelets, leukocytes, and complement [30, 44]. These concerns led thesurgical team at the University of Toronto (where hypothermia was introduced) to suggestwarm blood cardioplegia without hypothermia as a cardioprotective strategy, where thepatient and the heart are maintained at 37°C and the cardioplegic flow is deliveredcontinually when feasible. This concept is based on the fact that electromechanical arrestsubstantially 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 accomplishedby adding profound hypothermia. Therefore, they propose that myocardial oxygen demandscan 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 cardioplegicsolutions, and this has yet to be proven.There is limited current experimental infrastructure for the clinical application of thisattractive hypothesis, although preliminary results in patients are encouraging [30, 44, 46].The continuous warm cardioplegic approach is in contrast to early attempts of 37°Ccontinuous coronary perfusion with normal blood, where the energy requirements remainedhigh when the heart was either kept beating or fibrillated. An added potential advantage ofthis method is that ischemia is avoided if 37°C blood cardioplegic flow is continuous andpostischemic reperfusion injury cannot occur because the heart is maintained in a constantaerobic state. Finally, systemic normothermia may limit the possible detrimental effects ofhypothermic cardiopulmonary bypass on coagulation and other organ systems.Although early results are encouraging, they are not superior to results using techniqueswith an extensive experimental infrastructure in which warm and cold antegrade andretrograde methods are applied as described above. Subsequent experimental data nowshow some unforeseen problems of the warm continuous cardioplegic technique, and manyquestions have arisen and remain unanswered (see below). Experimental studies show thesuperiority of intermittent cold antegrade and antegrade/retrograde blood cardioplegictechniques over continuous warm antegrade or retrograde cardioplegia, especially inprotecting areas of jeopardized myocardium [47, 48]. Intermittent interruption of
  12. 12. continuous warm antegrade or retrograde cardioplegia as must be done clinically tooptimize visualization during construction of distal anastomoses is particularly deleteriousin vulnerable regions, whereas intermittent cold antegrade/retrograde cardioplegia providessuperior results under these circumstances [49].Additional missing data on the role of warm heart surgical techniques include (1) whatflow rates are needed to adequately supply the arrested heart, and whether continuousinfusion 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) howlong the blood flow can be interrupted safely before ischemic changes take place, and howthese changes can be overcome with resumption of cardioplegic flow, (3) what is the idealcardioplegic composition (ie, is it different from the composition used for intermittent coldblood cardioplegia), (4) whether warm heart operation, with the patient at 37°C, leads toincreased bleeding due to the inherently higher flow rates that must be maintained, (5)whether cerebral complications increase if nonpulsatile flows are used with inherentlylower perfusion pressure, and (6) whether more fatal ``perfusion accidents will occur dueto the limited time (3 to 4 minutes) available to the perfusionists to stop extracorporealcirculation and correct the problem before cerebral damage occurs.Finally, experimental and clinical studies have demonstrated that the normal andischemically damaged heart can be protected safely for 2 to 4 hours of aortic clamping withintermittent cold blood cardioplegia, especially if bracketed with an interval of warminduction and reperfusion to ``resuscitate the heart and ``limited reperfusion injury (seeearlier sections on Blood Cardioplegia and Warm Induction). These intermittentcardioplegia techniques provide the ideal technical conditions of a bloodless field neededfor surgical precision, while simultaneously ensuring metabolic correction of theconsequences of ischemia, which are minimized by hypothermic protection. Consequently,abandonment of cold cardioplegic techniques in favor of the warm approach is notrecommended until a sufficient infrastructure of data is accumulated to answer theaforementioned questions. Postoperative univentricular or biventricular failure or deathafter continuous warm retrograde blood cardioplegia reflects a problem that hypothermiaand antegrade cardioplegia might avoid, and which is caused directly by an inflexibleapproach based on the misconception that ``all is well if the heart is perfused continually.We suspect that warm blood cardioplegic techniques will become adjunctive tohypothermic techniques, rather an a replacement for them.Warm Blood Cardioplegia: Starting Points, End Points, and Median LethalDoseCardioplegic research has not, in general, followed established procedures for drug testing.The median lethal dose concept is used routinely in pharmacologic studies, whereby thestarting point is an intervention in a model that kills 50% of live organisms; its effectivenessor 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 startingpoint of most studies of myocardial protection is the normal heart, so that the median lethal
  13. 13. dose approach has no relevance to them, inasmuch as any intervention that fails to maintainbiochemical and mechanical integrity must be considered ineffective. Consequently, thenormal heart model is useful only to test the safety of interventions such as multidose coldblood cardioplegia that allow normal biochemical and mechanical function to recovercompletely 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 startingpoint 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 todevelop strategies intended to metabolically resuscitate the heart, because cold cardioplegiaconfers no metabolic benefit other than offsetting further damage. The concepts of warminduction and reperfusion of blood cardioplegia developed from such models, wherebyextensive testing of various cardioplegic modifications resulted in a regimen that restoredfunction to ischemically damaged hearts, with the rationale for individual factors describedpreviously. Normothermia is only one element in this regimen and is included to optimizethe rate of metabolic recovery, which is retarded by hypothermia.The objective of adding normothermic blood cardioplegia is to use a cardioprotectivestrategy in the impaired myocardium that acts in concert with mechanical repair to restorenear-normal biochemical and mechanical function (that is, a normal starting point).Conversely, cold cardioplegic techniques alone can only prevent further damage so thattotal reliance is placed on the mechanical benefits of operative correction to improvecardiac performance. For example, the operative mortality rate for the surgical treatment ofcardiogenic shock is approximately 50% with conventional hypothermic cardioprotectivetechniques because left ventricular power failure progresses unabatedly despiterevascularization [50, 51]. In contrast, use of warm blood cardioplegic induction andreperfusion lessens the duration of postoperative circulatory support and improvesmortality [52].Intermittent Warm Blood CardioplegiaIntermittent warm blood cardioplegia may theoretically prove beneficial withouthypothermic supplementation if the formulations result in metabolic resuscitation andlimitation of reperfusion damage, as documented previously when normothermic methodswere used as an adjunct to intermittent cold ischemia in energy-depleted hearts [14].Confirmation of this application of intermittent warm ischemia requires testing in globallyischemic hearts that would otherwise develop biochemical or mechanical dysfunction if nointervention was undertaken (for example, aortic unclamping without cardioplegia). Theimportance of this type of analysis is drawn from our previous studies showing coldintermittent blood cardioplegia that fully protected normal heart muscle for 4 hours, butfailed to amplify function in the stressed myocardium [8]. Postischemic dysfunction inhearts protected with 2 hours of intermittent cold blood cardioplegia introducedimmediately after 45 minutes of normothermic ischemia (ie, to simulate the time needed foroperative repair) was comparable with that when the aorta was unclamped immediatelyafter the 45-minute ischemic insult. The ``end point equalled the ``starting point.
  14. 14. The strategic goal is to make the ``end point exceed the ``starting point, so intermittentwarm cardioplegia would be considered ineffective if an end point equalled a starting pointof deranged metabolism and function as observed after simple aortic unclamping after aperiod of unprotected ischemia. Use of a normal heart to demonstrate that intermittentwarm blood cardioplegia restores normal metabolic and contractile function may lead to themisleading conclusion that intermittent warm ischemia is safe in jeopardized muscle. Forexample, our previous studies showing the limitations of intermittent cold bloodcardioplegia as the sole cardioprotective strategy in the stressed myocardium [8] paved theway for use of warm blood cardioplegic induction and reperfusion.Hopefully, subsequent studies in damaged hearts will be undertaken, because the resultsmay be of fundamental importance in planning cardioprotective strategies devoid of therecognized capacity of hypothermia to delay the rate of development of cell damage.Relatively homogeneous flow distribution via antegrade and retrograde delivery wouldprobably be needed for intermittent normothermic cardioplegia to be effective.Additionally, metabolic interventions that precondition the heart [53] must be evaluated inthe aforementioned way to justify their use in allowing exclusion of hypothermictechniques.ConclusionsThe versatility of blood cardioplegia provides the cardiac surgeon with a tool to activelytreat the jeopardized myocardium as well as to prevent ischemic damage, provided attentionis directed toward ensuring adequate delivering of the cardioplegic solutions. No exogenousblood is needed to deliver blood cardioplegia, as a readily available blood source existswithin the extracorporeal circuit during all cardiac operations when the patients bloodvolume mixes with the clear priming fluid. The expense of depriving the patient of thepotential benefits of blood cardioplegia includes increased perioperative mortality,prolonged intensive care unit stays, and development of late cardiac fibrosis owing tonecrosis 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 onlythe known benefits of using blood as the vehicle for delivering oxygenated cardioplegia.We are confident that further studies will reveal other naturally occurring bloodcomponents (ie, enzymes, cofactors, substrates, electrolytes) that are important and wouldotherwise need to be added to any artificially constructed solution.The objective of every cardiac operation must be a technically perfect anatomic result, andavoidance or limitation of intraoperative damage in pursuit of this goal. Two prerequisitesto accomplish these objectives are adequate visualization of the operative field to allow forsurgical precision, and use of cardioprotective techniques that exclude intraoperativedamage that can nullify the immediate and long-term benefits of surgical correction of anyacquired or congenital defect. Cardiac damage from inadequate myocardial protectionleading to low output syndrome can prolong hospital stay and cost, and may result in
  15. 15. delayed myocardial fibrosis. Efforts to avoid this problem have led to the development ofnumerous methods of intraoperative myocardial management.FootnotesPresented at the International Symposium on Myocardial Protection From SurgicalIschemic-Reperfusion Injury, Asheville, NC, Sep 25--28, 1994.Address reprint requests to Dr Buckberg, Department of Surgery, Rm B2-375 CHS, UCLAMedical Center, PO Box 95741, Los Angeles, CA 90095-1741.References 1. Nelson R, Fey K, Follette DM. The critical importance of intermittent infusion of cardioplegic solution during aortic cross-clamping. Surg Forum 1976;26:241–3. 2. Follette DM, Steed DL, Foglia RP, Buckberg GD. Advantages of intermittent blood cardioplegia over intermittent ischemia during prolonged hypothermic aortic clamping. Cardiovasc Surg 1978;58:1–200. 3. Follette DM, Mulder DG, Maloney JVJ, Buckberg GD. Advantages of blood cardioplegia over continuous coronary perfusion and intermittent ischemia. J Thorac Cardiovasc Surg 1978;76:604–19.[Medline] 4. Follette DM, Steed DL, Foglia RP. Reduction on postischemic myocardial damage by maintaining arrest during initial reperfusion. Surg Forum 1977;28:281–3. [Medline] 5. Follette DM, Fey K, Buckberg GD, et al. Reducing postischemic damage by temporary modification of reperfusate calcium, potassium, pH, and osmolarity. J Thorac Cardiovasc Surg 1981;82:221–38.[Abstract] 6. Rosenkranz ER, Buckberg GD, Mulder DG, Laks H. Warm induction of cardioplegia with glutamate-enriched blood in coronary patients with cardiogenic shock who are dependent on inotropic drugs and intraaortic balloon support: initial experience and operative strategy. J Thorac Cardiovasc Surg 1983;86:507–18. [Abstract] 7. Rosenkranz ER, Buckberg GD. Myocardial protection during surgical coronary reperfusion. J Am Coll Cardiol 1983;1:1235–46.[Medline] 8. Rosenkranz ER, Okamoto F, Buckberg GD, Robertson JM, Vinten-Johansen J, Bugyi H. Safety of prolonged aortic clamping with blood cardioplegia. III. Aspartate enrichment of glutamate-blood cardioplegia in energy-depleted hearts after ischemic and reperfusion injury. J Thorac Cardiovasc Surg 1986;91:428–35. [Abstract] 9. Partington MT, Acar C, Buckberg GD, Julia PL. Studies of retrograde cardioplegia. II. Advantages of antegrade/retrograde cardioplegia to optimize distribution in jeopardized myocardium. J Thorac Cardiovasc Surg 1989;97:613–22.[Abstract] 10. Ihnken K, Morita K, Buckberg GD, et al. The safety of simultaneous arterial and coronary sinus perfusion: experimental background and initial clinical results. J Cardiac Surg 1994;9:15–25.[Medline]
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