Safety of prolonged aortic clamping with blood cardioplegia

J

THoRAc CARDIOVASC SURG

88:395-401, 1984

Safety of prolonged aortic clamping with blood cardioplegia 1. Glutamate enrichment in normal hearts This study compares the protection provided by prolonged (4 hours) aortic clamping with glutamateenriched potassium blood cardioplegia (n = 8) to (1) prolonged (4 hours) aortic clamping with multidose potassium blood cardioplegia without glutamate (n = 4), (2) 4 hours of continuous perfusion of the beating empty heart(n = 7), and (3) 15 minutes of normothermic ischemia (n = 10~ According to measurements of myocardial oxygen uptake, left ventricular compliance, left ventricular contractility, and stroke work performance, no statistical difference could be detected between those hearts receiving blood cardioplegia either with or without glutamate enrichment. In both of these groups, myocardial protection was excellent, as demonstrated by the following: postischemic myocardial oxygen uptake 43 % (p < 0.05) above control, 95 % ± 6 % recovery of the left ventricular compliance, a 97 % ± 5 % return of the left ventricular contractility, and a 91 % ± 6% recovery of stroke work index. Contrary to the excellent recovery of those hearts receiving blood cardioplegic protection, those hearts undergoing 4 hours of continuous perfusion showed a 45 % ± 16 % (p < 0.05) loss of left ventricular compliance and a 72 % ± 8 % (p < 0.05) recovery of stroke work index; those hearts experiencing 15 minutes of normothermic ischemia showed a 74 % ± 6 % (p < 0.05) return of left ventricular compliance, a 30% ± 5% (p < 0.05) decrease in contractility, and a 56% ± 5% (p < 0.05) recovery of postischemic left ventricular stroke work.

John M. Robertson, M.D., Jakob Vinten-Johansen, Ph.D., Gerald D. Buckberg, M.D., Eliot R. Rosenkranz, M.D., and James V. Maloney, Jr., M.D., Los Angeles, Calif.

h e extent of myocardial ischemic damage, until now, has been thought to be determined principally by the duration of aortic clamping. The validity of this concept has been challenged by the development of safe techniques of cardioplegia to prevent ischemic injury.':' It appears now that the degree of intraoperative injury is related more to the failure of induction and maintenance of cardioplegia than the duration of ischemia."? For example, results following short intermittent periods of aortic clamping during coronary revascularization or continuous coronary perfusion with aortic valve replace-

Received for publication May 27, 1983. Accepted for publication Dec. 6, 1983. Address for reprints: Gerald D. Buckberg, M.D., UCLA Medical Center, Department of Surgery/Thoracic, Los Angeles, Calif. 90024.

ment are inferior to those with prolonged aortic clamping with cold blood cardioplegia.I, 2, 8 We believed previously that aortic clamping for as long as 2 hours was safe under ideal cold blood cardioplegic conditions. We must reappraise this safe limit because of a recent study showing that substrate enhancement of blood cardioplegia with glutamate both avoids and reverses ischemic damage in hearts not protected by cardioplegia.v'? The benefits of postischemic glutamate supplementation may be due to its improvement of anaerobic metabolism during clamping and recovery of oxidative metabolism after reperfusion.":" We reasoned, therefore, that its inclusion in our standard blood cardioplegic solution might extend the period of safe aortic clamping to as long as 4 hours. This study compares prolonged (4 hours) aortic clamping with blood cardioplegia with and without glutamate enrichment to (1) 4 hours of perfusion of the

395

The Journal of Thoracic and Cardiovascular Surgery

3 9 6 Robertson et al.

Table I. Composition of cardioplegic solution

Control

(4hr)

/(15Ln~

sr-c "'d",i~

3JOC Ischemia

I

Method

Principle 4°C Blood Cardioplegia

~

Immediate arrest

Potassium chloride

Decrease metabolic rate Avoid edema Substrate enhancement

Hypothermia (4°_8°) Osmolarity (360 mOsm) Monosodium glutamate 26 mmol

Oxygen delivery (aerobic metabolism) Appropriate pH Hypocalcemia

Blood

.G',lom,,"

(30miO'/

Postintervention

Fig. 1. Experimental protocol (see text for description).

beating empty heart, to simulate the more cumbersome operative conditions used by some to avoid ischemia during long operations, and (2) 15 minutes of normothermic ischemia, as might be used in short operations in which cardioplegic protection may be considered unnecessary. The results show that myocardial protection with blood cardioplegia with or without glutamate allowed complete functional recovery after 4 hours of aortic clamping. By comparison, there was substantial myocardial depression with prolonged coronary perfusion or 15 minutes of normothermic ischemia. Methods Twenty-nine adult mongrel dogs (17 to 24 kg) were premedicated with intramuscular morphine sulfate (2 rug/kg) and anesthetized with thiamylal (35 rug/kg) and chloralose (75 mg/kg/hr). After positive-pressure endotracheal ventilation was begun, a median sternotomy was performed and polyethylene catheters were placed into the aorta, coronary sinus, right ventricle, and left atrium for monitoring systemic pressures, collecting blood samples, and giving infusions. After systemic heparinization (3 mg/kg), total cardiopulmonary bypass (Optiflow bubble oxygenator, Cobe Laboratories, Lakewood, Colo.) was initiated with a mean arterial pressure of 100 mm Hg, a hematocrit value of 30% ± 5%, a body temperature of 37° C (except where noted), a pH of 7.4 ± 0.5, an oxygen tension of 150 ± 15 mm Hg, and a carbon dioxide tension of 40 ± 2 mm Hg. A balloon catheter was placed into the left ventricle through an apical stab wound. This balloon was completely compliant up to 30 ml (no intraballoon pressure at temperatures of 10° to 30° C) and was surrounded by a second, more rigid balloon (compliant at 30 ml) to prevent herniation through the mitral valve. Myocardial temperature was measured with a thermistor probe (Yellow Springs Instrument Co., Yellow Springs, Ohio) in the mid-septal wall, and systemic temperature was measured with a rectal probe. The mean septal temperature was 11.5° ± 0.6° C at the end of cardioplegic induction. The cardioplegic delivery system in this study was described recently."

20 mliq/L

pH 7.8 (tromethamine) CPD (Ca"" 0.3-0.7 mEq/L)

Legend: CPD, Citrate-phosphate dextrose.

Measurements. Total coronary blood flow was measured by collecting the right ventricular vent flow. Oxygen content was measured by the method of Behar and Severinghaus," and whole heart oxygen consumption (MV0 2) , expressed as ml oxygen/100 gm/min, was calculated from the equation: MV02 = CBF (A - V)

where CBF = coronary blood flow, A = arterial oxygen content, and V = coronary venous oxygen content. Left ventricular performance was evaluated by inscribing Sarnoff function curves with the right heart bypass method I 6 and by the isovolumetric method whereby intraventricular balloon volume is increased in 5 ml aliquots to 25 ml as described previously.I7 Contractility and compliance were assessed from the first derivative of left ventricular pressure trace (+dP/ dt) and end-diastolic pressure at a balloon volume of 25 ml. With Sarnoff function curves, values are expressed as stroke work index (gra-m/kg) and are calculated as follows: SWI

=

(MAP - LAP) x CO x 1.36 heart rate X body weight 100

where MAP = mean aortic blood pressure, LAP = left atrial pressure, and CO = cardiac output. We did not control heart rate, which varied between 145 and 165 beats/min. However, there was little change in rate (5 to 10 beats) during isovo1umetric or Sarnoff function curves. Statistical evaluation for group differences was performed by analysis of variance and for paired data by paired Student's t test. Values are expressed as mean ± standard error of mean. Significant differences were accepted at a p < 0.05 level. Procedure. Control measurements were made 15 minutes after beginning extracorporeal circulation and 30 minutes after aortic unclamping in hearts undergoing

Volume 88

Blood cardioplegia

Number 3 September, 1984

2.0

397

1°°1---------- ------------- ----

DNoGlutomote ~Glutomote

I

";;

Control O2

__Required

AORTA

240'

MINUTES

Fig. 2. Myocardial oxygen uptake during blood cardioplegic infusion (given every 30 minutes for 4 hours at 4° C). Values show oxygen uptake at cardioplegic induction (clamp aorta) and during the infusions given at 60, 120, 180, and 240 minutes. Note: (1) low· oxygen uptake during cardioplegic induction, (2) high oxygen uptake during reinfusions, and (3) comparable oxygen uptake with and without glutamate supplementation.

ischemia (with and without cardioplegia). Dogs were placed into four experimental groups (Fig. I). Beating empty state (continuous coronary perfusion. 4 hours). Seven dogs underwent 4 hours of extracorporeal circulation with the heart in the beating empty state without ischemia. Fifteen minutes of normothermic ischemic arrest. Ten dogs underwent 15 minutes of normothermic ischemia, and measurements were made 30 minutes after releasing the aortic clamp. Multidose administration ofglutamate-enriched cardioplegic solution. In eight dogs, the aorta was clamped for 4 hours. Immediate electromechanical arrest was achieved by infusing 350 ml of cold (4° to 8° C), glutamate-enriched (26 mmol/L), potassium blood cardioplegic solution at 50 mm Hg pressure (Table I). Replenishment was given for 2 minutes each 30 minutes with glutamate-enriched blood cardioplegic solution at 50 mm Hg. The last dose of cardioplegic solution was given at 9° C above septal temperature just before removing the aortic clamp. The pH of the cardioplegic solution was adjusted to the "appropriate" level for infusion temperature." The total cardioplegic dose was slightly greater in glutamate-treated hearts than in those subjected to multidose standard blood cardioplegia (2,631 ± 128 ml versus 2,447 ± 224 ml), as was the volume delivered during each reinfusion (285 ± 16 ml versus 262 ± 28 ml). Reinfusion volumes in each group, however, were comparable over the 4 hours of aortic clamping. Multidose standard blood cardioplegia (without glutamate). Four dogs underwent a similar 4 hour period of aortic clamping with multidose cold blood cardioplegia without glutamate supplementation.

L

I I

]

370C Perfusion (4 hr )

3JOC 4°C Blood Cardioplegia Ischemia (4hr) U5min)

~Glutamate Fig. 3. Left ventricular compliance (at 25 ml balloon volume) after 4 hours of continuous coronary perfusion and 30 minutes after 15 minutes of normothermic ischemia and 4 hours of blood cardioplegia. Note: Best recovery of compliance after cardioplegia (with and without glutamate).

100

1

- - --

I

%

Control +dP/dt 50

a

370C Perfusion (4 hr)

370C 4°C Blood Cardioplegia Ischemia (4hr) (15min)

~Glutamate Fig. 4. Left ventricular contractility at 25 mm balloon volume after 4 hours of coronary perfusion, 15 minutes of normothermic ischemia, and 4 hours of blood cardioplegia. Note: (I) reduced contractility after 15 minutes of normothermic ischemia and (2) normal contractility after continuous coronary perfusion and prolonged blood cardioplegia (with and without glutamate). +dPjdt, First derivative of left ventricular pressure.

Reperfusion was begun by lowering mean arterial pressure to 50 mm Hg just before removing the aortic clamp and raising it to 100 mm Hg over the next 3 minutes as electromechanical activity recovered. The heart was defibrillated as necessary when myocardial temperature reached 37° C.

Results Results are summarized in Table II and Figs. 2 to 5. Myocardial oxygen uptake. During control conditions, myocardial oxygen consumption averaged 5.0 ±

The Journal of Thoracic and Cardiovascular Surgery

3 9 8 Robertson et al.

Table

n 30 min after experimental intervention

Control Heart rate (beats/min)

MV02 (mi/IOO grn/beat) MV02 (mi/IOO gm/rnin) Extraction (%) Coronary flow (mi/IOO

154 ± 0.033 ± 5.0 ± 50 ± 59 ±

5 0.002 0.5 5 7

4 hours continuous coronary perfusion

150 ± 0.036 ± 5.5 ± 49 ± 62 ±

5 0.002 0.6 4 3

15 min ischemic arrest

150 ± 0.028 ± 4.1 ± 30 ± 83 ±

4 0.003 0.5 2 7

4 hr BCP arrest with glutamate

152 ± 0.047 ± 7.2 ± 42 ± 129 ±

4 0.004* 0.7* 4 24*

4 hr BCP arrest without glutamate

149 ± 0.049 ± 7.3 ± 44 ± 136 ±

7 0.009* 0.9* 6 21*

grn/rnin) Legend: BCP. Blood cardioplegia. MVO,. Myocardial oxygen consumption. Values are mean ± standard error of the mean. *p < 0.05 (from control).

0.5 ml/l00 gm/min with a coronary blood flow of 59 ± 7 ml/l00 gm/min in all groups. This level of oxygen uptake was maintained during the entire 4 hour observation period in dogs undergoing continuous perfusion (Table II). In dogs undergoing cardioplegic arrest, myocardial oxygen uptake fell to 0.2 ± 0.1 ml/l00 gm/rnin during the induction of cardioplegia (Fig. 2). Myocardial oxygen uptake during the intervals of replenishment rose to an average of 1.3 ± 0.1 ml/l00 gm/rnin; there was a tendency for oxygen uptake to increase with each infusion. Myocardial oxygen uptake during multidose blood cardioplegia was similar with and without glutamate supplementation (Fig. 2). Postischemic oxygen utilization measured 30 minutes after aortic unclamping was lowest (4.1 ± 0.5 ml/l00 gm/min) in dogs undergoing 15 minutes of normothermic ischemia. Conversely in hearts treated with blood cardioplegia (with or without glutamate), myocardial oxygen uptake rose significantly to 7.2 ± 0.7 ml/l00 gm/rnin (43% above control, p < 0.05). Left ventricular compliance. Left ventricular compliance measured isovolumetrically at a 25 ml ventricular volume fell to 55% ± 16% of control values in those hearts exposed to 4 hours of continuous coronary perfusion. A less severe, but significant reduction in compliance (74% ± 6% of control, p < 0.05) occurred in hearts subjected to only 15 minutes of normothermic ischemia. In addition, the rate of relaxation fell significantly (-dP/dt) to 72% of control value (p < 0.05). In contrast, left ventricular compliance remained normal (95% ± 6% of control) in hearts treated with multidose blood cardioplegia with or without glutamate, despite 4 hours of aortic clamping (Fig. 3). Left ventricular function. Left ventricular performance assessed by Sarnoff function curves on right heart bypass was reduced 44% in hearts subjected to 15 minutes of normothermic ischemia (Fig. 5). This

depressed performance resulted from both a 26% ± 6% reduction of compliance (p < 0.05) and a 30% ± 5% decrease in contractility (Figs. 3 and 4). Hearts receiving continuous coronary perfusion in the beating empty state demonstrated a 28% depression of ventricular performance when Sarnoff function curves were inscribed. This depression resulted primarily from a 45% ± 16% loss of compliance (Fig. 3) as contractility remained at normal levels. The best recovery of left ventricular performance occurred in those hearts protected with multidose blood cardioplegia. Recovery was comparable both with and without glutamate supplementation, with maintenance of normal compliance and contractility (Figs. 3 and 4) and with a 91% ± 6% recovery of stroke work index as determined by Sarnoff function curves (Fig. 5). Discussion The purposes of this study were to (I) determine if glutamate enrichment of our blood cardioplegic solution would increase its protective effect and allow prolongation of a safe duration of aortic clamping to 4 hours, (2) compare this prolonged blood cardioplegic arrest to an equal period of continuous perfusion of the beating empty heart, and (3) test the hypothesis that prolonged aortic clamping is safer with optimal myocardial protection than disregarding efforts at myocardial protection during brief (i.e., 15 minute) periods of normothermic ischemia. The results show that complete myocardial recovery is possible after as long as 4 hours of aortic clamping with blood cardioplegia (with and without glutamate), whereas significant functional depression occurs after an equal period of continuous coronary perfusion or as little as 15 minutes of normothermic ischemia. We selected for comparison the model of prolonged continuous coronary perfusion because we" considered this method of myocardial protection to be optimal

Volume 88 Number 3 September, 1984

before current cardioplegic techniques were developed. Additionally, it simulates a cumbersome method used by some surgeons to avoid ischemia during long operations (i.e., triple valve replacement). The data show that prolonged perfusion is not innocuous in that it causes a significant depression in myocardial compliance. Consequently, there is functional depression despite maintenance of normal contractility (Fig. 2). Fortunately, the magnitude of functional depression caused by prolonged continuous coronary perfusion and 15 minutes of normothermic ischemia was not severe; both groups could more than double their resting (control) stroke work indices before myocardial failure (i.e., left atrial pressure 25 rom Hg) occurred. When ventricular compliance is reduced clinically, a higher ventricular filling pressure is needed to generate adequate cardiac output. Our use of both isovolumetric and Sarnoff function curves demonstrates that reduced compliance was the primary cause of functional depression in hearts undergoing 4 hours of continuous coronary perfusion. The cause of depressed compliance was not apparent from our data. However, we doubt that myocardial edema was the responsible factor, since prolonged coronary perfusion does not cause myocardial edema.' Particulate matter, which exists in all extracorporeal circuits," may have contributed to the fall in compliance. Our data provide additional evidence to reject the concept that brief periods of normothermic ischemia are innocuOUS. 21-24 Fifteen minutes of normothermic ischemia, as might be used in patients with single coronary grafts or atrial septal defects, resulted in a 44% reduction in left ventricular performance, which persisted for at least 30 minutes after unclamping. The depression was due to both reduced left ventricular compliance and contractility (Figs. 3 and 4). Although it is likely that this moderate depression is reversible over time, it can be avoided completely by cardioplegic protection. The greater functional recovery seen after prolonged aortic clamping with appropriate blood cardioplegic protection compared to that seen following brief ischemia is consistent with the clinical observations made when these techniques are compared in patients undergoing coronary revascularization.'-" The major purpose of this study was to determine if glutamate supplementation of our standard blood cardioplegic solution would extend the safe duration of aortic clamping to 4 hours. We chose to study Lglutamate as a cardioplegic additive because (l) it is readily deaminated to a-keto glutarate, a Krebs cycle intermediate, (2) recent studies suggest that it is utilized by the myocardium during ischemia,":" (3) we9, 10 have

Blood cardioplegia 3 9 9

30r

..'

;'<"'1 No Glutamate

' r/ :

f/

:

.: I

SWI

(qrn-m/kq)

I :"

i

o

!: i

:"

BLOOD CARDIOPLEGIA

(4 hr)

/

/

_

.~._.

/

I

.

I

Coronary Perfusion (4hr)

(15 Ischemia min)

i

!I {

J~ !

i

:,'1

1.5;

i

I· Glutamate

I

10

20

30

LA P. (mrn Hq)

Fig. 5. Left ventricular performance assessed by right heart bypass function curves. Note: (1) worst performance after 15 minutes of normothermic ischemia and (2) better performance after 4 hours of blood cardioplegia (with and without glutamate) than after continuous coronary perfusion for 4 hours. SWI, Stroke work index. L.A.P., Left atrial pressure.

demonstrated that postischemic replenishment .of glutamate enhances oxidative metabolism and subsequent myocardial recovery, and (4) it could potentially increase anaerobic production of adenosine triphosphate during aortic clamping." 27 We anticipated that adding glutamate to blood cardioplegia would replenish Krebs cycle intermediates used during ischemia and thereby allow more normal oxygen utilization during multidose cardioplegic replenishments as well as during reperfusion. Unfortunately, the methods for direct measurement of amino acid in blood and tissue were not available to us, so that metabolic confirmation of this hypothesis is not possible from the study. The data show, however, that blood cardioplegia without glutamate provided complete protection for the 4 hour period of aortic clamping; oxygen uptake during cardioplegic replenishment was comparable to that with glutamate supplementation, and postischemic recovery of compliance, performance, and metabolism was excellent. There are at least two reasons why glutamate did not add to the benefits of cold blood cardioplegic solution used to prevent ischemic damage. First, the salutory effects of glutamate have previously been demonstrated only under normothermic conditions.v'<" Consequently, hypothermia itself may have reduced the efficiency of glutamate metabolism. Second, blood cardioplegic protection may have prevented myocardial injury during aortic clamping, so that there was no need for amino

400

The Journal of Thoracic and Cardiovascular Surgery

Robertson et al.

acid replenishment. Amino acid supplements may be necessary only under conditions of myocardial injury. Our studies were performed under ideal circumstances in which episodes of ischemia before aortic clamping did not occur, no problem with distribution of the cardioplegic solution was present (i.e., nonobstructed arteries), and the ventricle was normal. Such ideal conditions are uncommon clinically, for coronary artery disease and left ventricular hypertrophy may both limit the effectiveness of distribution of cardioplegic solution"? and reduce the tolerance to standard ischemic insults." Because of abundant evidence of glutamate utilization during ischemia, I 1-13 its ability to improve anaerobic energy production,":" its salutory effect in the postischemic period,9.10 and especially its documented capacity to enhance the benefits of blood cardioplegia in energy-depleted hearts,'? we believe strongly that amino acid supplementation of cardioplegic solutions will become a vital component in future efforts at intraoperative myocardial protection. Certainly, further study of glutamate and other amino acid cardioplegic supplements is required in energy-depleted hearts as well as in hearts with hypertrophy or coronary obstruction to confirm or reject this hypothesis. Our results may seem counterintuitive at first glance, in that a 4 hour period of aortic clamping was safer than a comparable interval of continuous coronary perfusion or as little as 15 minutes of normothermic ischemia. Under 1).0 circumstance should our fmdings be interpreted as suggesting that the duration of aortic clamping be prolonged unnecessarily. However, the data do point out that even brief periods of ischemia can cause functional changes which are avoidable with appropriate cardioplegic protection and that prolonged continuous coronary perfusion is not innocuous. These data lead us to conclude that the safe limit of cardioplegic aortic clamping has yet to be defmed and to suggest that the time-honored surgical preoccupation with "cross-clamp time" must be modified to consider "protection time" in its stead. REFERENCES Follette OM, Mulder DG, Maloney N lr, Buckberg GO: Advantages of blood cardioplegia over continuous coronary perfusion or intermittent ischemia. Experimental and clinical study. 1 THORAC CARDIOVASC SURG 76:604, 1978 2 Barner HB, Kaiser GC, Codd JE, Tyras OH, Pennington OG, Laks H, Willman VL: Clinical experience with cold blood as the vehicle for hypothermic potassium cardioplegia. Ann Thorac Surg 29:224, 1980 3 Catinella FP, Cunningham IN Jr, Adams PX, Snively SL, Gross RI, Spencer FC: Myocardial protection with cold

4

5

6

7

8

9

10

11

12

13

14 15

16

17

18

blood potassium cardioplegia during prolonged aortic cross-clamping. Ann Thorac Surg 33:228, 1982 Becker H, Vinten-lohansen 1, Buckberg GO, Follette DM, Robertson 1M: Critical importance of ensuring cardioplegic delivery with coronary stenoses. 1 THORAC CARDIOVASC SURG 81:507, 1981 Hilton Cl, Teubl W, Acker M, Levinson Hl, Mellard RW, Riddle R, McEnany MT: Inadequate cardioplegic protection with obstructed coronary arteries. Ann Thorac Surg 28:323, 1979 Grondin CM, Helias 1, Vouhe PR, Robert P: Influence of a critical coronary artery stenosis on myocardial protection through cold potassium cardioplegia. 1 THORAC CARDloVASC SURG 82:608, 1981 Coles lG, Wilson Gl, Tait GA, Klement P, Coles rc, Weisel RO, Baird Rl: Cardioplegia for severe coronary artery seizure. An improved technique using direct coronary artery infusion. Ann Thorac Surg 33:234, 1982 Olin CL, Bomfim V, Bendz R, Kaijser L, Strom si, Sylven CH: Myocardial protection during aortic valve replacement. 1 THORAC CARDIOVASC SURG 82:837, 1981 Lazar HL, Buckberg GO, Manganaro Al, Becker H, Maloney lV Jr: Reversal of ischemic damage with amino acid substrate enhancement during reperfusion. Surgery 80:702, 1980 Lazar HL, Buckberg GO, Manganaro AM, 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, 1980 Gailis L, Benmouyal: Endogenous alanine, glutamate, aspartate and glutamine in perfused guinea pig heart. Effect of substrates and cardioactive agents. Can 1 Biochern 51:11, 1973 Edington OW, Ward GR, Saville WA: Energy metabolism of working muscle. Concentration profiles of metabolites. Am 1 Physiol 224:1375, 1973 Taegtmeyer H: Metabolic adaption to myocardial hypoxia. Increased synthesis and release of succinic acid. Circulation 55, 56:Suppl 3:86, 1977 Buckberg GO: Myocardial preservation symposium. 1 THORAC CARDIOVASC SURG 82:875, 1981 Behar MG, Severinghaus lW: Calibration and a correction of blood O, content measured -by POz after CO saturation. 1 Appl Physiol 29:413, 1970 Hottenrott C, Maloney N Jr, Buckberg GO: Studies on the effects of ventricular fibrillation on the adequacy of regional myocardial flow. I. Electrical vs spontaneous fibrillation. 1 THORAC CARDIOVASC SURG 68:615, 1974 Follette OM, Fey K, Buckberg GO, Helly 11 lr, Steed OS, Foglia RP, Maloney lV lr: Reducing postischemic damage by temporary modification of reperfusate calcium, potassium, pH, and osmolarity. 1 THORAC CARDIOVASC SURG 82:221, 1981 Becker H, Vinten-lohansen 1, Buckberg GO, Robertson 1M, Leaf 10, Lazar HL, Manganaro AJ: Myocardial damage caused by keeping pH 7.40 during systemic deep

Volume 88 Number 3 September, 1984

hypothermia. J THORAC CARDIOVASC SURG 82:810, 1981 19 Buckberg GD, Olinger GN, Mulder 00, Maloney JV Jr: Depressed postoperative cardiac perforarnnce. Prevention by adequate myocardial protection during cardiopulmonary bypass. J THORAC CARDIOVASC SURG 70:974, 1975 20 Utley J, Carlson EL, Hoffman JIE, Martinez HM, Buckberg GD: Total and regional myocardial blood flow measurements with 25~; 97~ and filtered I-I O~ diameter microspheres and antipyrine. Circ Res 34:391, 1974 21 Wright RN, Levitsky S, Holland C, Feinberg H: Beneficial effects of potassium cardioplegia during intermittent aortic cross-clamping and reperfusion. J Surg Res 24:201, 1978 22 Gaudiani VA, Smith JH, Epstein SE: Alterations in regional contractility following cardiopulmonary bypass with intraoperative ischemia. J THORAC CARDIOVASC SURG 76:70, 1978 23 Smith HG, Kent KM, Epstein SE: Contractile damage from reperfusion after transient ischemia in the dog. J THORAC CARDIOVASC SURG 75:452, 1978

Blood cardioplegia

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24 Kane 11, Murphy ML, Bissett JK, deSoyza N, Doherty JE, Staub KD: Mitochondrial function, oxygen extraction, epicardial ST segment changes and tritiated digoxin distribution after reperfusion of ischemic myocardium. Am J Cardiol 36:218, 1975 25 Attarian DE, Jones RN, Currie WD, Hill RC, Sink 10, Olsen CO, Chitwood WR, Wechsler AS: Characteristics of chronic left ventricular hypertrophy induced by subcoronary valvular aortic stenosis. II. Response to ischemia. J THORAC CARDIOVASC SURG 81:389, 1981 26 Sanborn T, Gavin W, Berkowitz S, Perille T, Lesch M: Augmented conversion of aspartate and glutamate to succinate during anoxia in rabbit heart. Am J Physiol 6:535, 1979 27 Rau EE, Shine KI, Gervais A, Douglas AM, Amos EC III: Enhanced mechanical recovery of anoxic and ischemic myocardium by amino acid perfusion. Am J Physiol 236:H873, 1979