Accelerated myocardial metabolic recovery with terminal warm blood cardioplegia

J

THoRAc CARDIOVASC SURG

91:888-895, 1986

Accelerated myocardial metabolic recovery with terminal warm blood cardioplegia Although blood cardioplegia provides excellent protection, myocardial metabolic recovery is delayed. To evaluate the benefits of a terminal warm cardioplegic infllSion after cold blood cardioplegia, we performed a prospective randomized trial in 20 patients undergoing elective coronary bypass grafting. Eleven patients received cold blood cardioplegia and nine patients received cold blood cardioplegia and warm blood cardioplegia before cross-clamp removal (bot shot). The hot shot provided oxygen and removed excess lactate from the arrested heart. Mter the hot shot lactate was extracted by the heart and tissue adenosine triphosphate and glycogen concentrations were preserved. Atrial pacing and volume loading 3 and 4 hours postoperatively decreased myocardial lactate extraction after cold blood cardioplegia but increased lactate extractiop after the hot shot. Left atrial pressures were higher at similar end-diastolic volumes (by nuclear ventriculography), which suggested decreased diastolic compliance after cold blood cardioplegia. Terminal warm blood cardioplegia accelerated myocardial metabolic recovery, preserved high-energy phosphates, improved the metabolic response to postoperative hemodynamic stresses, and reduced left atrial pressures.

Kevin H. Teoh, M.D., George T. Christakis, M.D., Richard D. Weisel, M.D., Stephen E. Fremes, M.D., Donald A. G. Mickle, M.D., Alexander D. Romaschin, Ph.D., Reginald S. Harding, M.Sc., Joan Ivanov, R.N., M. Mindy Madonik, B.Sc., Ian M. Ross, C.P., C.C.P., Peter R. McLaughlin, M.D., and Ronald J. Baird, M.D., Toronto, Ontario, Canada

Although cold blood cardioplegia provided excellent myocardial protection, myocardial metabolic recovery was delayed.' The infusion of a warm blood cardioplegic solution, a "hot shot," before cross-clamp removal but after cold blood cardioplegia was intended to provide oxygen to the arrested heart and remove toxic products of anaerobic metabolism.i' The hot shot may also improve

From the Divisions of Cardiovascular Surgery, Clinical Biochemistry, and Nuclear Cardiology, the Toronto General Hospital and the University of Toronto, Toronto, Ontario, Canada. Supported by the Canadian Heart Foundation and the Heart and Stroke Foundation of Ontario. Presented in part at the Surgical Forum of the Seventy-first Clinical Congress of the American College of Surgeons, Chicago, III., October, 1985. Received for publication June 19, 1985. Accepted for publication July 23, 1985. Address for reprints: Richard D. Weisel, M.D., Cardiovascular Surgery, Toronto General Hospital, 200 Elizabeth St., Eaton North 13-224, Toronto, Ontario, Canada M5G 2C4.

888

hemodynamic and myocardial metabolic recovery. A prospective randomized trial was instituted to evaluate the effects of terminal warm blood cardioplegia. Methods Patient population. Twenty patients scheduled for elective coronary bypass grafting agreed to participate in this prospective, randomized trial comparing cold blood cardioplegia (n = 11) and cold blood cardioplegia with terminal warm blood cardioplegia (n = 9). Each patient signed a consent form approved by the institutional human experimentation committee. Patients were included in the study if they had double- or triple-vessel coronary artery disease, exertional angina resistant to medical therapy, and preserved left ventricular function (ejection fraction> 40% at preoperative contrast ventriculography). Additional clinical information is provided in Table I. Operative technique. The anesthetic management and conduct of cardiopulmonary bypass have been previously described.': 4 Blood cardioplegia was adrninis-

Volume 91 Number 6 June, 1986

tered with the Buckberg-Shiley* system, which delivered a crystalloid and oxygenated blood mixture at a 1:2 ratio into the aortic root at a temperature of 9° C. Proximal and distal anastomoses were constructed during a prolonged cross-clamp period. One liter of cold blood cardioplegic solution was infused into the aortic root at 70 mm Hg pressure to achieve arrest, 100 m1 was infused into each vein graft after completion of the distal anastomosis, and 400 m1 was infused into the aortic root (at a pressure of 60 mm Hg) after each proximal anastomosis was completed. Systemic rewarming was begun with the last distal anastomosis in both groups. In the group receiving the hot shot, an additional 500 m1 of warm blood cardioplegic solution was infused at 3r C into the aortic root at a pressure of 50 mm Hg before aortic unclamping. Measurements. Radial arterial, left atrial, pulmonary arterial, and coronary sinus thermodilution catheters were inserted intraoperatively. The following hemodynamic values were measured or derived by standard formulas1,4.5: pulse, left atrial pressure, systolic and mean arterial pressures, cardiac index (by thermodilution), and left ventricular stroke work index. During cardioplegia the time required to administer the desired volume was recorded to calculate the coronary blood flow (volume + time). Arterial and coronary sinus blood samples were assayed for oxygen tension, oxygen saturation,'] lactate.f and glycero1.§ Oxygen content was calculated from the oxygen tension and saturation measurements.vv' The cardiac extraction of oxygen, lactate, and glycerol was calculated as the difference between the arterial and coronary sinus contents of the respective metabolites. Coronary sinus blood flow was measured by the continuous thermodilution techniques of Ganz and colleagues." Transmural left ventricular biopsy specimens were obtained from the area judged to be most ischemic from the preoperative coronary angiograms and the area warmest after the first infusion.1 Samples were immediately immersed in liquid nitrogen, subsequently freezedried, and analyzed spectrofluorometricallyl for the 'Shiley Inc., Irvine, Calif. tCo-Oximeter, Instrumentation Laboratories, Lexington, Mass. tRapid Lactate Stat Pack Kit, Cal-Biochemical-Behring, La Jolla, Calif. §Enzymatic Triglyceride, Bochringer-Mannheim, Dorval, Quebec, Canada. IIGreiner Selective Analyzer II, Greiner Electronics, Langenthal, Switzerland, and Perkin-Elmer 650-105 Fluorescence Spectrophotometer, Perkin-Elmer, Norfolk, Conn.

889

Terminal warm blood cardioplegia

Table I. Clinical information Terminal Cold blood warm blood cardioplegia cardioplegia No, of patients Age (yr) NYHA 1/1I/1II/IV No, of diseased vessels Ejection fraction (%) No. of distal anastomoses Cross-clamp time (min) Bypass time (min) Mean myocardial temperature (0C) Highest postoperative CK-MB (U/L) Highest postoperative AST (U/L)

II 56 ± 8 2/3/5/1 2,7 ± 0,6 63 ± II

9

19 38 2 33 ± 12

52 ± 10 0/5/4/0 2.4 ± 0,7 54 ± 8 3,3 ± 0,5 66 ± 10 129 ± 21 15 ± 1 35 ± 7

66 ± 28

57 ± 11

3.7 ± 75 ± 136 ± 15 ±

0.9

Legend: NYHA, New York Heart Association. CK-MB, Cardiac isoenzyme of creatine kinase. AST. Aspartate aminotransferase.

tissue metabolites adenosine triphosphate (ATP), creatine phosphate (CP), glycogen, and lactate. Equilibrium gated nuclear ventriculograrns were performed in the intensive care unit between 3 and 5 hours postoperatively,I, 4, 5 Left ventricular end-diastolic volume index (ED VI) was calculated from the nuclearderived ejection fraction (EF), and the thermodilution stroke index (SI) by the formula: EDVI = (SI/EF). Left ventricular end-systolic volume index was calculated as the difference between the left ventricular enddiastolic volume index and the stroke index. Ventricular volumes were also calculated from the scintigraphic measurements.' Protocol for myocardial metabolic and hemodynamic measurements. Measurements were recorded during cardiopulmonary bypass before aortic occlusion, during the three or four aortic root infusions of the cardioplegic solution, at the time of cross-clamp release, at 10 minute intervals during the first hour after cross-clamp release, and at hourly intervals between 3 and 5 hours postoperatively. Left ventricular biopsy specimens were obtained before and immediately after aortic occlusion and after 30 minutes of reperfusion. Atrial pacing at 110 beats/min for 5 minutes was performed between 4 and 5 hours after cross-clamp removal in the intensive care unit. Volume loading was performed between 3 and 4 hours after cross-clamp removal by rapidly infusing 250 m1 of a colloid solution to raise the left atrial pressure 2 to 4 mm Hg. The response to volume loading was employed to evaluate myocardial performance (the relation between cardiac index or left ventricular stroke work index and left ventricular end-diastolic volume index), systolic

The Journal of

890

Teoh et al.

Thoracic and Cardiovascular Surgery

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function (the relation between systolic blood pressure and left ventricular end-systolic volume index), and diastolic function (the relation between left atrial pressure and left ventricular end-diastolic volume index). Statistical analysis. The Statistical Analysis System" programs were used for statistical analysis. Clinical data were compared by unpaired t tests, chi square tests, or Fisher's exact test where appropriate. The serial measurements were divided into the following time periods for analysis: during cardioplegic administration, during the initial reperfusion period on cardiopulmonary bypass, off bypass, and in the intensive care unit. Each interval was analyzed by separate two-way repeated measures analyses of variance by the general linear models procedure.t? Unpaired t tests or Duncan's multiple range t tests were employed to specify the difference between means when the p value associated ·SAS Institute. Cary. N. C.

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Fig. 1. Myocardial oxygen extraction (02Ex), lactate extraction (LEx), and coronary (cardioplegic) blood flow (CBF) during cardioplegia are depicted. Terminal warm blood cardioplegia (hot shot, HS) was delivered at a high flow rate and myocardial oxygen extraction was increased.

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with the F ratio was significant at the 0.05 level. A two-way analysis of variance was used to assess the metabolic response to atrial pacing and volume loading. Ventricular function was evaluated by two-way analyses of covariance. Continuous variables are presented as the mean and standard deviation in the text and tables and the mean and standard error of the mean in the figures. Statistical significance was assumed for p values less than 0.05. Results The clinical information is presented in Table I. The groups were similar with respect to sex (all male), age, preoperative ventricular function, and extent of coronary

Volume 91 Number 6 June, 1986

Terminal warm blood cardioplegia

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Table II. Response to atrial pacing and volume loading Baseline CSBF (mil min) Oxygen extraction (rnl/dl) Lactate extraction (rnmol /L) MWI (kg. m/min/nr')

193 6.9 0.59 3.3

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233 7.1 0,49 3.3

±

± ±

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Cold blood cardioplegia 90 208 ± 135 1.9 6.8 ± 1.6 0.3 0.31 ± 0.3 1.8 3.0 ± 0.8

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± 0.8 ± 1.7

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229 8.0 0.42 2.1

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Legend: CSBF, Coronary sinus blood flow. MWI, Minute work index. *Dilferent from cold blood cardioplegia by analysis of variance, p < 0.05.

disease. The intraoperative management was similar. There were no deaths or perioperative myocardial infarctions. Postoperative enzymes were not different in the two groups. Fig. 1 depicts the coronary (cardioplegic) blood flow and the myocardial extraction of oxygen and lactate during cardioplegic administration. The terminal warm cardioplegic solution was delivered at a higher flow rate to maintain an aortic root pressure of 50 mm Hg. The time required to administer the hot shot was significantly shorter than the time required to give the cold blood cardioplegia (cold cardioplegia, 84.4 ± 28.4 seconds: hot shot, 59.0 ± 2.2 seconds; p = 0.006). Both myocardial oxygen extraction and oxygen consumption were

increased during the hot shot. The hot shot washed out lactate and glycerol that had accumulated in the myocardium during cardioplegic arrest. The blood temperatures at the time of cross-clamp release were similar in the two groups (cold cardioplegia 32 ° ± 5 ° C; hot shot, 32° ± 4° C). After cross-clamp removal, sinus rhythm returned immediately after cold blood cardioplegia, but cardiac arrest persisted for 10 minutes after the hot shot. Sinus rhythm returned spontaneously within 20 minutes after cross-clamp removal in the group receiving the hot shot. Blood temperatures fell during the first 2 hours postoperatively and returned to normal 4 hours postoperatively, as we5 previously reported, but there was no difference between the two groups.

The Journal of

8 9 2 Teoh et al.

Thoracic and Cardiovascular Surgery

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The postoperative metabolic measurements are shown in Fig. 2. Measurements of coronary sinus blood flow were similar in the two groups. Myocardial oxygen extraction increased after cross-clamp release in both groups. Myocardial lactate extraction was observed after cross-clamp removal following the terminal warm blood cardioplegia, but lactate release was found after cold blood cardioplegia. The left ventricular biopsy results are presented in Fig. 3 and are expressed as percentage recovery from the baseline value before cardioplegia. There was no difference in the ATP, CP, lactate, or glycogen concentrations before the application of the cross-clamp and therefore the percentage recovery reflected the absolute values. Tissue ATP values were 80% of baseline after crossclamp removal in both groups. After cold blood cardioplegia, ATP levels fell to 50% of baseline 30 minutes after reperfusion but did not change after terminal warm blood cardioplegia. CP levels were maintained after cross-clamp removal in both groups, increased significantly 30 minutes after reperfusion following cold blood cardioplegia, but did not increase after terminal warm blood cardioplegia. Tissue lactate levels tended to be higher at cross-clamp removal after the cold blood cardioplegia, but the levels returned toward baseline values 30 minutes later in both groups. Significant glycogen depletion was found 30 minutes after reperfusion following cold blood cardioplegia but not terminal warm blood cardioplegia. Myocardial lactate extraction increased with both atrial pacing and volume loading after the terminal warm blood cardioplegia but decreased after cold blood

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cardioplegia (Fig. 4 and Table II). Coronary sinus blood flow, myocardial oxygen extraction, and minute work index were similar in the two groups (Table II). In the intensive care unit, left atrial pressures were higher after cold blood cardioplegia despite similar left ventricular end-diastolic volume indices (Fig. 5). Pulse, mean arterial pressure, cardiac index, and left ventricular stroke work index were similar in the two groups between 3 and 5 hours postoperatively. In response to volume loading, left atrial pressure increased more after cold blood cardioplegia despite a similar increase in left ventricular end-diastolic volume index (Fig. 6). Diastolic pressures were higher after cold blood cardioplegia by an analysis of covariance (p < 0.05). An analysis of the relation between left atrial pressures and diastolic volumes calculated from scintigraphic measurements also suggested depressed diastolic compliance (p < 0.05, by an analysis of covariance). Despite the differences in diastolic properties, there was no significant difference in systolic function (the relation between systolic blood pressure and end-systolic

Volume 91

Terminal warm blood cardioplegia

Number 6 June, 1986

o_e Hot

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volume index) or myocardial performance (the relation between stroke work index and end-diastolic volume index, Fig. 7). Discussion The addition of terminal warm blood cardioplegia after cold blood cardioplegia improved myocardial metabolic recovery, prevented the fall in high-energy phosphates during reperfusion, and induced a normal myocardial metabolic response to postoperative hemodynamic stresses. Myocardial metabolism. Terminal warm blood cardioplegia delivered oxygen to the arrested myocardium after a period of relative ischemia, which permitted partial repayment of the oxygen debt. The increased oxygen delivery was facilitated by coronary vasodilation and the warm cardiac temperatures.'? The warm blood cardioplegic solution washed out the products of anaerobic metabolism. During reperfusion, less lactate was found in the coronary sinus effluent and in the biopsy samples. In addition, myocardial lactate extraction returned sooner after warm blood cardioplegia. The inadequate myocardial lactate extraction after cold

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blood cardioplegia probably represents persistent anaerobic metabolism and regional lactate production despite net lactate extraction, as described by Gertz and colleagues. II Tissue glycogen levels fell during reperfusion after cold blood cardioplegia, perhaps because of persistent anaerobic metabolism. Other investigators have also found delayed recovery of lactate extraction after cold blood cardioplegia. Barner and associates I2 reported depressed lactate extraction during the first 30 minutes of reperfusion after cold blood cardioplegia in dogs. Buttner and colleagues" reported inadequate lactate extraction after cold blood cardioplegia in patients undergoing elective coronary bypass operations. ATP was depleted immediately after cross-clamp release in both groups. Further depletion was found with reperfusion after cold blood cardioplegia but not terminal warm blood cardioplegia. CP increased during reperfusion after cold blood cardioplegia. The fall in ATP and rebound increase in CP have been described as responses to ischemia. 14, 15 The preservation of ATP during reperfusion requires the availability of substrate, precursors, and mitochondrial mechanisms to phosphorylate adenosine monophosphate to ATP.I6-19 Cunningham and associates" found depressed ATP levels associated with mitochondrial ultrastructural changes after inadequate blood cardioplegia. Terminal warm blood

894

Teoh et al.

The Journal of Thoracic and Cardiovascular Surgery

cardioplegia may provide precursors and may have restored mitochondrial capability to maintain ATP levels. Atrial pacing and volume loading were performed to elicit the metabolic response to hemodynamic stresses.21• 22 Terminal warm blood cardioplegia preserved myocardial metabolism in response to stress, which suggested adequate myocardial protection. Myocardial lactate extraction decreased after cold blood cardioplegia despite increases in work, which suggested the use of alternate substrates or ischemic anaerobic metabolism in response to stress. Ventricular function. Both myocardial performance and systolic function were preserved postoperatively in both groups. However, in response to the stresses of atrial pacing and volume loading, left atrial pressures were higher at similar end-diastolic volume indices, which suggested greater diastolic stiffness after cold blood cardioplegia. Higher left atrial pressures may reflect ischemic myocardial metabolism.> 23, 24 This study suggested that terminal warm blood cardioplegia prolonged cardiac arrest during reperfusion and permitted restoration of high-energy stores and cellular repair rather than electromechanical work. Follette and associates 2• 3 found that maintenance of arrest with hyperkalemic reperfusate during initial reperfusion improved postischemic oxygen uptake, myocardial performance, and diastolic compliance. Rearresting the heart with blood cardioplegia (secondary cardioplegia) has also been found to be beneficial in reducing postischemic damage." Substrate enhancement" may permit even better metabolic recovery. Terminal warm blood cardioplegia influenced subtle indices of metabolic and functional recovery but did not influence any clinical event after elective coronary bypass. However, these patients were at low risk of perioperative ischemia. The risk is higher for patients who require urgent revascularization because of uncontrolled ischemia, and terminal warm blood cardioplegia may improve their surgical results. Because no adverse effects of warm blood cardioplegia were encountered, we would recommend a "hot shot" whenever cold blood cardioplegia is employed for myocardial protection. We wish to express our appreciation to Barbara Brown, B.A., for assistance with the biochemical measurements, Peter Evans, B.A., for assistance with hemodynamic and clinical data acquisition, Penelope J, Maton, B.Sc., Yasmin Jivraj, R.T,(N.M.), and Sylvain Houle, M.D., for nuclear data acquisition and analysis, and to Ms. Catherine Andrews for preparation of the manuscript. We wish to thank the perfusionists: Katherine Benedek, e.e.P., Arnold Benak, e.e.P., Mark Henderson, e.C.P., Jennifer McDonough, e.e.P., and Talara HilI, e.C.P. We also wish to extend our appreciation to

the nurses and physicians of the cardiovascular operating room and intensive care unit of Toronto General Hospital for their assistance. REFERENCES Fremes SE, Christakis GT, Weisel RD, Mickle DAG, Madonik MM, Ivanov J, Harding R, Seawright SJ, Houle S, McLaughlin PR, Baird RJ: A clinical trial of bloodand crystalloid cardioplegia. J THORAC CARDIOVASC SURG 88:726-741,1984 2 Follette DM, Steed DL, Foglia RP, Fey KH, Buckberg GD: Reduction of post-ischemic myocardial damage by maintaining arrest during initial reperfusion. Surg Forum 28:281-283,1977 3 Follette DM, Fey KH, Steed DL, Foglia RP, Buckberg GD: Reducing reperfusion injury with hypocalcemic, hyperkalemic, alkalotic blood during reoxygenation. Surg Forum 29:284-286, 1978 4 Weisel RD, Fremes SE, Baird RJ, Ivanov J, Madonik MM, Mickle DAG: Improved myocardial protection with blood and crystalloid cardioplegia. J Vase Surg 1:656-659, 1984 5 Fremes SE, Weisel RD, Mickle DAG, Ivanov J, Madonik M, Seawright SJ, Houle S, McLaughlin PR, Baird RJ: Myocardial metabolism and ventricular function following cold potassium cardioplegia. J THORAC CARDIOVASC SURG 89:531-546,1985. 6 Ganz W, Tamura K, Marcus HS, Donoso R, Toshida S, Swan HJC: Measurement of coronary sinus blood flow by continuous thermodilution in man. Circulation 44:181195,1971 7 Burns RJ, Nitkin RS, Weisel RD, Houle S, Prieur TG, McLaughlin PR, Druck MN: Optimized count-based scintigraphic left ventricular volume measurement. Can J Cardiol 1:42-46, 1985 8 Goodnight JH, SaIl JP, Sarie WS: The GLM procedure, SAS User's Guide: Statistics, AA Ray, JP SaIl, M, Shaffer, eds., Cary, N. C, 1982, SAS Institute Inc., pp 139-199 9 Freund RJ, Littell RC: SAS for Linear Models. A Guide to ANOVA and GLM Procedures, Cary, N C, 1981,SAS Institute Inc. 10 Magovern GJ, Flaherty JT, Gott VL, Bulkley BH, Gardner TJ: Failure of blood cardioplegia to protect myocardium at lower temperatures. Circulation 66:60-67, 1982 II Gertz EW, Wisneski JA, Neese R, Bristow JD, Searle GL, Hanlan JT: Myocardial lactate metabolism. Evidence of lactate release during net chemical extraction in man. Circulation 63:1273-1279, 1981 12 Barner HB, Laks H, Codd JE, Standeven JW, JeIlinek M, Kaiser GC, Menz LJ, Tyras DH, Pennington DG, Hahn JW, Willman VL: Cold blood as the vehicle for potassium cardioplegia. Ann Thorac Surg 28:509-521, 1979 13 Buttner EE, Karp RB, Reeves JG, Oparil S, Brummett C, McDaniel HG, Smith LE, Kreusch G: A randomized comparison of crystalloid and blood-containing cardioplegic solutions in 60 patients. Circulation 69:973-982, 1982

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Terminal warm blood cardioplegia

Number 6 June, 1986

14 Engelman RM, Rousou lH, Dobbs W, Pels MA, Longo F: The superiority of blood cardioplegia in myocardial preservation. Circulation 62:62-66, 1980 15 Rousou lH, Engleman RM, Dobbs WA, Anisimowich L: Metabolic enhancement of myocardial preservation during cardioplegic arrest. Surg Forum 34:332-334, 1983 16 Pasque MK, Wechsler AS: Metabolic intervention to affect myocardial recovery following ischemia. Ann Surg 200:1-12, 1984 17 Riebel DK, Rovetto Ml: Myocardial ATP synthesis and mechanical function following oxygen deficiency. Am 1 Physiol 234:H620-H624, 1978 18 Foker JE, Einzig S, Wang T, Anderson RW: Adenosine metabolism and myocardial preservation. Consequences of adenosine catabolism on myocardial high-energy compounds and tissue blood flow. 1 THORAC CARDIOVASC SURG 80:506-516, 1980 19 Vary TC, Angelakos ET, Schaffer SW: Relationship between adenine nucleotide metabolism and irreversible ischemic tissue damage in isolated perfused rat heart. Circ Res 45:218-225, 1979 20 Cunningham lH, Adams PX, Knopp EA, Baumann FG, Snively SL, Gross RI, Nathan 1M, Spencer FC: Preservation of ATP, ultrastructure, and ventricular function after aortic cross-clamping and reperfusion. Clinical use of blood potassium cardioplegia. 1 THORAC CARDIOVASC SURG 78:708-720, 1979 21 Weisel RD, Bums Rl, Baird Rl, Hilton lD, Ivanov 1,

22

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Mickle DAG, Teoh KH, Christakis GT, Evans Pl, Scully HE, Goldman BS, McLaughlin PR: Optimal postoperative volume loading. 1 THORAC CARDIOVASC SURG 85:552563, 1985 Weisel RD, Burns Rl, Baird Rl, Hilton lD, Ivanov 1, Mickle DAG, Teoh KH, Christakis GT, Evans Pl, Scully HE, Goldman BS, McLaughlin PR: A comparison of volume loading and atrial pacing following aortocoronary bypass. Ann Thorac Surg 36:332-344, 1983 Fremes SE, Weisel RD, Baird Rl, Mickleborough LL, Bums Rl, Teasdale Sl, Ivanov 1, Seawright Sl, Madonik MM, Mickle DAG, Scully HE, Goldman BS, McLaughlin PR: Effects of postoperative hypertension and its treatment. 1 THORAC CARDIOVASC SURG 86:47-56, 1983 Aroesty 1M, McKay RG, Heugr GV, Royal HD, Als AV, Grossman W: Simultaneous assessment of left ventricular systolic and diastolic dysfunction during pacing-induced ischemia. Circulation 71:889-900, 1985 Lazar HL, Buckberg GD, Manganaro Al, Foglia RP, Becker H, Mulder DG, Maloney lV lr: Reversal of ischemic damage with secondary blood cardioplegia. 1 THORAC CARDIOVASC SURG 78:688-697, 1979 Lazar HL, Buckberg GD, Manganaro Al, Becker H: Myocardial energy replenishment and reversal of ischemic damage by substrate enhancement of secondary blood cardioplegia with amino acids during reperfusion. 1 THORAC CARDIOVASC SURG 80:350-359, 1980