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Ann Thorac Surg 1995;60:819-823
© 1995 The Society of Thoracic Surgeons
Thoracic and Cardiovascular Division, Department of Surgery, University of Virginia Health Sciences Center, Charlottesville, Virginia
Abstract
Background. Advances in myocardial protection have been instrumental in making cardiac surgery safer. Debate exists over the optimal medium and the optimal temperature for cardioplegia. Currently blood cardioplegia is preferred over crystalloid; the optimal temperature, however, remains controversial.
Methods. Both warm and cold blood cardioplegia use potassium-induced electromechanical arrest, thereby reducing oxygen consumption by 90% in the working heart. Hypothermic blood cardioplegia given every 15 to 30 minutes provides a bloodless operative field and reduces oxygen consumption an additional 5% to 20%. Continuous warm cardioplegia avoids the deleterious effects of hypothermic ischemia and minimizes reperfusion injury. Perfusion is often interrupted for 5 to 10 minutes to allow adequate visualization of the operative site. Both warm and cold cardioplegia can be given either antegrade or retrograde.
Results. Retrospective studies from Toronto support the safety and efficacy of warm cardioplegia. Two large prospective, randomized trials of warm cardioplegia versus intermittent cold blood or cold crystalloid cardioplegia demonstrated equally low incidences of death, perioperative myocardial infarction, and need of intraaortic balloon pump support.
Conclusions. Warm blood cardioplegia represents the latest development in myocardial protection. Preliminary studies support its efficacy. Additional studies are needed to determine the ideal route of delivery and to identify any risks associated with the inherent warm cardiopulmonary bypass required.
The remarkable advances in cardiac surgery over the last 40 years have led to the concept of ``routine'' open heart surgery. Although advances in cardiac surgical technique, cardiac anesthesia, and critical care have all contributed to reducing the morbidity and the mortality of cardiac operations, the evolution of intraoperative myocardial protection has been equally critical. A tremendous body of literature has documented the physiologic basis of current cardioprotective methods and the debate over the optimal technique. This report briefly reviews the development of these techniques and the physiologic basis of the newest trend in myocardial protection: continuous warm blood cardioplegia.
Hypothermia and Electromechanical Arrest
All techniques of intraoperative myocardial protection attempt to match oxygen supply with oxygen demand. Myocardial oxygen demand is determined primarily by electromechanical activity and secondarily by basal metabolic rate and myocardial wall tension. The most common technique of myocardial protection reduces oxygen demand by minimizing electromechanical work with potassium-induced arrest and reducing basal metabolic rate with hypothermia. Hypothermia has been an integral component of myocardial protection during cardiac operations since its introduction by Bigelow and associates [1, 2] in 1950. They demonstrated consistent survival and reduced systemic oxygen consumption in dogs after systemic hypothermia to 20°C. Lower temperatures were associated with recalcitrant ventricular fibrillation on rewarming. Subsequent studies in isolated hearts demonstrated that hypothermia decreases myocardial metabolism [3, 4]. Later, hypothermia to 18°C alone was shown to provide nearly complete recovery of myocardial function after 60 minutes of global ischemia [5].
Electromechanical arrest was introduced by Melrose and co-workers [6] in 1955. Using intracoronary infusions of potassium citrate, they achieved rapid, reproducible onset of ventricular arrest with prompt return of sinus rhythm on restoration of coronary perfusion in open-chest dogs. Electromechanical arrest reduces myocardial oxygen consumption 60% in the empty, beating heart [7] and up to 90% in the working heart [8] at normothermia. Hypothermia can reduce oxygen consumption another 5% to 20% in the arrested heart. The additive protection of hypothermia and potassium arrest was subsequently shown by several investigators [9, 10]. Consequently, intermittent hypothermic potassium-enriched cardioplegia became accepted as state of the art for intraoperative myocardial protection.
Blood Versus Crystalloid
During the 1970s, investigators debated the optimal medium for delivery of cardioplegia. Blood cardioplegia was argued to be the better medium because of its greater oxygen-carrying capacity compared with crystalloid cardioplegia. At that time, most asanguineous cardioplegic solutions were unoxygenated. Crystalloid cardioplegia, even when oxygenated, contains only a fourth as much oxygen as blood cardioplegia [11, 12]. Buckberg and associates [13–15] clearly demonstrated the superiority of blood cardioplegia over crystalloid cardioplegia; they noted several advantages in addition to greater oxygen content including superior buffering capacity by blood protein histidine groups, improved microvascular flow secondary to rheologic effects, erythrocyte free radical scavengers, and less edema. Other investigators [16] have demonstrated improved preservation of myocardial ultrastructure and adenosine triphosphate levels and better oxygen extraction with blood cardioplegia.
Temperature for Cardioplegia
The debate over the optimal temperature for cardioplegia continues. Surgeons who favor crystalloid cardioplegia agree that it should be given at low temperatures (4° to 10°C) to maximize myocardial cooling and metabolic inhibition [17]. However, the ideal temperature for blood cardioplegia remains controversial. Buckberg [13] argued that myocardial temperatures lower than 20°C are unnecessary given that the oxygen demand of an arrested heart at this temperature is only 0.3 mL • 100 g-1 • min-1. Unlike asanguineous cardioplegic solutions, oxygen availability in blood cardioplegia is influenced by temperature because of the rightward shift in the oxyhemoglobin saturation curve in response to hypothermia. In vitro studies [18] have shown that at 20°C, only 50% of the total oxygen content of blood cardioplegia is available to tissue and that this number drops an additional 30% when the temperature is lowered to 10°C. Several investigators [18, 19] have demonstrated diminished efficacy of blood cardioplegia with lower temperatures. Other deleterious effects of hypothermia include inadequate cardioplegia delivery because of sludging, activation of cold agglutinins, and formation of rouleaux. However, more recent studies [11, 16] have demonstrated that cold (4° to 10°C) blood cardioplegia adequately restores myocardial function to baseline levels after prolonged periods of arrest and that blood cardioplegia at 10°C or 20°C is equally effective in maintaining myocardial oxygen extraction, a sensitive marker of myocyte function [12]. Studies [11, 20] documenting greater than predicted oxygen delivery from hypothermic blood cardioplegia suggest that other factors must favorably influence oxygen unloading, most likely myocardial tissue acidosis and hypercarbia.
Another criticism of intermittent hypothermic cardioplegia relates to the energy balance of the heart during arrest. Even a profoundly hypothermic, arrested myocardium requires some energy to maintain intracellular homeostasis. At 10°C, the arrested myocardium requires 0.14 mL of oxygen per 100 g per minute, approximately 95% less than normal [21]. In the absence of adequate oxygen supply, as could be found between doses of intermittent cardioplegia, the myocardium has to rely on anaerobic glycolysis for energy production. Depletion of high-energy phosphates, elevation of myocardial isoenzymes, and recovery of less than 100% of contractile force after intermittent hypothermic cardioplegia suggest that anaerobic metabolism is incapable of completely meeting the metabolic demands of the cold, arrested heart [22]. Deep hypothermia may actually inhibit energy production through glycolysis to a greater degree than energy consumption [23]. There are additional drawbacks to hypothermia including membrane destabilization [24], Na-K adenosine triphosphatase inhibition and resultant edema [24], calcium sequestration [25], and the need of a longer period of reperfusion to rewarm the heart, thereby increasing the potential for reperfusion injury and any associated reperfusion arrhythmias.
Warm Heart Surgery
Principles
Several refinements of hypothermic blood cardioplegia laid the groundwork for warm heart surgery. First, it was recognized that noncoronary collateral flow from the pericardium resulted in washout of cardioplegia, thereby allowing resumption of electromechanical work, the major determinant of myocardial oxygen consumption. Buckberg and colleagues [26] emphasized the advantages of intermittent replenishment of cardioplegia in terms of maintaining electromechanical arrest, buffering acidosis to maintain the energy-producing enzymatic machinery necessary, replenishing high-energy phosphates, restoring Krebs cycle intermediates like glutamate, and counteracting edema formation by providing a hyperosmolar load.
Second, normothermic induction of arrest with oxygenated cardioplegia was proposed to serve as active resuscitation of a metabolically deprived myocardium and was shown to lead to improved metabolic recovery after reperfusion. The maintenance of a blood-perfused, normothermic, arrested state during the first 5 minutes of cardioplegia infusion allowed metabolic activity to be directed toward reparative processes [27].
Third, reperfusion injury, characterized by intracellular calcium accumulation, edema, and inability to utilize delivered oxygen, was recognized as a potential pitfall of any cardiac operation requiring cross-clamping of the aorta. Subsequently a modified warm terminal cardioplegic perfusion or ``hot shot'' was given just before removal of the cross-clamp to maintain arrest while providing oxygen, enhance substrate, counter acidosis with alkaline reperfusate, temporarily chelate calcium, and reperfuse at a lower pressure with a hyperosmolar solution to limit edema formation. The functional and metabolic benefits of such a modified reperfusion was demonstrated by Teoh and co-workers [28] in a report on elective bypass operations.
Warm induction of blood cardioplegia and terminal ``hot shots'' share in common the principle of continuous perfusion with warm oxygenated blood enriched with potassium to maintain electromechanical arrest. It was logical to propose that the ideal state for the heart during a cardiac operation, a state that would avoid the disadvantages of intermittent hypothermic cardioplegia, would consist of continuous normothermic perfusion with oxygenated potassium-enriched blood.
Studies
Lichtenstein and associates [29] first reported the use of warm heart surgery in 1989 when they described the safe use of continuous warm cardioplegia for a patient requiring a cross-clamp time of 6
hours. In 1991, the same group [30] reported the results in 121 consecutive patients undergoing coronary artery bypass operations using a combination of continuous normothermic perfusion and electromechanical arrest. All patients underwent systemic cooling to 33°C and received 37°C blood cardioplegia in an antegrade fashion. Cardioplegia was occasionally interrupted for periods of up to 15 minutes to assist in visualization. This warm group of patients was compared with an historical cohort of 133 consecutive patients who received cold (10°C) continuous blood cardioplegia with systemic cooling to 30°C and topical iced saline to keep myocardial temperature at 15°C and were operated on by the same surgeon.
The two groups were identical in terms of preoperative New York Heart Association classification, age, need of urgent revascularization, and number of grafts. Intraoperatively, warm cardioplegia was associated with a significantly shorter period of reperfusion before discontinuation of cardiopulmonary bypass. This was at least partially attributable to the 99% rate of spontaneous resumption of sinus rhythm in the warm group compared with 10% in the cold group. There was no significant difference in overall mortality between the groups. However, patients receiving continuous warm blood cardioplegia sustained significantly fewer perioperative myocardial infarctions (1.7% versus 6.8%; p < 0.05), demonstrated a higher postpump cardiac output (4.9 ± 1.0 L/min versus 3.7 ± 0.6 L/min; p < 0.001), and had a lower incidence of low-output syndrome (3.3% versus 13.5%; p < 0.005). Lichtenstein and associates pointed out that with continuous warm blood cardioplegia, ``the crossclamp merely serves to separate a low-potassium sanguineous solution perfusing the periphery from a higher-potassium solution perfusing the coronaries.'' They argued that in an arrested heart, the relatively minor reduction in oxygen demand afforded by hypothermia renders the short (<15 minutes) periods of interrupted cardioplegia delivery ``relatively unimportant.'' Further studies are needed to determine the maximum duration of safe warm ischemia in the arrested heart. Until then, absolute attention must be paid to keeping the heart quiescent during any period of interrupted perfusion.
In a second retrospective study, Lichtenstein and co-workers [31] looked at the outcomes in a select group of patients at higher risk for perioperative complications. Two historical cohorts of patients undergoing coronary artery bypass grafting within 6 hours to 1 week of an acute myocardial infarction were compared. The warm group consisted of 51 patients who received antegrade warm blood cardioplegia similar to the group in the first study [30]. The cold group consisted of 64 patients who received antegrade continuous 4°C blood cardioplegia with systemic cooling (28°C) and topical slush to keep myocardial temperatures at 15°C. As in the first series, warm cardioplegia was associated with shorter reperfusion times and nearly uniform return of normal sinus rhythm.
Despite Lichtenstein and co-workers' admission that warm cardioplegia is a more cumbersome technique, aortic cross-clamp times were similar in the two groups (58 ± 13.7 minutes in the cold group versus 64 ± 15.2 minutes in the warm group). Several advantages were found in the warm group, most significantly a lower 30-day mortality rate (0% versus 10.9%; p < 0.05) and a decreased requirement of postoperative intraaortic balloon pump support (0% versus 12.5%; p < 0.05). There was a trend toward a reduced incidence of perioperative myocardial infarction (2% versus 9.3%) and low-output syndrome (6.3% versus 14%) associated with the use of warm cardioplegia, although this did not reach significance. These results led Lichtenstein and co-workers to suggest that continuous warm cardioplegia may provide added myocardial protection for patients with limited cardiac reserve.
The preliminary clinical success by the Toronto group prompted several investigators to study warm cardioplegia in animal models. Guyton's group [32] compared intermittent cold crystalloid and intermittent cold blood cardioplegia with continuous warm blood cardioplegia in an open-chest canine model of 15 minutes of global ischemia before induction of cardioplegic arrest for 60 minutes. A surgically placed snare kept the left anterior descending coronary artery occluded for the first 15 minutes of cardioplegia to simulate surgical revascularization of acutely ischemic myocardium. A combination of antegrade and retrograde induction and retrograde maintenance were used in the warm blood group. Overall left ventricular systolic performance and diastolic compliance were significantly better in the warm blood group. In addition, there was decreased electrocardiographic evidence of myocardial injury associated with warm blood cardioplegia. However, all hearts displayed light microscopic changes consistent with ischemia-reperfusion injury. Similarly, myocardial edema was the same for all three groups. Guyton's group concluded that continuous warm blood cardioplegia maintained with retrograde perfusion is effective and may be advantageous in the setting of acute ischemia; for the majority of elective cases, however, there is not enough evidence to support its routine use.
Unanswered Questions
As with intermittent hypothermic cardioplegia, the question of which route of delivery is best remains unanswered for warm blood cardioplegia. The Toronto group [31, 33] achieved success with both antegrade and retrograde delivery. However, animal studies have called into question the effectiveness of antegrade delivery in settings of obstructed coronary flow. In a swine model of acute coronary occlusion, Misare and colleagues [34] used antegrade induction and maintenance of warm blood cardioplegia and demonstrated worse global and regional functional recovery compared with antegrade hypothermic blood cardioplegia. In open-chest-swine, Matsuura and co-workers [35] demonstrated better myocardial preservation after 90 minutes of regional ischemia and 45 minutes of cardioplegic arrest with retrograde warm cardioplegia compared with antegrade warm cardioplegia. A combination of antegrade and retrograde cold cardioplegia provided an equivalent degree of myocardial preservation as retrograde warm cardioplegia.
Another question concerns the ideal flow rate to maintain adequate oxygen and cardioplegic arrest. Adequate delivery of oxygen is critical during normothermic arrest, as the metabolic rate is still on the order of 10% of normal. Under these conditions, oxygen delivery is determined by cardioplegic flow rates, hemoglobin levels, and temperature.
In one of the few prospective, randomized trials studying warm blood cardioplegia, Yau and colleagues [36] randomized patients to receive high-flow (100 mL/min) + high-hemoglobin (8 g/dL), low-flow (50 mL/min) + low-hemoglobin (5 g/dL), high-flow + low-hemoglobin, or low-flow + high-hemoglobin antegrade warm cardioplegia during elective coronary artery bypass. All patients had normal left ventricular performance preoperatively. There were no differences in clinical outcome in this small study (7 patients per group). However, immediately after release of the cross-clamp, significantly higher coronary sinus flows and oxygen consumption were noted in the low-flow + low-hemoglobin group compared with the other groups, a finding suggesting the incurrence of an oxygen debt during arrest. In addition, low-flow + low-hemoglobin cardioplegia was associated with significantly lower diastolic compliance and myocardial performance during the immediate postoperative period.
In all groups, cardioplegia was not delivered during 40% to 50% of the cross-clamp time because of periodic 8 to 10-minute interruptions to complete the anastomoses. According to the authors [36], the unavoidable interruptions of flow during warm heart operations mandate that hemoglobin levels and flow rates be kept at a minimum of 8 g/dL and 100 mL/min, respectively, to assure adequate oxygen delivery. Others [37, 38] have recommended rates as high as 150 to 250 mL/min, particularly for patients with left ventricular hypertrophy or for redo operations.
Although it is difficult to dispute the physiologic advantages of continuous warm blood cardioplegia for myocardial protection, a recent report by Martin and colleagues [39] at Emory University School of Medicine highlighted some of the clinically relevant disadvantages associated with warm heart surgery. In a prospective, randomized trial of warm blood cardioplegia, they enrolled 493 patients to receive 35°C warm cardioplegia with antegrade induction and retrograde maintenance and compared them with 508 patients receiving 8°C intermittent crystalloid cardioplegia. Systemic temperatures were maintained higher than 35°C in the warm group and lower than 28°C in the cold group. All patients underwent elective coronary artery bypass grafting and were similarly matched in terms of demographics and preoperative functional status.
Myocardial protection was adequate in both groups as evidenced by the equally low incidences of postoperative myocardial infarction (0.8% in the cold group and 1.2% in the warm group), death (1.6% in the cold group and 1.0% in the warm group), and need of intraaortic balloon counterpulsation (2.0% in the cold group and 1.4% in the warm group). Of greater concern, however, was the significantly higher incidence of total neurologic events (4.5% versus 1.4%) and perioperative stroke (3.1% versus 1.0%) in the warm group. Hyperglycemia, loss of the neuroprotective effects of moderate hypothermia, and embolic phenomena were offered as possible explanations for the higher stroke rate. In conclusion, the authors [39] stated that continuous warm blood cardioplegia had no benefit over intermittent cold blood cardioplegia in elective coronary artery bypass operations with short cross-clamp times and was associated with a higher incidence of perioperative neurologic events.
Another prospective, randomized trial [40] in more than 1,700 patients receiving either continuous warm or intermittent cold blood cardioplegia also found no differences in death rates, postoperative myocardial infarctions, or need of intraaortic balloon pump support. However, in contrast to the Emory University study, these investigators did not find a higher incidence of stroke associated with warm cardioplegia. Avoidance of retrograde delivery and use of slightly lower systemic temperatures were offered as possible explanations for the lower stroke rates in the second study.
Other systemic effects of warm cardiopulmonary bypass were reported by Christakis and colleagues [41] as part of a multicenter prospective, randomized trial of warm heart surgery. Compared with intermittent cold blood cardioplegia, warm cardioplegia is associated with higher total volumes of cardioplegia, more frequent use of high potassium cardioplegia to obliterate periodic episodes of electric activity, higher incidence of systemic hyperkalemia despite equal urine outputs, lower systemic vascular resistance, and greater use of crystalloid and 
-agonists to maintain perfusion pressures. Activation of the complement system and neutrophil degranulation could mediate the fall in systemic vascular resistance. The greater use of -agonists raises the possibility of internal mammary vasospasm [42]. DiNardo and associates [42] warn against the use of warm cardioplegia in patients with renal impairment.
Summary
Continuous warm blood cardioplegia is a promising addition to the growing field of myocardial protection. The need of continued refinements in intraoperative myocardial management is apparent given the larger number of high-risk patients undergoing coronary artery bypass grafting. Warm cardioplegia provides the cardiac surgeon a means to avoid the race against aortic cross-clamp time by eliminating hypothermic ischemia and reperfusion injury. Disadvantages include suboptimal visualization, increased cardioplegic requirements, increased risks of complications such as systemic emboli associated with higher pump rates, and consequences of normothermic cardiopulmonary bypass including complement activation, increased use of pressor agents, and greater systemic fluid requirements. Several questions remain to be answered including optimal flow rates, method of delivery, safe duration of cardioplegic interruptions, and ideal systemic temperature. Perhaps ``lukewarm'' heart surgery will provide some of the solutions.
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 Kron, Department of Surgery, University of Virginia School of Medicine, Box 181, Charlottesville, VA 22908.
References
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