Conti~~uous Hypothermic Arrest Versus Intermittent Ischemia for Myocardial Protection During Coronary Revascularhation J. Kenneth Koster, Jr., M.D., Lawrence H. Cohn, M.D., John J. Collins, Jr., M.D., J. H. Sanders, M.D., James E. Muller, M.D., and Eliot Young, M.D.

ABSTRACT To assess the safety of two commonly used methods of myocardial protection, 144 consecu- tive patients who underwent coronary artery bypass grafting for chronic disabling or unstable angina were studied. Profound local cardiac hypothermia (LCH) with a single continuous period of ischemic arrest was used in 71 patients and compared with intermittent ischemia with intervening periods of reperfusion in 73 patients. Both groups were similar in age, sex distribution, number of obstructed coro- nary arteries, and number of coronary arterial bypass grafts performed. The electrocardiogram, serum glutamic oxaloacetic transaminase (SGOT), lactate dehydrogcnase (LDH), and creatine phosphokinase (CPK) were measured preoperatively, the day of op- eration, and for two days postoperatively. The opera- tive mortality was 0.7010. The overall perioperative myocardial infarction rate defined by QRS criteria was 6.3%. In the LCH group the infarction rate was 4.270, and in the ischemia group, 8.2%. Although mean initial postoperative SGOT and LDH were noticeably lower in the LCH group, other enzyme values, including CPK, did not differ noticeably be- tween the groups. These data indicate that a single continuous period of ischemic arrest with profound local cardiac hypothermia as well as intermittent aortic cross-clamping with moderate systemic hypotherrnia are safe techniques for protecting the myocardium during coronary revascularization.

During coronary bypass operations, a quiet, bloodless field is desirable for performance of the distal coronary anastomoses. In most in- stances, :some form of cardiac arrest with inter-

From the Departments of Surgery and Medicine, Harvard Medical School and Peter Bent Brigham Hospital, Boston, MA. Presented (st the Thirteenth Annual Meeting of The Society of Thoracic Surgeons, Jan 24-26, 1977, San Francisco, CA. Address reprint requests to Dr. Koster, Peter Bent Brigham Hospital, 721 Huntington Ave, Boston, MA 02115.

ruption of coronary blood flow is required. Al- though this may be achieved with various tech- niques, the optimal method for myocardial pro- tection is undetermined. This report examines the use of profound local cardiac hypothermia with a single period of ischemic arrest and compares it with the use of moderate systemic hypothermia, ventricular fibrillation, and in- termittent ischemic intervals for the perfor- mance of the graft-to-coronary anastomoses in coronary bypass operations.

Materials and Methods The data for analysis were obtained retrospec- tively from records of 144 consecutive patients who underwent coronary artery bypass grafting for chronic disabling or unstable angina pectoris at the Peter Bent Brigham Hospital from April, 1975, through March, 1976. Patients who underwent coronary artery bypass grafting with concomitant valve replacement or ventricular aneurysmectomy were excluded from this se- ries, as were patients in preoperative car- diogenic shock.

Two parallel groups were established on the basis of the method of myocardial protection utilized during performance of the distal coro- nary anastomoses. In Group I, 73 patients underwent intermittent ischemia by means of moderate systemic hypothermia and electri- cally induced ventricular fibrillation. Intermit- tent aortic cross-clamping was employed for periods of 5 to 15 minutes to allow the distal coronary anastomoses to be performed in a bloodless field. In Group 11, 71 patients under- went moderate systemic hypothermia and elec- trically induced ventricular fibrillation; one con- tinuous period of aortic cross-clamping was utilized for all distal coronary anastomoses with myocardial protection provided by local pro- found cardiac hypothermia (LCH) by means of a

330

331 Koster et al: Hypothermic Arrest vs. Intermittent Ischemia

continuous circulating bath of iced (4°C) Ring- er's lactate within the pericardial cavity.

In both groups cardiopulmonary bypass, uti- lizing a disposable bubble oxygenator, was car- ried out with a single right atrial cannula for venous drainage and an ascending aortic can- nula for arterial perfusion. During cooling to 28" to 30°C on bypass, the coronary anatomy was inspected and the ascending aortic adventitia was trimmed in preparation for construction of the proximal graft anastomoses. After electrical induction of ventricular fibrillation, the aorta was clamped intermittently with intervening periods of perfusion (Group I) or continuously with local cardiac hypothermia (Group 11) for construction of the distal graft-to-coronary anas- tomoses with a single continuous 6-0 Prolene suture. All Group I patients had apical venting of the left ventricle, whereas the majority of Group I1 patients had no ventricular venting. In both groups, systemic rewarming was begun after the distal anastomoses had been con- structed and while the proximal aorta-to-graft anastomoses were being performed over a par- tially occluding aortic clamp, allowing reperfu- sion of the heart. The hearts were electrically defibrillated near the completion of rewarming.

Evidence of perioperative myocardial injury was sought by measuring serum enzyme levels-serum glutamic oxaloacetic trans- aminase (SGOT), lactate dehydrogenase (LDH), creatine phosphokinase (CPK)-and analysis of twelve-lead electrocardiograms (ECG). These studies were obtained preoperatively, im- mediately postoperatively, and on the first two postoperative days. ECGs were read by Dr. Mul- ler, who had no knowledge of the operative technique employed. Perioperative infarction was defined by the appearance of new Q-waves or, in certain instances, the loss of R-wave volt- age supported by vectorcardiogram. Late car- diac status was assessed eight weeks postop- eratively with follow-up examination, which included chest roentgenogram and ECG with specific documentation of functional classifica- tion.

Both groups were similar in sex and age dis- tribution. In Group I there were 62 men and 11 women whose ages ranged from 32 to 76 years (mean 51 years). In Group I1 there were 61

men and 10 women with an age range between 27 and 71 years (mean, 54.4 years).

Results Both groups were comparable in the number of coronary arteries significantly diseased (> 70% arteriographic luminal narrowing). In Group I, an average of 2.48 vessels were severely occluded, 2.44 in Group 11.

Electrocardiographic evidence of previous myocardial infarction (MI) was present in 88 pa- tients operated upon (61%). Forty-three patients (59%) in Group I and 45 (63%) in Group I1 had had a prior MI (Table 1).

Cardiopulmonary bypass time was similar in both groups. Perfusion time ranged from 34 to 151 minutes (mean, 95 minutes) in Group I and 25 to 150 minutes (mean, 86 minutes) in Group 11. Total cardiac ischemia (aortic cross- clamp) time was significantly greater ( p < 0.001) in the LCH group; 0 to 63 minutes (mean, 25 minutes) in Group I, 9 to 79 minutes (mean, 48 minutes) in Group 11.

The number of grafts performed was similar for both groups (Table 2). In Group I, 73 patients had a mean of 2.4 grafts (7 single, 33 double, 31 triple, 2 quadruple); in Group 11,71 patients had a mean of 2.5 grafts (6 single, 28 double, 35 triple, and 2 quadruple).

There was 1 operative death (0.07O/0), which occurred in the LCH group (1.4%). A 67-year- old man with triple-vessel disease died of an anterior MI two days after incomplete revas- cularization when his diseased intramyocardial left anterior descending artery could not be lo- cated for grafting.

Table 1 . Comparison of Patient Characteristics in the Ischemia and LCH Groups

Factors Group I Group I1 (Ischemia) (LCW

Age (yr) 51.0 (32-76) 52.4 (27-71) Sex 0.17 0.15 No. of diseased 2.48 2.44

ECG evidence of 43/73 (59%) 45/71 (63%) vessels

prior infarction

LCH = local cardiac hypothermia.

332 The Annals of Thoracic Surgery Vol 24 No 4 October 1977

Table 2. Distribution of 144 Grafts Performed

No. Grafts Performed

Group I Group I1 (Ischemia) (LCW

Single 7 6 Double 33 28 Triple 31 35 Quadruple 2 2 Mean grafts 2.4 2.5

per patient

LCH = local cardiac hypothermia.

The overall perioperative infarction rate de- fined by QRS criteria was 6.3% (9 patients): 6 patients (8.2%) in Group I, 3 patients (4.2%) in Group I1 (Table 3).

Mean serum enzyme levels (SGOT, LDH, CPK) obtained immediately after operation and on the first two postoperative days were ele- vated in both groups (Figs 1-3). Mean SGOT and LDH values tended to be slightly lower in Group 11, but this difference was statistically significant only for the immediate postoperative measure- ment ( p <: 0.02). CPK measurements did not differ significantly between the two groups at any time. Correlation of serum enzyme levels with electrocardiographic evidence of peri- operative infarction showed that, although mean postoperative values for SGOT, LDH, and CPK were higher in patients exhibiting Q-waves tlhan in those without them, the differ- ence was not statistically significant (all p > 0.20).

Serum enzyme levels were generally higher with longer cardiopulmonary bypass times. However, a significant correlation of enzyme elevation with bypass time was found only for

Table 3. Di:;tribution of Perioperative Myocardial Infarction

Group I Group I1 (73 Patients) (71 Patients) Total MI

Fatal 0 1(1.4%) 1(0.7%) Nonfatal 6 (8.2%) 2 (2.8%) 8 (5.6%)

Total (YO) 8.2 4.2 6.3

MI = myocardial infarction.

SGOT values on the first postoperative day in patients with perfusion times greater than two hours (p = 0.03). There was no significant differ- ence in enzyme levels for patients with perfu- sion times over two hours between the two groups.

The incidence of prior MI in patients sustain- ing perioperative infarctions-6 of 9 patients (67%)-did not differ significantly from the incidence of prior infarction48 patients (61°/0)-for the entire series.

There was no correlation between occurrence of perioperative infarction with either perfusion time or aortic clamping time for either group. Mean perfusion time was 89 minutes in Group I (infarct) as opposed to 96 minutes (no infarct); mean aortic clamping times were 24 minutes (infarct) and 25 minutes (no infarct). In Group 11, mean perfusion time was 83 minutes (infarct) versus 86 minutes (no infarct); mean aortic clamping time was 43 minutes (infarct) as op- posed to 48 minutes (no infarct). Of the 9 perioperative infarctions occurring in this se- ries, 8 were in patients with triple-vessel disease, suggesting a positive correlation. However, statistical significance was not gained ( p = 0.06), possibly because of the few patients involved.

Comment Since the advent of direct aortocoronary bypass procedures, operative techniques have evolved according to efforts to simplify the operative procedure hnd to minimize intraoperative myo- cardial injury. With recognition of the technical advantages of aortic cross-clamping to provide adequate exposure for precise construction of the distal graft anastomoses in aortocoronary bypass operations, many surgeons have used intermittent ischemic arrest with low mortality, a low incidence of perioperative infarction, and excellent late clinical results [5, 141. An alterna- tive technique of profound local cardiac hypothermia with continuous aortic clamping has been applied less widely to operations for ischemic heart disease, although its efficacy in valvular [3] and congenital [lo] cardiac surgery is well recognized and its safety documented for aortocoronary bypass procedures 181.

The present study compares local cardiac

333 Koster et al: Hypothermic Arrest vs. Intermittent Ischemia

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hypothermia and prolonged aortic clamping with the widely used technique of induced ven- tricular fibrillation in conjunction with intermit- tent aortic cross-clamping in similar groups of patients who underwent coronary revasculari- zation. Hospital mortality was low (0.7%) with either technique and compares favorably with current reports of 1.8 to 3.3% mortality for coro- nary bypass procedures [12-141. The 1 death (in the LCH group) is believed to have origi- nated from a technical problem rather than from deficient myocardial protection during the operation.

The overall incidence of perioperative infarc- tion according to QRS criteria was acceptably low (6.2%) in comparison with currently re- ported rates of 3.6 to 23% [9, 11, 12, 141. Al- though the rate of perioperative infarction was lower in the LCH group, this difference was not statistically significant.

The morbidity and mortality of perioperative infarction was low. When infarction did occur, it was usually "silent." Of the 9 perioperative in- farctions, 1 was fatal and another was associated with ventricular arrhythmias. The remainder showed no evidence of either early electrical and hemodynamic instability or late functional im- pairment attributable to myocardial injury.

The incidence of perioperative myocardial in- jury is undoubtedly greater than indicated by QRS criteria alone, but an accurate assessment of nontransmural injury is difficult, in part be- cause the relationship of elevated serum enzyme levels alone to major myocardial injury is un- clear [21. Current use of CPK-MB (myocardial basic) isoenzymes and myocardial scans may clarify this. In this series, both groups demon- strated postoperative serum enzyme elevations which, with 1 exception, were similar, suggest- ing that both techniques are associated with a similar degree of intraoperative myocardial in- jury. In the few instances when extreme post- operative enzyme elevations occurred, there was no clinical evidence of cardiac functional impairment, either immediately postopera- tively or at later follow-up examination. In con- trast to studies showing correlation of serum enzyme levels (SGOT and CPK [151 and SGOT [9]) with ECG evidence of myocardial infarction, the enzyme levels of patients in this study with

334 The Annals of Thoracic Surgery Vol 24 No 4 October 1977

QRS changes of infarction were not significantly greater than the levels in those without. The only perioperative event with which a significantly greater degree of postoperative enzyme rise could be statistically correlated was a perfusion time longer than two hours.

From thle low mortality rate, the low incidence of perioperative infarction, and the absence of late evidence of ventricular dysfunction ob- served with both methods, we conclude that both induced ventricular fibrillation with in- termitten.t aortic cross-clamping and profound local cardiac hypothermia with continuous aor- tic cross-,clamping are safe techniques for the performance of aortocoronary bypass grafting.

References 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

Brewer DL, Bilbro RH, Bartel AG: Myocardial in- farction as a complication of coronary bypass surgery. Circulation 47:58, 1973 Codd JE, Kaiser GC, Weins RD: Myocardial in- jury and bypass grafting: value of serum enzymes in diagnosis. J Thorac Cardiovasc Surg 70:489, 1975 Cohn LH, Collins JJ: Local cardiac hypothermia for myocardial protection. Ann Thorac Surg 17:135, 1974 Espinoza J, Lipski J, Litwak R, et al: New Q-waves after coronary artery surgery for angina pectoris. Am J Cardiol 33:221, 1974 Flemma RJ, Singh HM, Tector AJ, et al: Factors predictive of perioperative myocardial infarction during coronary operations. Ann Thorac Surg 21:215, 1976 Ghani MF, Parker BM, Smith JR: Recognition of myocardial infarction after cardiac surgery and its relation to cardiopulmonary bypass. Am Heart J 88:18, 1974 Greenberg BH, McCallister BD, Frye RL, et al: Serum glutamic oxaloacetic transaminase and electrocardiographic changes after myocardial re- vascularization procedures in patients with coro- nary artery disease. Am J Cardiol 26:135, 1970 Griepp RB, Stinson EB, Oyer PE: The superiority of aortic cross-clamping with profound local hypothermia for myocardial protection during aorto- coronary bypass grafting. J Thorac Car- diovasc Surg 70:995, 1975 Kansal S, Roitman D, Kouchoukos N, et al: Is- chemic myocardial injury following aorto- coronary bypass surgery. Chest 67:20, 1975 Lamberti JJ, Cohn LH, Laks H: Local cardiac hypothermia for myocardial protection during correction of congenital heart disease. Ann Thorac Surg 20:446, 1975

11. Langdon RA, Wiles JC, Peduzzi PN, et al: Inci- dence and mortality of perioperative myocardial infarction in patients undergoing coronary artery bypass grafts (abstract). Circulation 53,54: Suppl 264, 1976

12. Morton BC, McLaughlin PR, Trimble AS, et al: Myocardial infarctions in coronary artery surgery. Circulation 51,52: Suppl 1:198, 1975

13. Ray JF, Tewksbury DA, Myers WO, et al: Can the frequency of myocardial infarction be reduced during coronary artery operations. Ann Thorac Surg 23:14, 1977

14. Reul GJ, Cooley DA, Sandiford FM: Aortocoro- nary artery bypass-present indications and risk factors. Arch Surg 111:414, 1976

15. Rose MR, Glassman E, Isom OW, et al: Electro- cardiographic and serum enzyme changes of myocardial infarction after coronary artery surgery. Am J Cardiol 33915, 1974

Discussion DR. TODD M. GREHL (Sacramento, CA): The question of whether intermittent or continuous coronary perfu- sion, depending on the surgical procedure, is better than hypothermic ischemic arrest for myocardial pro- tection is one that has been bantered about for several years. At present there is no well-defined solution to the question. Obviously, both techniques are work- able if used appropriately.

I was trained at the Palo Alto ”fountain of iced saline,” and I am somewhat prejudiced in favor of local hypothermic anoxic protection of the myocar- dium. We have found it an extremely safe and reliable technique, particularly in teaching hospitals, where variable time limits are often involved in various sur- gical procedures.

Approximately ten years ago we were using inter- mittent coronary artery perfusion during aortic valve replacements.Because of coronary cannula dislodge- ment, that was, at best, intermittent coronary perfu- sion. Over the years we have come to rely exclusively on ischemic hypothermia because of its safety and simplicity.

In a patient suffering from aortic valve disease as well as triple coronary artery disease, the arteriogram demonstrated generalized hypokinesia of the an- terior, apical, and septa1 walls of the left ventricle as well as calcific aortic valvular stenosis and aortic val- vular insufficiency. High-grade lesions in the left coronary vascular bed were present, necessitating triple-bypass grafting as well as aortic valve replace- ment. After placing the patient on cardiopulmonary bypass, arresting the heart, and cross-clamping the aorta, we resected the aortic valve. The pericardium was continuously irrigated with ice-cold saline solu- tion at 4°C so as to maintain an asystolic, nonfibrillat- ing heart.

335 Koster et al: Hypothermic Arrest vs. Intermittent Ischemia

The aortic valve was sized, the three vein grafts anastomosed distally, the aortic valve sutured into position, the aortotomy closed, the aortic cross-clamp removed, and the proximal anastomoses carried out.

Often the heart will be defibrillated to allow it to contract empty while we continue with the proximal vein graft anastomoses. This shortens the fibrillation time imposed upon the heart.

In our patient the cross-clamp time was two hours. The total time on bypass was two and one-half hours. The preoperative and the immediate postoperative ECGs showed no noticeable changes. The CPK, LDH, and SGOT were slightly elevated. The maximum value of each was as follows: CPK, 680; LDH, 275; and SGOT, 50. The patient was discharged ten days post- operatively and has remained on digoxin because of intermittent episodes of atrial fibrillation during the six months since operation. He has otherwise re- turned to normal activities.

DR. RICHARD ENGELMAN (Chicago, IL): The critical feature of this study is the duration of reperfusion, which was approximately five minutes. Previous work from our laboratory has shown the consequence of repeated inadequate reperfusion to be develop- ment of myocardial edema and ultimate endocardial ischemia.

In recent clinical and experimental work from our institution in which we have attempted to define what constitutes adequate reperfusion after ischemic arrest, we have compared both the six limb leads and the endocardial ECG during reperfusion, when the ventricle is beating, with the same cardiograms prior to ischemic arrest and at the same myocardial temper- ature. When the postischemic cardiogram returns to baseline, reperfusion is deemed adequate. We have termed this duration the recovery time.

In a swine preparation, after 30 minutes of ischemia and 15 minutes of reperfusion, while the lead I1 ECG appeared near baseline, there was still residual is- chemia in the endocardial unipolar electrogram. In a clinical case, ischemia was noted during reperfusion in the endocardial ECG while not grossly obvious in any of the three limb leads recorded at the same time.

In our first 27 patients with coronary artery disease, the mean recovery time was 52.5% of the preceding mean ischemic arrest duration. This means that 15 minutes of ischemic arrest in patients with coronary disease required an average of 7.5 minutes for adequate reperfusion. The endocardial ECG recovery time was longer than limb lead recovery time in 33% of the patients, equal in 38%' and shorter in 29%. We concluded that for determination of optimal reperfu- sion based on the ECG, both limb lead and endocar- dial ECGs are required.

I would ask the authors, first, if they believe poten- tial residual ischemia, and therefore the untoward effects of reperfusion, could have contributed to the results. Second, might the presence of continuous

fibrillation during reperfusion, which was a feature of this study, have contributed to intraoperative infarc- tion?

DR. BENSON B . ROE (San Francisco, CA): Dr. Koster and his group have again demonstrated the clinical and logical efficacy of prolonged ischemia under proper myocardial protection for prolonged periods. For the past three years we have been proponents of a single coronary washout with isosmolar, balanced electrolyte-glucose solution to produce hypothermic afibrillatory arrest with capillary perfusion.

In 204 patients who had periods of ischemia during a single perfusion, the majority defibrillated spon- taneously and only a few required inotropic support; neither result correlates with duration of ischemia. All patients were removed from bypass without diffi- culty, and only 1 patient with very poor myocardial contractility required balloon pumping for 24 hours. The longest ischemia period was 208 minutes, and 8 patients had more than two hours of ischemia without sequelae. This modality is effective for long periods and can perhaps be augmented by improved so- lutions and supplementary surface cooling.

I endorse this study and predict that coronary per- fusion with intermittent cross-clamping will soon disappear from our clinical experience.

DR. A. SCHACHNER (New York, NY): This important study actually represents a retrospective analysis.

In the Buffalo General Hospital we have conducted a prospective study of 10 patients in whom the follow- ing variables were measured: preoperative and se- quential postoperative cardiac dynamics, simultane- ous serial coronary sinus and mixed venous samples for CPK isoenzymes and lactate, sequential ECG re- cording, the need for postoperative inotropic support, and prebypass and postoperative reperfusion core biopsies of the left ventricle for electron microscopy. The average aortic occlusion time was 82% minutes, ranging from 38 to 122 minutes of aortic cross- clamping. The average number of grafts was 3.6 per patient.

Hypothermic cardiac arrest was achieved by a method described by us. The aorta is cross-clamped while a cold (7" to 10°C) perfusate is pumped into the left ventricular cavity through a specially designed double-armed catheter at the rate of 250 to 300 ml per minute. The heart generates the power to perfuse and wash out its own coronary circulation, arrests after 2 to 3 minutes of perfusion, and renders an excellent operative field (flaccid and dry) for distal coronary artery anastomosis. The myocardium is selectively cooled to temperatures between 15" and 18°C. The CPK-MB levels and lactate production were very low in this group of patients (measured in both coronary sinus and mixed venous blood). Electron microscopy revealed no ultrastructural damage.

In conclusion, this method gives a safe period of

336 The Annals of Thoracic Surgery Vol 24 No 4 October 1977

myocardial protection even when the period of cross-clamping is extended beyond two hours. Total CPK values are extremely misleading in a surgical patient, but when based on the dynamics of CPK-MB appearance and lactate production, multiple sequen- tial blood sampling, especially in the immediate post- operative period, may be of substantial importance for the correct diagnosis of an ischemic insult.

DR. KOSTER: We concur and are familiar with Dr. En- gelman’s work. In the strictest interpretation of the data we pr’esented, we cannot state which technique is superior. However, in recognizing the potential deleterious effects of inadequate perfusion and the

fact that continuous ventricular fibrillation in an is- chemic heart theoretically can be bad, we can say that we, like Dr. Grehl, are clinically inclined to use local cardiac hypothermia now.

We have been interested in Dr. Roe’s cold washout work. We believe that, in essence, we are using the same effective modality, that is, profound cardiac hypothermia.

In reply to Dr. Schachner, we are currently using CPK-MB and myocardial scanning to sensitively as- sess myocardial injury. But again, I would emphasize that I think the relationship of perioperative CPK-MB elevations per se and permanent myocardial func- tional damage is as yet not totally worked out.

Notice from the American Board of Thoracic Surgery

The 1977 annual certifying examination of the Please address all communications to the American Board of Thoracic Surgery (written American Board of Thoracic Surgery, 14624 E and oral) will be held in Chicago in March, 1978. Seven Mile Rd, Detroit, MI Final datle for filing application was August 1, 1977.

48205.