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Cold hyperkalemic cardiac arrest versus intermittent aortic cross-clamping and topical hypothermia for coronary bypass surgery
Cold hyperkalemic cardiac arrest versus intermittent aortic cross-clamping and topical hypothermia for coronary bypass surgery Two hundred consecutive cases of aorta-coronary bypass operations were studied retrospectively to compare two methods of myocardial preservation. Patients with preoperative low cardiac output states, preoperative ventricular arrhythmias requiring treatment, and those who required concomitant additional procedures were excluded. Group I comprised the last 100 cases in which intermittent aortic cross-clamping and topical cardiac hypothermia were used for myocardial preservation. Group II comprised the following first 100 cases in which cold hyperkalemic solution (modified Roe's solution) was injected into the aortic root for myocardial preservation. Mean total aortic cross-clamp times were 40 minutes in Group I and 44 minutes in Group II. Mean perfusion times were 2 hours 21 minutes in Group I and 1 hour 56 minutes in Group II (p < 0.01). This difference is due to the longer period of reperfusion required in Group I. In the postoperative period, electrocardiographic evidence of perioperative myocardial infarction developed in 8 percent of Group I as opposed to 2 percent in Group II (p = 0.02). Arrhythmias requiring treatment were seen in 28 percent of Group I and 8 percent of Group II patients (p < 0.001). Mean CPK II was 54 I.U. in Group I and 22 I.U. in Group II (p < 0.0001). CPK II elevation over 100 I.U., thought to be indicative of myocardial infarction, was seen in 15 percent of Group I and 3 percent in Group II (p < 0.01). There were two hospital deaths in Group I and one hospital death in Group II. These results indicate that protecting the myocardium with cold hyperkalemic arrest (with modified Roe's solution) is superior to use of intermittent cross-clamping, and topical cardiac hypothermia for aorta-coronary bypass surgery.
M. Gokuldas Adappa, M.D., Lester B. Jacobson, M.D., Roland Hetzer, M.D., J. Donald Hill, M.D., Barbra Kamm, M.A., and William J. Kerth, M.D., San Francisco, Calif.
Aorta-coronary bypass operations for coronary artery disease have now been done for almost ten years.':" As anticipated, operative results have improved, operative mortality rate has decreased, and the operation has gained wide acceptance and even enthusiasm in many quarters. Even so, the incidence of perioperative myocardial infarction is disconcertingly high for placid acceptance." One of the major reasons for this high incidence is inadequate myocardial protection. From the Department of Cardiovascular Surgery, Pacific Medical Center, Institutes of Medical Sciences, Heart Research Institute, San Francisco, Calif. 94115. Address for reprints: William J. Kerth, M.D., Pacific Medical Center, P.O. Box 7999, San Francisco, Calif. 94120. Read at the Third Annual Meeting of The Samson Thoracic Surgical Society, Colorado Springs, Colorado, June 4-7, 1977.
0022-5223/78/0275-0171$00.80/0 © 1978 The C. V. Mosby Co.
Despite two decades of experience with open-heart surgery there is no known or proved method to protect the myocardium entirely against the detrimental effects of ischemia during surgery. Interruption of coronary circulation greatly facilitates many of the open-heart procedures and is definitely helpful in achieving good distal anastomoses in coronary bypass surgery. Miller and associates," in their excellent national survey of techniques used in coronary artery surgery, showed that the vast majority of these operations are performed with interruption of coronary circulation. Research workers and clinicians have been trying to achieve better myocardial protection during ischemia by cooling the myocardium, using cardioplegia to conserve the high-energy phosphates, and preventing platelet aggregates from jeopardizing the microcirculation in the postischemic period. 171
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Table I. Cardioplegic solution used Components
Five percent dextrose/water Potassium chloride Sodium chloride Magnesium sulfate Sodium bicarbonate Solu-Medrol pH Osmolality
1-------Value
1,000 C.c. 20 mEg. 27 mEg. 3 mEg. 2.4 mEg. 250 mg. 7.4 332
Elective normothermic ischemia, which was used for a short period of time, was significantly damaging to the myocardium." Coronary cannulation and perfusion in valvular surgery provides limited myocardial protection in a fibrillating heart?: 8 and is technically troublesome" and hazardous on occasion. to Griepp and colleagues!' showed that topical hypothermia and intermittent cross-clamping are better tolerated than is perfusion of a fibrillating heart during coronary surgery. Sapsford and associates, 12 in discussing aortic valve surgery, compared mild hypothermia with coronary perfusion in a beating heart to topical cold ischemic arrest alone and found little difference up to 68 minutes. However, Stiles and co-workers" have shown that topical hypothermia is not a reliable method of cooling the myocardium. Various pharmacologic agents have been used to protect the myocardium, such as high-energy solutions'": pretreatment with propranolol, nitroglycerine or mannitol." Kirsch!" used procaine and magnesium aspartate, and Bretschneider'? advocated sodium and calcium depletion with procaine for cardioplegia and demonstrated higher myocardial survival rates after ischemia. Melrose." was the first to try using potassium to achieve cardioplegia, but this method fell into disrepute because hypothermia was not combined with cardioplegia and potassium was used as citrate in a very high concentration. Gay 19 in experimental studies and Benson Roe 20 clinically have used potassium-containing solutions for cardioplegia and have demonstrated good results when this type of cardioplegia is combined with hypothermia. Steroids have been proposed to stabilize the lysosomal membrane and prevent disruption during ischemia. 21 Postbypass treatment with dipyridamole has been suggested'f to prevent platelet aggregates forming during ischemia and causing microembolization. Since April, 1976, we have been using a cardioplegic solution which is a modification of the solution described by Benson Roe one year ago at the meeting of The Samson Thoracic Surgical Society. We add 250
mg. of methylprednisolone per liter and use sodium bicarbonate instead of trimethamine (Table I). We have now compared the results of these cases with those obtained prior to April, 1976, when intermittent crossclamping and topical hypothermia were used.
Patients Two hundred consecutive cases of aorta-coronary bypass surgery were studied. These included the last 100 consecutive patients in whom intermittent aortic cross-clamping was used and the following first 100 consecutive patients in whom modified Roe's solution was used for cardioplegia. Patients with preoperative low output cardiac states requiring treatment, preoperative ventricular arrhythmias requiring treatment, and those who had concomitant procedures such as a valve replacement or resection of a ventricular aneurysm were excluded. Patients who had reoperations for coronary bypass or who had preinfarction angina were included.
Methodology In the 100 consecutive cases that form Group I, in which the operations were done with intermittent aortic cross-clamping from June of 1975 to April of 1976, cardiopulmonary bypass was initiated with a single aortic cannula and either a single right atrial cannula or two caval cannulas. The blood temperature was brought down to between 28 and 30° C. The left ventricle was vented either through the apex of the left ventricle or through the left atrium. The heart was cooled topically by cold Ringer's lactate solution and later cold normal saline, which was converted to slush whenever possible before application to the pericardial sac. The aorta was then cross-clamped and a distal anastomosis was done. The aortic clamp was then released and the proximal anastomosis performed with a partial occlusion clamp. The heart was defibrillated during the latter part of this anastomosis if it had, not I spontaneously defibrillated. A similar procedure was repeated depending upon the number of vessels to be bypassed. Generally, for three vessels the order of bypass grafting was the circumflex, the left anterior descending, and the right coronary artery. In the second consecutive series, beginning in April of 1976, which formed Group II of this experience, cardiopulmonary bypass was initiated in a similar manner and the blood temperature cooled to 28° C as described. The left ventricle was vented, again either through the atrium or ventricle. The site of distal bypass was identified on the circumflex and anterior descending vessels before the cardioplegic solution was
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used, because it may be difficult to identify and dissect out the vessels once the cardioplegic solution has been introduced. The ascending aorta was then crossclamped and the aortic root perfused with the cardioplegic solution with a temperature of 6 to 7° C. through a No. 13 needle or a No. 14 gauge Teflon cannula. The pressure in the aortic root was generally around 80 mm. Hg. The solution was perfused until the electrocardiogram demonstrated no electrical activity and the heart was uniformly cold. When the heart was cooled by this method, the temperature within the myocardium was usually around 15° C. The amount of cardioplegic solution used varied from 600 to 850 c.c. In general, all distal anastomoses were done with a single aortic cross-clamp, except when the cross-clamp period exceeded 45 minutes or when the heart showed return of electrical activity. In these cases, the heart was reperfused by injecting cardioplegic solution into the aortic root. After the distal anastomoses were completed, the proximal anastomoses were done with a partial occlusion clamp on the ascending aorta. The patients were rewarmed during the performance of the proximal anastomosis. The patients were analyzed with respect to age, sex, preoperative left ventricular end-diastolic pressure, number of vessels bypassed, the period of aortic cross-clamping, and the period of perfusion. The postoperative electrocardiographic changes were reviewed for evidence of myocardial infarction or arrhythmias or both. An independent cardiologist rereviewed all electrocardiograms without knowledge of the individual patient or other results. These electrocardiographic changes plus evidence of low cardiac output and elevation of creatine phosphokinase (CPK II) fraction in the first 3 consecutive postoperative days were the major parameters used for comparison of these two techniques of myocardial preservation in this study. Results Patient age, sex, number of vessels bypassed, and preoperative left ventricular end-diastolic pressures were comparable in the two groups (Tables II to IV). Mean total aortic cross-clamp time was 40 minutes in Group I and 44 minutes in Group II (Table V). The somewhat increased aortic cross-clamp time, which is not statistically significant, was probably due to the 3 to 5 minute period required for infusion of the cardioplegic solution. The mean perfusion times of 2 hours 21 minutes in Group I and I hour 56 minutes in Group II were significantly different (p < 0.01) (Table V). The shorter
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Table II. Age and sex
I
Age (yr.) Range Mean Sex Male Female
Group I
Group II
37-75 56
32-77 56
87 13
80 20
Table III. No. of vessels bypassed Vessel
I
One Two Three Four
Group I
, - -Group - -II ---
37
21 54
40
20 3
23 2
Table IV Mean LVEDP* 20
Group I Group II
19
"Left ventricular end-diastolic pressure.
Table V
Clamp time Mean Longest Mean perfusion time* *p
Group I
Group II
40 min. I hr., 23 min. 2 hr., 21 min.
I hr., 20 min. I hr., 56 min.
44 min.
< 0.01.
perfusion time in Group II patients is believed to be due to better protection of the myocardium and, therefore, a faster return to an acceptable electrocardiogram before termination of the cardiopulmonary bypass. In Group II patients the myocardium generally defibrillated more easily or spontaneously and took up the load faster, so that the reperfusion time was reduced. In the postoperative electrocardiograms, 8 percent of Group I patients exhibited new significant Q waves as opposed to 2 percent in Group II. This difference is statistically significant to p = 0.02. Postoperative arrhythmias requiring treatment were seen in 28 percent of Group I patients as opposed to 8 percent of Group II patients (p < 0.001). CPK II fraction was a mean of 54 I. U. in Group I as opposed to 22 I. U. in Group II patients (p < 0.0001). CPK II was elevated above 80 I. U. in 22 percent of Group I patients as opposed to 5
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Table VI. CPK II Group /
Group II
p Value
Mean LU.
54
22
0.0001
>80 LU. >100 LU.
22 15
5 3
0.001 0.01
Table VII. Patients with LBBB*
CPKII(LU.) Mean (LU.)
Group/(N = 4)
GroupIl(N = 3)
20,28,59,67 43
29,31,66 45
"Left bundle branch block.
percent of Group II patients (p < 0.001). CPK elevation over 100 J. U., thought to be indicative of myocardial infarction, was seen in 15 percent of Group I patients as compared to 3 percent in Group II patients (p < 0.01) (Table VI). One of these patients in Group II had a normal CPK II level in the first 2 postoperative days, but on the third postoperative day a rise in CPK II and evidence of infarction in the electrocardiogram suddenly developed. This was probably due to occlusion of a graft, although this patient was not restudied. Low cardiac output requiring treatment was seen in 8 percent of Group I patients and 4 percent of Group II patients. Left bundle branch block was seen in an additional 4 percent of Group I patients and 3 percent of Group II patients. In general, the CPK II level in the group of patients with left bundle branch block was surprisingly low, averaging 44 J.U., with a maximum of 67 J.U. (Table VII). There were two hospital deaths in Group I patients. One patient had an intraoperative myocardial infarction and multiple pulmonary emboli and died on the fifth postoperative day largely because of the pulmonary emboli. A second patient with a 95 percent lesion of the left main coronary artery, severe four vessel disease, and a large, poorly functioning left ventricle with an apical aneurysm received a double coronary bypass but died in the operating room, unable to be weaned from cardiopulmonary bypass despite use of the intraaortic balloon. There was only one death in the Group II series. This patient died on the fifth postoperative day of mediastinal bleeding, having been given anticoagulants for pulmonary emboli. There was no evidence of intraoperative myocardial infarction in this patient. Discussion
Intraoperative and perioperative infarction are known to occur in coronary artery surgery and are more
frequent in aortic valve surgery. The reported incidence is 5 to 20 percent.v 23 and is higher in isolated reports. The major factors influencing the incidence are (1) hypotension and inadequate myocardial perfusion during the prebypass stage;" (2) damage to the coronary arteries, kinking of the grafts;" or damage to the myocardium owing to technical reasons, and (3) inadequate myocardial protection. The first two factors have been overcome to a large extent by use of intra-aortic balloon pumping and better anesthetic and operative techniques. One of the major remaining areas for improvement is in myocardial preservation. The electrocardiogram has been used as an indicator of infarction but has its own limitations, especially in postoperati ve patients. 26 It recently has been suggested that CPK II fraction is a good indicator of myocardial damage due to any cause. CPK II in our hospital is determined by an electrophoretic method. 27 We and others feel that a CPK II level over 100 J. U. is a definite indication of myocardial infarction." The fact that the incidence of myocardial infarction as evidenced by CPK II over 100 J. U. is higher than that indicated by a new Q wave in the electrocardiogram is, we feel, due to disseminated myocardial damage in a few of the cases. The current method used to protect the myocardium enables us (1) to achieve prompt and homogenous cooling of the myocardium, (2) to achieve cardiac standstill in a very short period and thus conserve high-energy phosphates, and (3) to eliminate the cellular elements from the coronary arterial tree and thus protect the microcirculation from platelet aggregation and sludging. The potassium, magnesium, and low sodium act as cardioplegics, sodium bicarbonate acts as a buffer, and methylprednisolone helps in stabilizing the membrane. Even though we have analyzed only the results of coronary artery surgery in two comparable groups, we use the same method in all forms of surgery in which coronary circulation is interrupted. So far we have managed more than 350 cases by this method, and the longest ischemic period has been 145 minutes in a case of double valve replacement. We have found the method to be extremely satisfactory. CPK II fraction, which we believe is a better quantitative parameter for estimating myocardial damage, has been reduced to 25 percent of that seen in Group J. The incidence of perioperative infarctions and troublesome postoperative arrhythmias has been a source of concern to us and to others. Indeed, a recent review! on unstable angina states that the "surgical management of unstable angina cannot be justified from the basis of prevention of myocardial infarction because of the high incidence of perioperative infarction despite a low
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mortality. " We believe that the incidence of perioperative infarction can be lowered to an acceptable level by adequately preserving the myocardium and that troublesome postoperative arrhythmias can be minimized. REFERENCES Favaloro RG: Saphenous vein graft in the surgical treatment of coronary artery disease. Operative technique. J THORAC CARDIOVASC SURG 58: 178-185, 1969 2 Kerth WJ: Aortocoronary bypass grafts. J THORAC CARDIOVASC SURG 57:487-492, 1969 3 Johnson WD, Lepley D Jr: An agressive surgical approach to coronary disease. J THORAC CARDIOVASC SURG 59:128-138, 1970 4 Hultgren HN, Pfeifer JF, Angell WW, et al: Unstable angina. Comparison of medical and surgical management. Am J Cardiol 39:735-740, 1977 5 Miller DW Jr, Hessel EA II, Wintersheid LC, Merendino KA, Dillard DH: Current practice of coronary artery bypass surgery. Results of a national survey. J THoRAc CARDIOVASC SURG 73:75-83, 1977 6 MacGregor DC, Wilson GJ, Tanaka S, Holness DE, Lixfeld W, Silver MD, Rubis LJ, Goldstein W, Gunstensen J: Ischemic contractions of the left ventricle. Production and prevention. J THORAC CARDIOVASC SURG 70:945954, 1975 7 Hottenrott CE, Towers B, Kurkji HJ, Maloney JV, Buckberg G: The hazard of ventricular fibrillation in hypertrophied ventricles during cardiopulmonary bypass. J THORAC CARDIOVASC SURG 66:742-753, 1973 8 Buckberg GD, Hottenrott CE: Ventricular fibrillation. Its effect on myocardial flow, distribution and performance. Ann Thorac Surg 76:20, 1975 9 Robicsek FT, Daugherty HK, Mullen DC: Myocardial protection during open heart surgery. Coronary perfusion vs. topical cardiac hypothermia. Ann Thorac Surg 10:340, 1970 10 Fishman NH, Youker JE, Roe BB: Mechanical injury to the coronary arteries during operative cannulation. Am Heart J 75:26-33, 1968 II Griepp RB, Stinson EB: Oyer PE, Copeland JG, Shumway NE: The superiority of aortic cross-clamping with profound local hypothermia for myocardial protection during aorta-coronary bypass grafting. J THORAC CARDIOVASC SURG 70:995, 1975 12 Sapsford RN, Blackstone EH: Kirklin JW et al: Coronary perfusion vs. cold ischaemic arrest during aortic valve surgery. A randomized study. Circulation 49: 1190, 1976 13 Stiles QR, Hughes RK, Lindesmith GG: Effectiveness of topical cardiac hypothermia. J THoRAc CARDIOVASC SURG 73:176-180, 1977 14 Levitsky S: Protection of myocardium with high energy solutions. Ann Thorac Surg 20:86, 1975 15 Hickey PA: Prevention of intraoperative myocardial injury by pretreatment with pharmacological agents. Ann Thorac Surg 20:101, 1975
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16 Kirsch U, Rodewald G, Kalmar P: Induced ischemic arrest. Clinical experience with cardioplegia in open-heart surgery. J THORAC CARDIOVASC SURG 63:121, 1972 17 Bretschneider HJ: Ueberlebenszeit und Wiederbelebungszeit des Herzens bei Normo und Hypothermie. Verh Dtsch Ges Kreislaufforsch 30: 11, 1964 18 Melrose DG, Dryer B, Bentall J: Elective cardiac arrest. Preliminary communication. Lancet 2:21, 1955 19 Gay WA: Potassium-induced cardioplegia. Ann Thorac Surg 20:95-100, 1975 20 Roe BB, Hutchinson JC, Fishman NH, Ullyot OJ, Smith DL: Myocardial protection with cold, ischemic, potassium-induced cardioplegia. J THoRAc CARDIOVASC SURG 73:366-374, 1977 21 Busuttil RW, George WJ, Hewitt RL: Protection effect of methylprednisolone on the heart during ischemic arrest. J THORAC CARDIOVASC SURG 70:955-965, 1975 22 Feinberg J, Levitsky S: Post bypass treatment. Ann Thorac Surg 20:106, 1975 23 Ullyot OJ, Wisnesky J, Sullivan RW, Gertz EW, Ryan C: The impact of coronary artery bypass on late myocardial infarction. J THORAC CARDIOVASC SURG 73:165-175, 1977 24 Oldham HN Jr, Roe CR, Young WG Jr, Dixon SH Jr: Intraoperative detection of myocardial damage during coronary artery surgery by creatinine phosphokinase isoenzyme analysis. Surgery 74:917-925, 1973 25 Hutchinson GM, Bulkley BH: Mechanisms of occlusion of saphenous vein-coronary artery "jump" grafts. J THORAC CARDIOVASC SURG 73:660-667, 1977 26 Schrank JP, Slabaugh TK, Beckwith JR: The incidence and clinical significance of ECG- VCG changes of myocardial infarction following aortocoronary saphenous vein bypass surgery. Am Heart J 87:46-54 1974 27 Elenitch, FR: Fluorometric techniques in clinical chemistry. Boston, 1973, Little, Brown & Company 28 Ray JF, Tewksbury DA, Meyer WO, et al: Can the frequency of myocardial infarction be reduced during coronary artery operation? Ann Thorac Surg 23: 16, 1977
Discussion DR. QUENTIN R. STILES Los Angeles, Calif.
The topic of myocardial protection is, in my opinion, the most important aspect of cardiac surgery today. Occasionally, patients undergoing myocardial revascularization fail to survive because of low cardiac output following termination of cardiopulmonary bypass. Some survive only with the help of an intra-aortic balloon assist. These cases are very infrequent, but more common is the need for inotropic drugs postoperatively. This is circumstantial evidence that the coronary bypass operation sometimes produces the very cardiac injury which it was designed to prevent. Even though intraoperative cardiac injury may seem rare, we must examine these cases very carefully and attempt to minimize them. The authors have shown that their method of myocardial
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176 Adappa et al,
protection using cardioplegic, hypothermic arrest is superior to ischemic arrest with extemal topical cooling. Their data are very similar to ours, and we have been using a similar method of cold cardioplegic arrest for about 2 years with some 500 cases. More reports such as this are needed, because there remain pockets of resistance where groups are still using ischemic arrest, or even ventricular fibrillation, to achieve the necessary operative conditions for coronary surgery. My guess is that many cardiac surgeons do not know their incidence of intraoperative or iatrogenic myocardial infarction. In our series we are not sure of its incidence, not because we do not look for evidence of myocardial injury postoperatively, but because the definition of anatomic injury is so vague and uncertain. The time-honored diagnostic tool, the electrocardiogram, in my opinion, is of highly questionable value in the postoperative patient. On several occasions in our series, loss of R waves or new Q waves have been noted, only to be reversed in the electrocardiogram taken a day or two later. These changes may be due to shifts in position of the heart or electrodes because of the sternotomy, atelectasis, shallow breathing, bandages, or other reasons. Intraoperative myocardial injury tends to be subendocardial, whereas conventional myocardial infarctions more often are transmural, adding further complexities to the electrocardiographic interpretation of a perioperative myocardial infarction. The surgeon's problem is in interpreting the electrocardiographic interpretation. The CPK fractionation method does seem to give a reasonably reliable index of myocardial injury. Perhaps a word of explanation about this test might be of help to some. Total CPK is elevated following any operation in which muscle tissue is injured. In our recent experience, total CPK averages 575 units with a range from 100 to 2,000 units following coronary surgery and bears no relation to myocardial injury. More specific information can be obtained by fractionating the CPK analysis into three groups. The MB fraction, or CPK II, is a specific test to report myocardial damage, and this can be done in one of two ways. The quantitative column technique reports the MB fraction directly in units, but it is a time-consuming and costly procedure best suited to research projects. The electrophoretic method reports the myocardial fraction as a percentage of the total CPK value. About 3 percent, or 10 units, is the minimal detectable level. Among 50 consecutive patients whom we treated by coronary bypass, five had some detectable rise in CPK II, and ofthese, two had values above 100 units. This would be a 4 percent incidence of perioperative myocardial infarction by the authors' criteria. In the other three patients with detectable CPK II, the value averaged 55 units. I suppose this should be classified as an additional 6 percent incidence of possible or minor myocardial damage. In only two of these five patients, one with 143 units of CPK II and the other with 43 units, was there electrocardiographic confirmation of myocardial injury, and in none of them would a perioperative infarct have been suspected on purely clinical grounds. We were not taking CPK II tests routinely prior to the initiation of our use of the cardioplegic solution 2 years ago,
so I cannot give a comparison as the authors did. From a clinical view, however, it is evident that our myocardial protection method has resulted in significant improvement. Previously, Isuprel or dopamine was frequently needed in the immediate postoperative period; now they are rarely used. The low output syndrome is rare. Postoperatively, the balloon pump is almost never used unless the patient needed it preoperatively. We all, in our group, are so confident of this method that we use it for nearly all patients when cardiopulmonary bypass is used. This includes infants and babies. Our principles of myocardial protection for patients undergoing coronary surgery are as follows: I. Cool the heart uniformly by total body cooling to 25° C. before aortic cross-clamping. Cool the myocardium further by an aortic root infusion after clamping. 2. Obtain quick cardiac arrest after cross-clamping by means of a cold cardioplegic solution. The solution we use has 20 mEq. of K+ and I Gm. of procaine hydrochloride per liter at 10° C., and it is buffered to a pH of 7.8. 3. Continue a slow infusion of this solution during the ischemic period. 4. The upper limits of tolerance for the duration of aortic cross-clamping are not known, but we try not to exceed I hour. We have gone 90 minutes with no apparent myocardial damage. 5. Do not release the clamp intermittently, as this probably will increase the total ischemic period and may be more harmful than a single ischemic period. 6. Release the aortic clamp slowly with the pump flow turned down to prevent a high pressure surge into the coronary arteries. 7. Give an adequate period of recovery with a vented, nonworking heart after coronary perfusion has been reinstituted. I congratulate the authors for their timely study. I am in full agreement with their results. DR. BENSON ROE San Francisco, Calif.
As a long-time, enthusiastic proponent of the technique which Dr. Adappa's group has studied, I, too, am delighted with their findings. In the last 31;2 years, since we began the routine use of cold potassium-induced cardioplegia, there have been about 130 papers in the United States literature alone on the subject of myocardial preservation. Most of these papers substantiate the protection afforded by hypothermia, and many of them allude to the theoretical and laboratory benefits of the adjuncts. Potassium has both technical and theoretical benefit, but there is no firm clinical evidence that this or any of the several other proposed adjuncts significantly add to myocardial protection. Regrettably, our clinical convictions prevent us from conducting appropriate randomized studies to assess these modalities. Scores of technical variables in cardiac surgery simply do not remain constant in a series which is evaluated subsequent to the control group. One item of particular concern to me is the effect of un-
Volume 75 Number 2 February, 1978
identifiable air emboli to the coronaries. We all exercise elaborate care to evacuate air, but inevitably some air remains after any cardiac opening despite elaborate measures to evacuate it. Doppler studies have demonstrated that fact on several occasions. Coronary surgery is not open-heart surgery, so why open the heart unnecessarily for left ventricular venting? One of the fringe benefits of the aortic root injection technique is the large needle hole which allows for left-sided decompression during the aortic cross-clamp period. Dr. Adappa and his colleagues have substantiated the clinical efficacy of homogeneous cooling versus the less consistent surface diffusion cooling suggested by Shumway's group. Although I share their belief in the benefits of potassium and steroids, these effects remain to be proved. DR. DONALD W. MILLER Seattle, Wash.
I am afraid my comments will support those pockets of resistance that Dr. Stiles mentioned. Richard Anderson and I recently conducted a study similar to the one reported by Dr. Adappa, and we compared two techniques of myocardial protection. Concurrently, we operated upon 50 consecutive patients who were similar by a number of clinical variables. One of us used mild systemic hypothermia, then a bypass, cold potassium/induced cardioplegia, and ischemic arrest intervals ranging from 10 to 36 minutes with a mean of 17 minutes. The other used systemic hypothermia only, no vents, and intermittent ischemic arrest with mean cross-clamp times of 12.8 minutes. We measured the CPK II izoenzyme, using a quantitative assay as Dr. Stiles distinguished. We measured the value serially six times during the hospitalization and used a modification of the column method which allows for rapid separation. The only significant difference was that the average ischemic arrest intervals in the group having cold potassiuminduced cardioplegia were somewhat higher. There was no difference in hospital deaths, although one occurred in the first group. The incidence of pathological Q waves was identical in the two groups, and the peak postoperative CPK II or MB CPK isoenzyme in units per liter was not significantly different, ranging from 8 to 261 with a normal in our laboratory of I to 6 units per liter. The other interesting aspect was that the peak value of the MB CPK isoenzyme occurred immediately after surgery at 0 hours in over 80 percent of the patients. I would like to ask Dr. Adappa when his CPK II values were measured after surgery. Correlating the peak postoperative value with the total duration of ischemic arrest for both groups in all patients, we found that there was really no apparent difference between nonvented ischemic arrest and perfusion hypothermia with the ischemic intervals employed in this study. These data suggest that no other myocardial protection technique in addition to mild systemic hypothermia is neces-
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sary for coronary bypass surgery, so long as distal anastomoses are constructed with ischemic arrest intervals not exceeding 15 to 20 minutes. The use of cold hyperkalemic cardiac arrest and its variance with perfusion hypothermia appear to be beneficial only when periods of ischemic arrest of longer than 20 minutes are employed. DR. ALAN T. MARTY Portland, Ore.
I rise to support the authors' conclusions by reporting a comparison of postbypass cardiac enzymes in two consecutive groups of patients operated upon by Dr. Adel Matar and myself. In the first group, intermittent ventricular fibrillation, ischemic arrest, and interval defibrillation were utilized during performance of the coronary anastasmoses. In the second group, a cardioplegic solution at 4° C. was infused into the aortic root. The number of grafts per patient averaged 3.2 in the fibrillation group versus 3.6 in the cardioplegic group. All 86 patients were core-cooled to 30° C. Two thirds of them had ejection fractions of less than 0.5. All survived. The most striking difference in postoperative enzymes was noted for serum glutamic oxaloacetic transaminose (SOOn. The first postoperative SOOT sample, taken upon arrival in the recovery area, was clearly lower in the cardioplegic group than in the fibrillation group. The second SOOT sample, taken on the first postoperative morning, was again clearly lower in the cardioplegic group. Both the first and second postoperative median SOOT values were 55 in the cardioplegic group (normal range 8 to 40 units). In contrast, the median first and second postoperative SOOT values in the fibrillation group were 100 and 155 respectively. The first and second postoperative median total CPK values were also lower in the cardioplegic group, being 265 and 506 as compared to 433 and 645, respectively, in the fibrillation group. Of interest, we did not find any significant difference between the two groups in regard to the median CPK MB values as determined by the Rao method, which is a quantitative nonelectrophoretic method. However, like the authors, we found that no patient in the cardioplegic group had a first postoperative CPK MB level over 80 I. U. By contrast, there was a 12 percent incidence of CPK MB levels over 80 I. U. in the fibrillation group. We thus believe that cold potassium-induced cardioplegic arrest is a promising method of myocardial protection. DR. LAWRENCE I. BONCHEK Milwaukee, Wis.
I perhaps represent another pocket of resistance, as do Drs. Miller and Anderson, so in complimenting the authors for directing our attention toward the importance of effective intraoperative myocardial preservation, I am also concerned that survival and the absence of gross evidence of infarction do not guarantee the absence of myocardial injury. In the paper presented, the difference in the incidence of low output did not appear to me to be statistically significant.
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Adappa et al.
Thoracic and Cardiovascular Surgery
Unfortunately, we are all familiar with individual patients who do well initially after bypass grafting but who, on late postoperative studies, are found to have impaired left ventricular function despite patent grafts. I believe it would be helpful to have a sensitive means of assessing left ventricular function. On our service, we have been carrying out left ventricular function curves intraoperatively before and after cardiopulmonary bypass to assess our methods of myocardial preservation. I wish to ask the authors if they have information about objective assessment of left ventricular function either intraoperatively or early or late postoperatively. We have demonstrated to our own satisfaction that intermittent ischemic arrest with adequate reperfusion in the beating heart provides good myocardial protection. Since going to Milwaukee, our perioperative infarction rate by electrocardiographic criteria has been 2 percent, and in the last 150 cases the only death has not been related to myocardial preservation. We have not used inotropic agents for the past 8 months on any coronary bypass patient, and we have never used the balloon pump to wean a patient from bypass after coronary surgery because of low cardiac output. I do not resist cardioplegia, and I use it routinely for valve surgery, but I do not think that it needs to be used for coronary bypass surgery. I would also ask the authors what their findings would be if they included rather than excluded patients with preoperative low output or left ventricular aneurysm. It is in this group that subtle damage would be more apparent and more damaging.
DR. A D A P P A (Closing) I thank Dr. Stiles for his kind remarks. We also feel that the electrocardiogram has its own pitfalls, especially in the immediate postoperative periods. CPK II elevation greater than 100 I. U. was seen in 3 percent of patients, but in one of these patients the elevation developed on the third postoperative day. On the first 2 postoperative days the CPK II value was normal. However, on the third day, he developed evidence of electrocardiographic changes, new Q waves, as well as a CPK II value of 270 I. U. We feel this was due to graft occlusion rather than intraoperative infarct. I thank Dr. Benson Roe for his kind remarks. We also use the large needle hole to remove the air, and we also occlude the right coronary artery while releasing the clamp. Dr. Miller, we measured CPK II on the first 3 postoperative days. The first sample may have been taken from 10 to about 16 hours after the operation. Dr. Bonchek, we have not done any left ventricular function studies intraoperatively or later. We excluded the patients who had low output preoperatively, because some of them already had electrocardiographic changes, and it would be difficult to compare such changes postoperatively. Patients requiring resection of a left ventricular aneurysm were also excluded because there were no guidelines as to how the electrocardiogram should look following resection of the aneurysm.
Information for authors Most of the provisions of the Copyright Act of 1976 became effective on January 1, 1978. Therefore, all manuscripts must be accompanied by the following statement, signed by each author: "The undersigned author(s) transfers all copyright ownership of the manuscript entitled (title of article) to The C. V. Mosby Company in the event the work is published. The author(s) warrants that the article is original, is not under consideration by another journal, and has not been previously published." Authors will be consulted, when possible, regarding republication of their material.
M. Gokuldas Adappa, M.D., Lester B. Jacobson, M.D., Roland Hetzer, M.D., J. Donald Hill, M.D., Barbra Kamm, M.A., and William J. Kerth, M.D., San Francisco, Calif.
Aorta-coronary bypass operations for coronary artery disease have now been done for almost ten years.':" As anticipated, operative results have improved, operative mortality rate has decreased, and the operation has gained wide acceptance and even enthusiasm in many quarters. Even so, the incidence of perioperative myocardial infarction is disconcertingly high for placid acceptance." One of the major reasons for this high incidence is inadequate myocardial protection. From the Department of Cardiovascular Surgery, Pacific Medical Center, Institutes of Medical Sciences, Heart Research Institute, San Francisco, Calif. 94115. Address for reprints: William J. Kerth, M.D., Pacific Medical Center, P.O. Box 7999, San Francisco, Calif. 94120. Read at the Third Annual Meeting of The Samson Thoracic Surgical Society, Colorado Springs, Colorado, June 4-7, 1977.
0022-5223/78/0275-0171$00.80/0 © 1978 The C. V. Mosby Co.
Despite two decades of experience with open-heart surgery there is no known or proved method to protect the myocardium entirely against the detrimental effects of ischemia during surgery. Interruption of coronary circulation greatly facilitates many of the open-heart procedures and is definitely helpful in achieving good distal anastomoses in coronary bypass surgery. Miller and associates," in their excellent national survey of techniques used in coronary artery surgery, showed that the vast majority of these operations are performed with interruption of coronary circulation. Research workers and clinicians have been trying to achieve better myocardial protection during ischemia by cooling the myocardium, using cardioplegia to conserve the high-energy phosphates, and preventing platelet aggregates from jeopardizing the microcirculation in the postischemic period. 171
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Table I. Cardioplegic solution used Components
Five percent dextrose/water Potassium chloride Sodium chloride Magnesium sulfate Sodium bicarbonate Solu-Medrol pH Osmolality
1-------Value
1,000 C.c. 20 mEg. 27 mEg. 3 mEg. 2.4 mEg. 250 mg. 7.4 332
Elective normothermic ischemia, which was used for a short period of time, was significantly damaging to the myocardium." Coronary cannulation and perfusion in valvular surgery provides limited myocardial protection in a fibrillating heart?: 8 and is technically troublesome" and hazardous on occasion. to Griepp and colleagues!' showed that topical hypothermia and intermittent cross-clamping are better tolerated than is perfusion of a fibrillating heart during coronary surgery. Sapsford and associates, 12 in discussing aortic valve surgery, compared mild hypothermia with coronary perfusion in a beating heart to topical cold ischemic arrest alone and found little difference up to 68 minutes. However, Stiles and co-workers" have shown that topical hypothermia is not a reliable method of cooling the myocardium. Various pharmacologic agents have been used to protect the myocardium, such as high-energy solutions'": pretreatment with propranolol, nitroglycerine or mannitol." Kirsch!" used procaine and magnesium aspartate, and Bretschneider'? advocated sodium and calcium depletion with procaine for cardioplegia and demonstrated higher myocardial survival rates after ischemia. Melrose." was the first to try using potassium to achieve cardioplegia, but this method fell into disrepute because hypothermia was not combined with cardioplegia and potassium was used as citrate in a very high concentration. Gay 19 in experimental studies and Benson Roe 20 clinically have used potassium-containing solutions for cardioplegia and have demonstrated good results when this type of cardioplegia is combined with hypothermia. Steroids have been proposed to stabilize the lysosomal membrane and prevent disruption during ischemia. 21 Postbypass treatment with dipyridamole has been suggested'f to prevent platelet aggregates forming during ischemia and causing microembolization. Since April, 1976, we have been using a cardioplegic solution which is a modification of the solution described by Benson Roe one year ago at the meeting of The Samson Thoracic Surgical Society. We add 250
mg. of methylprednisolone per liter and use sodium bicarbonate instead of trimethamine (Table I). We have now compared the results of these cases with those obtained prior to April, 1976, when intermittent crossclamping and topical hypothermia were used.
Patients Two hundred consecutive cases of aorta-coronary bypass surgery were studied. These included the last 100 consecutive patients in whom intermittent aortic cross-clamping was used and the following first 100 consecutive patients in whom modified Roe's solution was used for cardioplegia. Patients with preoperative low output cardiac states requiring treatment, preoperative ventricular arrhythmias requiring treatment, and those who had concomitant procedures such as a valve replacement or resection of a ventricular aneurysm were excluded. Patients who had reoperations for coronary bypass or who had preinfarction angina were included.
Methodology In the 100 consecutive cases that form Group I, in which the operations were done with intermittent aortic cross-clamping from June of 1975 to April of 1976, cardiopulmonary bypass was initiated with a single aortic cannula and either a single right atrial cannula or two caval cannulas. The blood temperature was brought down to between 28 and 30° C. The left ventricle was vented either through the apex of the left ventricle or through the left atrium. The heart was cooled topically by cold Ringer's lactate solution and later cold normal saline, which was converted to slush whenever possible before application to the pericardial sac. The aorta was then cross-clamped and a distal anastomosis was done. The aortic clamp was then released and the proximal anastomosis performed with a partial occlusion clamp. The heart was defibrillated during the latter part of this anastomosis if it had, not I spontaneously defibrillated. A similar procedure was repeated depending upon the number of vessels to be bypassed. Generally, for three vessels the order of bypass grafting was the circumflex, the left anterior descending, and the right coronary artery. In the second consecutive series, beginning in April of 1976, which formed Group II of this experience, cardiopulmonary bypass was initiated in a similar manner and the blood temperature cooled to 28° C as described. The left ventricle was vented, again either through the atrium or ventricle. The site of distal bypass was identified on the circumflex and anterior descending vessels before the cardioplegic solution was
Volume 75 Number 2 February, 1978
used, because it may be difficult to identify and dissect out the vessels once the cardioplegic solution has been introduced. The ascending aorta was then crossclamped and the aortic root perfused with the cardioplegic solution with a temperature of 6 to 7° C. through a No. 13 needle or a No. 14 gauge Teflon cannula. The pressure in the aortic root was generally around 80 mm. Hg. The solution was perfused until the electrocardiogram demonstrated no electrical activity and the heart was uniformly cold. When the heart was cooled by this method, the temperature within the myocardium was usually around 15° C. The amount of cardioplegic solution used varied from 600 to 850 c.c. In general, all distal anastomoses were done with a single aortic cross-clamp, except when the cross-clamp period exceeded 45 minutes or when the heart showed return of electrical activity. In these cases, the heart was reperfused by injecting cardioplegic solution into the aortic root. After the distal anastomoses were completed, the proximal anastomoses were done with a partial occlusion clamp on the ascending aorta. The patients were rewarmed during the performance of the proximal anastomosis. The patients were analyzed with respect to age, sex, preoperative left ventricular end-diastolic pressure, number of vessels bypassed, the period of aortic cross-clamping, and the period of perfusion. The postoperative electrocardiographic changes were reviewed for evidence of myocardial infarction or arrhythmias or both. An independent cardiologist rereviewed all electrocardiograms without knowledge of the individual patient or other results. These electrocardiographic changes plus evidence of low cardiac output and elevation of creatine phosphokinase (CPK II) fraction in the first 3 consecutive postoperative days were the major parameters used for comparison of these two techniques of myocardial preservation in this study. Results Patient age, sex, number of vessels bypassed, and preoperative left ventricular end-diastolic pressures were comparable in the two groups (Tables II to IV). Mean total aortic cross-clamp time was 40 minutes in Group I and 44 minutes in Group II (Table V). The somewhat increased aortic cross-clamp time, which is not statistically significant, was probably due to the 3 to 5 minute period required for infusion of the cardioplegic solution. The mean perfusion times of 2 hours 21 minutes in Group I and I hour 56 minutes in Group II were significantly different (p < 0.01) (Table V). The shorter
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Table II. Age and sex
I
Age (yr.) Range Mean Sex Male Female
Group I
Group II
37-75 56
32-77 56
87 13
80 20
Table III. No. of vessels bypassed Vessel
I
One Two Three Four
Group I
, - -Group - -II ---
37
21 54
40
20 3
23 2
Table IV Mean LVEDP* 20
Group I Group II
19
"Left ventricular end-diastolic pressure.
Table V
Clamp time Mean Longest Mean perfusion time* *p
Group I
Group II
40 min. I hr., 23 min. 2 hr., 21 min.
I hr., 20 min. I hr., 56 min.
44 min.
< 0.01.
perfusion time in Group II patients is believed to be due to better protection of the myocardium and, therefore, a faster return to an acceptable electrocardiogram before termination of the cardiopulmonary bypass. In Group II patients the myocardium generally defibrillated more easily or spontaneously and took up the load faster, so that the reperfusion time was reduced. In the postoperative electrocardiograms, 8 percent of Group I patients exhibited new significant Q waves as opposed to 2 percent in Group II. This difference is statistically significant to p = 0.02. Postoperative arrhythmias requiring treatment were seen in 28 percent of Group I patients as opposed to 8 percent of Group II patients (p < 0.001). CPK II fraction was a mean of 54 I. U. in Group I as opposed to 22 I. U. in Group II patients (p < 0.0001). CPK II was elevated above 80 I. U. in 22 percent of Group I patients as opposed to 5
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Table VI. CPK II Group /
Group II
p Value
Mean LU.
54
22
0.0001
>80 LU. >100 LU.
22 15
5 3
0.001 0.01
Table VII. Patients with LBBB*
CPKII(LU.) Mean (LU.)
Group/(N = 4)
GroupIl(N = 3)
20,28,59,67 43
29,31,66 45
"Left bundle branch block.
percent of Group II patients (p < 0.001). CPK elevation over 100 J. U., thought to be indicative of myocardial infarction, was seen in 15 percent of Group I patients as compared to 3 percent in Group II patients (p < 0.01) (Table VI). One of these patients in Group II had a normal CPK II level in the first 2 postoperative days, but on the third postoperative day a rise in CPK II and evidence of infarction in the electrocardiogram suddenly developed. This was probably due to occlusion of a graft, although this patient was not restudied. Low cardiac output requiring treatment was seen in 8 percent of Group I patients and 4 percent of Group II patients. Left bundle branch block was seen in an additional 4 percent of Group I patients and 3 percent of Group II patients. In general, the CPK II level in the group of patients with left bundle branch block was surprisingly low, averaging 44 J.U., with a maximum of 67 J.U. (Table VII). There were two hospital deaths in Group I patients. One patient had an intraoperative myocardial infarction and multiple pulmonary emboli and died on the fifth postoperative day largely because of the pulmonary emboli. A second patient with a 95 percent lesion of the left main coronary artery, severe four vessel disease, and a large, poorly functioning left ventricle with an apical aneurysm received a double coronary bypass but died in the operating room, unable to be weaned from cardiopulmonary bypass despite use of the intraaortic balloon. There was only one death in the Group II series. This patient died on the fifth postoperative day of mediastinal bleeding, having been given anticoagulants for pulmonary emboli. There was no evidence of intraoperative myocardial infarction in this patient. Discussion
Intraoperative and perioperative infarction are known to occur in coronary artery surgery and are more
frequent in aortic valve surgery. The reported incidence is 5 to 20 percent.v 23 and is higher in isolated reports. The major factors influencing the incidence are (1) hypotension and inadequate myocardial perfusion during the prebypass stage;" (2) damage to the coronary arteries, kinking of the grafts;" or damage to the myocardium owing to technical reasons, and (3) inadequate myocardial protection. The first two factors have been overcome to a large extent by use of intra-aortic balloon pumping and better anesthetic and operative techniques. One of the major remaining areas for improvement is in myocardial preservation. The electrocardiogram has been used as an indicator of infarction but has its own limitations, especially in postoperati ve patients. 26 It recently has been suggested that CPK II fraction is a good indicator of myocardial damage due to any cause. CPK II in our hospital is determined by an electrophoretic method. 27 We and others feel that a CPK II level over 100 J. U. is a definite indication of myocardial infarction." The fact that the incidence of myocardial infarction as evidenced by CPK II over 100 J. U. is higher than that indicated by a new Q wave in the electrocardiogram is, we feel, due to disseminated myocardial damage in a few of the cases. The current method used to protect the myocardium enables us (1) to achieve prompt and homogenous cooling of the myocardium, (2) to achieve cardiac standstill in a very short period and thus conserve high-energy phosphates, and (3) to eliminate the cellular elements from the coronary arterial tree and thus protect the microcirculation from platelet aggregation and sludging. The potassium, magnesium, and low sodium act as cardioplegics, sodium bicarbonate acts as a buffer, and methylprednisolone helps in stabilizing the membrane. Even though we have analyzed only the results of coronary artery surgery in two comparable groups, we use the same method in all forms of surgery in which coronary circulation is interrupted. So far we have managed more than 350 cases by this method, and the longest ischemic period has been 145 minutes in a case of double valve replacement. We have found the method to be extremely satisfactory. CPK II fraction, which we believe is a better quantitative parameter for estimating myocardial damage, has been reduced to 25 percent of that seen in Group J. The incidence of perioperative infarctions and troublesome postoperative arrhythmias has been a source of concern to us and to others. Indeed, a recent review! on unstable angina states that the "surgical management of unstable angina cannot be justified from the basis of prevention of myocardial infarction because of the high incidence of perioperative infarction despite a low
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Number 2 February, 1978
mortality. " We believe that the incidence of perioperative infarction can be lowered to an acceptable level by adequately preserving the myocardium and that troublesome postoperative arrhythmias can be minimized. REFERENCES Favaloro RG: Saphenous vein graft in the surgical treatment of coronary artery disease. Operative technique. J THORAC CARDIOVASC SURG 58: 178-185, 1969 2 Kerth WJ: Aortocoronary bypass grafts. J THORAC CARDIOVASC SURG 57:487-492, 1969 3 Johnson WD, Lepley D Jr: An agressive surgical approach to coronary disease. J THORAC CARDIOVASC SURG 59:128-138, 1970 4 Hultgren HN, Pfeifer JF, Angell WW, et al: Unstable angina. Comparison of medical and surgical management. Am J Cardiol 39:735-740, 1977 5 Miller DW Jr, Hessel EA II, Wintersheid LC, Merendino KA, Dillard DH: Current practice of coronary artery bypass surgery. Results of a national survey. J THoRAc CARDIOVASC SURG 73:75-83, 1977 6 MacGregor DC, Wilson GJ, Tanaka S, Holness DE, Lixfeld W, Silver MD, Rubis LJ, Goldstein W, Gunstensen J: Ischemic contractions of the left ventricle. Production and prevention. J THORAC CARDIOVASC SURG 70:945954, 1975 7 Hottenrott CE, Towers B, Kurkji HJ, Maloney JV, Buckberg G: The hazard of ventricular fibrillation in hypertrophied ventricles during cardiopulmonary bypass. J THORAC CARDIOVASC SURG 66:742-753, 1973 8 Buckberg GD, Hottenrott CE: Ventricular fibrillation. Its effect on myocardial flow, distribution and performance. Ann Thorac Surg 76:20, 1975 9 Robicsek FT, Daugherty HK, Mullen DC: Myocardial protection during open heart surgery. Coronary perfusion vs. topical cardiac hypothermia. Ann Thorac Surg 10:340, 1970 10 Fishman NH, Youker JE, Roe BB: Mechanical injury to the coronary arteries during operative cannulation. Am Heart J 75:26-33, 1968 II Griepp RB, Stinson EB: Oyer PE, Copeland JG, Shumway NE: The superiority of aortic cross-clamping with profound local hypothermia for myocardial protection during aorta-coronary bypass grafting. J THORAC CARDIOVASC SURG 70:995, 1975 12 Sapsford RN, Blackstone EH: Kirklin JW et al: Coronary perfusion vs. cold ischaemic arrest during aortic valve surgery. A randomized study. Circulation 49: 1190, 1976 13 Stiles QR, Hughes RK, Lindesmith GG: Effectiveness of topical cardiac hypothermia. J THoRAc CARDIOVASC SURG 73:176-180, 1977 14 Levitsky S: Protection of myocardium with high energy solutions. Ann Thorac Surg 20:86, 1975 15 Hickey PA: Prevention of intraoperative myocardial injury by pretreatment with pharmacological agents. Ann Thorac Surg 20:101, 1975
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16 Kirsch U, Rodewald G, Kalmar P: Induced ischemic arrest. Clinical experience with cardioplegia in open-heart surgery. J THORAC CARDIOVASC SURG 63:121, 1972 17 Bretschneider HJ: Ueberlebenszeit und Wiederbelebungszeit des Herzens bei Normo und Hypothermie. Verh Dtsch Ges Kreislaufforsch 30: 11, 1964 18 Melrose DG, Dryer B, Bentall J: Elective cardiac arrest. Preliminary communication. Lancet 2:21, 1955 19 Gay WA: Potassium-induced cardioplegia. Ann Thorac Surg 20:95-100, 1975 20 Roe BB, Hutchinson JC, Fishman NH, Ullyot OJ, Smith DL: Myocardial protection with cold, ischemic, potassium-induced cardioplegia. J THoRAc CARDIOVASC SURG 73:366-374, 1977 21 Busuttil RW, George WJ, Hewitt RL: Protection effect of methylprednisolone on the heart during ischemic arrest. J THORAC CARDIOVASC SURG 70:955-965, 1975 22 Feinberg J, Levitsky S: Post bypass treatment. Ann Thorac Surg 20:106, 1975 23 Ullyot OJ, Wisnesky J, Sullivan RW, Gertz EW, Ryan C: The impact of coronary artery bypass on late myocardial infarction. J THORAC CARDIOVASC SURG 73:165-175, 1977 24 Oldham HN Jr, Roe CR, Young WG Jr, Dixon SH Jr: Intraoperative detection of myocardial damage during coronary artery surgery by creatinine phosphokinase isoenzyme analysis. Surgery 74:917-925, 1973 25 Hutchinson GM, Bulkley BH: Mechanisms of occlusion of saphenous vein-coronary artery "jump" grafts. J THORAC CARDIOVASC SURG 73:660-667, 1977 26 Schrank JP, Slabaugh TK, Beckwith JR: The incidence and clinical significance of ECG- VCG changes of myocardial infarction following aortocoronary saphenous vein bypass surgery. Am Heart J 87:46-54 1974 27 Elenitch, FR: Fluorometric techniques in clinical chemistry. Boston, 1973, Little, Brown & Company 28 Ray JF, Tewksbury DA, Meyer WO, et al: Can the frequency of myocardial infarction be reduced during coronary artery operation? Ann Thorac Surg 23: 16, 1977
Discussion DR. QUENTIN R. STILES Los Angeles, Calif.
The topic of myocardial protection is, in my opinion, the most important aspect of cardiac surgery today. Occasionally, patients undergoing myocardial revascularization fail to survive because of low cardiac output following termination of cardiopulmonary bypass. Some survive only with the help of an intra-aortic balloon assist. These cases are very infrequent, but more common is the need for inotropic drugs postoperatively. This is circumstantial evidence that the coronary bypass operation sometimes produces the very cardiac injury which it was designed to prevent. Even though intraoperative cardiac injury may seem rare, we must examine these cases very carefully and attempt to minimize them. The authors have shown that their method of myocardial
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176 Adappa et al,
protection using cardioplegic, hypothermic arrest is superior to ischemic arrest with extemal topical cooling. Their data are very similar to ours, and we have been using a similar method of cold cardioplegic arrest for about 2 years with some 500 cases. More reports such as this are needed, because there remain pockets of resistance where groups are still using ischemic arrest, or even ventricular fibrillation, to achieve the necessary operative conditions for coronary surgery. My guess is that many cardiac surgeons do not know their incidence of intraoperative or iatrogenic myocardial infarction. In our series we are not sure of its incidence, not because we do not look for evidence of myocardial injury postoperatively, but because the definition of anatomic injury is so vague and uncertain. The time-honored diagnostic tool, the electrocardiogram, in my opinion, is of highly questionable value in the postoperative patient. On several occasions in our series, loss of R waves or new Q waves have been noted, only to be reversed in the electrocardiogram taken a day or two later. These changes may be due to shifts in position of the heart or electrodes because of the sternotomy, atelectasis, shallow breathing, bandages, or other reasons. Intraoperative myocardial injury tends to be subendocardial, whereas conventional myocardial infarctions more often are transmural, adding further complexities to the electrocardiographic interpretation of a perioperative myocardial infarction. The surgeon's problem is in interpreting the electrocardiographic interpretation. The CPK fractionation method does seem to give a reasonably reliable index of myocardial injury. Perhaps a word of explanation about this test might be of help to some. Total CPK is elevated following any operation in which muscle tissue is injured. In our recent experience, total CPK averages 575 units with a range from 100 to 2,000 units following coronary surgery and bears no relation to myocardial injury. More specific information can be obtained by fractionating the CPK analysis into three groups. The MB fraction, or CPK II, is a specific test to report myocardial damage, and this can be done in one of two ways. The quantitative column technique reports the MB fraction directly in units, but it is a time-consuming and costly procedure best suited to research projects. The electrophoretic method reports the myocardial fraction as a percentage of the total CPK value. About 3 percent, or 10 units, is the minimal detectable level. Among 50 consecutive patients whom we treated by coronary bypass, five had some detectable rise in CPK II, and ofthese, two had values above 100 units. This would be a 4 percent incidence of perioperative myocardial infarction by the authors' criteria. In the other three patients with detectable CPK II, the value averaged 55 units. I suppose this should be classified as an additional 6 percent incidence of possible or minor myocardial damage. In only two of these five patients, one with 143 units of CPK II and the other with 43 units, was there electrocardiographic confirmation of myocardial injury, and in none of them would a perioperative infarct have been suspected on purely clinical grounds. We were not taking CPK II tests routinely prior to the initiation of our use of the cardioplegic solution 2 years ago,
so I cannot give a comparison as the authors did. From a clinical view, however, it is evident that our myocardial protection method has resulted in significant improvement. Previously, Isuprel or dopamine was frequently needed in the immediate postoperative period; now they are rarely used. The low output syndrome is rare. Postoperatively, the balloon pump is almost never used unless the patient needed it preoperatively. We all, in our group, are so confident of this method that we use it for nearly all patients when cardiopulmonary bypass is used. This includes infants and babies. Our principles of myocardial protection for patients undergoing coronary surgery are as follows: I. Cool the heart uniformly by total body cooling to 25° C. before aortic cross-clamping. Cool the myocardium further by an aortic root infusion after clamping. 2. Obtain quick cardiac arrest after cross-clamping by means of a cold cardioplegic solution. The solution we use has 20 mEq. of K+ and I Gm. of procaine hydrochloride per liter at 10° C., and it is buffered to a pH of 7.8. 3. Continue a slow infusion of this solution during the ischemic period. 4. The upper limits of tolerance for the duration of aortic cross-clamping are not known, but we try not to exceed I hour. We have gone 90 minutes with no apparent myocardial damage. 5. Do not release the clamp intermittently, as this probably will increase the total ischemic period and may be more harmful than a single ischemic period. 6. Release the aortic clamp slowly with the pump flow turned down to prevent a high pressure surge into the coronary arteries. 7. Give an adequate period of recovery with a vented, nonworking heart after coronary perfusion has been reinstituted. I congratulate the authors for their timely study. I am in full agreement with their results. DR. BENSON ROE San Francisco, Calif.
As a long-time, enthusiastic proponent of the technique which Dr. Adappa's group has studied, I, too, am delighted with their findings. In the last 31;2 years, since we began the routine use of cold potassium-induced cardioplegia, there have been about 130 papers in the United States literature alone on the subject of myocardial preservation. Most of these papers substantiate the protection afforded by hypothermia, and many of them allude to the theoretical and laboratory benefits of the adjuncts. Potassium has both technical and theoretical benefit, but there is no firm clinical evidence that this or any of the several other proposed adjuncts significantly add to myocardial protection. Regrettably, our clinical convictions prevent us from conducting appropriate randomized studies to assess these modalities. Scores of technical variables in cardiac surgery simply do not remain constant in a series which is evaluated subsequent to the control group. One item of particular concern to me is the effect of un-
Volume 75 Number 2 February, 1978
identifiable air emboli to the coronaries. We all exercise elaborate care to evacuate air, but inevitably some air remains after any cardiac opening despite elaborate measures to evacuate it. Doppler studies have demonstrated that fact on several occasions. Coronary surgery is not open-heart surgery, so why open the heart unnecessarily for left ventricular venting? One of the fringe benefits of the aortic root injection technique is the large needle hole which allows for left-sided decompression during the aortic cross-clamp period. Dr. Adappa and his colleagues have substantiated the clinical efficacy of homogeneous cooling versus the less consistent surface diffusion cooling suggested by Shumway's group. Although I share their belief in the benefits of potassium and steroids, these effects remain to be proved. DR. DONALD W. MILLER Seattle, Wash.
I am afraid my comments will support those pockets of resistance that Dr. Stiles mentioned. Richard Anderson and I recently conducted a study similar to the one reported by Dr. Adappa, and we compared two techniques of myocardial protection. Concurrently, we operated upon 50 consecutive patients who were similar by a number of clinical variables. One of us used mild systemic hypothermia, then a bypass, cold potassium/induced cardioplegia, and ischemic arrest intervals ranging from 10 to 36 minutes with a mean of 17 minutes. The other used systemic hypothermia only, no vents, and intermittent ischemic arrest with mean cross-clamp times of 12.8 minutes. We measured the CPK II izoenzyme, using a quantitative assay as Dr. Stiles distinguished. We measured the value serially six times during the hospitalization and used a modification of the column method which allows for rapid separation. The only significant difference was that the average ischemic arrest intervals in the group having cold potassiuminduced cardioplegia were somewhat higher. There was no difference in hospital deaths, although one occurred in the first group. The incidence of pathological Q waves was identical in the two groups, and the peak postoperative CPK II or MB CPK isoenzyme in units per liter was not significantly different, ranging from 8 to 261 with a normal in our laboratory of I to 6 units per liter. The other interesting aspect was that the peak value of the MB CPK isoenzyme occurred immediately after surgery at 0 hours in over 80 percent of the patients. I would like to ask Dr. Adappa when his CPK II values were measured after surgery. Correlating the peak postoperative value with the total duration of ischemic arrest for both groups in all patients, we found that there was really no apparent difference between nonvented ischemic arrest and perfusion hypothermia with the ischemic intervals employed in this study. These data suggest that no other myocardial protection technique in addition to mild systemic hypothermia is neces-
Myocardial preservation
177
sary for coronary bypass surgery, so long as distal anastomoses are constructed with ischemic arrest intervals not exceeding 15 to 20 minutes. The use of cold hyperkalemic cardiac arrest and its variance with perfusion hypothermia appear to be beneficial only when periods of ischemic arrest of longer than 20 minutes are employed. DR. ALAN T. MARTY Portland, Ore.
I rise to support the authors' conclusions by reporting a comparison of postbypass cardiac enzymes in two consecutive groups of patients operated upon by Dr. Adel Matar and myself. In the first group, intermittent ventricular fibrillation, ischemic arrest, and interval defibrillation were utilized during performance of the coronary anastasmoses. In the second group, a cardioplegic solution at 4° C. was infused into the aortic root. The number of grafts per patient averaged 3.2 in the fibrillation group versus 3.6 in the cardioplegic group. All 86 patients were core-cooled to 30° C. Two thirds of them had ejection fractions of less than 0.5. All survived. The most striking difference in postoperative enzymes was noted for serum glutamic oxaloacetic transaminose (SOOn. The first postoperative SOOT sample, taken upon arrival in the recovery area, was clearly lower in the cardioplegic group than in the fibrillation group. The second SOOT sample, taken on the first postoperative morning, was again clearly lower in the cardioplegic group. Both the first and second postoperative median SOOT values were 55 in the cardioplegic group (normal range 8 to 40 units). In contrast, the median first and second postoperative SOOT values in the fibrillation group were 100 and 155 respectively. The first and second postoperative median total CPK values were also lower in the cardioplegic group, being 265 and 506 as compared to 433 and 645, respectively, in the fibrillation group. Of interest, we did not find any significant difference between the two groups in regard to the median CPK MB values as determined by the Rao method, which is a quantitative nonelectrophoretic method. However, like the authors, we found that no patient in the cardioplegic group had a first postoperative CPK MB level over 80 I. U. By contrast, there was a 12 percent incidence of CPK MB levels over 80 I. U. in the fibrillation group. We thus believe that cold potassium-induced cardioplegic arrest is a promising method of myocardial protection. DR. LAWRENCE I. BONCHEK Milwaukee, Wis.
I perhaps represent another pocket of resistance, as do Drs. Miller and Anderson, so in complimenting the authors for directing our attention toward the importance of effective intraoperative myocardial preservation, I am also concerned that survival and the absence of gross evidence of infarction do not guarantee the absence of myocardial injury. In the paper presented, the difference in the incidence of low output did not appear to me to be statistically significant.
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Adappa et al.
Thoracic and Cardiovascular Surgery
Unfortunately, we are all familiar with individual patients who do well initially after bypass grafting but who, on late postoperative studies, are found to have impaired left ventricular function despite patent grafts. I believe it would be helpful to have a sensitive means of assessing left ventricular function. On our service, we have been carrying out left ventricular function curves intraoperatively before and after cardiopulmonary bypass to assess our methods of myocardial preservation. I wish to ask the authors if they have information about objective assessment of left ventricular function either intraoperatively or early or late postoperatively. We have demonstrated to our own satisfaction that intermittent ischemic arrest with adequate reperfusion in the beating heart provides good myocardial protection. Since going to Milwaukee, our perioperative infarction rate by electrocardiographic criteria has been 2 percent, and in the last 150 cases the only death has not been related to myocardial preservation. We have not used inotropic agents for the past 8 months on any coronary bypass patient, and we have never used the balloon pump to wean a patient from bypass after coronary surgery because of low cardiac output. I do not resist cardioplegia, and I use it routinely for valve surgery, but I do not think that it needs to be used for coronary bypass surgery. I would also ask the authors what their findings would be if they included rather than excluded patients with preoperative low output or left ventricular aneurysm. It is in this group that subtle damage would be more apparent and more damaging.
DR. A D A P P A (Closing) I thank Dr. Stiles for his kind remarks. We also feel that the electrocardiogram has its own pitfalls, especially in the immediate postoperative periods. CPK II elevation greater than 100 I. U. was seen in 3 percent of patients, but in one of these patients the elevation developed on the third postoperative day. On the first 2 postoperative days the CPK II value was normal. However, on the third day, he developed evidence of electrocardiographic changes, new Q waves, as well as a CPK II value of 270 I. U. We feel this was due to graft occlusion rather than intraoperative infarct. I thank Dr. Benson Roe for his kind remarks. We also use the large needle hole to remove the air, and we also occlude the right coronary artery while releasing the clamp. Dr. Miller, we measured CPK II on the first 3 postoperative days. The first sample may have been taken from 10 to about 16 hours after the operation. Dr. Bonchek, we have not done any left ventricular function studies intraoperatively or later. We excluded the patients who had low output preoperatively, because some of them already had electrocardiographic changes, and it would be difficult to compare such changes postoperatively. Patients requiring resection of a left ventricular aneurysm were also excluded because there were no guidelines as to how the electrocardiogram should look following resection of the aneurysm.
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