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Ann Thorac Surg 1995;60:824-832
© 1995 The Society of Thoracic Surgeons
Division of Cardiovascular Surgery, The Toronto Hospital, University of Toronto, Toronto, Ontario, Canada
Abstract
Background. The contemporary results of coronary artery bypass grafting using a variety of myocardial preservation techniques are excellent. In recent years, the number of ``high-risk'' patients referred for operation has increased, thus necessitating continued advances in surgical myocardial protection.
Methods. In this article, we review recent advances in clinical myocardial protective techniques and emphasize studies conducted at The Toronto Hospital. Further, on the basis of promising current research, we speculate on future prospects for myocardial protection.
Results. At The Toronto Hospital, we converted from crystalloid to intermittent cold blood cardioplegia in 1985. We demonstrated that ``continuous'' cardioplegic strategies may help resuscitate the ischemic myocardium and reduce operative complications in high-risk patients. Further improvements in myocardial protection will require refinements in cardioplegic solution temperature, direction of delivery, and additives to ``precondition'' the myocardium against ischemic damage.
Conclusions. Major advances that meet the requirements of an increasingly high risk patient population have been made in surgical myocardial protection in recent years. The future is bright for continued progress in this area.
The contemporary results of coronary artery bypass grafting (CABG) are excellent. Many studies have shown that CABG relieves angina and reduces mortality in patients with left main or proximal left anterior descending coronary artery stenoses, severe triple-vessel disease, refractory unstable angina, or left ventricular dysfunction [1, 2]. Of concern to cardiac surgeons, however, is that in recent years, the proportion of ``high-risk'' patient referrals is increasing.
We [3] reviewed the cases of 7,334 patients undergoing CABG between 1982 and 1986. In this patient population, we found the independent predictors of operative mortality to be urgent revascularization, reoperation, impaired left ventricular function, and increasing age. We also found that the proportion of patients seen with one or more of these risk factors had risen significantly from 1982 to 1986. Despite the increasing numbers of these high-risk patients, the operative mortality rate remained constant at 3.7%, which is perhaps reflective of improved techniques of anesthesia, surgical technique, and myocardial protection. However, the rate of nonfatal cardiac morbidity increased from 10.1% in 1982 to 13.3% in 1986 (p < 0.05).
These results indicate that we must continue to develop improved techniques of myocardial protection to resuscitate the ischemic myocardium and reduce operative complications in the increasing high-risk patient population requiring surgical revascularization. This ar-ticle reviews many important controversies in the development of myocardial protective strategies for CABG starting with the advent of blood cardioplegia. We emphasize the results we have obtained at The Toronto Hospital. In addition, we speculate on future developments that will maintain or further improve operative results.
Hypothermic Blood Cardioplegia
In the mid 1980s, surgeons at many institutions began to switch from unoxygenated crystalloid cardioplegic solutions to oxygenated blood cardioplegia. In Toronto, Fremes and colleagues [4] performed a randomized clinical trial of blood versus crystalloid cardioplegia. Blood cardioplegia was found to enhance aerobic metabolism during aortic cross-clamping, thereby increasing myocardial oxygen consumption and reducing anaerobic lactate production [4]. Postoperative ventricular function was also improved (Fig 1
). In addition, adenosine triphosphate (ATP) levels were better preserved by blood cardioplegia. Other investigators [5] confirmed the superiority of blood cardioplegic solutions.
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The standard technique of delivery of blood or crystalloid cardioplegia employs multiple intermittent infusions during the cross-clamp period. Our group [6] found that cold cardioplegia administered in this fashion results in perioperative myocardial metabolic dysfunction. The dysfunction may be due to the washout of Krebs cycle intermediates such as glutamate and aspartate. In support of this hypothesis is a study by Rosenkranz and colleagues [7], who demonstrated that warm induction with glutamate-enriched cardioplegia improved metabolic recovery in energy-depleted hearts. In Toronto, Teoh and co-workers [8] found that warm induction with glutamate-aspartate cardioplegia was beneficial in reducing mortality and morbidity but only in patients undergoing urgent operation for unstable angina. Cardioplegic substrate enhancement with glutamate and aspartate may offer benefits only to patients who are seen with critical preoperative myocardial ischemia.
Normothermic Cardioplegia: The Concept Is Born
Teoh and colleagues [9] reported in 1986 that a terminal infusion of warm blood cardioplegia immediately before cross-clamp removal (a ``hot shot'') resulted in prolongation of electromechanical arrest, improvement in aerobic metabolism (Fig 2), and increased diastolic compliance (Fig 3). The beneficial effect was ascribed to cardiac normothermia, which permitted early temperature-dependent mitochondrial respiration and ATP generation. The ATP produced under these conditions was used for repair of ischemic cellular injury and restoration of depleted energy stores and not for contractile activity, as the heart was still arrested [10].
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Antegrade Normothermic Cardioplegia
The apparent benefits of maintaining cardiac normothermia at the beginning [12] and at the end [9] of the cross-clamp period led Lichtenstein and associates [13] in Toronto to ask whether maintaining the heart at 37°C throughout the duration of aortic cross-clamping would be beneficial. Buckberg and colleagues [14] had demonstrated a fivefold decline in oxygen consumption (from 5.6 to 1.1 mL•100 g-1•min-1) in canine hearts arrested under normothermic conditions. Reducing the myocardial temperature from 37° to 18°C resulted in a much smaller decline in oxygen consumption (from 1.1 to 0.31 mL•100 g-1•min-1). This study suggested that cardioplegia need not be cold to be effective. Citing the many known deleterious effects of cardiac hypothermia, including impairment of mitochondrial energy generation, substrate utilization, and membrane stabilization, Lichtenstein and coauthors [13] proposed that maintaining cardiac temperatures at 37°C throughout the cross-clamp period might improve perioperative myocardial metabolism. However, to meet the higher oxygen demand of an arrested normothermic heart, a continuous infusion of cardioplegia would be necessary.
The clinical use of normothermic blood cardioplegia as a primary means of myocardial protection began in Toronto in 1987. The first reports of experience with this technique appeared in 1991. Lichtenstein and colleagues [13] described the results for 121 consecutive patients receiving antegrade normothermic blood cardioplegia during CABG. Compared with a historical cohort of 133 patients receiving antegrade hypothermic blood cardioplegia, these patients had a significant reduction in perioperative infarction and the need of postoperative intraaortic balloon pump support. The operative mortality rate fell from 2.2% to 0.9%, although this decrease was not significant. Spontaneous resumption of sinus rhythm occurred in more than 99% of patients receiving warm blood cardioplegia but only 11% of patients receiving cold cardioplegia. The morbidity and mortality in this series was low even though normothermic cardioplegia delivery required interruption for up to 15 minutes to allow visualization of distal anastomoses.
We performed a variety of studies to determine the optimal flow rates and hemoglobin concentrations for warm blood cardioplegia. We [11] examined myocardial metabolism and ventricular function in patients undergoing elective CABG who received antegrade normothermic blood cardioplegia at varying cardioplegic flow rates and hemoglobin concentrations. Flow rates of 80 mL/min or greater with a hemoglobin concentration of 80 g/L (a 4:1 dilution of blood to crystalloid) maintained aerobic metabolism during cardioplegic arrest and enhanced myocardial systolic performance and diastolic relaxation (Fig 4) compared with cold cardioplegia [11, 15]. However, when normothermic cardioplegia was given at flow rates of less than 80 mL/min with a hemoglobin concentration of 50 g/L (a 2:1 dilution of blood to crystalloid), hearts became ischemic, an ``oxygen debt'' was incurred, and anaerobic glycolysis led to the accumulation and washout of lactate (Fig 5). The metabolic abnormalities seen after low-hemoglobin, low-flow warm cardioplegia were associated with impaired myocardial performance and decreased diastolic compliance. We recommend, therefore, that antegrade normothermic blood cardioplegia be delivered at flow rates of 80 mL/min or greater with a hemoglobin concentration of at least 80 g/L.
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The disadvantages of retrograde cardioplegia are related to venovenous shunting through arteriosinusoidal and thebesian vessels, which may limit nutrient flow to only 30% to 70% of the volume delivered [22]. Retrograde cardioplegia may also fail to protect the right ventricle and posterior septum [18]. In addition, coronary sinus pressures during cardioplegia delivery must be limited to 40 mm Hg to prevent coronary sinus injury, perivascular hemorrhage, and edema.
To determine the optimal retrograde warm delivery rate, we [22] studied 57 patients undergoing elective CABG. We attempted to improve retrograde delivery of cardioplegia to the posterior wall and septum by placing the retrograde cardioplegia cannula into the coronary sinus and then slowly withdrawing it until the posterior interventricular vein became distended. With this placement technique, coronary sinus pressures were maintained lower than 40 mm Hg at flow rates up to 300 mL/min during warm heart operations. In the initial low-flow study, administration of 50 mL/min (n = 9), 75 mL/min (n = 11), or 100 mL/min (n = 7) was associated with high lactate production during the cross-clamp period. At 50 minutes of cardioplegic arrest, the coronary venous effluent pH was low in all groups.
These results prompted the subsequent high-flow study, where 30 patients all received flows of 100, 200, and 300 mL/min in randomized order during the cross-clamp period. Administration of 200 mL/min or higher minimized lactate production and maintained coronary venous pH within the physiologic range. Comparison of the low-flow and high-flow data showed significantly less myocardial lactate release in the high-flow group and immediate restoration of coronary venous pH on removal of the cross-clamp, findings suggestive of myocardial hypoperfusion with flows of 100 mL/min or less (Fig 6).
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To address this issue, Matsuura and co-workers [23] assessed the effect of cardioplegic interruption on myocardial metabolism and function. In a porcine model using 90 minutes of regional coronary ischemia with 45 minutes of cardioplegia, retrograde warm blood cardioplegia given continuously or with three 7-minute periods of flow interruption resulted in a larger infarct size, more myocardial acid production, and a reduction in echocardiographic wall motion compared with intermittent cold antegrade/retrograde cardioplegia. These data imply that delivery of retrograde cardioplegia results in a significant myocardial perfusion defect. Indeed, our initial echocardiographic studies [24] with sonicated albumin added to the cardioplegia suggest multiple myocardial perfusion defects including but not limited to the right ventricle and posterior septum with retrograde compared with antegrade cardioplegia. Further, we demonstrated a correlation between these perfusion defects and abnormalities in myocardial metabolism.
Systemic Temperature Control During Normothermic Cardioplegia
The advent of warm heart surgery was accompanied by normothermic systemic perfusion. We [25] reviewed our initial experience with this technique and found that warm perfusion was associated with critical vasodilation on bypass requiring high doses of pressor agents to maintain systemic arterial blood pressure greater than 50 mm Hg. However, intraoperative systemic normothermia prevented cold-induced platelet injury and significantly reduced postoperative bleeding and blood bank requirements [26]. Similarly, patients who received tranexamic acid, aprotinin, or 
-aminocaproic acid also had very little bleeding postoperatively, and therefore pharmacologic pretreatment of patients kept hypothermic could mimic the beneficial effects of normothermic systemic perfusion.
A report by Martin and colleagues [27] from Emory University School of Medicine in Atlanta suggested that normothermic systemic perfusion increased the neurologic risk of warm heart operations. In their prospective, randomized trial (suspended after 1,000 patients because of the high incidence of neurologic injury associated with normothermia), they found the incidence of both transient and persistent neurologic deficits was doubled with warm versus cold perfusion. In contrast, neither the Toronto prospective, randomized trial [28] nor the investigations of Flack and co-workers [29] demonstrated more neurologic complications with warm than cold perfusion.
It is possible that the high neurologic complication rate seen by Martin and associates was related to the use of a partial occlusion clamp to complete proximal vein graft anastomoses. In patients with diffuse atherosclerotic disease involving the ascending aorta, use of this clamp could result in embolization of debris to the brain. In this setting, patients perfused normothermically would likely sustain more damage than patients perfused hypothermically. The partial occlusion clamp was not used in either the Toronto or the Springfield trial, which may explain the contrasting results.
Although we did not find a high incidence of neurologic abnormalities in patients kept warm, we believe that normothermia imposes a higher risk of neurologic complications if embolic episodes occur or if there is a mechanical failure of the cardiopulmonary bypass circuitry. Therefore, we have adopted an alternative systemic perfusion protocol, and we allow the pump circuit temperature to drift to between 29° and 32°C during the operative procedure. This technique of passive cooling may be better tolerated than either active cooling or active warming, both of which can cause greater inflammatory reactions to cardiopulmonary bypass with resultant postoperative organ dysfunction. This passive cooling process has been employed in our last few trials [22, 30–33] and appears to be the best compromise for warm heart surgery.
Systemic rewarming should be performed slowly and cautiously to avoid excessive brain temperatures. We tend to begin rewarming 20 minutes before removal of the cross-clamp, and we attempt to avoid heating the blood to greater than 38°C. To avoid warm cardiac ischemia, rewarming is usually commenced during the internal mammary–left anterior descending coronary artery anastomosis. The mammary artery is then allowed to provide coronary flow during the last few proximal vein graft anastomoses to ensure perfusion of the left anterior descending territory. Systemic hyperkalemia usually maintains cardiac arrest. This prolonged (20-minute) ``hot shot'' usually results in immediate recovery of normal sinus rhythm with cross-clamp release, and bypass can be discontinued within 5 minutes.
Future Directions in Myocardial Protection
Cold cardioplegia does not permit immediate resuscitation of the ischemic myocardium, but the cooled myocardium is relatively protected against perfusion defects inherent to both antegrade and retrograde delivery. Warm cardioplegia may maintain normal aerobic metabolism during arrest, but continuous administration of warm cardioplegia is usually not possible during coronary bypass procedures, as it impedes visualization for construction of distal anastomoses. Discontinuation of warm cardioplegia for up to 15 minutes results in normothermic cardiac ischemia, and currently it is not known if these brief ischemic periods are safe.
Future developments in cardioplegia technology will likely focus on refinement of temperature and direction of cardioplegia delivery as well as modification of the composition of the cardioplegic infusate to increase its cardioprotective capacity.
The Optimal Cardioplegic Temperature
To avoid the potential hazards associated with normothermic or hypothermic cardioplegic temperature, it may be advantageous to deliver ``lukewarm'' or ``tepid'' (29°C) cardioplegia. In a recent study [31] involving 72 patients undergoing isolated CABG at this institution, antegrade tepid cardioplegia reduced lactate and acid production during cardiac arrest compared with antegrade warm (37°C) cardioplegia and improved postoperative left ventricular function compared with antegrade cold (10°C) cardioplegia.
Combination of Antegrade and Retrograde Cardioplegia
A proposed solution to overcome the limitations of antegrade and retrograde cardioplegia is a combined antegrade and retrograde infusion [32]. In a recent study of 75 patients undergoing isolated CABG, we [32] observed that a continuous infusion of retrograde cardioplegia with intermittent antegrade infusions of normothermic blood cardioplegia reduced lactate production, preserved ATP stores, and may have provided better overall perfusion of the heart during the cross-clamp period than delivery by antegrade or retrograde techniques alone.
Tepid Combination Cardioplegia
The previous studies suggest that the myocardial response to arrest under the conditions of cardiac surgery may be optimized by combined antegrade and retrograde cardioplegia. We [33] evaluated the metabolic and functional response to this cardioplegic technique in patients undergoing CABG and found tepid superior to cold or warm.
Cardioplegic Additives
GLUCOSE, INSULIN, AND POTASSIUM.
In 1965, Sodi-Pollaris and co-workers [34] used glucose-insulin-potassium (GIK) solutions to decrease electrocardiographic abnormalities in acutely infarcting myocardium. Since then, GIK solutions have been used to limit ischemic necrosis and improve ventricular function with varying degrees of success.
Under unstressed conditions, approximately 60% of myocardial energy requirements is satisfied by utilization of free fatty acids [35]. However, under conditions of ischemia, free fatty acid metabolism may induce damage on reperfusion through generation of free radicals from fatty acid end products [36]. However, glucose may be a superior substrate under conditions of ischemia, as glycolytic pathways appear to be required for the maintenance of cellular integrity under these conditions [37].
Although early studies using GIK solutions in regional myocardial ischemia were promising [37], it became apparent that any protective effect could be lost under conditions of severe ischemia through accumulation of lactate and decrease in ventricular function [38]. In many cellular systems, the coupling between glycolytic flux and the Krebs cycle is loose. It is, therefore, possible to drive glycolytic nicotinamide adenine dinucleotide (reduced form) (NADH) production irrespective of the capacity of mitochondrial respiration to reoxidize the surplus of NADH formed. Thus, high external glucose concentrations may stimulate glycolysis to such an extent that the cytoplasm becomes more reduced, resulting in conversion of pyruvate to lactate by lactate dehydrogenase. Under conditions of severe ischemia, glycolysis–Krebs cycle uncoupling stimulated by administration of high external glucose concentrations (the ``Crabtree'' effect [39]) may result in detrimentally large amounts of lactate accumulation. Consistent with this hypothesis is the conclusion drawn from a recent review [40] of the use of GIK in myocardial ischemia that GIK appears best suited to situations where some collateral tissue perfusion persists to prevent excessive lactate accumulation.
With the advent of more ``continuous'' techniques of cardioplegia administration, GIK cardioplegia may provide improved substrate delivery for high-risk revascularization procedures and may offer the additional advantage of prevention of serum hyperkalemia associated with excessive cardioplegia administration.
ANTIOXIDANTS.
Free radical–induced lipid peroxidation of the cell membrane disrupts myocardial metabolism and function. Weisel and colleagues [41] demonstrated increased levels of phospholipid-conjugated dienes, markers of free radical–mediated cell membrane damage, at 3 and 60 minutes after cross-clamp removal in the coronary sinus blood of 10 patients undergoing CABG. The first burst of free radicals came with reperfusion. The second release of conjugated dienes occurred 5 minutes after protamine sulfate administration and was likely secondary to complement-activated leukocyte deposition in the myocardium and the resulting leukocyte respiratory burst and release of oxygen free radicals.
An extensive volume of research has been published about the potential efficacy of antioxidant cardioplegic additives to limit myocardial damage after ischemia. In our laboratory, the water-soluble antioxidants ascorbic acid and Trolox (a water-soluble analogue of 
-tocopherol) were effective in limiting free radical damage in cultured human ventricular myocytes, but catalase and superoxide dismutase were not, perhaps because of their inability to cross the cardiac sarcolemma [42]. Both ascorbic acid and Trolox were subsequently shown to significantly reduce infarct size in a canine model of regional myocardial ischemia [43].
Pretreatment may enhance antioxidant defenses and reduce ischemic injury. Long-term administration of an antioxidant such as vitamin E [44], heat shock [45], or recurrent episodes of brief ischemia [46] may not be practiced because of the prolonged time course required for development of protection, particularly for patients requiring an emergent bypass procedure for unstable angina. However, addition of other compounds with antioxidant effects such as deferoxamine [47], 21-amino steroid compounds (``lazaroids'') [48], and water-soluble polyethylene glycol conjugates of antioxidant enzymes such as superoxide dismutase [49] to cardioplegia has been shown to be beneficial. These and similar additives may upregulate antioxidant defenses and prevent ischemic injury during urgent bypass operations.
NITRIC OXIDE.
Nitric oxide is a unique endogenously produced, labile gas that is moderately soluble in water. This simple diatomic molecule exists in at least three forms. Perhaps the most important of these is the free radical species because its capacity for rapid diffusion across cell membranes makes it ideally suited for transcellular communication [50]. In 1980, Furchgott and Zawadzki [51] discovered a potent vasodilatory compound released from endothelium named endothelium-derived relaxing factor, which subsequently was shown to be the nitric oxide radical [52]. Nitric oxide is produced from the terminal guanidine nitrogen atom or atoms of the amino acid L-arginine by the enzyme nitric oxide synthetase and functions in a wide variety of biologic roles including neurotransmission, blood pressure regulation, and immunomodulation.
In the cardiovascular system, nitric oxide synthesis stimulated by cytokine production appears to have a myocardial depressant effect [53]. However, the antiplatelet and antineutrophil effects of this molecule as well as its potent coronary vasodilatory actions may explain its salutary effects in reducing postischemic reperfusion damage [54]. There is, therefore, some controversy regarding the usefulness of nitric oxide as a cardioprotective agent. Further studies are required to determine the efficacy of nitric oxide pharmacology as an enhancement to cardioplegia.
``Ischemic Preconditioning''
Surgeons have attempted to minimize the potentially harmful effects of myocardial ischemia-reperfusion injury by optimizing cardioplegic solutions and modifying reperfusion conditions. Although brief episodes of cardiac ischemia may be associated with mechanical and metabolic dysfunction (``stunning'') [55], brief ischemia has also been shown to protect against damage resulting from a subsequent prolonged ischemic episode. This phenomenon, known as ischemic preconditioning, has been well studied since its original description in 1986 [56]. Surgical models of cardioplegic arrest and reperfusion have suggested that the preconditioned arrested heart may have increased tolerance for prolonged ischemia and improved functional recovery during reperfusion [57].
Preconditioning was initially established in a variety of animal species, and now considerable evidence suggests a similar effect in humans. Preconditioning may reduce the ischemic injury associated with percutaneous transluminal coronary angioplasty [58], but the extent of ischemia associated with this intervention is probably too small to expect a substantial benefit from preconditioning. Induction of preconditioning could reduce ischemic injury during cardiac operations where ischemic conditions may be prolonged, particularly for high-risk patients. Yellon and colleagues [59] recently reported preserved myocardial ATP levels in patients undergoing CABG when the myocardium had been preconditioned with intermittent aortic cross-clamping on cardiopulmonary bypass. A more attractive (and less traumatic) prospect for the cardiac surgeon would be the instillation in cardioplegia of a pharmacologic additive that provides the preconditioning effect.
Przyklenk and associates [60] demonstrated the possibility of a humoral mediator of preconditioning when they reported a reduction in infarct size in the left anterior descending region after 1 hour of sustained occlusion of the left anterior descending coronary artery after a preconditioning stimulus applied to the circumflex region. Adenosine may be the preconditioning mediator. Adenosine is known to be released from myocardium seconds after the onset of ischemia [61] and can induce most of the effects of preconditioning [62].
In our laboratory, we [63] developed a model of ischemia-reperfusion injury using pure monolayer cultures of nonbeating human ventricular cardiomyocytes. In this model, we found that a brief episode of ischemia and reperfusion reduces the cellular injury and increases cellular survival resulting from a subsequent prolonged ischemic episode. After preconditioning, the myocytes produced less hydrogen ion and lactate and released less lactate dehydrogenase into the perfusion fluid during prolonged ischemia, with a reduction in the rate of ATP depletion. These results with those in the literature suggest that the arrested heart may benefit from preconditioning.
Preliminary studies in this model suggest that the myocytes release adenosine into the overlying supernatant in response to brief simulated ischemia and that exogenously administered adenosine protects the cells against prolonged ischemia (unpublished data). The use of adenosine clinically may be limited by its marked vasodilatory effects. However, adenosine analogues with cardioprotective but only minor vasodilatory effects may be useful as cardioplegic additives.
Conclusion
Techniques of myocardial preservation are constantly being refined. The advent of normothermic blood cardioplegia has challenged the classic hypothermia paradigm of cardioprotection, which went unquestioned for 30 years. Cardiac surgeons have multiple options for the induction and maintenance of myocardial arrest during operation; these include the composition, the temperature, and the direction of cardioplegia administration. Current research indicates a bright future for further improvements in myocardial protection during cardiac operations.
Acknowledgments
Supported by the Medical Research Council of Canada (grant MT9829) and the Heart and Stroke Foundation of Ontario (grant B2267).
Doctors Ikonomidis and Rao are Fellows of the Heart and Stroke Foundation of Ontario, and Dr Weisel is a career investigator of the Heart and Stroke Foundation of Ontario.
Footnotes
Presented at the International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, Sept 25–28, 1994.
Address reprint requests to Dr Weisel, Toronto General Hospital, 200 Elizabeth St, EN 14-215, Toronto, ON M5G 2C4, Canada.
References
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