Ann Thorac Surg 1997;63:98-104
© 1997 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Is Warm Retrograde Blood Cardioplegia Better Than Cold for Myocardial Protection?
Andreas Kamlot, MD,
Stephen D. Bellows, BS,
Boris Z. Simkhovich, MD, PhD,
Sharon L. Hale, BS,
Atsushi Aoki, MD,
Robert A. Kloner, MD, PhD,
Gregory L. Kay, MD
Heart Institute, Good Samaritan Hospital, and Division of Surgical Research, Department of Surgery, University of California of Los Angeles, Los Angeles, California
Accepted for publication July 26, 1996.
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Abstract
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Background. This study tests the hypothesis that continuous normothermic retrograde blood cardioplegia is superior to cold intermittent blood cardioplegia in protecting the left and right side of the heart transmurally during an extended cross-clamping period.
Methods. Twelve anesthetized, open chest dogs were placed on cardiopulmonary bypass and randomized to receive continuous warm (n = 6) or intermittent cold cardioprotection (n = 6) during a 3-hour aortic cross-clamp period. Transmural left ventricular muscle biopsy specimens were taken before the initiation of cardiopulmonary bypass and 90 and 180 minutes after cross-clamping. Right ventricular (RV) biopsy specimens were taken 180 minutes after aortic cross-clamping. Biopsy specimens were analyzed for adenosine triphosphate, creatine phosphate, and lactate levels and for morphologic changes via electron microscopy.
Results. At the end of 180 minutes of cardiopulmonary bypass, the adenosine triphosphate contents of endocardial and epicardial halves of the left ventricular myocardium were only slightly degraded in both cardioplegia groups; a significantly greater reduction in adenosine triphosphate levels occurred in the RV of the warm compared with the cold group (p < 0.02). The difference in creatine phosphate values in the left ventricle between the cold group (35.2 ± 23.4 nmol/mg cardiac protein) and the warm animals (64.4 ± 24.9 nmol/mg cardiac protein) was not statistically significant, but the RV creatine phosphate stores were significantly better preserved in the warm compared with the cold cardioplegia group (p < 0.02). Lactate levels increased to a similar extent in both groups, but both values rose significantly over baseline (p < 0.03). Importantly the electron microscopic score of the left ventricle and RV indicated that cells were reversibly and not irreversibly damaged with both cardioplegic protections.
Conclusions. These results suggest the following: (1) Chemical arrest is a major contributor of myocardial preservation during diastolic arrest as used in clinical cardiac surgery. (2) Both methods preserve the ultrastructure of the myocytes transmurally during 3 hours of aortic cross-clamping. (3) Both techniques protect the RV and left ventricle; however, to provide optimal protection of the RV, alternated retrograde and antegrade perfusion might be beneficial over retrograde cardioplegia flow alone, in particular with warm cardioplegia.
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Introduction
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See also page 104.
Myocardial protection techniques during aortic cross-clamping have been improved in the last two decades. Based on the concept that hypothermia, introduced by Bigelow and associates in 1950 [1], is the single most important component of myocardial protection [2], cold intermittent cardioplegia became a standard technique to preserve the heart during aortic cross-clamping (ischemic period). Two conceptual limitations of this technique are (1) intermittent administration of cold cardioplegia does not prevent ischemia and the concomitant conversion to anaerobic metabolism, and (2) hypothermia, per se, has deleterious effects on membrane stability, myocardial metabolism, calcium homeostasis, and cellular oxygen uptake [3, 4]. These concerns, in addition to the findings by Bernhard and colleagues [5] and more recently by Buckberg and associates [6] that electromechanical arrest of a working heart at normothermia decreases O2 consumption by 90% with only a slight further decrease in O2 consumption resulting from hypothermia, led to the hypothesis that continuous infusion of warm cardioplegia would provide superior protection during prolonged surgical procedures by both eliminating ischemia during the cross-clamp period and avoiding the confounding effects of hypothermia [7]. With use of the normothermic continuous cardioplegia technique, cardiac diastolic arrest is maintained with high potassium and the heart is perfused retrogradely through the coronary sinus with warm blood cardioplegia throughout the procedure. This technique has shown positive results in clinical settings [7]; however, there is little known about the basic science of the technique. The purpose of this study was therefore to evaluate on a biochemical and morphologic basis (1) whether normothermic blood cardioplegia maintains greater myocardial protection than cold ischemic cardioplegia, (2) if both cardioplegic methods preserve the left and right side of the heart, and (3) whether or not myocardial preservation is transmural in both techniques.
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Material and Methods
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Twelve mongrel dogs weighing 18 to 25 kg were anesthetized with intravenous sodium pentobarbital at a dosage of 35 mg/kg (supplemental doses as needed), intubated, and ventilated with room air. The surgical sites were shaved, cleaned with alcohol/povidone iodine, and draped. From a supine position the left femoral artery and femoral vein were cannulated with Pharmaseal extension tubes (Baxter Healthcare Corp, Valencia, CA) using a routine surgical cut-down technique. The venous line was connected to a heparinized normal saline solution drip for fluid and drug administration; the arterial line provided blood pressure monitoring. A median sternotomy was performed to expose the heart, which was suspended in a pericardial cradle. The right atrium was cannulated using a 30F William Harvey two-stage venous cannula (Bard, Santa Ana, CA), and via the right atrium a 14F Retroplegia Coronary Sinus Cannula (Research Medical Inc, Salt Lake City, UT) was inserted into the coronary sinus. The ascending aorta was exposed and cannulated using an 18F THI Aortic Perfusion Cannula (Argyle, St. Louis, MO). A 16-gauge aortic root cannula (DLP, Grand Rapids, MI) was inserted into the proximal portion of the aorta to be used for antegrade cardioplegia and as a vent.
The study protocol is shown in Figure 1
. Baseline transmural biopsy specimens were taken from the left ventricular apex using a pleural biopsy tool, to measure levels of adenosine triphosphate (ATP), creatine phosphate (CP), and lactate. Animals were then randomly assigned to receive either continuous retrograde administration of warm blood cardioplegia (n = 6) or intermittent retrograde cold blood cardioplegia (n = 6). Cardiopulmonary bypass (CPB) was established, followed by aortic root cross-clamping. Biopsies were repeated in the apex of the left ventricle (LV) for the above measurements at 90 minutes and in the LV and right ventricle (RV) at 180 minutes (end of experiment). Additional heart samples were obtained at the end of the experiment for electron microscopy.
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Fig 1. . Protocol used to compare warm versus cold cardioplegia. (ATP = adenosine triphosphate; cp = creatine phosphate; EM = electron microscopy.)
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This study was approved by the Institutional Animal Care and Use Committee of the Hospital of the Good Samaritan (an American Association for Accreditation of Laboratory Animal Care-accredited institution). All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication 86-23, revised 1985).
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Protocol 1 (Cold Cardioplegia)
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Cardiopulmonary bypass was established with a body core temperature of 28°C. A crystalloid cardioplegia and blood mixture in a ratio of 1:4 was initially administered for 3 to 5 minutes at a flow rate of 1.125 mL•min-1•kg-1 body mass in an antegrade fashion at a temperature of 4°C. Crystalloid cardioplegia mixture contained potassium chloride, 120 mEq; tromethamine, 30 mEq; nitroglycerin, 0.8 mg; and recombinant human insulin, 20 U; mixed in 500 mL 10% dextrose in water. The heart was topically cooled with 100 mL of iced saline solution every 20 minutes. Maintenance cold cardioplegia was given retrogradely each 20 minutes for 2 minutes at a flow rate of 50 to 100 mL/min with an average perfusion rate of approximately 75 mL/min. The cardioplegia flow was continuously adjusted to maintain the coronary sinus pressure between 40 and 50 mm Hg.
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Protocol 2 (Warm Cardioplegia)
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Cardiopulmonary bypass was carried out with a body core temperature of 37°C. Cardioplegic infusion was initiated in an antegrade fashion using a crystalloid-blood (ratio 1:4) solution at 37°C for 3 to 5 minutes at a flow rate of 1.125 mL•min-1•kg-1 body mass. The cardioplegic mixture was composed of potassium chloride, 50 mEq; tromethamine, 6 mEq; magnesium sulfate, 9 mEq; and citrate-phosphate-dextrose solution, 10 mL; mixed in 500 mL 5% dextrose in water. Cardioplegic infusion was then switched to retrograde maintenance for the entire duration of the experiment. The cardioplegia was composed of potassium chloride, 25 mEq; magnesium sulfate, 9 mEq; and citrate-phosphate-dextrose, 20 mL in 250 mL of 5% dextrose in water at a flow rate of 50 to 100 mL/min with an average perfusion rate of 80 mL/min. The cardiolegia flow was continuously adjusted to maintain the coronary sinus pressure between 40 and 50 mm Hg.
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Determination of Levels of High-Energy Phosphates and Lactate
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In vivo tissue biopsy specimens were obtained with a pleural biopsy tool. After removal from the heart, tissue biopsy specimens were flash frozen in liquid nitrogen, divided into subendocardial and subepicardial myocardium sections (Fig 2), and stored at -70°C for subsequent analysis. Homogenization of samples was performed in 0.4 N perchloric acid, followed by neutralization with a phosphate buffer. The suspension was then centrifuged, the supernatant was removed, and pellets were resuspended in 1 N NaOH. Aliquots of the supernatant were taken for the enzymatic measurement of ATP and CP using the Lowry and Passoneau method [8], and for lactate determination using a Sigma diagnostic kit (No. 826-UV; Sigma, St. Louis, MO). Pellets were used for protein determination. Values of ATP, CP, and lactate level are given as nanomoles per milligram of cardiac protein (nmol/mg protein).
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Fig 2. . Division of transmural left ventricular myocardial biopsy samples into subendocardial and subepicardial portions.
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Electron Microscopic Evaluation
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Transmural biopsy specimens for electron microscopic analysis were obtained in vivo and rapidly placed in Karnovsky's fixative, followed by postosmication, serial dehydration, and staining with uranyl acetate and lead nitrate.
Evaluation of photomicrographs was based on an electron microscopic scoring system from 0 to 4, such that a score of 0 was normal, 0.5–2 reversible injury, and 3–4 irreversible injury. Seven to eight fields per heart were assessed. Photographs were scored blindly as to group, using the following scoring system:
0 = Normal 0.5 = Minimal intracellular edema 1 = Definite edema–intermyofibrillar and intramitochondrial; early nuclear chromatin clumping and margination; and early loss of glycogen 2 = More marked edema; mitochondrial swelling; nuclear chromatin clumping and margination; and glycogen loss 3 = Severe edema; subsarcolemmal blebs; contraction bands; mitochondrial amorphous, granular densities are present; and breaks in sarcolemmal membrane 4 = Architectural disruption; contraction bands; breaks in sarcolemmal membrane; and mitochondrial amorphous, granular densities are present
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Statistics
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Myocardial ATP, CP, and lactate content were analyzed using two-way repeated-measures analysis of variance testing for time and group effects (SAS, version 6.01; Cary, NC). When a value of p less than 0.05 was found for a main effect, differences between means were evaluated by the method of contrasts. Data for levels in the right ventricle were evaluated by Student's t test. The electron microscopic scores were analyzed by nonparametric analysis using the method of Wilcoxon.
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Results
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Biochemical Indices
Biochemical indices are shown in Table 1.
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Table 1. . Biochemical Data During 3 Hours of Aortic Cross-Clamping (nmol/mg cardiac protein; mean ± standard deviation)
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MYOCARDIAL ADENOSINE TRIPHOSPHATE CONCENTRATION.
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Average myocardial ATP concentrations in the LV were similar in both groups at baseline. The ATP concentrations in the LV were only modestly depleted over 3 hours of aortic cross-clamping, with no significant difference between the cold and warm cardioplegia groups or between subendocardial and subepicardial sections. In contrast, ATP content at 180 minutes of CPB in the RV was significantly higher in dogs with cold cardioprotection (47.8 ± 15.3 nmol/mg protein) compared with those that received warm cardioplegia (27.6 ± 7.5 nmol/mg protein; p < 0.02).
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MYOCARDIAL CREATINE PHOSPHATE CONCENTRATION.
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Baseline content of CP was similar in both groups. The CP stores in the LV in both cardioplegia groups gradually decreased over 3 hours of aortic cross-clamping, in both subendocardial and subepicardial sections. The changes were not significantly different over time or between groups. In contrast, after 180 minutes of CPB, myocardial CP levels in the RV were higher in the warm group than in the cold group (36.5 ± 19.7 versus 11.9 ± 8.4 nmol/mg protein; p < 0.02).
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MYOCARDIAL LACTATE LEVEL CHANGES.
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Lactate levels in the LV increased significantly over time in the subepicardial and subendocardial sections in both groups (p < 0.03). However, there was no significant difference for LV and RV values between cold and warm cardioplegia.
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Morphologic Findings
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Morphologic findings in the myocardium are shown in Figures 3, 4, and 5. Three hours of aortic cross-clamping with either cold or warm cardioplegic arrest did not result in microscopic evidence of myocardial necrosis. Rather, all animals showed evidence of reversible transmural injury in both ventricles. Mild edema and glycogen loss were the most common findings without other significant changes. Specifically, seven to eight fields of view per animal were assessed using a well-established semiquantitative scoring system (see Material and Methods section). The mean electron microscopic score for LV was 0.8 ± 0.4 for animals receiving intermittent cold cardioplegia versus 0.9 ± 0.4 for dogs in the warm continuous cardioplegia group (p = not significant). Right ventricular electron microscopic scores were 1.6 ± 0.7 in the cold versus 1.0 ± 0.6 in the warm cardioplegic heart (p = not significant). The range of scores and their variability between animals within a group and within each animal itself were minor (<0.7).
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Fig 3. . Electron micrograph obtained from the left ventricle after cold intermittent blood cardioplegia for 3 hours. The nucleus (upper part of picture), sacromers, and mitochondria are intact. A few lipid droplets are present. (Uranyl acetate and lead citrate; x20,000 before 54% reduction.)
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Fig 4. . Electron micrograph of canine left ventricle after continuous warm blood cardioplegia for 3 hours. There is intermyofibrillar edema and glycogen loss. The mitochondria are intact. (Uranyl acetate and lead citrate; x20,000 before 50% reduction.)
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Fig 5. . Electron microscopic (EM) morphology scores from all 6 animals in the warm and cold cardioplegia groups. Evaluation of photomicrographs was based on an EM scoring system from 0 to 4, such that a score of 0 was normal, 0.5–2 reversible injury, and 3–4 irreversible injury (see Material and Methods section).
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Comment
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This study shows that cold intermittent and warm continuous retrograde infusion of blood cardioplegia provide similar levels of ultrastructural and biochemical protection of the heart for 3 hours of aortic cross-clamping. Both methods preserved the ultrastructure of the myocytes transmurally during this prolonged period of CPB. In general, the ultrastructure of the cells revealed evidence of mild reversible rather than irreversible injury, despite the fact that the aortic cross-clamp period was 3 hours. There were minor differences in the patterns of biochemical changes in the myocardium. The CP stores in the RV were better preserved after 180 minutes of CPB in the warm continuous group, but cold cardioplegia better preserved ATP in the RV after the same period of aortic cross-clamping. These results suggest that chemical arrest is a major contributor of myocardial preservation during diastolic arrest as used in clinical cardiac surgery. Therefore, it is imperative for the surgeon to assure complete cardiac arrest throughout the procedure. Both techniques protect the RV and LV; however, to provide optimal protection of the RV, alternated retrograde and antegrade perfusion might be beneficial over retrograde cardioplegia flow alone, in particular with warm cardioplegia.
These results are in line with the findings from our recent canine reperfusion study [9]. After 3 hours of aortic cross-clamping with cold intermittent and warm continuous cardioplegic protection of the myocardium, high-energy phosphate levels, hemodynamics, and left ventricular function showed mild abnormalities in both groups, with reversible morphologic tissue injury detected by electron microscopy. Both warm and cold models exhibited stunning of the LV during the early hours of reperfusion. Analysis of LV ejection fraction and LV wall thickening in the cold and warm cardioplegia groups showed no difference in the incidence of hypokinesis when the analysis was normalized to systemic vascular resistance baseline values (Fig 6). Reperfusion in that study did not cause any significant worsening of myocardial biochemistry and morphology. Cell edema rather than necrosis was detected during the reestablishment of blood flow. Therefore, reperfusion injury appeared to be an amplification of the ischemic damage, rather than a separate injury form.
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Fig 6. . Area left ventricular (LV) ejection fraction (A) and posterior LV wall thickening (B) at 1 and 2 hours after bypass expressed as a percent of their baseline values and plotted as a function of the percent change in systemic vascular resistance during the protocol. Regression analysis predicted that if systemic vascular resistance remained unchanged at 100% of baseline, area ejection fraction and LV wall thickening would be modestly depressed at 86% and 82% of baseline, respectively. Observations of hypokinesis (LV function < 100% of baseline) despite a reduction in systemic vascular resistance (ie, data points within the shaded quadrant) represent unequivocal instances of stunned myocardium. Fisher's exact test revealed no difference in the incidence of stunned myocardium in dogs that received warm versus cold cardioplegia. (Squares = data points at 1 hour after bypass; triangles = data points at 2 hours after bypass.) (Reprinted with permission from Przyklenk K, Atsushi A, Bellows S, et al. Stunned myocardium following prolonged CPB: effect of warm versus cold cardioplegia in the canine model. J Card Surg 1994;9(Suppl) :506–16.)
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Our results are in accord with the findings by Bernhard and colleagues [5] and Buckberg and associates [6] that electromechanical arrest of the heart at normothermia decreases O2 consumption by 90% with only a small additional benefit attributed to profound hypothermia. A further decrease of O2 consumption by hypothermia, to minimize cellular production and accumulation of anaerobic metabolic products, might be counteracted by the leftward shift of the O2 dissociation curve and the disturbance of cellular enzyme function, membrane stability, pH and osmotic homeostasis, calcium sequestration, glucose utilization, and ATP generation and utilization [3, 4, 10–12]. In the present study cold retrograde cardioplegia resulted in the breakdown of CP and increased lactate production during cardioplegic arrest, indicating significant anaerobic metabolism.
Other investigators have supported the role of electromechanical uncoupling rather than hypothermia as a major contributor to cardiac protection during aortic cross-clamping. They demonstrated increased O2 consumption per heartbeat in hypothermia because of the inhibition of calcium removal with subsequent increase in contractility [11]. In other words, if heart rate were kept constant, myocardial O2 consumption would increase nearly fourfold as temperature drops from 37°C to 20°C [6].
However, if cardioplegia is administrated in an intermittent fashion to achieve a clear operative field, interrupted nutrient supply at physiologic temperature is insufficient to satisfy the residual metabolic demand of the myocardium. A switch to tissue hypothermia would be mandatory. Matsuura and colleagues [13] showed superior myocardial preservation with cold intermittent versus warm intermittent cardioprotection.
On the other hand, the results of Lichtenstein and associates [14] regarding diminished myocardial infarction rate, decreased intraaortic balloon pump demand, and increased cardiac output after CPB with warm continuous cardioplegia administration differed from our investigation of myocardial energetics and morphology. The approach to improve cellular metabolism and to conserve high-energy phosphates by continuous perfusion of normothermic blood cardioplegia during CPB might be counteracted by inadequate blood supply to myocardial tissue by retrograde perfusion alone. In our study, warm retrograde cardioplegia resulted in a breakdown of ATP and increased lactate production during cardioplegic arrest, which are hallmarks of anaerobic metabolism. Previous investigations have shown that continuous retrograde delivery of normothermic blood cardioplegia can be associated with significant shunting through arteriosinusoidal and thebesian systems, limiting nutritive cardioplegic flow [15]. Increasing retrograde cardioplegic flow rates may expand shunt volume without increasing nutrient flow to the myocardium [16]. Salerno and associates [17] described another possible reason for the impairment of myocardial preservation during continuous retrograde administration of cardioplegia: there is a tendency for displacement of the coronary sinus cannula, especially if the heart is moved.
The method of simultaneous perfusion of the heart from the arterial and venous side by Ihnken and co-workers [18] seems to be a promising concept to provide superior protection of especially the RV during CPB, but its advantage has not been shown yet. After the investigators tested the safety of this perfusion technique in the experimental model, they substantially altered the method in the clinical application.
In the present study, the trend toward better preservation of myocardial CP stores in the warm cardioplegia group at 180 minutes of aortic cross-clamping and the gap between cellular ATP and CP levels in the cold cardioplegia group may be explained by the model of the "creatine-phosphorylcreatine energy shuttle" by Bessman and Fonyo from 1966 [19]: at the myofibrillar site CP reacts with adenosine diphosphate to produce creatine and ATP for muscle contraction. This creatine migrates to the mitochondria, where nascent ATP produces CP and immediately restores adenosine diphosphate. The CP returns to the myofibril to fuel further contractions.
In our study, the warm cardioplegia group maintained a higher degree of oxidative phosphorylation coupled with mitochondrial ATP production. Mitochondrial creatine kinase catalyzes the formation of CP with mitochondrial generated ATP. In contrast, the cold heart is not capable of sufficiently restoring mitochondrial ATP, due to hypothermia and ischemia [3]. Because mitochondrial creatine kinase preferentially utilizes de novo mitochondrial ATP as a substrate for CP synthesis rather than cytoplasmic ATP [20], the cold myocyte is unable to restore CP levels. However, the preservation of cellular ATP levels in the cold-arrested heart is a result of depressed ATPase activity [10] and of shifting ATP away from myofibrils into the cytoplasm, leading to the observed gap between myocardial ATP and CP levels in the cold heart.
In the present study, retrograde perfusion with warm continuous and cold intermittent blood cardioplegia provide similar levels of ultrastructural and biochemical protection for the left and right side of the heart during 3 hours of aortic cross-clamping. A potential limitation of this study is a small sample size. Although our data are based on 6 animals in each group, we cannot exclude the possibility that if more animals had been tested, small differences in the two groups may have reached statistical significance.
Our findings of better preserved ATP stores in the RV after 180 minutes of aortic cross-clamping in the cold versus warm cardioplegia group may be explained by the application of cold cardioplegia and topical cooling to the underperfused RV. Partington and associates [15] showed a disparity between capillary flow and myocardial cooling during retrograde delivery, suggesting a drainage pattern whereby cold cardioplegia retroperfused via the coronary sinus may bypass the capillary bed and traverse venovenous connections [21] and exert cooling without providing nutritive flow.
Our findings suggest that chemical arrest is a major contributor of myocardial preservation during diastolic arrest in this experimental model of cardiac surgery, and that a further attempt to diminish O2 consumption by hypothermia or to improve myocardial metabolism by normothermic continuous perfusion plays just a minor role in the protective effect within 3 hours of aortic cross-clamping. Therefore, it is imperative for the surgeon to assure complete cardiac arrest throughout the procedure. Both warm and cold blood cardioplegia provide safe protection of LV and RV transmurally for 3 hours of aortic cross-clamping. However, to provide optimal protection of the RV, alternated retrograde and antegrade perfusion might be beneficial over retrograde cardioplegia flow alone, in particular with warm cardioplegia. Neither of the two cardioprotective techniques was able to prevent net myocardial lactate production, high-energy phosphate depletion, or edema formation during cardioplegic arrest. Therefore, further investigations are mandatory to further improve cardiac protection, especially in high-risk patients and in difficult procedures requiring a long aortic cross-clamping time.
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Acknowledgments
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We thank Dr Samuel P. Bessman for his outstanding supportive efforts in discussing our findings.
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Footnotes
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Address reprint requests to Dr Kay, Heart Institute, Good Samaritan Hospital, 1225 Wilshire Blvd, Los Angeles, CA 90017.
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References
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- Ikonomidis JS, Yau TM, Weisel RD, et al. Optimal flow rates for warm retrograde cardioplegia. J Thorac Cardiovasc Surg 1994;107:510–9.[Abstract/Free Full Text]
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- Bessman SP, Fonyo A. The possible role of the mitochondrial bound creatine kinase in regulation of mitochondrial respiration. Biochem Biophys Res Commun 1966;22:597–602.[Medline]
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Abstract
Introduction
