A clinical trial of blood and crystalloid cardioplegia

J

THoRAc CARDIOVASC SURG

88:726-741, 1984

A clinical trial of blood and crystalloid cardioplegia Although experimental studies suggest that blood cardioplegia provides better protection than crystalloid cardioplegia,cHnicai studies bave been inconclusive. Ninety patients undergoing coronary bypass grafting were randomized to receive either blood (n = 43) or crystalloid cardioplegia (n = 47). The incidence of perioperative myocardial infarction was lower with blood cardioplegia (blood, n =0; crystalloid, n =5; p = 0.(6), and the maximum MB isoenzyme of creatine kinase was significantly less with blood cardioplegia (blood, 26.3 ± 12.6 U IL; crystalloid, 35.6 ± 17.0 U II., mean ± standard deviation; p < 0.02.) Sixty patients (blood cardioplegia,n = 28; crystalloid cardioplegia,n = 32) bad more sensitive measurements to assess the metabolic response to aortic occlusion and to compare the metabolic and ftmctional recovery from the operation. Coronary sin~ blood flow (by the continuo~ thermodilution technique) was significantly lower after cross-clamp removal with blood cardioplegia (blood, 160 ± 100 ml/min; crystalloid, 220 ± 120 ml/min; p < 0.05), indicating less reactive hyperemia. The cardiac production of lactate was significantly less with blood cardioplegia during aortic occlusion (blood, -0.5 ± 0.9 mmol/L; crystalloid, -0.9 ± 0.9 mmol/L; p < 0.05) and immediately after aortic declamping (blood, -0.2 ± 0.4 mmoljL; crystalloid, -0.7 ± 0.7 mmol/L; p < 0.01). Thermodiilution cardiac output measurements permitted calculation of the left ventricular stroke work index, and nuclear ventriculograms permitted calculation of the left ventricular end-diastolicvolume index and end-systolic volume index. Myocardial performance, systolic elastance, and diastolic compliance were determined from volume loading studies (250 to 500 mI colloid) performed 2 to 4 hours postoperatively. Myocardial performance (the left ventricular stroke work index-left ventricular end-diastolic volume index relation) and systolic elastance (the systolic bloodpressure-left ventricularend-systolic volume index relation)were significantly better with blood cardioplegia (p < 0.01 by multivariate analysis~ diastolic compliance(the left atrial pressure-left ventricular end-diastolic volume index relation) was similar. Blood cardioplegia reduced ischemic injury, decreased anaerobic metabolism during arrest, and permitted better ftmctional recovery. Blood cardioplegia provides superior protection for elective coronary bypass grafting and may improve the cHnicai results in patients with lDtable angina and in other high-risk patients.

Stephen E. Fremes, M.D. (by invitation), George T. Christakis, M.D. (by invitation), Richard D. Weisel, M.D., Donald A. G. Mickle, M.D. (by invitation), M. Mindy Madonik, B.Sc. (by invitation), Joan Ivanov, R.N. (by invitation), Reginald Harding, M.Sc. (by invitation), Susan J. Seawright, R.T. (N.M.) (by invitation), Sylvain Houle, M.D., Ph.D. (by invitation), Peter R. McLaughlin, M.D. (by invitation), and Ronald J. Baird, M.D., Toronto. Ontario. Canada

Blood cardioplegia (BCP) provided better myocardial protection than crystalloid cardioplegia (CCP) in From the Divisions of Cardiovascular Surgery, Biochemistry, and Nuclear Cardiology, the Toronto General Hospital and the University of Toronto. Toronto. Ontario, Canada. Supported by the Canadian and Ontario Heart Foundations, the Medical Research Council of Canada, and the Cardiovascular Research Fund of the University of Toronto. Read at the Sixty-fourth Annual Meeting of The American Association for Thoracic Surgery, New York, N. Y.. May 7-9. 1984. Address for reprints: Richard D. Weisel, M.D., DivisionofCardiovascular Surgery, Toronto General Hospital, 200 Elizabeth St., Eaton North 13-224, Toronto, Ontario. Canada M5G 1L7.

726

most laboratory experiments." However, clinical trials have not conclusively demonstrated an advantage with BCP.5-11 The reasons for the discrepancy may include both the formulation of the solutions" and the methods of delivery, including the pressure, volume, and frequency of administration.v 10.12, 13 In addition, the duration of aortic occlusion' and the myocardial temperature achieved":" produce significant variations in clinical practice. The distribution of the cardioplegic solution may be more important in patients with coronary artery disease than the vehicle employed.v" In previous studies'<" with CCP, a prolonged cross-clamp technique provided

Volume 88 Number 5, Part 1 November, 1984

more homogenous cooling, decreased cardiac creatine kinase (CK) isoenzyme release, and allowed for earlier metabolic recovery than the traditional cardioplegic technique. The administration of both BCP and CCP solutions must attempt to reduce heterogenous delivery and minimize nonuniform protection. This study was instituted to compare the metabolic and hemodynamic recovery of patients undergoing elective myocardial revascularization in a prospective randomized trial. BCP and CCP solutions were administered by means of a prolonged cross-clamp technique" designed to ensure uniform protection with either solution. Methods Patient population. Ninety patients scheduled for elective aortacoronary bypass grafting agreed to participate in a prospective randomized trial comparing BCP (n = 43) and CCP (n = 47). Each patient signed a consent form approved by the institutional human experimentation committee. Then clinical information was collected and postoperative cardiac enzymes were determined (Table 1).25 Randomization was stratified on the basis of estimated preoperative risk (low, n = 60; high, n = 30). The low-risk and high-risk groups differed significantly on the basis of age (p < 0.01), sex distribution (p < 0.001), and preoperative left ventricular function (p < 0.01). Sixty low-risk patients (BCP, n = 28; CCP, n = 32) with good left ventricular function at preoperative cardiac catheterization (estimated ejection fraction greater than 40%) had an extensive evaluation of the intraoperative protection and hemodynamic and metabolic recovery. Thirty high-risk patients (BCP, n = 15; CCP, n = 15) had clinical information and postoperative enzyme determinations only. Operative technique. The anesthetic management and conduct of cardiopulmonary bypass have been previously described.i" 25, 27 The technique of cardioplegic delivery was recently presented in detail." Briefly, 1 L of either BCP or CCP was infused into the proximal aortic root initially. The aortic root pressure was monitored with a separate 16 Fr. catheter and maintained at 70 to 80 mm Hg. CCP was delivered with a pressure bag and a cooling coil. The temperature was 5° to 6° C in the aortic root as measured with a needle thermistor in five patients. BCP was administered with the Buckberg-Shiley" system, which mixes and cools a hyperkalemic crystalloid concentration with oxygenated blood in a I :2 dilution to achieve a [mal electrolyte concentration similar to the crystalloid solution employed in this hospital (Table 11). The aortic root temperature of the *Shiley Inc.• Irvine, Calif.

Blood and crystalloid cardioplegia

727

Table I. Clinical information Patients Age (yr) Sex (M/F) NYHA (I/II/Ill/IV) Diseased vessels (1/2/3) Left main stenosis (yes/no) Bypasses (1/2/3/4/5) CPB time (min) Cross-clamp time (min) Mortality (yes/no) MI (yes/no) Low output syndrome (yes/no) 1ABP (yes/no) Highest CK-MB (U/L) Highest AST (U/L)

BCP

I

I

CCP

Ip Value

47 56.2 ± 8.5 42/5 4/13/22/8 1/17/29

0.59 1.00 0.99 0.26

8/35

2/45

0.04

1/8/13/16/5 112.9 ± 26.0 63.3 ± 17.2 0/43 0/43 2/42

0/5/14/24/4 113.5 ± 20 63.4 ± 15.0 1/46 5/42 6/41

0.51 0.90 0.97 1.00 0.06 0.27

0/43 26.3 ± 12.6 71.5 ± 60.1

1/46 35.6 ± 17.1 91.1 ± 65.5

om

43 55.2 ± 8.9 38/5 4/13/19/7 3/10/30

1.00

0.14

Legend: The preoperative, intraoperative. and postoperative clinical details of patients subjected to blood (BCP) and crystalloid cardioplegia (CCP) are presented. The p values refer to the results of t tests for continuous variables and chi square or Fisher's exact test for categorical variables. NYHA, New York Heart Association. CPB, Cardiopulmonary bypass. MI, Myocardial infarction. IABP. Intra-aortic balloon pumping. CK-MB, Cardiac isoenzyme of creatine kinase. AST. Aspartate aminotransferase.

Table II. Cardioplegic solutions Na (mmoljL) K (mmoljL) Mg (mmoljL) Ca (rnmol/L) Cl (mmol/L) S02 (rnrnol/L) HCO, (rnmol/L) Glucose (rnmol/L) THAM (rnrnol/L) CPD (ml/L) Hematocrit (%)

CCP

BCP additive

27 20 3 0 47 3 0 280 4 0 0

0 60 9 0 60 9 0 280 12 20 0

~70 25 3 1 77 3 17 115 4 7 15

Legend:The composition of the crystalloid solution (CCP), the blood cardioplegia (BCP) additive. and the approximate final concentration of the blood cardioplegic solution (BCP) used in this study is presented. CPD, Citratephosphate-dextrose.

BCP solution was 10° to 12° C as measured in five patients. Proximal and distal anastomoses were constructed during a prolonged aortic cross-clamp period.>" During construction of the proximal anastomoses with either BCP or CCP protection, a hypokalemic (potassium chloride 4 mmoljL) crystalloid solution was instilled under gravity into the proximal aortic root to prevent coronary air embolism. Approximately 100 rnl of cardioplegic solution was infused into each vein graft after completion of the distal anastomosis, and 400 rnl was

The Journal of Thoracic and Cardiovascular Surgery

7 2 8 Fremes et af.

instilled into the aortic root after completion of each proximal anastomosis. Systemic rewarming was commenced during construction of the final distal anastomosis. Warm BCP was not employed.P" Measurements. The following catheters were inserted intraoperatively: radial arterial, left atrial, and pulmonary arterial. Hemodynamic measurements included pulse, left atrial pressure, systolic blood pressure, mean arterial pressure, diastolic blood pressure, and cardiac output (by thermodilution). Derived hemodynamic measurements included cardiac index, stroke index, left ventricular stroke work index, left ventricular minute work index, and systemic vascular resistance index by standard formulas.v" A double thermistor coronary sinus catheter* was inserted in each patient for blood sampling and measurement of coronary sinus blood flow. Arterial and coronary sinus blood samples were assayed for oxygen tension (Po 2) , oxygen saturation, t pH, lactated and glycerol.§ Oxygen content (0 2 Con) was derived from the hemoglobin (Hb), the oxygensaturation (S), the (systemic or myocardial) temperature corrected P0 2 (Po 2TB) and oxygen (a0 2TB) according to the formula": O 2 Con = 1.39 X Hb X S/IOO + aD 2 TB X P0 2 TB

The extraction of oxygen, lactate, and glycerol was calculated as the difference between either the arterial or the aortic root and the coronary sinus content of oxygen, lactate, and glycerol, respectively. Coronary sinus blood flow was measured by the continuous thermodilution technique of Ganz and colleagues." Myocardial oxygen consumption, lactate flux, and glycerol flux were calculated as the product of coronary sinus blood flow and the respective arterialcoronary sinus content differences. Regional myocardial temperatures were monitored with needle thermistors after administration of cardioplegic solution in the distribution of the left anterior descending, circumflex, and right coronary arteries. The regions were graded according to the preoperative angiogram as to the likelihood of cooling.25 Transmural left ventricular biopsy specimensII were obtained from the region subserved by the most stenotic vessel. Biopsy specimens were immediately submerged "Wilton Webster Laboratories, Altadena, Calif. tCo-Oximeter, Instrumentation Laboratories, Lexington, Mass. tRapid Lactate Stat Pack Kit, Cal-Biochemical-Behring, La Jolla, Calif. §Enzymatic triglyceride, Boehringer-Mannheim, Dorval. Quebec. Canada. [Tru-Cut, Travenol Laboratories, Inc., Deerfield, IlL

in liquid nitrogen and subsequently freeze-dried. The tissue metabolites of adenosine triphosphate (ATP), creatine phosphate, glycogen, and lactate were subsequently analyzed spectrofluorometrically,"" Equilibrium gated nuclear ventriculograms were performed in the intensive care unit between 2 and 6 hours postoperatively as described in previous publications." 25. 27 Left ventricular end-diastolic volume index (LVEDVI) was calculated from the nuclear derived ejection fraction (LVEF) and the thermodilution stroke' index (SI) by the formula: EDVI = (SIjEF). Left ventricular end-systolic volume index was calculated as the difference between the left ventricular end-diastolic volume index and the stroke index. To obtain estimates of left ventricular volumes independent of the thermodilution cardiac output measurements, cardiac volumes were also calculated directly from the scintigraphic counts" as developed by Links and colleagues.36 Protocol for metabolic and hemodynamic measurements. Serial measurements were recorded on cardiopulmonary bypass prior to aortic occlusion, during the three aortic root infusionsof cardioplegic solution,at the time of cross-clamp removal, at 10 minute intervals during the first hour, at hourly intervals between 2 and 6 hours, and again at 24 hours postoperatively. Left ventricular biopsy specimens were obtained on cardiopulmonary bypass prior to aortic occlusion, within 2 minutes of cross-clamp removal, and again after 30 minutes of reperfusion. Volume loading and atrial pacing were performed between 2 and 4 hours after cross-clamp removal. Volume loading was performed by rapidly infusing 250 to 500 ml of a colloid solution in order to raise the left atrial pressure 2 to 4 mm Hg. 37• 38 Atrial pacing was instituted at 110 beats/min for 5 minutes." Sedation was maintained with parenteral diazepam (5 mg) and morphine (5 mg) as necessary during the first 6 hours. Patients who had postoperative hypertension (mean arterial pressure >95 mm Hg: BCP, n 15; 15; CCP, n 21) were treated with nitroprusside or nitroglycerin to maintain the mean arterial pressure at 85 mm Hg, and the measurements during treatment were excluded from the analysis. Sufficient fluids were infused to maintain the left atrial pressure near 10 mm Hg if the patients were hemodynamically stable, since previous studies had demonstrated this to be an optimal preload for patients recovering from elective operations." Six patients had

=

=

"Greiner Selective Analyzer 11, Greiner Electronics, Langenthal, Switzerland. Perkin-Elmer 650-1OS Fluorescence Spectrophotometer, Perkin-Elmer, Norfolk, Conn.

Volume 88 Number 5, Part 1 November, 1984

Blood and crystalloidcardioplegia 7 2 9

CK-MB U/L 32

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Fig. 1. The mean and standard error of the sequential creatine kinase MB (CK-MB) measurements obtained in patients who received blood and crystalloid cardioplegia. The curves were significantly different by analysis of variance (ANOVA), p = Differences between means were specified by unpaired t tests. XCL, Cross-clamp.

om.

incomplete postoperative studies. The specific reasons were as follows: myocardial infarction and associated hemodynamic instability (CCP, one patient); exacerbation of chronic obstructive lung disease necessitating aminophylline (CCP, one patient); postoperative bleeding (CCP one patient; BCP, one patient); exacerbation of preoperative renal failure necessitating low-dose dopamine (BCP, one patient); and temporary complete heart block necessitating atrioventricular sequential pacing (BCP, one patient). Ventricular function. Diastolic compliance, systolic elastance, and myocardial performance were determined from the volume loading data. Diastolic compliance, the relation between the left atrial pressure or the natural logarithm of the left atrial pressure and the left ventricular end-diastolic volume index,39,40 was determined by an analysis of covariance." Systolic elastance was evaluated from the ratio of the radial arterial systolic pressure and the left ventricular end-systolic volume index." The relationship between the systolic blood pressure and the left ventricular end-systolic volume index" was also determined by a covariant and multivariate analysis." Myocardial performance, the relationship between the cardiac index, stroke index, or the left ventricular stroke work index and the left atrial pressure or the left ventricular end-diastolic volume index, was evaluated by an analysis of covariance and multivariate analysis.

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Fig. 2. The mean and standard error of the intramyocardial temperatures measured by needle thermistors following each of three aortic root infusions for blood and crystalloid patients. Regions were classified as most ischemic, intermediate. and least ischemic on the basis of the coronary angiogram. Temperatures were significantly higher with blood cardioplegia in all distributions. Significant temperature gradients were present between each region. Statistical analysis was similar to that presented in Fig. I.

Statistical analysis. Statistical analysis was performed by Statistical Analysis System* programs. The serial measurements were divided into the following time periods: on cardiopulmonary bypass prior to aortic occlusion; during cardioplegic administration; during the initial reperfusion period; and in the intensive care unit. Separate two-way repeated measures analyses of variance were performed by the general linear models procedure.t'" Unpaired t tests or least square means" were employed to specify differences between means when the p value associated with the F ratio was significant at the 0.05 level. The response to volume loading and atrial pacing was analyzed by analysis of variance. Analysis of covariance or multivariate analysis was employed to assess the ventricular function data. Clinical data were compared by unpaired t tests, chi square tests, or Fisher's exact test where appropriate. Categorical data are summarized as the absolute fre·SAS Institute Inc., Cary, N. C.

730

The Journal of Thoracic and Cardiovascular Surgery

Fremes et al.

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Time Fig. 3. The mean and standard error of the cardiac extractions of oxygen (alEx), lactate (LEx), and glycerol (GlyEx) in blood and crystalloid patients are depicted. The values were equivalent prior to aortic cross-clamping (PRE XCL). Analysis of variance was employed to test for overall differences between blood and crystalloid cardioplegia during each of the major measurement periods, which are identified in the figure by vertical lines. Unpaired t tests were employed to specify differences between means if the initial F test for that interval was significant, p < 0.05. CPS, Cardioplegic infusion. XCL OFF, Cross-clamp off. CPB, Cardiopulmonary bypass.

quency or percent frequency. Continuous variables are summarized as the mean and standard deviation in the text and tables and the mean and standard error in the figures. Statistical significance is assumed for p values less than 0.05.

Results Clinical data. The preoperative clinical characteristics of the patient population were analyzed (Table I). The patient groups had similar age and sex distributions. Left main disease was significantly more common in the BCP group (p = 0.04). Preoperative radionuclide ventriculography was performed in the 60 low-risk patients with postoperative functional assessment to evaluate baseline similarity. The left ventricular ejection fraction both at rest (BCP, 62.5% ± 7.4%; CCP, 61.6% ± 7.7%;

p = 0.66) and in response to exercise (BCP, 62.9% ± 7.8%; CCP, 58.8% ± 9.2%; p = 0.10) was not different between the two groups. Additional intraoperative and postoperative clinical results are presented in Table II. The intraoperative management was similar. One high-risk CCP patient with poor preoperative ventricular function died on the first postoperative day of a perioperative myocardial infarction. Five patients who received CCP had evidence of a perioperative myocardial infarction (defmed as the appearance of a new Q wave, loss of R waves, or a new left bundle branch block with cardiac enzyme elevations), whereas no BCP patient had this complication. The incidence of low output syndrome (defmed as the requirement of inotropes for greater than 30 minutes or intra-aortic balloon counterpulsation for maintenance of

Volume 88

Blood and crystalloid cardioplegia 7 3 1

Number 5, Part 1 November, 1984

a systolic blood pressure greater than 80 mm Hg) was not different between BCP and CCP patients. Low output syndrome occurred more frequently in the 30 high-risk patients (high-risk, n = 5; low-risk,n = 3). The incidence of myocardial infarction and low output were less, but not significantly different, with BCP than CCP in high-risk and low-risk strata separately. Ischemic injury, as assessed by the highest CK-MB achieved or analysis of the entire CK-MB time curve, was significantlylower with BCP than CCP in the entire study population (Table II, Fig. 1), in the low-riskstrata alone, and when the patients with a perioperative myocardial infarction were excluded. The highest aspartate aminotransferase was not significantly different between BCP and CCP patients (p = 0.14). Temperatures. Myocardial temperatures were consistently warmer with BCP than CCP (Fig. 2). The result was verified whether the data were analyzed according to degree of stenosis on the preoperative angiogram (Fig. 2), the precise anatomic region from which the temperatures were obtained, or the mean of the myocardial temperatures. Significant temperature gradients persisted between regions supplied by mildly versus critically diseased vessels with both BCP and CCP despite vein graft infusions, but gradients tended to increase with BCP and decrease with CCP. Metabolism. Fig. 3 demonstrates the myocardial extractions of oxygen, lactate, and glycerol postoperatively. The groups were similar prior to aortic crossclamping. Oxygen extraction during cardioplegic administration was significantly greater with BCP than CCP during each infusion. The recovery of oxygen extraction was identical with both BCP and CCP after cross-damp removal. Lactate release during cardioplegia and during initial reperfusion was significantly less with BCP, and normal lactate extraction was achieved earlier. Glycerol release during cardioplegia and during initial reperfusion was reduced with BCP, and normal extraction was achieved more rapidly. Lactate and glycerol extraction were not statistically different later than 1 hour after cross-clarnp removal. Fig. 4 illustrates the thermodilution coronary sinus blood flow measurements and the calculated oxygen eonsumption and flux of lactate and glycerol. Coronary sinus blood flow was elevated initially after cross-clamp removal in CCP but not BCP patients, suggesting that reactive hyperemia had occurred with CCP. Coronary sinus flow increased more with BCP at the termination of cardiopulmonary bypass than with CCP. Coronary sinus flow was significantly higher 24 hours postoperativelyin both groups but was not different between BCP or CCP patients. Myocardial oxygen consumption dif-

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fered slightly within the first hour after cross-clamp removal but not thereafter. Myocardial lactate flux was significantly greater with BCP than CCP during the initial reperfusion period but not thereafter. Similarly, myocardial glycerol flux was greater with BCP than CCP immediately after aortic declamping but not at later. The temperature-corrected pH of the cardioplegic

The Journal of Thoracic and Cardiovascular Surgery

7 3 2 Fremes et al.

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solution was lower with BCP (BCP, 7.63 ± 0.07; CCP, 8.02 ± 0.54, p < 0.01), and the coronary effluent pH was higher (BCP, 7.61 ± 0.07; CCP, 7.32 ± 0.31, p < 0.01). The transcardiac pH gradient was significantly less with BCP than with CCP (BCP, -0.03 ± 0.05; CCP, -0.61 ± 0.50, p < 0.01). Values taken during reperfusion were identical. The serial left ventricular biopsy results are presented in Fig. 5. ATP decreased significantly with BCP and CCP both immediately and 30 minutes after crossclamp removal as compared to values measured before cross-elamping. After cross-clamp removal, the ATP values tended to decrease less in the BCP group (-15%, P = 0.32) than in the CCP group (-27%, p = 0.08). Myocardial lactate increased significantly during aortic occlusion and decreased significantly with reperfusion with both BCP and CCP. Tissue lactate accumulation tended to be less with BCP (p = 0.13). Glycogen and creatine phosphate did not change significantly with aortic occlusion in either BCP or CCP patients. Creatine phosphate was significantly greater with BCP than CCP (p = 0.05). Serial hemodynamics. The responses of the principal hemodynamic measurements are presented in Fig. 6. Measurements obtained 1 hour after aortic declamping were collected in the operating room, whereas the 2 to

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Fig. 6. The mean and standard error of the principal hemodynamic variables are demonstrated for blood and crystalloid patients. Statistically significant differences with respect to time were present for each variable measured, but not between blood and crystalloid cardioplegia. C/. Cardiac index. LAP, Left atrial pressure. MAP, Mean arterial pressure. LVSWl. Left ventricular stroke work index. SVRJ. Systemic vascular resistance index.

24 hour measurements were obtained in the intensive care unit. Although no statistically significant differences were detected between BCP and CCP, significant differences with respect to time were demonstrated for each variable.

Volume 88 Number 5, Part 1

Blood and crystalloid cardioplegia 7 3 3

November, 1984

Fig. 7 depicts the nuclear ventriculographic results. Global left ventricular ejection fraction was greater with BCP than with CCP. The average postoperative left ventricular ejection fraction was 60.9% ± 12.1% in BCP patients and 50.7% ± 12.5% in CCP patients (p < 0.01). The difference between BCP and CCP patients was present in groups with a preoperative nuclear ejection fraction of less than 60% (BCP, 58.6% ± 12.2%; CCP, 47.1% ± 7.7%; p < 0.01) or greater than 60% (BCP, 62.5% ± 10.5%; CCP, 53.2% ± 15.7%; p < 0.01). Left ventricular end-diastolic volume indices tended to be smaller with BCP than with CCP (p = 0.14 by analysis of variance). Left ventricular end-systolic volume indices were significantly smaller with BCP than with CCP. Similar differences were observed when the scintigraphic volumes were analyzed (results not depicted). Response to volume loading and atrial pacing. The hemodynamic response to volume loading is demonstrated in Fig. 8. Neither pulse nor left ventricular ejection fraction changed significantly with volume loading. Other hemodynamic variables increased significantly with both BCP and CCP. Mean arterial pressure (p = 0.08) and left ventricular stroke work index (p = 0.08) tended to increase more in patients who received BCP than CCP. Atrial pacing produced a similar increase in pulse (BCP, 31.8 ± 10.2 beats/min; CCP, 27.9 ± 12.4 beats/min) in the two groups and a decrease in the following: stroke index (BCP, -9.4 ± 5.0 ml/m'; CCP, -6.9 ± 4.3 ml/m-); left ventricular stroke work index (BCP, -9.8 ± 14.2 gm. m/m 2; CCP, -7.4 ± 6.4 gm . m/rn'); left ventricular enddiastolic volume index (BCP, -16.0 ± 12.5 ml/m-; CCP, -14.2 ± 12.9 ml/rn'), and left ventricular endsystolic volume index (BCP, -6.3 ± 8.9 ml/m'; CCP, -6.8 ± 10.3 ml/rrr'). Neither cardiac index nor left atrial pressure changed significantly in either group, whereas mean arterial pressure (p = 0.08) and systemic vascular resistance index (p = 0.06) tended to increase and left ventricular ejection fraction to decrease (p = 0.06) in both groups. The metabolic response to volume loading and atrial pacing is demonstrated in Table III. Coronary sinus blood flow and myocardial oxygen consumption increased significantly with volume loading after both BCP and CCP. Lactate extraction did not change and myocardial lactate flux tended to increase in both BCP and CCP patients. With atrial pacing, coronary sinus blood flow and myocardial oxygen consumption increased with BCP but not CCP. Lactate extraction

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hours

Fig. 7. The mean and standard deviation of the nuclear ventriculographic data are presented. The left ventricular ejection fraction (LVEF) was used to calculate the left ventricular end-diastolic volume index (LVEDVl) and endsystolic index (LVESVI). Statistical analysis was similar to that presented in Fig. 1.

and myocardial lactate flux tended to decrease more with BCP than with CCP. Ventricular function. Diastolic compliance, the relationship between the left atrial pressure or the natural logarithm of the left atrial pressure and the left ventricular end-diastolic volume index, was not significantly different between the patient groups (Fig. 9). The two curves had similar slopes and intercepts and represented different portions of the same pressure-volume relation. Systolic elastance was significantly greater with BCP than CCP by multivariate analysis (Fig. 9) but not by an analysis of covariance. The systolic blood pressure/ left ventricular end-systolic pressure ratios were greater with BCP than with CCP (Table IV). Atrial pacing increased and volume loading decreased the ratios significantly, but the responses were not different between BCP and CCP patients. Myocardial performance between 2 and 4 hours postoperatively was significantly better with BCP than with CCP (Fig. 10) by a multivariate analysis (p < 0.01). The slopes of the stroke index (p = 0.02) and the left ventricular stroke work index (p = 0.05) curves

The Journal of Thoracic and Cardiovascular Surgery

7 3 4 Fremes et al.

o Crystalloid

~Blood

10

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8

I1MAP mmHg

I1LAP mmHg .7

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Change with Volume Loading

UP < 0.01

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Fig. 8. The hemodynamic response to volume loading between 2 and 4 hours postoperatively is demonstrated for blood and crystalloid cardioplegia. Abbreviations are presented in Figs. 6 and 7. 14

,,

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Fig. 9. The diastolic and systolic pressure volume relations in response to volume loading are depicted with blood and crystalloid cardioplegia. Diastolic compliance did not differ between the two groups. Systolic elastance was significantly greater by a multivariate analysis, p < 0.01. SOP, Systolic blood pressure. Other abbreviations are presented in Figs. 6 and 7.

and the position of the cardiac index curve (0 = 0.01) were significantly greater by an analysis of covariance. Similar results were obtained when left atrial pressure was employed as a measure of preload, as diastolic compliance did not differ between the two groups.

Multidose BCP provided better myocardial protection for elective coronary bypass grafting in this prospective randomized trial. Ischemic injury as assessed by CK-MB determinations or electrocardiograms was reduced. The metabolic response to aortic occlusion and the initial metabolic recovery were improved. Early postoperative ventricular function was greater with BCP than with CCP. Excellent experimental results have been achieved with BCP in several animal models.!" The advantages of BCP are reduced at the low myocardial temperatures commonly achieved during clinical practice. CCP provides excellent myocardial protection at these temperatures because myocardial metabolism is more profoundly depressed. At lower temperatures, the myocardial protection provided by BCP may be reduced because of increased oxygen-hemoglobin affinity":" or altered blood rheology affecting cardioplegic distribution.P" Excellent clinical results have been achieved with BCP in several nonradomized series.46-49 Several randomized or matched-pair trials"?' comparing BCP and CCP have been inconsistent: Two were positive7• 11; two were suggestive-"; and two were clearly negative.v'? In none of these studies was BCP inferior to CCP. Temperatures. Myocardial temperatures were significantly dependent on both the degree of coronary occlusion and the cardioplegic vehicle. Despite systemic hypothermia (25 0 C) and a prolonged cross-clamp technique, nonhomogenous myocardial cooling was present with both BCP and CCP. Marked regional differences were documented, but transmural variations in temperature were not investigated.

Volume 88 Number 5. Part 1 November, 1984

Blood and crystalloid cardioplegia 7 3 5

Table ill BCP Pre

CCP

I

I

Pre

Post

Volume loading

CSBF (ml/rnin) O,Ex (ml/dl) LEx (rnmol/L) GlyEx (",molfL) MV02 (rnl/rnin) MVL (umol/min) MVGly (umol/min)

180 ± 110 6.4 ± 1.7 0.43 ± 0.36 19.7 ± 32.4 11.5±7.4 71 ± 72 3.0 ± 4.1

220 ± 6.3 ± 0.41 ± 16.4 ± 14.4 ± 96 ± 5.1 ±

130 2.4 0.58 24.8 10.0 138 9.2

CSBF (rnl/rnin) O,Ex (ml/dl) LEx (mmol/L) GlyEx (umol/L) MV02 (ml.Zmin) MVL (",mol/min) MVGly (",mol/min)

210 ± 5.8 ± 0.37 ± 13.5 ± 13.0 ± 78 ± 3.1 ±

260 ± 6.1 ± 0.20 ± 17.1 ± 16.5 ± 46 ± 3.1 ±

160 1.8 0.26 31.1 12.1 65 7.2

150 ± 6.8 ± 0.38 ± 16.6 ± 9.6 ± 63 ± 2.2 ±

Post

P Value pre-post

p Value MJCP-!KCP

120 2.2 0.33 39.8 6.7 85 4.6

200 ± 6.6 ± 0.36 ± 19.7 ± 12.8 ± 83 ± 3.3 ±

150 2.9 0.36 34.5 9.2 138 6.7

0.0001 0.47 0.84 0.99 0.002 0.07 0.23

0.66 0.38 0.98 0.55 0.97 0.77 0.69

150 2.3 0.30 27.2 9.5 105 7.5

180 ± 6.8 ± 0.37 ± 22.2 ± 11.9 ± 73 ± 3.3 ±

140 1.9 0.31 40.1 8.9 89 5.1

0.05 0.87 0.001 0.41 0.06 0.10 0.39

0.02 0.26 0.10 0.77 0.007 0.09 0.40

Atrial pacing

120 2.1 0.30 18.6 9.1 62 4.7

190 ± 6.9 ± 0.41 ± 14.7 ± 12.6 ± 73 ± 1.5 ±

Legend: The changes of the principal metabolic variables in response to volume loading and atrial pacing are demonstrated. O,Ex, Oxygen extraction. LEx, Lactate extraction. GlyEx, Glycerol extraction. CSBf, Coronary sinus blood flow. MVO" Myocardial oxygen consumption. MVL, Myocardial lactate flux, MVGly, Myocardial glycerol flux. BCP refers to the change induced by atrial pacing or volume loading in BCP patients, and CCP refers to the change induced in CCP patients. The p values refer to the results of the analysis of variance.

Table IV BCP Pre

CCP

I

Post

Post

P Value pre-post

p Value BCP-CCP

5.5 ± 2.7 5.9 ± 2.8

4.9 ± 2.8 5.2 ± 3.2

0.001 0.002

0.04 0.009

5.1 ± 3.0 5.6 ± 2.9

6.6 ± 3.8 6.7 ± 4.2

0.009 0.01

0.02 0.005

Pre

I

Volume loading SBP/LVESVI(TD) (mm Hg/mL/m') SBP/LVESVI(Sc) (mm Hg/ml/rrr')

9.3 ± 4.7 11.7 ± 6.4

SBP/LVESVI(TD) (mm Hg/rnl/rn") SBP/LVESVI(Sc) (mm Hg/ml/rn')

7.2 ± 4.1 10.1 ± 5.3

7.5 ± 4.0 9.4 ± 5.3 Atrial pacing

9.4 ± 4.5 11.7 ± 7.7

Legend:The ratios of the systolic blood pressure (SBP) and the left ventricular end-systolic volume index (LVESVI) are demonstrated before (Pre) and following (Post) atrial pacing and volume loading. Values are derived from the thermodilution stroke index (TD) or directly from the scintigraphic data (Sc). The p values refer to the results of the analysis of variance.

The myocardial temperatures achieved with BCP were significantly warmer than those achieved with CCP secondary to the warmer temperatures of the solutions (BCP, 10° to 12° C; CCP, 5° to 6° C). The discrepancy was more pronounced after the second and third infusions, as the myocardial temperature tended to be warmer with BCP after the initial injection. The cooling efficiency of the Buckberg-Shiley system is inversely proportional to the flow rate of the cardioplegic solution, which was pressure regulated in this study. Flow rates increased during the second and third infusions with BCP as critical lesions were bypassed. Chitwood and colleagues50 suggested that flow increased paradoxically with hypothermic perfusion. Balderman and associates" recommended the addi-

tion of topical hypothermia to CCP, whereas Barner," Catinella," and their colleagues advocated topical hypothermia to be employed with BCP. Larger volumes of cardioplegic solution, as employed by Engelman, Rousou, and Lemeshow,!" may offer superior protection because of cooler temperatures. Topical hypothermia may reduce the nonhomogenous cooling we detected with both BCP and CCP. Metabolism. Coronary sinus blood flow was elevated after aortic declamping with CCP but not BCP. Reactive hyperemia probably resulted from incomplete myocardial protection. Excessivecoronary flow was demonstrated upon immediate reperfusion with CCP in previous studies from this institution.52 Our current results resemble those obtained in canine experiments by Taka-

The Journal of Thoracic and Cardiovascular Surgery

7 3 6 Fremes et al.

• Blood ... Crystalloid Blood cntterent than Crystalloid

·p
3.0

E

~

2.5

...J

13

2.0

40 LVEDVI

50

60

40

50

60

mUm'

Fig. 10. The relation between the cardiac index (Cl], stroke index (SI), and left ventricular stroke work index v.s WI) and left ventricular end-diastolic volume index (L VED VI) in response to volume loading between 2 and 4 hours is demonstrated. Myocardial performance was significantly better with blood cardioplegia by an analysis of covariance and multivariate analysis. (L

moto,' Bing," and their associates. Studies involving a different method of blood flow assessment in patients having aorta-coronary bypass- 10 suggested that myocardial perfusion in the immediate postclamp period was lower with BCP than with CCP. Upon discontinuation of cardiopulmonary bypass, coronary sinus blood flow increased in patients protected with BCP but not CCP. This fact suggests a greater oxygen demand (and greater contractility) with BCP and CCP. Cardiac oxygen extraction during arrest was greater with BCP than with CCP. The oxygen content of the BCP solution was 8.9 ± 2.2 ml/dl whereas the content of the CCP solution was 0.65 ± 0.24 ml/dl, Myocardial oxygen extraction with CCP has been reported as 0.3 ml/dl (63%) during aorta-coronary bypass grafting,' 0.5 ml/dl (62%) in swine experiments,' 0.46 ml/dl (52%) in canine experiments," and 0.6 ml/dl (60%) in hypertrophied pig hearts." With BCP, an oxygen extraction of 1.2 ml/dl (14%) has been reported in patients having coronary bypass,' 5.8 ml/dl (41%) in normal pig hearts,' and 5.0 ml/dl (42%) in hypertrophied pig hearts. 55 Recalculation of our data shows that oxygen extraction averaged 0.3 ml/dl (46%) with CCP and 0.9 ml/dl (10%) with BCP. Despite the lower percentage oxygen extraction, total oxygen extraction (in milliliters per deciliter) was greater with BCP because of the greater oxygen delivery. Oxygen extraction with CCP is dependent on the oxygen P0 2 tension, which decreased from 164 ± 33 mm Hg in the aortic root to 59 ± 23 mm Hg in the coronary sinus. BCP can deliver oxygen both in solution and bound to hemoglobin. The P0 2 of BCP

averaged 292 ± 46 mm Hg and that of the coronary sinus effluent averaged 130 ± 111 mm Hg. Approximately equivalent amounts of dissolved and bound oxygen were extracted by the myocardium. That coronary effluent saturation was usually greater than 95% suggests increased oxygen-hemoglobin affinity. Alternative explanations include defective oxygen utilization or decreased requirements. Oxygenated CCP solutions': 17,54 or blood substitute (F1uosol DA) emulsions55, 56 may unload more oxygen but are currently more cumbersome to administer. BCP improved oxygenation and decreased lactate production during cardioplegic arrest and immediate reperfusion. That lactate was produced despite reoxygenation with BCP suggests a need for larger volumes or more frequent reinfusion. Tait and associates" also found similar lactate release during BCP despite a considerably smaller cardioplegic glucose concentration. Therefore, lactate release was probably related to the degree of oxygenation rather than the concentration of glucose. That the tissue lactate accumulation was lower in the hearts receiving BCP, despite the warmer myocardial temperatures, suggests that aerobic pathways were utilized. After declamping, lactate production or washout was less with BCP than CCP. Metabolic recovery was delayed with CCP, although normal lactate extraction and virtually normal tissue lactate values were found 30 minutes after cross-clamp removal. The reduced lactate production with BCP was associated with less tissue acidosis.58 With CCP, tissue acidosis

Volume 88 Number 5, Part 1 November, 1984

resulted from anaerobic hydrogen ion production and the limited buffering capacity of most CCP solutions.57 BCP buffers the tissue pH through red cell, protein, and phosphate mechanisms. Although controversy exists regarding the optimal pH management.P-v" recent studies suggest that acidosis may contribute to the ischemia-induced abnormalities of calcium exitationcontraction coupling." Patient studies have shown a correlation between the intramyocardial pH and clinical

outcome." Cardiac glycerol production was employed as a marker of myocardial lipolysis.v-? Glycerol production could reflect either lipid or phospholipid catabolism. With ischemia, cardiac triglycerides undergo lipolysis, glycerol is released,and acyl-CoA, acyl-earnitine, and tissue free fatty acids accumulate, which can further contribute to cellular dysfunction.v" Cardiac lipolysis was reduced with BCP relative to CCP, despite lipases and catecholamines present within the BCP solution. BCP provides albumin, which can combine with and eliminate free fatty acids, whereas CCP, which does not contain albumin, would be associated with their accumulation. Biopsy specimens. Cardiac glycogen levels are considered to be protective for ischemic hearts as, during ischemia, glycogenolysis occurs to provide substrate for anaerobic energy production.s':" No significant change in myocardial glycogen occurred with either method of cardioplegia; however, glycogen tended to increase with CCP and to decrease with BCP during the arrest period. Elevated potassium concentrations can inhibit phosphorylase and promote glycogen formation," whereas BCP solutions, which contain catecholamines, may activate phosphorylases and stimulate glycogenolysis." The high cardioplegic concentration of glycose may enhance glucose transport by mass action and promote glycogen formation. Myocardial protection, as assessed by the preservation of tissue ATP and creatine phosphate, tended to be better with BCP than CCP. Significant ATP depletion occurred with both methods of protection during the arrest, but subsequent depletion was less with BCP. Creatine phosphate was slightly but significantly greater with BCP. These results are at variance with studies of Cunningham and associates," who found that ATP increased with BCP, and Balderman and colleagues," who found that ATP was maintained during reperfusion with CCP. A marked decrease in creatine phosphate with ischemia was not observed in these studies, as samples were obtained during early reperfusion when creatine phosphate may have been repleted.':"

Blood and crystalloid cardioplegia

7 37

These results suggest that high-energy phosphates were better maintained by oxidative metabolism. Bodenhamer and colleagues" found that the isolated addition of oxygen to CCP maintained ATP and total adenine content in comparison to an nonoxygenated control group. Other metabolic additives, in particular Krebs cycle intermediates or precursors, may be equal or superior in this regard" Metabolic response to stress. Volume loading and atrial pacing were performed to estimate the metabolic response to hemodynamic stress.37, 38, 52 Volume loading increased coronary sinus blood flow and myocardial oxygen consumption commensurate with the increase in cardiac work. Metabolic deterioration was not observed in either BCP or CCP patients. Volume loading has previously been demonstrated to be more effective than atrial pacing in improving metabolism and stabilizing hemodynamics." Atrial pacing decreased lactate extraction and myocardial lactate flux, an effect which indicates incomplete metabolic recovery during the early postoperative period. The use of an alternative substrate cannot be excluded. Previous studies have shown that lactate extraction decreased in response to pacing between 2 and 4 hours postoperatively, whereas lactate extraction increased between 4 and 6 hours." The findings in the current study indicate that myocardial metabolism is vulnerable to hemodynamic stress in the early postoperative period which should be avoided during this vulnerable period. Ventricular function. Left ventricular systolic function was improved with BCP, although diastolic compliance was similar. Ventricular function was analyzed with nuclear ventriculographic techniques. Left ventricular ejection fraction was elevated in patients who received BCP. However, ejection fraction was not employed as an isolated measure of ventricular function because of its dependence of loading conditions." The nuclear derived ejection fraction provided estimates of left ventricular end-diastolic and end-systolic volumes, which, when combined with pressure measurements, allowed for evaluation of myocardial performance, systolic elastance, and diastolic compliance. Myocardial performance and systolic elastance were increased with BCP in comparison to CCP between 2 and 4 hours. Similar conclusions were obtained from an analysis of the entire hemodynamic recovery data (Figs. 6 and 7). These results demonstrate that cardiac index and left ventricular stroke work index were generally greater with BCP, whereas the left atrial pressure and the left ventricular end-diastolic volume index were less. Systemic arterial pressure was identical, whereas the left

The Journal of Thoracic and Cardiovascular Surgery

7 3 8 Fremes et al.

ventricular end-systolic volume index was lower. That hemodynamic measurements obtained at 24 hours were similar suggests that the differences of postoperative ventricular function between BCP and CCP were temporary. In studies by Roberts and colleagues,"left ventricular ejection fraction was greater in the early postoperative period with BCP than with CCP in patients with a diminished ejection fraction «40%) preoperatively. Our patient population with early postoperative nuclear ventriculography had preserved left ventricular function preoperatively; however, analysis of the results obtained in those patients with a preoperative left ventricular ejection fraction less than or greater than 60% demonstrated that the relative improvement was not restricted to patients with the least functional reserve. Current methods of myocardial protection allow for superb operating conditions with minimal attendent morbidity and mortality for elective operations in lowrisk subpopulations.":" Clearly, the results are less optimal in certain high-risk subgroups and provide a rationale for studies investigating alternative cardioplegic techniques. The 60 patients who had postoperative metabolic and hemodynamic measurements were carefully selected and had a low risk of operation by age, sex, and left ventricular functional criteria. BCP was superior in the subgroup with the best prognosis by sensitive endpoints; however, little relative clinical improvement was detected. The study was not designed to determine the clinical effectiveness in patients with an elevated risk of operation, but current investigations are considering this question. BCP provides superior protection for elective coronary bypass grafting and may improve the clinical results in patients with unstable angina or in other high-risk patients. We extend our appreciation to Ms. Betty Kuzin, B.A., for statistical consultation, Ms. Penelope J. Maton, B.Sc., for nuclear data acquisition and analysis, Ms. Barbara Brown, B.Sc., for biochemical measurements, Mr. Jose Chang, B.Sc., and Rick Malthaner, B.Sc., for assistance with hemodynamic and clinical data acquisition, and to Catherine Andrews for preparation of the manuscript. We wish to thank the perfusionists: Ian Ross, c.c.P., Katherine Benedict, c.c.P., Jennifer McDonough, C.C.P., and Talara Hill, C.c.P. We also wish to extend our appreciation to the nurses and physicians of the cardiovascular operating rooms and intensive care unit for their assistance.

3

4

5

6

7

8

9

10

II

12

13

14

REFERENCES Engelman RM, Rousou JH, Dobbs W, Pels MA, Longo F: The superiority of blood cardioplegia in myocardial preservation. Circulation 62:62-66, 1980 2 Feindel CM, Tait GA, Wilson GJ, Klement P, MacGregor DC: Multidose blood versus crystalloid cardioplegia.

15

16

Comparison by quantitative assessment of irreversible myocardial injury. J THORAC CARDIOVASC SURG 87:585595, 1984 Takamoto S, Levine FH, LaRaia PJ, Adzick NS, Fallon JT, Austen WG, Buckley MJ: Comparison of single-dose and multiple-dose crystalloid and blood potassium cardioplegia during prolonged aortic occlusion. J THORAC CAR. DlOVASC SURG 79:19-28, 1980 Barner HB, Laks H, Codd JE, Standeven JW, Jellinek M, Kaiser GC, Menz U, Tyras DH, Pennington 00, Hahn JW, Willman VL: Cold blood as the vehicle for hypothermic potassium cardioplegia. Ann Thorac Surg 28:509521, 1979 Engelman RM, Rousou JH, Lemeshow S, Dobbs WA: The metabolic consequences of blood and crystalloid cardioplegia. Circulation 64:67-74, 1981 Shapira N, Kirsh M, Jochim K, Behrendt DM: Comparison of the effect of blood cardioplegia on myocardial contractility in man. J THORAC CARDIOVASC SURG 80:647655, 1980 Singh AK, Farrugia R, Teplitz C, Karlson KE: Electrolyte versus blood cardioplegia. Randomized clinical and myocardial ultrastructural study. Ann Thorac Surg 33:218227, 1982 Roberts AJ, Moran JM, Sanders JH, Spies SM: Clinical evaluation of the relative effectiveness of multidose crystalloid and cold blood potassium cardioplegia in coronary artery bypass graft surgery. A nonrandomized match-pair analysis. Ann Thorac Surg 33:421, 432, 1982 Bomfun V, Kaijser L, Bendz R, Sylven C, Olin C: Myocardial protection during aortic valve replacement. Comparison between sanguineous and asanguineous cardioplegic solutions. Scand J Thorac Cardiovasc Surg 15:135-139, 1981 Engelman RM, Rousou JH, Lemeshow S: High-volume crystalloid cardioplegia. An improved method of myocardial preservation. J THORAC CARDIOVASC SURG 86:87-96, 1983 Codd JE, Barner HB, Pennington 00, Merjavy JP, Kaiser GC, Devine L, Willman VL: Intraoperative myocardial protection. Ann Thorac Surg (in press) Hearse OJ, Brairnbridge MV, Jynge P: Protection of the ischemic myocardium, Cardioplegia, New York, 1981 Raven Press Robertson JM, Buckberg GD, Vinten-JohansenJ, Leaf JD: Comparison of distribution beyond coronary stenoses of blood and asanguineous cardioplegic solutions. J THORAC CARDIOVASC SURG 86:80-86, 1983 Tyers GFO, Williams EH, Hughes HC, Todd GJ: Effect of perfusate temperature on myocardial protection from ischemia. J THORAC CARDIOVASC SURG 73:766-771, 1977 Rosenfeldt FL, Sabiston DC: The relationship between myocardial temperature and recovery after experimental cardioplegic arrest. J THORAC CARDIOVASC SURG 84:656666, 1982 Johnson RE, Dorsey LM, Moye SJ, Hatcher CR, Guyton

Volume 88 Number 5, Part 1 November, 1984

RA: Cardioplegic infusion. The safe limits of pressure and temperature. J THORAC CARDIOVASC SURG 83:813-823, 1982 . 17 Digerness SB, Vanini V, Wideman FE: In vitro comparison of oxygen availability from asanguineous and sanguineous cardioplegic media. Circulation 64:80-83, 1981 18 Magovern CJ, Flaherty IT, Gott VL, Bulkley BH, Gardner TJ: Failure of blood cardioplegia to protect myocardium at lower temperatures. Circulation 66:60-67, 1982 19 Chitwood WR, Hill RC, Kleinman LH, Wechsler AS: Transmural myocardial flow distribution during hypothermia. Effects of coronary inflow restriction. J THORAC CARDIOVASC SURG 86:61-69, 1983 20 Becker H, Vinten-Johansen J, Buckberg GD, Follette DM, Robertson JM: Critical importance of ensuring cardioplegic delivery with coronary stenosis. J THORAC CARDIOVASC SURG 81:507-515, 1981 21 Daggett WM, Kacocks MA, Coleman WS, Johnson RG, Lowenstein E, Vander Salm TJ: Myocardial temperature mapping. J THORAC CARDIOVASC SURG 82:883-888, 1981 22 Dorsey LN, Colgan TK, Silverstein JI, Hatcher CR, Guyton RA: Alterations in regional myocardial function after heterogenous cardioplegia. J THORAC CARDIOVASC SURG 86:70-79, 1983 23 Grondin CM, Helias J, Vouhe PR, Robert P: Influence of a critical coronary artery stenosis on myocardial protection through cold potassium cardioplegia. J THORAC CARDIOVASC SURG 82:608-615, 1981 24 Weisel RD, Hoy FBY, Baird RJ, Ivanov J, Hilton JD, Burns RJ, Mickle DAG, Mickleborough LL, Scully HE, Goldman BS, McLaughlin PR: Comparison of alternative cardioplegic techniques. J THORAC CARDIOVASC SURG 86:97-107, 1983 25 Weisel RD, Hoy FBY, Baird RJ, Ivanov J, Burns RJ, Madonik M, McLaughlin PR: Improved myocardial protection during a prolonged cross-clamp period. Ann Thorae Surg 36:664-674, 1983 26 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 27 Fremes SE, Weisel RD, Baird RJ, Mickleborough LL, Burns RJ, Teasdale SJ, Ivanov J, Seawright SJ, Madonik MM, Mickle DAG, Scully HE, Goldman BS, McLaughlin PR: The effects of postoperative hypertension and its • treatment. J THORAC CARDIOVASC SURG 86:47-56, 1983 28 Rousou JH, Engelman RM, Dobbs WA: Experimental evaluation of secondary blood cardioplegia. J Surg Res 34:104-110,1983 29 Follette DM, Fey K, Buckberg GD, Helly JJ, Steed DL, Foglia RP, Maloney JV: Reducing postischemic damage by temporary modification of reperfusate calcium, potassium, pH, and osmolarity. J THORAC CARDIOVASC SURG 82:221-238, 1981 30 Weisel RD, Lipton IH, Lyall RN, Baird RJ: Cardiac

Blood and crystalloidcardioplegia 7 3 9

metabolism and performance following cold potassium cardioplegia. Circulation 58:Suppl 1:217-226, 1978 31 Weisel RD, Goldman BS, Lipton IH, Teasdale S, Mickle DAG, Baird RJ: Optimal myocardial protection. Surgery 84:812-821, 1978 32 Weisel RD: Techniques of measuring pulmonary function in the critically ill, Acute Respiratory Failure: Etiology and treatment, HB Hechtman ed., Boca Raton, 1979, CRC Press Inc. 33 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 34 Harris RC, Hultman E, Nordesjo LO: Glycogen, glycolytic intermediates and high-energy phosphates determined in biopsy samples of musculus quadriceps femoris of man at rest. Methods and variance of values. Scand J Clin Lab Invest 33:109-113,1974 35 Burns RJ, Druck MN, Woodward DS, Houle S, McLaughlin PR: Repeatability of estimates of leftventricular volume from blood-pool counts. Concise communication. J Nucl Med 24:775-781,1983 36 Links JM, Becker LC, Shinkledecker JC, Gutman P, Burow RD, Nickoloff EC, Anderson PD, Wagner HN: Measurement of absolute left ventricular volume by gated blood pool studies. Circulation 65:82-91, 1982 37 Weisel RD, Burns RJ, Baird RJ, Hilton JD,. Ivanov J, Mickle DAG, Teoh KH, Christakis GT, Evans PJ, Scully HE, Goldman BS, McLaughlin PR: Optimal postoperative volume loading. J THORAC CARDIOVASC SURG 86:4756, 1983 38 Weisel RD, Burns RJ, Baird RJ, Hilton JD, Ivanov J, Mickle DAG, Teoh KH, Christakis GT, Evans PJ, Scully HE, Goldman BS, McLaughlin PR: A comparison of volume loading and atrial pacing following aortocoronary bypass. Ann Thorac Surg 36:332-344, 1983 39 Mirsky I: Myocardial mechanics, Handbook of Physiology, Cardiovascular System, Vol I, Sec 2, RM Berne, N Sperelakis, SR Geiger, 008., Bethesda, 1979, American Physiological Society, pp 497-531 40 Mirsky I, Rankin JS: The effects of geometry, elasticity and external pressures on the diastolic pressure-volume and stiffness-stress relationship. How important is the pericardium? Circ Res 44:601-611, 1979 41 Goodnight JH, SaIl JP, Sarle WS: The GLM procedure, SAS User's Guide: Statistics, AA Ray, JP SaIl, M Saffer, 008., Cary, N. c, 1982, SAS Institute Inc., pp 139-199 42 Sagawa K: The end-systolic pressure-volume relation of the ventricle. Definitions, modifications and clinical use. Circulation 63:1223-1227, 1981 43 Sarle WS: The cancorr procedure, SAS User's Guide: Statistics, AA Ray, JP SaIl, M Saffer, 008., Cary, N. C., 1982, SAS Institute Inc., pp 297-308 44 Freund RJ, Littell RC: SAS for linear models. A guide to ANOVA and GLM procedures. Cary, N. C., 1981, SAS Institute Inc. 45 O'Neill MJ, Francalancia N, Wolf PD, Parr GVS,

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Waldhausen lA: Resistance differences between blood and crystalloid cardioplegic solutions with myocardial cooling. 1 Surg Res 30:354-360, 1981 46 Laks H, Barner HB: Cold blood cardioplegia. 1 THORAC CARDIOVASC SURG 77:319-322, 1979 47 Catinella FP, Cunningham IN Jr, Adams PX, Snively SN, Gross RI, Spencer FC: Myocardial protection with cold blood potassium cardioplegia during prolonged aortic cross-clamping. Ann Thorac Surg 33:228-233, 1982 48 Cunningham IN Jr, Adams PX, Knopp EA, Baumann FC, Snively SL, Gross RI, Nathan 1M, Spencer FC: Preservation of ATP, ultrastructure, and ventricular function after aortic cross-clamping and reperfusion. 1 THORAC CARDIOVASC SURG 78:708-720, 1979 49 Barner HB, Kaiser GC, Codd lE, Tyras DH, Pennington DG, Laks H, William VL: Clinical experience with cold blood as the vehicle for hypothermic potassium cardioplegia. Ann Thorac Surg 29:224-227, 1980 50 Chitwood WR, Sink 10, Hill RC, Wechsler A, Sabiston DC lr: The effects of hypothermia on myocardial oxygen consumption and transmural coronary blood flow in the potassium-arrested heart. Ann Surg 190: 106-116, 1980 51 Balderman SC, Bhayana IN, Binette P, Chan A, Gage AA, Adler RH: Perioperative preservation of myocardial ultrastructure and high-energy phosphates in man. 1 THORAC CARDIOVASC SURG 82:860-869, 1981 52 Fremes SE, Weisel RD, Baird RJ, Mickle DAG, McLaughlin PR: Delayed recovery of myocardial metabolism. Surg Forum 34:261-264, 1983 53 Bing OHL, LaRaia Pl, Gaasch WH, Spadaro 1, Franklin A, Weintraub RM: Independent protection provided by red blood cells during cardioplegia. Circulation 66:81-84, 1982 54 Bodenhamer RM, DeBoer LMV, Geffin GA, O'Keefe DD, Fallon IT, Aretz TH, Haas GS, Daggett WM: Enhanced myocardial protection during ischemic arrest. Oxygenation of a crystalloid cardioplegic solution. 1 THORAC CARDIOVASC SURG 85:769-780, 1983 55 Novick RJ, Stefaniszyn Hl, Morin lE, Salerno TA: Preservation of the hypertrophied pig heart. Superior hemodynamic recovery after prolonged aortic clamping with Fluosol cardioplegia. Surg Forum 34:321-324, 1983 56 Bolling SF, Flaherty IT, Bulkley BH, Gott VL, Gardner Tl: Improved myocardial preservation during global ischemia by continuous retrograde coronary sinus perfusion. 1 THORAC CARDIOVASC SURG 86:659-666, 1983 57 Tait GA, Booker PD, Wilson Gl, Coles lG, Steward Dl, MacGregor DC: Effect of multidose cardioplegia and cardioplegic solution on myocardial tissue acidosis. 1 THORAC CARDIOVASC SURG 83:824-829, 1982 58 Garlick PB, Radda GK, Seeley Pl: Studies of acidosis in the ischemic heart by phosphorus nuclear magnetic resonance. Biochem 1 184:547-554, 1979 59 Nugent WC, Levine FH, Liapis CD, LaRaia Pl, Tsai C-H, Buckley Ml: Effect of the pH of cardioplegic solution on postarrest myocardial preservation. Circulation 66:Suppl 1:68-72, 1982

60 Hess ML, Okabe E, Kontos HA: Proton and free oxygen radical interaction with calcium transportsystem of cardiac sarcoplasmic reticulum. 1 Mol Cell Cardiol 13:767772, 1981 61 Khuri SF, losa M, Marston W, Braunwald NS, Smith B, Tow D, Van Cisin M, Barsamian EM: The first report of intramyocardial pH in man. II. Assessment of adequacy of myocardial preservation. 1 THORAC CARDIOVASC SURG 86:667-678, 1983 62 Vik-Mo H, Mj~ OD: Influence of free fatty acids on myocardial oxygen consumption and ischemic injury. Am 1 Cardiol 48:361-365, 1981 63 Katz AM, Messineo FC: Lipid-membrane interactions and the pathogenesis of ischemic damage in the myocardium. Circ Res 48: 1-16, 1981 64 Randle RJ, Tubbs PK: Carbohydrate and fatty acid metabolism, Handbook of Physiology, Cardiovascular System, Vol I, Sec 2, RM Berne, N Sperelakis, SR Geiger, eds., Bethesda, 1979, American Physiological Society, pp 413-459 65 Hewitt RL, Lolley DM, Adrouny GA, Drapanas T: Protective effect of glycogen and glucose in the anoxic arrested heart. Surgery 75:1-10, 1974 66 Wittnich C, Chiu RC1, McArdle AH: Protection of ischemic myocardium. The roles of nutrition and myocardial glycogen. Can 1 Surg 25:534-537, 1982 67 Largis EE, Ashmore 1, Toomey RE: Effect of varying K+ concentrations on phosphorylase activity, lipolysis and cAMP levels in perfused rat heart. Pro Soc Exp BioI Moo 141:31-37, 1972 68 Rousou lH, Engelman RM, Dobbs WA, Anisimowich L: Metabolic enhancement of myocardial preservation during cardioplegic arrest. Surg Forum 34:332-334, 1983 69 Braunwald E, Ross 1 lr: Control of cardiac performance, Handbook of Physiology, Cardiovascular System, Vol I, Sec 2, RM Berne, N Sperelakis, SR Geiger, eds., Bethesda, 1979, American Physiological Society, pp 533-580 70 Miller DC, Stinson EB, Oyer PE, lamieson SW, Mitchell RS, Reitz BA, Baumgartner WA, Shumway NE: Discriminant analysis of the changing risks of coronary artery operations. 1 THORAC CARDIOVASC SURG 85:197-213, 1983 71 Unstable angina pectoris: National cooperative study group to compare medical and surgical therapy. III. Results in patients with S-T segment elevation during pain. Am 1 Cardiol 45:819-824, 1980 72 Fisher LD, Kennedy lW, Davis KB, Maynard C, Fritz lK, Kaiser G, Myers WO: Association of sex, physical size, and operative mortality after coronary artery bypass in the Coronary Artery Surgery Study (CASS). 1 THORAC CARDIOVASC SURG 84:334-341, 1982

Discussion DR. 10HN ROUSOU Springfield. Mass.

Not long ago we published our data from a very similar clinical trial of BCP versus CCP. As in the present study, we

Volume 88 Number 5, Part 1 November, 1984

found a higher myocardial oxygen extraction from CCP than from BCP-63% versus 14.5%. Also, there was a higher production of lactate by the myocardium during the arrest period with CCP, as the present study showed-o.18 versus

0.1. Both studies demonstrate a critical period of about 20 minutes of reperfusion, with arrest periods of about an hour, beforethe oxygen extraction ability of the myocardium returns to control levels. However, we could not show, as did the authors, a difference in coronary blood flow and lactate production during reperfusion. In closing, I would ask the authors to comment on three points: (I) the dichotomy between their high-energy phosphates, which were not different between the two groups, and other metabolic and hemodynamic results; (2) the absence of albumin and/or mannitol as well as calcium from their CCP solution but not from the BCP solution; and (3) the optimum myocardial temperature for BCP. MR. MARK V. BRAIMBRIDGE London, England

I would like to make three points, because it is still true that 10 years after the rebirth of cardioplegia we do not know whether we ought to be using oxygenated or unoxygenated solutionsclinically. The first point is that, experimentally, Dr. Lary Robinson in our laboratory has recently shown that there is a wide difference between the CCP solutions used in North America with regard to their myocardial protective factors. The particular type of solution used here was relatively less effective than some others. Second, oxygenated solutions, whether CCP or BCP, can experimentally be shown to have better protective properties than unoxygenated solutions. When we try to reproduce these experiments clinically, the situation becomes different. We have to use complex derived variables which, as Dr. Spotnitz has shown, have many factors that are impossible to control in the clinical situation or evoke equivocal results from energyrich phosphate measurements. Almost all of the clinical articles in the literature show no significant difference between oxygenated and unoxygenated solutions. The third factor that we may not consider enough is what one might term "quality of life," in this case, quality of life for the surgeon rather than for the patient. This comprises three things: surgical convenience; the fmancial cost, particularly in Europe, of using complex cardioplegic equipment; and the time one has to spend up at night with the patient if one has not preserved the myocardium properly. I understand that, despite having shown experimentally that an oxygenated solution is better than an unoxygenated solution, Dr. Daggett has not changed to oxygenated solution. When it comes to our actual choice, therefore, of whether to use an oxygenated or unoxygenated solution, the whole question is still very much in the balance. I would like to ask Dr. Fremes what he and his group are using now, after having completed this study. Are they using BCP or CCP solutions?

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DR. FREMES (Closing) I wish to thank the discussants for their comments. In response to Dr. Rousou's questions, I can speculate and offer some opinions, but the data are not available to completely answer his concerns. His first question concerned the dichotomy between the high-energy phosphates and the postoperative left ventricular function. There are many potential explanations for this dichotomy. First, BCP may have preserved high-energy phosphates and improved postoperative ventricular function better than CCP, but statistical significance was not achieved because of interpatient sampling or assay variation. In support of this explanation, both ATP and creatine phosphate levels were greater with BCP. Second, there may not be a strict correlation between the postoperative high-energy phosphates and postoperative ventricular function. Irreversible injury results in profound depression of tissue ATP levels. However, Dr. Buckberg's laboratory has suggested that the rates of ATP generation or utilization may be more important than the absolute amount. In addition, the studies by Dr. Rousou and his colleagues suggested that secondary BCP maintained postoperative ATP levels but resulted in depressed postoperative ventricular function. Postoperative function may depend more on the ATP levels in certain intracellular pools than in the total tissue levels. To explore this possibility, we are attempting to fractionate our biopsy specimens and analyze subcellular components accurately. Dr. Rousou's second question involved the differences in osmotic and oncotic pressure in the two solutions. Both the CCP and the BCP solutions contained elevated concentrations of glucose,and the osmolarity of the CCP solution was, in fact, greater than that of the BCP solution (380 versus 340 mOsm/L). However, the presence of albumin or mannitol in the BCP solution may decrease cellular edema, and the addition of these to a CCP solution may be of some benefit. The optimal concentration of calcium in the clinical cardioplegic solution is difficult to define. Recently published studies at the Banting Institute in Toronto comparing the effects of a BCP solution, our CCP solution, and an extracellular CCP solution with calcium suggested that the calcium-containing extracellular CCP solution did not improve protection. With respect to the differences in temperature, we believe that a greater margin of safety is obtained when the myocardial temperatures are below 15a C. With extreme hypothermia, it is important to maintain a low hematocrit value. I can answer Dr. Braimbridge's question more accurately. In patients undergoing elective coronary revascularization, the results with both BCP and CCP are excellent, and either agent can be used. However, our study found an important, statistically significant improvement in myocardial function and metabolism when BCP is employed. We are currently comparing BCP and CCP solutions in patients requiring urgent operation for unstable angina. We would anticipate a clinically significant improvement in this group.