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Intraoperative myocardial protection by cardioplegia in hypothermia
Intraoperative myocardial protection by cardioplegia in hypothermia Clinical findings Following animal experiments, intraoperative protection of the myocardium was used clinically. It consisted of an initial cardiac arrest, according to the method of Kirsch, and subsequent aerobic cardioplegic coronary perfusion in hypothermia lasting 6 to 8 minutes until a myocardial temperature of 20° C. or below was reached. Oxidative metabolism was maintained by the cardioplegic perfusate used. Cardioplegia, stabilizing of membranes, and hypothermia at 20° C. reduce the energy requirements of the myocardium to I to 2 percent of normal. At the onset of the subsequent phase of ischemia, stores of energy-rich phosphate compounds were normal. Under these clinical conditions at 20° C., the tolerance for ischemia lasted for 120 minutes, since t-ATP was reached only at this time. This period of ischemia was long enough for most of the open-heart procedures. Out of 445 patients operated on by means of this myocardial protection method, 10 died, three of them because of technical errors made when this method was still new (overdistension). One death was caused by insufficient myocardial protection. Investigations into postoperative levels of the heart-specific creatine kinase isoenzyme CK-MB revealed no ischemic lesion of the myocardium. The procedure requires strict maintenance of some methodological preconditions, such as keeping the initial ischemic phase as short as possible, limiting the pressure of perfusion to 20 to 30 mm. Hg, controlling myocardial temperature, and preventing overdistension of the paralyzed ventricles. Measured against the rate of postoperative low-output syndrome and the ensuing mortality rate, as well as the number of postoperative infarctions following aorta-eoronary artery bypass operations, hypothermic cardioplegic coronary perfusion with initial cardiac arrest, according to the method of Kirsch, in our experience is superior to hypothermal ischemia, intermittent reperfusion, and coronary perfusion of the beating or fibrillating heart.
N. Bleese, V. Doring, P. Kalmar, H. Pokar, M. -J. Polonius, D. Steiner, and G. Rodewald, Hamburg, West Germany
T his is a report on clinical experience with a method of protecting the myocardium by means of hypothermal cardioplegia. This method has been used in 445 openheart procedures. The aim of intraoperative myocardial protection is to prevent damage to the function and structure of the myocardium. None of the methods employed up till now was fully able to guarantee this; in certain circumFrom the Abteilung fiir Herz- und Gefasschirurgie und experimentelle Kardiologie der Chirurgischen Universitatsklinik, Hamburg-Eppendorf, West Germany. Received for publication April 19, 1977. Accepted for publication July 25, 1977. Address for reprints: Abteilung fiir Herz- und Gef3{3chirurgie und experimentelle Kardiologie der Chirurgischen Universitatsklinik Hamburg-Eppendorf, Martinistr. 52, 2000 Hamburg 20, West Germany. 0022-5223/78/0375-0405$00.90/0
stances, quite apart from the technical problems involved, coronary perfusion of a beating or fibrillating heart can lead to regional myocardial ischemia. The advantage of methods which do not involve coronary perfusion is that one operates on an arrested heart emptied of blood. The disadvantage, however, is that tolerance of ischemia cannot be accurately assessed, since in the usual clinical procedures the energy requirements of the arrested heart are not reduced enough or conditions are not standardized. According to Bretschneider,' the limit of "practical survival time" is reached when the myocardial adenosine triphosphate (ATP) content drops to 70 percent of the normal (called t-ATP). Thereafter the first irreversible metabolic and structural lesions occur, leading to permanently decreased function after reanimation.':" In normothermia t-ATP is reached after only
© 1978 The C. V. Mosby Co.
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Table I. Cardioplegic solution for cardiac arrest induced by injection (Kirsch solution)* lngedient
\----m-M----
Magnesium aspartate Procaine HCI n-Sorbitol
80 II 247
'Cardioplegin, Dr. Franz Kohler KG, 0-6146 Aisbach.
Table II. Cardioplegic solution for coronary perfusion 6% Hydroxyethyl starch' 2 mM Magnesium aspartate 4 mM Procaine HCI 0.5 mM CaCI. 5 mMKCI 25 mM NaHC03 10 mM n-Glucose 200 mM n-Mannitol 250 mg. 6-Methyl prednisolone/per litert 20 mg. Gentamycin/per liter Total Na+ content: 50 mM Osmolarity: 320 mOsmol Colloid osmotic pressure: 46 em. H.O pH: 7.40 Po.: >600 mm. Hg 'Dr. E. Fresenius, 0-6380 Bad Homburg v.d.H. tUrbason, Hoechst AG, 0-6000 Frankfurt/Main 71.
10 minutes of cardiac arrest induced by plain ischemia. Even in deep hypothermia at 15° C. the so-called "practical survival time" -following the QIO rulecould be extended only to 45 minutes in animal experiments. The reason for this unsatisfactory situation is that ischemia-induced cardiac arrest is brought about by the loss of ATP. During the arrest the anaerobic metabolism cannot make up for a further loss of ATP, because the membrane ATPases are not inhibited. 4 Cardiac arrest by plain ischemia is the result of a shortage of energy-rich phosphate compounds in the contractile apparatus. On the other hand, cardiac arrest induced by cardioplegia results in excitation-contraction uncoupling, so that the stores of energy-rich phosphate compounds remain undepleted. Furthermore, cardioplegic solutions (procaine, sodium depletion, magnesium) not only stabilize the membrane potential but also reduce the metabolism during arrest by inhibiting membrane ATPases. Other cardioplegic solutions, (for instance, potassium) induce immediate arrest but cannot sufficiently reduce the ATP-splitting by membrane ATPases during the arrest, since they have no membrane-stabilizing effect. 1, 4, 5 Clinically proved cardioplegic solutions with a membrane-stabilizing effect have been introduced by
Bretschneider! (sodium and calcium depletion, procaine) and by Kirsch and associates. 6, 7 (magnesium aspartate, procaine). The cardioplegic solutions containe procaine, which stabilizes the membranes by inhibiting sodium permeation. In addition, both solutions are free of sodium and calcium, so that action potentials are prevented and excitation-contraction is uncoupled. The high concentration of magnesium in the Kirsch solution enhances these effects, so that a rapid cardiac arrest can be induced. In animal experiments where both these methods were combined with hypothermia, the practical survival time could be considerably prolonged, so that t-ATP at 15° C. was reached only after 250 to 280 minutes.J- 4 Judged by the results of the animal experiments, these cardioplegic solutions combined with deep hypothermia of the heart seem to provide the ideal way of protecting the myocardium during arrest, as this method makes it possible to operate on an arrested, relaxed, and empty heart for a sufficiently long period while still guaranteeing safe reanimation. Under clinical conditions, however, it was impossible to reduce the myocardial temperature evenly enough to 15 to 20° C. while still maintaining the oxidative metabolism with any of the methods used so far. Since the only way to rapidly reduce the temperature of the whole myocardium in the operating room is by perfusion, and not just surface cooling," we developed a method combining initial cardiac arrest induced by Kirsch solution and additional coronary perfusion with a cardioplegic perfusate. This cardioplegic coronary perfusate is itself designed to permanently perfuse the arrested heart. Thereby arrest, metabolic balance, and structure were maintained. In animal experiments hearts treated in this manner had no edema, even after cardioplegic coronary perfusion lasting more than 3 hours, and could be reanimated normally. 9-12 Under clinical conditions it would be feasible to use such a continuous cardioplegic perfusion for the period in which the intracardiac or coronary procedure is performed. Although this is still worth considering, until now we have used-for practical reasons-an initial hypothermic cardioplegic coronary perfusion until a myocardial temperature of 15 to 20° C. has been reached. After that the practical survival time of the arrested human heart under hypothermic cardioplegia is 120 minutes.
Method Composition of cardioplegic solutions. Magnesium aspartate-procaine solution prepared
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according to the method of Kirsch. 7 This solution is used for the initial cardiac arrest. The cardioplegically active compounds are magnesium aspartate and procaine hydrochloride, used in combination with sodium and calcium withdrawal (for composition see Table I). Cardioplegic coronary perfusate. The cardioplegic coronary perfusate is an electrolyte-containing, erythrocyte-free, 6 percent hydroxyethyl starch solution, saturated with carbogen at 4° C. (Table II). The solution has an osmolarity of 320 Mosmol per liter, and the colloid osmotic pressure is about 46 cm.H 20 . At a temperature of 37° C. the solution has a pH of 7.4. The cardioplegically active components are procaine (4 mM) and a sodium content reduced to 50 mM. The solution contains 10 mM glucose as substrate. To improve microcirculation and to stabilize the lysosomes, 250 mg. of 6-methylprednisolone per liter are added to the solution;" To maintain sterility during oxygenation, 20 mg. of gentamicin per liter are added to the perfusate. Preparation of the perfusate. Hydroxyethyl starch, magnesium aspartate, procaine, calcium chloride, potassium chloride, glucose, and mannitol are sterilized together in an aqueous solution. Immediately before use, sodium bicarbonate, 6-methylprednisolone, and gentamicin in aqueous solution are added. To oxygenate the solution, it is bubbled with carbogen (95 percent O2- 5 percent CO 2) through a long metal cannula, with fine-bore holes at the side, in a bath of ice. To oxygenize the perfusate and equilibrate the pH value will take about 30 minutes. The perfusate can then be pumped through a second, large-bore metal cannula into the precooled perfusion system (Fig. 1). Surgical procedure. After connection of the heartlung machine with cannulation of both venae cavae (Fig. 2), and transition to total bypass at a body temperature between 30 and 32° c., both ventricles are drained. This is essential to avoid an overflow of cardioplegic solutions, especially the Kirsch solution, into the pulmonary and systemic circulation, as this could cause disturbances in coagulation due to magnesium; furthermore, this avoids overdistension of the ventricle relaxed by cardioplegia and prevents the blood of the left ventricle from overflowing into the aortic root, thereby washing the cardioplegic solution out of the coronary arteries. The system of tubes leading from the pump to the aortic root must be precooled with isotonic glucose or mannitol solution and/or perfusate before coronary perfusion begins, so that the temperature of the cooled perfusate at the end of the pipe system does not exceed 10° C. This also applies when perfusion is intermittent.
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®
t t
t CD
t
t
Fig. 1. Setupfor the cardioplegic coronary perfusion system, when separate cannulation of the coronary artery ostia is needed. 1, Pumps; 2, Iced solution for precooling of the perfusion lines; 3, Iced cardioplegic perfusate; 4, Icebox; 5, System for oxygenation and drainage of the perfusate; 6, bubble trap; 7, automatic pressure regulation devise (according to Dreissen, The Netherlands); 8, Cannulas for selective coronary perfusion. The ascending aorta is cross-clamped. The Kirsch solution is injected either proximal to the clamp into the aortic root or, following aortotomia (in the case of aortic valve replacement, for instance), with the help of an angiocatheter into the coronary arteries. Normally 100
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SYSTEM for cordioplegic coronary perfusion (Fig. .1)
-
SUCTION
Fig. 2. Sites for cannulation of the "extracorporal circulation system" and the "cardioplegic coronary perfusion system." ECG, Electrocardiogram. R.A., Right atrium. R.V., Right ventricle. L.A., Left atrium. L.V., Left ventricle.
Table III. Initial hypothermic cardioplegic coronary perfusion: flow rates, coronary perfusion time, myocardial temperatures Temperature (0 C) at end of perfusion time
Operative procedure
No.*
Coronary perfusion (m/.lmin.)
Perfusion time (min.)
RV posterior wall
RVanterior wall
LV posterior wall
LV anterior wall
Septum
ACVB: Single Double Triple Aortic val ve replacement Mitral valve replacement Aortic and mitral valve replacement
17 68 67 88 77 30
90 87 83 126 120 liS
± 26 ± 24 ± 22 ± 28
± 44 ± 24
6.8 8.2 8.3 9.4 6.6 8.4
± ± ± ±
1.9 2.9 4.3 2.9 ± 1.6 ± 2.4
19 18 18 18 18 17
± ± ± ± ± ±
3 3 3 3 3 2
18 17 17 18 18 18
± ± ± ± ± ±
3 2 3 3 3 2
17 17 17 17 17 17
± ± ± ± ± ±
3 3 3 3 3 2
18 18 17 17 16 17
± ± ± ± ± ±
3 3 3 3 3 3
18 17 18 17 16 16
± ± ± ± ± ±
2 2 3 3 2 2
'Number of patients examined.
to 150 ml. of the Kirsch solution is enough to bring about cardiac arrest. As soon as cardiac arrest has been induced, hypothermic coronary perfusion is started with our oxygenated cardioplegic solution cooled to +4° C. Hypothermia induced by coronary perfusion is backed up by additional surface cooling of the heart with cooled isotonic glucose or mannitol solution. (To avoid diffusion of sodium ions into the myocardium we use isotonic glucose or mannitol solution instead of Ringer's solution for surface cooling.)
The posterior wall of the heart is insulated from the mediastinum. The pressure in the aortic root is measured continuously during injection and perfusion and should not exceed 50 to 70 mm. Hg during the injection of Kirsch solution. During the cardioplegic coronary perfusion the pressure must be kept between 20 and maximally 30 mm. Hg to avoid myocardial edema." During perfusion via the coronary ostia (for instance, in replacement of an aortic valve) each ostium is perfused with a pressure-regulated pump. During cardioplegic coronary perfusion the temperature in the myocardium
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is measured as different locations with thin-needle thermistors (Tele-Thermometer, Yellow Spring Instrument Co.), i.e., deep in the muscle of the anterior and posterior walls of both ventricles, and also in the septum. Cardioplegic coronary perfusion is usually stopped when temperatures of at least 20° C. have been reached, since under these conditions the tolerable period of ischemia is about 120 minutes, provided surface cooling is continued, so that a constant myocardial temperature is guaranteed. Should the heart warm up again faster then expected during the period of ischemia, or should mechanical activity start, cardioplegic coronary perfusion can be resumed at any stage and carried on either continuously or intermittently. However, in each case we perform a short reperfusion of 3 to 4 minutes after 50 to 60 minutes of cardioplegic arrest, to wash out lactate and blood and to restore cardioplegia. The flow rates and the time needed to lower the temperature of the heart are shown in Table 1lI.
Results Between August, 1975, and June, 1977, we used this method of hypothermic cardioplegic coronary perfusion in 445 patients who underwent open-heart procedures. Operative procedures and hospital deaths are presented in Table IV. Ten patients died (2.2 percent). Causes of death are shown in Table V. A total of 214 patients underwent coronary bypass surgery. In 21 cases a single, in 78 a double, and in 92 a triple, quadruple, or quintuple, aorta-coronary artery vein bypass (ACVB) was carried out. In 23 cases ACVB was combined with aneurysmectomy. In all cases, aortic anastomoses without extracorporal circulation (ECC) were established first. Then cannulas for ECC were positioned in the usual manner. After total bypass had been started, cardiac arrest and hypothermic cardioplegic perfusion were carried out. The cardioplegic perfusion was stopped when a myocardial temperature of at least 20° C. was reached. Then the peripheral anastomoses were made during a single period of cardiac arrest. As Table VI shows, the periods of ischemia differed significantly, depending on the number of peripheral anastomoses and the times needed for weaning off bypass. The values of mean left atrial pressure and of oxygen saturation of mixed venous blood were normal about 18 hours after the operation without the use of any sympathicomimetics. Table VII shows the rate of perioperative infarctions in patients surviving coronary bypass surgery, which is independent of the number of implanted veins and of
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Table IV. Hypothermic cardioplegia: patients, diagnosis, and hospital deaths (August, 1975, to April, 1977)
Diagnosis
No.
Aortic valve replacement
109
Mean age (min. /max.) 39
Deaths No.
I
%
0
(I 1/68)
Mitral valve replacement
87
Double valve replacement
35
Coronary heart disease
214
Total
445
47 ( 14/69) 45 ( 15/63) 54 (37/73)
2
2.3
2
5.7
6
2.8
10
2.2
Table V. Causes of death Deaths Diagnosis
No·1 %
Valve replacement (n = 231)
4
1.7
Coronary heart disease (n = 214)
6
2.8
10
2.2
Total,445
Cause of death 3 Overdistended left ventricle (on table) I Cerebral ischemia (postoperati ve day 7) 4 Myocardial infarction due to surgical problems (2 intraoperative, 2 postoperative) I Unknown postoperative day 10 I Failure of myocardial protection
the aortic cross-clamping time. The diagnosis of perioperative infarctions was proved by ECG (persistent loss of R-wave, new Q-wave >2 mV., >0.04 sec.) and enzymatically by the CK-MB-method (50 U. per liter 12 hours postoperative, immunologic-photometric method [Merck-I-Test, E.Merck, Darmstadt, Germany]). Valve replacement was carried out in 231 patients (see Table VIII). In 109 cases an aortic valve, in 87 cases a mitral valve, and in 35 cases aortic and mitral valves were replaced. With few exceptions patients with aortic valve disease showed signs of severe left ventricular hypertrophy and lesions. Two thirds of the patients with mitral and double valve problems were in Stage III and one third were in Stage IV of the N.Y.H.A. classification. The periods of ischemia varied according to the procedures, but reperfusion times did not vary significantly. Eighteen hours postoperatively the mean left atrial
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Table VI. Coronary heart disease: aortic cross-clamping time, reperfusion time, oxygen saturation of mixed venous blood and mean left atrial pressure (mean ± standard deviation) /8 hr. postop.
Aortic crossclamping time
Surgical procedure: ACVB Single (n = 21) Double (n = 78) Triple, quadruple, quintuple (n = 92) Combined with aneurysmectomy (n = 23)
55 ± 79 ± 106 ± 85 ±
Reperfusion time
25 16 22 38
18 23 30 35
± 7 ± 10
± 12 ± 15
I
SV0 2(%Hb0 2 ) 75 75 75 75
± ± ± ±
LA mean (mm. Hg) 9 9 9 10
6 6 6 6
± 3 ± 3
± 3
± 3
Table VII. Coronary heart disease: rate of perioperative myocardial infarction of survivors Infarctions
Aortic cross-clamping time (min.)
Surgical procedure: ACVB
55 79 106 85
Single (n = 21) Double (n = 78) Triple, quadruple, quintuple (n = 92) Combined with aneurysmectomy (n = 23)
± 25 ± 16
± 22 ± 38
214
Total
I
No.
%
2 2
3 2.2
4
1.9
Table VIII. Valve replacement: aortic cross-clamping time, reperfusion time, oxygen saturation of mixed venous blood and mean left atrial pressure (mean ± standard deviation) (August, 1975, to June, 1977)
Surgical procedure Aortic valve replacement (n = 109) Mitral valve replacement (n = 87) Double valve replacement (n = 35) Total (n = 231)
/8 hr postop.
Aortic crossclamping time
Reperfusion time
Sli0 2 (%Hb0 2 )
86 ± 21 57 ± 13 106 ± 24
24 ± 10 25 ± 14 31 ± 23
76 ± 6 80 ± 6 71 ± 8
pressure after double valve replacement was on average 1 to 3 mm. Hg higher and the oxygen saturation of mixed venous blood 5 to 9 percent Hb0 2 lower than after single valve replacement. Discussion
Some methodological preconditions must be maintained for heart arrest by cardioplegia and deep hypothermia. It is important that the period of ischemia between cross-clamping the aorta and injecting the Kirsch solution be kept as short as possible. The initial cardiac arrest must be accomplished rapidly and completely, and the change to cardioplegic coronary perfusion must be carried out without losing any time. On the one hand it is essential to keep the loss of energy-rich phosphate compounds in ischemia as low as possible, and on the other hand to re-establish the oxydative metabolism as quickly as possible by means of the cardioplegic perfusion. This applies in particular
I
LA mean (mm Hg) 10 ± 3 12 ± 3 13 ± 4
to injection and perfusion via the coronary ostia since, by applying the solutions into the aortic root, cardiac arrest can be accomplished immediately after crossclamping the aorta, followed by cardioplegic perfusion. In every case (Table III) flow rates averaging 80 to 120 ml. per minute could be achieved by restricting the perfusion pressure to between 20 and maximally 30 mm. Hg. This was sufficient to cool the myocardium of both ventricles during an average perfusion time of 6 to 10 minutes down to temperatures averaging 16 to 19° c., with a small standard deviation. The temperatures of the ventricular septum were down to 16 to 18° C. with a small standard deviation. In a few cases perfusion for up to 15 minutes was necessary to achieve this drop in temperature. Furthermore, Table III shows the flow rates of coronary perfusion and perfusion times needed to achieve a myocardial temperature of less than 20° C. in ACVB and mitral valve replacement, perfusion is via the aortic
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hematocri t (%)
28
4 11
100
24 21,8±4,5 20
min 15,5 max 28,0 60
16
.-
40
12
20
8
30 4
2 4 (min) cardiop1egic perfusion
6
Fig. 3. Hematocrit of perfusate collected in coronary sinus during 7 minutes of cardioplegic perfusion after initial cardioplegic arrest by Kirsch solution and during 6 minutes of cardioplegic reperfusion after 50 minutes of ischemia (n = 10). root; in aortic and double valve replacement it is via the coronary ostia. Mean values for perfusion rates are significantly lower for coronary diseases than for valve diseases (p < 0.01). The mean values for perfusion times needed to cool the moycardium are significantly lower in coronary and mitral valve diseases than in diseases of the aortic valve (p < 0.01). These results demonstrate that neither stenoses of coronaries nor myocardial hypertrophy need entail a limitation on using hypothermia by perfusion. Cooling by coronary perfusion due to convection is superior to surface cooling due to diffusion," as far as time required and uniformity of cooling in all the myocardial areas are concerned. When the coronary is being perfused via the aortic root, it is vital that the aortic valve close under a perfusion pressure of 20 to 30 mm. Hg. It becomes obvious that the valve is inadequate when no pressure can be built up in the aortic root despite an increase in perfusion flow rate, and when the perfusate can be sucked up via the drainage of the left ventricle. In such cases an attempt should first be made to close the valve by increasing the suction on the left ventricle. If this fails, cardioplegic coronary perfusion is stopped and the heart is reanimated by opening the aortic clamp. While the heart is being reperfused, a coronary cannula system is prepared. Then the aorta is cross-clamped again
60
(min Ischemia) 120
Fig. 4. CK-MB levels 12 hours postoperative plotted versus time of total ischemia in hypothermia and cardioplegia in 110 consecutive patients. Two-variable linear regression: y = 0.15x + 12.57. Coefficient of correlation 0.185 (Po.os = 0.195; no correlation). and an aortotomia is performed in order to perfuse via the coronary ostia. The problem of insufficient closure of aortic valves did not occur in ACVB procedures; it was observed only three times when replacing mitral valves. In both normothermal and hypothermal induced ischemic arrest the loss of energy-rich phosphate compounds sets in at once. 1. 4,12 Hypothermic cardioplegic coronary perfusion, on the other hand, can satisfy the myocardial oxygen requirements and thereby prevents the splitting of these compounds, because the oxydative metabolism remains unaffected during the undercooling phase. Thus ischemia starts with normal levels of energy-rich phosphate compounds on an intact fine structure. In contrast to the usual coronary perfusion of a beating or fibrillating heart,'! the distribution of the perfusate in a cardioplegically arrested heart is almost undisturbed.t?- 11, 13. 15 At the beginning of the following phase of ischemia, therefore, conditions are more or less identical for all myocardial areas. According to our theoretical calculations and the results of animal experiments, the energy demand of the myocardium at 20° C. and in cardioplegia is reduced to 1 to 2 percent of the normal value. In isolated hearts in animal experiments t-ATP is more than 200 minutes. I, 4 Under clinical conditions, however, t-ATP was reached after 120 minutes. 10 Since the temperature can be kept more or less constant, one is led to wonder whether cardioplegia remains effective under clinical conditions. In fact, we often observed after aortic crossclamping and aortotomy a retrograde blood flow out of
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the coronary ostia, caused by irregular collateral circulation; despite aortic cross-clamping and skillful drainage of the left and right ventricle, we saw blood flowing out of the opened coronary artery in ACVB surgery. This irregular collateral circulation washes out the cardioplegic solution and may suspend cardioplegia and hypothermia. Fig. 3, for instance, shows that 50 minutes after the intial cardioplegic coronary perfusion the hematocrit in the coronary system increased up to 21.8 ± 4.5 percent. We therefore routinely use a short cardioplegic reperfusion after 50 minutes to restore cardioplegia and hypothermia. The perfusion solution (see Table II) is free of blood to prevent intravascular clotting. The oxygen supply to the cardioplegic hypothermic myocardium is maintained by bubbling the perfusion mixture with carbogen at 4° C. prior to bypass. 10 At this temperature the solution contains at least 3 volumes percent of oxygen so that the myocardial energy balance is guaranteed. Because the perfusion pressure of the erythrocyte-free solution is fully transmitted to the capillaries, and because lymphatic drainage in the cardioplegic, relaxed myocardium is stopped, there is a risk of edema if perfusion pressure exceeds a colloid-osmotic pressure of 46 cm.H 20 in the perfusion solution, and if no corticosteroids are added. 13 In animal experiments it could be shown that under the conditions described above, even after perfusion up to 3 hours, there was neither myocardial edema nor alteration in metabolism and fine structure.": 11 Out of 445 patients operated upon, 10 died (2.2 percent). Of the patients with ACVB, four patients died of a myocardial infarction caused by technical problems during the operation. Another fatal infarction was probably caused by insufficient myocardial protection due to overlooked myocardial rewarming during cardiac arrest. Four other patients survived after perioperative infarctions brought on by factors not related to myocardial ischemia (see also Table VII). None of the 109 patients with aortic valve replacement died. Two out of 87 patients with mitral valve replacement died, as did two with double valve replacement. One of them died on the seventh postoperative day following a cerebral ischemia caused by severe arrhythmia. The other three patients died of acute overdistension of the left ventricle, as shown in Table V. In these cases the aortic valve proved insufficient during reperfusion. After the aortic clamp had been opened the left ventricle, still paralyzed, became over-
distended due to insufficient drainage. In all three cases the heart could eventually be reanimated and had a normal ECG, but none could take a normal work load, and the patients therefore died on the operating table. Overdistension of the relaxed hypothermic ventricle is a special problem for any type of cardioplegia, and can be avoided by skillful ventricular drainage (see "surgical procedure," under Methods). Reperfusion time after opening the aortic clamp averages 18 to 35 minutes (see Tables VI & VIII). Except in a few cases, the differences are not the result of different aortic cross-clamping times. Experience has shown that a heart has usually completely recovered after normally reperfuse for roughly this length of time. Only in a few cases were sympathicomimetics needed postoperatively. We could back up these results by investigating the postoperative level of the heart specific creatine kinase isoenzyme CK-MB. Fig. 4 demonstrates CK-MB levels in 100 consecutive patients over 12 hours postoperatively plotted versus times of total myocardial ischemia in cardioplegia and profound hypothermia. The mean CK-MB level in our series is 23 ± 18 U. per liter (immunological method). Two variable linear regression analyses and the coefficient cf correlation show no correlation (p = 0.05) between ischemic stress and CK-MB levels: enzyme levels are considered to be elevated by ventricular incisions and not by ischemic lesions. REFERENCES
2
3
4
5
6
Bretschneider HJ: Uberlebenszeit und Wiederbelebungszeit des Herzens bei Normo- und Hypothermie, Verh Dtsch Ges Kreislaufforsch 30: II, 1964 Stemmer EA, McCart P, Stanton WW, Thibault W, Dearden LS, Conolly JE: Functional and structural alterations in the myocardium during aortic cross-clamping. J THoRAc CARDIOVASC SURG 70:666, 1975 Wukasch DC, Reul GJ, Milam JD, Halman GL, Cooley DA: The "stone heart" syndrome. Surgery 72: 1071 , 1972 Doring V, Baumgarten HG, Bleese N, Kalmar P, Pokar H, and Gercken G: Metabolism and structure of the magnesium aspartate-procaine-arrested ischemic heart of rabbit and man. Basic Res Cardiol 71: 119, 1976 Kalmar P, Bleese N, Doring V, Gercken G, Kirsch U, Lierse W, Pokar H, Polonius M-J, Rodewald G: Induced ischemic arrest. Clinical and experimental results with magnesium asparate-procaine solution (Cardioplegin). J Cardiovasc Surg 16:470, 1975 Bleese N, Kalmar P, Pokar H, Polonius M-J, Rodewald G, Rodiger W: Diagnostik, Hiiufigkeit und Bedeutung des "low output syndroms" fiir die postoperative Phase nach Mitralklappenersatz, Thoraxchirurgie 23:343, 1975
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7 Kirsch U, Rodewald G, Kalmar P: Induced ischemic arrest. Clinical experience with cardioplegia in open-heart surgery. J THORAC CARDIOVASC SURG 63:121, 1972 8 Shumway NE, Lower RR, Stofer RC: Selective hypothermia of the heart in anoxic cardiac arrest. Surg Gynecol Obstet 109:750, 1959 9 B1eese N, Doring V, Gercken G, Pokar H, Rodewald G: Long-time cardiac arrest by cardioplegic perfusion. Tenth Congress of the European Society for Experimental Surgery, Paris, April 6·9, 1975. 10 B1eese N, Doring V. Gercken G, Kalmar P, Lierse W, Pokar H, Polonius M-J, Steiner 0, Rodewald G: Langzeitherzstillstand durch cardioplegische Coronarperfusion. Thoraxchirurgie 24:468, 1976 II Doring V, Gercken G, B1eese N, Pokar H, Rodewald G: Long time cardiac arrest by cardioplegic coronary perfusion. Pfliigers Arch 355:R 10 (Suppl), 1975
12 Doring V, Baumgarten HG, Pokar H, Gercken G: Metabolism and fine structure of the Mg t t-procainearrested perfused heart. Basic Res Cardiol 70:186, 1975 13 Steiner 0, B1eeseN, Doring V, Riesner K: Prevention of edema during coronary perfusion with cardioplegic solution. Thoraxchirurgie 25:235, 1977 14 Hottenrott CE, Maloney JV, Buckberg G: Studies of the effects of ventricular fibrillation on the adequacy of regional myocardial blood flow. J THORAC CARDIOVASC SURG 68:615, 1974 15 Kalmar P, B1eese N, Kirsch U, Lutz G, Pokar H, Rodewald G: Kombination von Kardioplegie und Coronarperfusion bei Herzoperationen in Normothermie, Thoraxchirurgie 20:427, 1972
N. Bleese, V. Doring, P. Kalmar, H. Pokar, M. -J. Polonius, D. Steiner, and G. Rodewald, Hamburg, West Germany
T his is a report on clinical experience with a method of protecting the myocardium by means of hypothermal cardioplegia. This method has been used in 445 openheart procedures. The aim of intraoperative myocardial protection is to prevent damage to the function and structure of the myocardium. None of the methods employed up till now was fully able to guarantee this; in certain circumFrom the Abteilung fiir Herz- und Gefasschirurgie und experimentelle Kardiologie der Chirurgischen Universitatsklinik, Hamburg-Eppendorf, West Germany. Received for publication April 19, 1977. Accepted for publication July 25, 1977. Address for reprints: Abteilung fiir Herz- und Gef3{3chirurgie und experimentelle Kardiologie der Chirurgischen Universitatsklinik Hamburg-Eppendorf, Martinistr. 52, 2000 Hamburg 20, West Germany. 0022-5223/78/0375-0405$00.90/0
stances, quite apart from the technical problems involved, coronary perfusion of a beating or fibrillating heart can lead to regional myocardial ischemia. The advantage of methods which do not involve coronary perfusion is that one operates on an arrested heart emptied of blood. The disadvantage, however, is that tolerance of ischemia cannot be accurately assessed, since in the usual clinical procedures the energy requirements of the arrested heart are not reduced enough or conditions are not standardized. According to Bretschneider,' the limit of "practical survival time" is reached when the myocardial adenosine triphosphate (ATP) content drops to 70 percent of the normal (called t-ATP). Thereafter the first irreversible metabolic and structural lesions occur, leading to permanently decreased function after reanimation.':" In normothermia t-ATP is reached after only
© 1978 The C. V. Mosby Co.
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Table I. Cardioplegic solution for cardiac arrest induced by injection (Kirsch solution)* lngedient
\----m-M----
Magnesium aspartate Procaine HCI n-Sorbitol
80 II 247
'Cardioplegin, Dr. Franz Kohler KG, 0-6146 Aisbach.
Table II. Cardioplegic solution for coronary perfusion 6% Hydroxyethyl starch' 2 mM Magnesium aspartate 4 mM Procaine HCI 0.5 mM CaCI. 5 mMKCI 25 mM NaHC03 10 mM n-Glucose 200 mM n-Mannitol 250 mg. 6-Methyl prednisolone/per litert 20 mg. Gentamycin/per liter Total Na+ content: 50 mM Osmolarity: 320 mOsmol Colloid osmotic pressure: 46 em. H.O pH: 7.40 Po.: >600 mm. Hg 'Dr. E. Fresenius, 0-6380 Bad Homburg v.d.H. tUrbason, Hoechst AG, 0-6000 Frankfurt/Main 71.
10 minutes of cardiac arrest induced by plain ischemia. Even in deep hypothermia at 15° C. the so-called "practical survival time" -following the QIO rulecould be extended only to 45 minutes in animal experiments. The reason for this unsatisfactory situation is that ischemia-induced cardiac arrest is brought about by the loss of ATP. During the arrest the anaerobic metabolism cannot make up for a further loss of ATP, because the membrane ATPases are not inhibited. 4 Cardiac arrest by plain ischemia is the result of a shortage of energy-rich phosphate compounds in the contractile apparatus. On the other hand, cardiac arrest induced by cardioplegia results in excitation-contraction uncoupling, so that the stores of energy-rich phosphate compounds remain undepleted. Furthermore, cardioplegic solutions (procaine, sodium depletion, magnesium) not only stabilize the membrane potential but also reduce the metabolism during arrest by inhibiting membrane ATPases. Other cardioplegic solutions, (for instance, potassium) induce immediate arrest but cannot sufficiently reduce the ATP-splitting by membrane ATPases during the arrest, since they have no membrane-stabilizing effect. 1, 4, 5 Clinically proved cardioplegic solutions with a membrane-stabilizing effect have been introduced by
Bretschneider! (sodium and calcium depletion, procaine) and by Kirsch and associates. 6, 7 (magnesium aspartate, procaine). The cardioplegic solutions containe procaine, which stabilizes the membranes by inhibiting sodium permeation. In addition, both solutions are free of sodium and calcium, so that action potentials are prevented and excitation-contraction is uncoupled. The high concentration of magnesium in the Kirsch solution enhances these effects, so that a rapid cardiac arrest can be induced. In animal experiments where both these methods were combined with hypothermia, the practical survival time could be considerably prolonged, so that t-ATP at 15° C. was reached only after 250 to 280 minutes.J- 4 Judged by the results of the animal experiments, these cardioplegic solutions combined with deep hypothermia of the heart seem to provide the ideal way of protecting the myocardium during arrest, as this method makes it possible to operate on an arrested, relaxed, and empty heart for a sufficiently long period while still guaranteeing safe reanimation. Under clinical conditions, however, it was impossible to reduce the myocardial temperature evenly enough to 15 to 20° C. while still maintaining the oxidative metabolism with any of the methods used so far. Since the only way to rapidly reduce the temperature of the whole myocardium in the operating room is by perfusion, and not just surface cooling," we developed a method combining initial cardiac arrest induced by Kirsch solution and additional coronary perfusion with a cardioplegic perfusate. This cardioplegic coronary perfusate is itself designed to permanently perfuse the arrested heart. Thereby arrest, metabolic balance, and structure were maintained. In animal experiments hearts treated in this manner had no edema, even after cardioplegic coronary perfusion lasting more than 3 hours, and could be reanimated normally. 9-12 Under clinical conditions it would be feasible to use such a continuous cardioplegic perfusion for the period in which the intracardiac or coronary procedure is performed. Although this is still worth considering, until now we have used-for practical reasons-an initial hypothermic cardioplegic coronary perfusion until a myocardial temperature of 15 to 20° C. has been reached. After that the practical survival time of the arrested human heart under hypothermic cardioplegia is 120 minutes.
Method Composition of cardioplegic solutions. Magnesium aspartate-procaine solution prepared
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according to the method of Kirsch. 7 This solution is used for the initial cardiac arrest. The cardioplegically active compounds are magnesium aspartate and procaine hydrochloride, used in combination with sodium and calcium withdrawal (for composition see Table I). Cardioplegic coronary perfusate. The cardioplegic coronary perfusate is an electrolyte-containing, erythrocyte-free, 6 percent hydroxyethyl starch solution, saturated with carbogen at 4° C. (Table II). The solution has an osmolarity of 320 Mosmol per liter, and the colloid osmotic pressure is about 46 cm.H 20 . At a temperature of 37° C. the solution has a pH of 7.4. The cardioplegically active components are procaine (4 mM) and a sodium content reduced to 50 mM. The solution contains 10 mM glucose as substrate. To improve microcirculation and to stabilize the lysosomes, 250 mg. of 6-methylprednisolone per liter are added to the solution;" To maintain sterility during oxygenation, 20 mg. of gentamicin per liter are added to the perfusate. Preparation of the perfusate. Hydroxyethyl starch, magnesium aspartate, procaine, calcium chloride, potassium chloride, glucose, and mannitol are sterilized together in an aqueous solution. Immediately before use, sodium bicarbonate, 6-methylprednisolone, and gentamicin in aqueous solution are added. To oxygenate the solution, it is bubbled with carbogen (95 percent O2- 5 percent CO 2) through a long metal cannula, with fine-bore holes at the side, in a bath of ice. To oxygenize the perfusate and equilibrate the pH value will take about 30 minutes. The perfusate can then be pumped through a second, large-bore metal cannula into the precooled perfusion system (Fig. 1). Surgical procedure. After connection of the heartlung machine with cannulation of both venae cavae (Fig. 2), and transition to total bypass at a body temperature between 30 and 32° c., both ventricles are drained. This is essential to avoid an overflow of cardioplegic solutions, especially the Kirsch solution, into the pulmonary and systemic circulation, as this could cause disturbances in coagulation due to magnesium; furthermore, this avoids overdistension of the ventricle relaxed by cardioplegia and prevents the blood of the left ventricle from overflowing into the aortic root, thereby washing the cardioplegic solution out of the coronary arteries. The system of tubes leading from the pump to the aortic root must be precooled with isotonic glucose or mannitol solution and/or perfusate before coronary perfusion begins, so that the temperature of the cooled perfusate at the end of the pipe system does not exceed 10° C. This also applies when perfusion is intermittent.
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®
t t
t CD
t
t
Fig. 1. Setupfor the cardioplegic coronary perfusion system, when separate cannulation of the coronary artery ostia is needed. 1, Pumps; 2, Iced solution for precooling of the perfusion lines; 3, Iced cardioplegic perfusate; 4, Icebox; 5, System for oxygenation and drainage of the perfusate; 6, bubble trap; 7, automatic pressure regulation devise (according to Dreissen, The Netherlands); 8, Cannulas for selective coronary perfusion. The ascending aorta is cross-clamped. The Kirsch solution is injected either proximal to the clamp into the aortic root or, following aortotomia (in the case of aortic valve replacement, for instance), with the help of an angiocatheter into the coronary arteries. Normally 100
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SYSTEM for cordioplegic coronary perfusion (Fig. .1)
-
SUCTION
Fig. 2. Sites for cannulation of the "extracorporal circulation system" and the "cardioplegic coronary perfusion system." ECG, Electrocardiogram. R.A., Right atrium. R.V., Right ventricle. L.A., Left atrium. L.V., Left ventricle.
Table III. Initial hypothermic cardioplegic coronary perfusion: flow rates, coronary perfusion time, myocardial temperatures Temperature (0 C) at end of perfusion time
Operative procedure
No.*
Coronary perfusion (m/.lmin.)
Perfusion time (min.)
RV posterior wall
RVanterior wall
LV posterior wall
LV anterior wall
Septum
ACVB: Single Double Triple Aortic val ve replacement Mitral valve replacement Aortic and mitral valve replacement
17 68 67 88 77 30
90 87 83 126 120 liS
± 26 ± 24 ± 22 ± 28
± 44 ± 24
6.8 8.2 8.3 9.4 6.6 8.4
± ± ± ±
1.9 2.9 4.3 2.9 ± 1.6 ± 2.4
19 18 18 18 18 17
± ± ± ± ± ±
3 3 3 3 3 2
18 17 17 18 18 18
± ± ± ± ± ±
3 2 3 3 3 2
17 17 17 17 17 17
± ± ± ± ± ±
3 3 3 3 3 2
18 18 17 17 16 17
± ± ± ± ± ±
3 3 3 3 3 3
18 17 18 17 16 16
± ± ± ± ± ±
2 2 3 3 2 2
'Number of patients examined.
to 150 ml. of the Kirsch solution is enough to bring about cardiac arrest. As soon as cardiac arrest has been induced, hypothermic coronary perfusion is started with our oxygenated cardioplegic solution cooled to +4° C. Hypothermia induced by coronary perfusion is backed up by additional surface cooling of the heart with cooled isotonic glucose or mannitol solution. (To avoid diffusion of sodium ions into the myocardium we use isotonic glucose or mannitol solution instead of Ringer's solution for surface cooling.)
The posterior wall of the heart is insulated from the mediastinum. The pressure in the aortic root is measured continuously during injection and perfusion and should not exceed 50 to 70 mm. Hg during the injection of Kirsch solution. During the cardioplegic coronary perfusion the pressure must be kept between 20 and maximally 30 mm. Hg to avoid myocardial edema." During perfusion via the coronary ostia (for instance, in replacement of an aortic valve) each ostium is perfused with a pressure-regulated pump. During cardioplegic coronary perfusion the temperature in the myocardium
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is measured as different locations with thin-needle thermistors (Tele-Thermometer, Yellow Spring Instrument Co.), i.e., deep in the muscle of the anterior and posterior walls of both ventricles, and also in the septum. Cardioplegic coronary perfusion is usually stopped when temperatures of at least 20° C. have been reached, since under these conditions the tolerable period of ischemia is about 120 minutes, provided surface cooling is continued, so that a constant myocardial temperature is guaranteed. Should the heart warm up again faster then expected during the period of ischemia, or should mechanical activity start, cardioplegic coronary perfusion can be resumed at any stage and carried on either continuously or intermittently. However, in each case we perform a short reperfusion of 3 to 4 minutes after 50 to 60 minutes of cardioplegic arrest, to wash out lactate and blood and to restore cardioplegia. The flow rates and the time needed to lower the temperature of the heart are shown in Table 1lI.
Results Between August, 1975, and June, 1977, we used this method of hypothermic cardioplegic coronary perfusion in 445 patients who underwent open-heart procedures. Operative procedures and hospital deaths are presented in Table IV. Ten patients died (2.2 percent). Causes of death are shown in Table V. A total of 214 patients underwent coronary bypass surgery. In 21 cases a single, in 78 a double, and in 92 a triple, quadruple, or quintuple, aorta-coronary artery vein bypass (ACVB) was carried out. In 23 cases ACVB was combined with aneurysmectomy. In all cases, aortic anastomoses without extracorporal circulation (ECC) were established first. Then cannulas for ECC were positioned in the usual manner. After total bypass had been started, cardiac arrest and hypothermic cardioplegic perfusion were carried out. The cardioplegic perfusion was stopped when a myocardial temperature of at least 20° C. was reached. Then the peripheral anastomoses were made during a single period of cardiac arrest. As Table VI shows, the periods of ischemia differed significantly, depending on the number of peripheral anastomoses and the times needed for weaning off bypass. The values of mean left atrial pressure and of oxygen saturation of mixed venous blood were normal about 18 hours after the operation without the use of any sympathicomimetics. Table VII shows the rate of perioperative infarctions in patients surviving coronary bypass surgery, which is independent of the number of implanted veins and of
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Table IV. Hypothermic cardioplegia: patients, diagnosis, and hospital deaths (August, 1975, to April, 1977)
Diagnosis
No.
Aortic valve replacement
109
Mean age (min. /max.) 39
Deaths No.
I
%
0
(I 1/68)
Mitral valve replacement
87
Double valve replacement
35
Coronary heart disease
214
Total
445
47 ( 14/69) 45 ( 15/63) 54 (37/73)
2
2.3
2
5.7
6
2.8
10
2.2
Table V. Causes of death Deaths Diagnosis
No·1 %
Valve replacement (n = 231)
4
1.7
Coronary heart disease (n = 214)
6
2.8
10
2.2
Total,445
Cause of death 3 Overdistended left ventricle (on table) I Cerebral ischemia (postoperati ve day 7) 4 Myocardial infarction due to surgical problems (2 intraoperative, 2 postoperative) I Unknown postoperative day 10 I Failure of myocardial protection
the aortic cross-clamping time. The diagnosis of perioperative infarctions was proved by ECG (persistent loss of R-wave, new Q-wave >2 mV., >0.04 sec.) and enzymatically by the CK-MB-method (50 U. per liter 12 hours postoperative, immunologic-photometric method [Merck-I-Test, E.Merck, Darmstadt, Germany]). Valve replacement was carried out in 231 patients (see Table VIII). In 109 cases an aortic valve, in 87 cases a mitral valve, and in 35 cases aortic and mitral valves were replaced. With few exceptions patients with aortic valve disease showed signs of severe left ventricular hypertrophy and lesions. Two thirds of the patients with mitral and double valve problems were in Stage III and one third were in Stage IV of the N.Y.H.A. classification. The periods of ischemia varied according to the procedures, but reperfusion times did not vary significantly. Eighteen hours postoperatively the mean left atrial
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Table VI. Coronary heart disease: aortic cross-clamping time, reperfusion time, oxygen saturation of mixed venous blood and mean left atrial pressure (mean ± standard deviation) /8 hr. postop.
Aortic crossclamping time
Surgical procedure: ACVB Single (n = 21) Double (n = 78) Triple, quadruple, quintuple (n = 92) Combined with aneurysmectomy (n = 23)
55 ± 79 ± 106 ± 85 ±
Reperfusion time
25 16 22 38
18 23 30 35
± 7 ± 10
± 12 ± 15
I
SV0 2(%Hb0 2 ) 75 75 75 75
± ± ± ±
LA mean (mm. Hg) 9 9 9 10
6 6 6 6
± 3 ± 3
± 3
± 3
Table VII. Coronary heart disease: rate of perioperative myocardial infarction of survivors Infarctions
Aortic cross-clamping time (min.)
Surgical procedure: ACVB
55 79 106 85
Single (n = 21) Double (n = 78) Triple, quadruple, quintuple (n = 92) Combined with aneurysmectomy (n = 23)
± 25 ± 16
± 22 ± 38
214
Total
I
No.
%
2 2
3 2.2
4
1.9
Table VIII. Valve replacement: aortic cross-clamping time, reperfusion time, oxygen saturation of mixed venous blood and mean left atrial pressure (mean ± standard deviation) (August, 1975, to June, 1977)
Surgical procedure Aortic valve replacement (n = 109) Mitral valve replacement (n = 87) Double valve replacement (n = 35) Total (n = 231)
/8 hr postop.
Aortic crossclamping time
Reperfusion time
Sli0 2 (%Hb0 2 )
86 ± 21 57 ± 13 106 ± 24
24 ± 10 25 ± 14 31 ± 23
76 ± 6 80 ± 6 71 ± 8
pressure after double valve replacement was on average 1 to 3 mm. Hg higher and the oxygen saturation of mixed venous blood 5 to 9 percent Hb0 2 lower than after single valve replacement. Discussion
Some methodological preconditions must be maintained for heart arrest by cardioplegia and deep hypothermia. It is important that the period of ischemia between cross-clamping the aorta and injecting the Kirsch solution be kept as short as possible. The initial cardiac arrest must be accomplished rapidly and completely, and the change to cardioplegic coronary perfusion must be carried out without losing any time. On the one hand it is essential to keep the loss of energy-rich phosphate compounds in ischemia as low as possible, and on the other hand to re-establish the oxydative metabolism as quickly as possible by means of the cardioplegic perfusion. This applies in particular
I
LA mean (mm Hg) 10 ± 3 12 ± 3 13 ± 4
to injection and perfusion via the coronary ostia since, by applying the solutions into the aortic root, cardiac arrest can be accomplished immediately after crossclamping the aorta, followed by cardioplegic perfusion. In every case (Table III) flow rates averaging 80 to 120 ml. per minute could be achieved by restricting the perfusion pressure to between 20 and maximally 30 mm. Hg. This was sufficient to cool the myocardium of both ventricles during an average perfusion time of 6 to 10 minutes down to temperatures averaging 16 to 19° c., with a small standard deviation. The temperatures of the ventricular septum were down to 16 to 18° C. with a small standard deviation. In a few cases perfusion for up to 15 minutes was necessary to achieve this drop in temperature. Furthermore, Table III shows the flow rates of coronary perfusion and perfusion times needed to achieve a myocardial temperature of less than 20° C. in ACVB and mitral valve replacement, perfusion is via the aortic
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hematocri t (%)
28
4 11
100
24 21,8±4,5 20
min 15,5 max 28,0 60
16
.-
40
12
20
8
30 4
2 4 (min) cardiop1egic perfusion
6
Fig. 3. Hematocrit of perfusate collected in coronary sinus during 7 minutes of cardioplegic perfusion after initial cardioplegic arrest by Kirsch solution and during 6 minutes of cardioplegic reperfusion after 50 minutes of ischemia (n = 10). root; in aortic and double valve replacement it is via the coronary ostia. Mean values for perfusion rates are significantly lower for coronary diseases than for valve diseases (p < 0.01). The mean values for perfusion times needed to cool the moycardium are significantly lower in coronary and mitral valve diseases than in diseases of the aortic valve (p < 0.01). These results demonstrate that neither stenoses of coronaries nor myocardial hypertrophy need entail a limitation on using hypothermia by perfusion. Cooling by coronary perfusion due to convection is superior to surface cooling due to diffusion," as far as time required and uniformity of cooling in all the myocardial areas are concerned. When the coronary is being perfused via the aortic root, it is vital that the aortic valve close under a perfusion pressure of 20 to 30 mm. Hg. It becomes obvious that the valve is inadequate when no pressure can be built up in the aortic root despite an increase in perfusion flow rate, and when the perfusate can be sucked up via the drainage of the left ventricle. In such cases an attempt should first be made to close the valve by increasing the suction on the left ventricle. If this fails, cardioplegic coronary perfusion is stopped and the heart is reanimated by opening the aortic clamp. While the heart is being reperfused, a coronary cannula system is prepared. Then the aorta is cross-clamped again
60
(min Ischemia) 120
Fig. 4. CK-MB levels 12 hours postoperative plotted versus time of total ischemia in hypothermia and cardioplegia in 110 consecutive patients. Two-variable linear regression: y = 0.15x + 12.57. Coefficient of correlation 0.185 (Po.os = 0.195; no correlation). and an aortotomia is performed in order to perfuse via the coronary ostia. The problem of insufficient closure of aortic valves did not occur in ACVB procedures; it was observed only three times when replacing mitral valves. In both normothermal and hypothermal induced ischemic arrest the loss of energy-rich phosphate compounds sets in at once. 1. 4,12 Hypothermic cardioplegic coronary perfusion, on the other hand, can satisfy the myocardial oxygen requirements and thereby prevents the splitting of these compounds, because the oxydative metabolism remains unaffected during the undercooling phase. Thus ischemia starts with normal levels of energy-rich phosphate compounds on an intact fine structure. In contrast to the usual coronary perfusion of a beating or fibrillating heart,'! the distribution of the perfusate in a cardioplegically arrested heart is almost undisturbed.t?- 11, 13. 15 At the beginning of the following phase of ischemia, therefore, conditions are more or less identical for all myocardial areas. According to our theoretical calculations and the results of animal experiments, the energy demand of the myocardium at 20° C. and in cardioplegia is reduced to 1 to 2 percent of the normal value. In isolated hearts in animal experiments t-ATP is more than 200 minutes. I, 4 Under clinical conditions, however, t-ATP was reached after 120 minutes. 10 Since the temperature can be kept more or less constant, one is led to wonder whether cardioplegia remains effective under clinical conditions. In fact, we often observed after aortic crossclamping and aortotomy a retrograde blood flow out of
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the coronary ostia, caused by irregular collateral circulation; despite aortic cross-clamping and skillful drainage of the left and right ventricle, we saw blood flowing out of the opened coronary artery in ACVB surgery. This irregular collateral circulation washes out the cardioplegic solution and may suspend cardioplegia and hypothermia. Fig. 3, for instance, shows that 50 minutes after the intial cardioplegic coronary perfusion the hematocrit in the coronary system increased up to 21.8 ± 4.5 percent. We therefore routinely use a short cardioplegic reperfusion after 50 minutes to restore cardioplegia and hypothermia. The perfusion solution (see Table II) is free of blood to prevent intravascular clotting. The oxygen supply to the cardioplegic hypothermic myocardium is maintained by bubbling the perfusion mixture with carbogen at 4° C. prior to bypass. 10 At this temperature the solution contains at least 3 volumes percent of oxygen so that the myocardial energy balance is guaranteed. Because the perfusion pressure of the erythrocyte-free solution is fully transmitted to the capillaries, and because lymphatic drainage in the cardioplegic, relaxed myocardium is stopped, there is a risk of edema if perfusion pressure exceeds a colloid-osmotic pressure of 46 cm.H 20 in the perfusion solution, and if no corticosteroids are added. 13 In animal experiments it could be shown that under the conditions described above, even after perfusion up to 3 hours, there was neither myocardial edema nor alteration in metabolism and fine structure.": 11 Out of 445 patients operated upon, 10 died (2.2 percent). Of the patients with ACVB, four patients died of a myocardial infarction caused by technical problems during the operation. Another fatal infarction was probably caused by insufficient myocardial protection due to overlooked myocardial rewarming during cardiac arrest. Four other patients survived after perioperative infarctions brought on by factors not related to myocardial ischemia (see also Table VII). None of the 109 patients with aortic valve replacement died. Two out of 87 patients with mitral valve replacement died, as did two with double valve replacement. One of them died on the seventh postoperative day following a cerebral ischemia caused by severe arrhythmia. The other three patients died of acute overdistension of the left ventricle, as shown in Table V. In these cases the aortic valve proved insufficient during reperfusion. After the aortic clamp had been opened the left ventricle, still paralyzed, became over-
distended due to insufficient drainage. In all three cases the heart could eventually be reanimated and had a normal ECG, but none could take a normal work load, and the patients therefore died on the operating table. Overdistension of the relaxed hypothermic ventricle is a special problem for any type of cardioplegia, and can be avoided by skillful ventricular drainage (see "surgical procedure," under Methods). Reperfusion time after opening the aortic clamp averages 18 to 35 minutes (see Tables VI & VIII). Except in a few cases, the differences are not the result of different aortic cross-clamping times. Experience has shown that a heart has usually completely recovered after normally reperfuse for roughly this length of time. Only in a few cases were sympathicomimetics needed postoperatively. We could back up these results by investigating the postoperative level of the heart specific creatine kinase isoenzyme CK-MB. Fig. 4 demonstrates CK-MB levels in 100 consecutive patients over 12 hours postoperatively plotted versus times of total myocardial ischemia in cardioplegia and profound hypothermia. The mean CK-MB level in our series is 23 ± 18 U. per liter (immunological method). Two variable linear regression analyses and the coefficient cf correlation show no correlation (p = 0.05) between ischemic stress and CK-MB levels: enzyme levels are considered to be elevated by ventricular incisions and not by ischemic lesions. REFERENCES
2
3
4
5
6
Bretschneider HJ: Uberlebenszeit und Wiederbelebungszeit des Herzens bei Normo- und Hypothermie, Verh Dtsch Ges Kreislaufforsch 30: II, 1964 Stemmer EA, McCart P, Stanton WW, Thibault W, Dearden LS, Conolly JE: Functional and structural alterations in the myocardium during aortic cross-clamping. J THoRAc CARDIOVASC SURG 70:666, 1975 Wukasch DC, Reul GJ, Milam JD, Halman GL, Cooley DA: The "stone heart" syndrome. Surgery 72: 1071 , 1972 Doring V, Baumgarten HG, Bleese N, Kalmar P, Pokar H, and Gercken G: Metabolism and structure of the magnesium aspartate-procaine-arrested ischemic heart of rabbit and man. Basic Res Cardiol 71: 119, 1976 Kalmar P, Bleese N, Doring V, Gercken G, Kirsch U, Lierse W, Pokar H, Polonius M-J, Rodewald G: Induced ischemic arrest. Clinical and experimental results with magnesium asparate-procaine solution (Cardioplegin). J Cardiovasc Surg 16:470, 1975 Bleese N, Kalmar P, Pokar H, Polonius M-J, Rodewald G, Rodiger W: Diagnostik, Hiiufigkeit und Bedeutung des "low output syndroms" fiir die postoperative Phase nach Mitralklappenersatz, Thoraxchirurgie 23:343, 1975
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7 Kirsch U, Rodewald G, Kalmar P: Induced ischemic arrest. Clinical experience with cardioplegia in open-heart surgery. J THORAC CARDIOVASC SURG 63:121, 1972 8 Shumway NE, Lower RR, Stofer RC: Selective hypothermia of the heart in anoxic cardiac arrest. Surg Gynecol Obstet 109:750, 1959 9 B1eese N, Doring V, Gercken G, Pokar H, Rodewald G: Long-time cardiac arrest by cardioplegic perfusion. Tenth Congress of the European Society for Experimental Surgery, Paris, April 6·9, 1975. 10 B1eese N, Doring V. Gercken G, Kalmar P, Lierse W, Pokar H, Polonius M-J, Steiner 0, Rodewald G: Langzeitherzstillstand durch cardioplegische Coronarperfusion. Thoraxchirurgie 24:468, 1976 II Doring V, Gercken G, B1eese N, Pokar H, Rodewald G: Long time cardiac arrest by cardioplegic coronary perfusion. Pfliigers Arch 355:R 10 (Suppl), 1975
12 Doring V, Baumgarten HG, Pokar H, Gercken G: Metabolism and fine structure of the Mg t t-procainearrested perfused heart. Basic Res Cardiol 70:186, 1975 13 Steiner 0, B1eeseN, Doring V, Riesner K: Prevention of edema during coronary perfusion with cardioplegic solution. Thoraxchirurgie 25:235, 1977 14 Hottenrott CE, Maloney JV, Buckberg G: Studies of the effects of ventricular fibrillation on the adequacy of regional myocardial blood flow. J THORAC CARDIOVASC SURG 68:615, 1974 15 Kalmar P, B1eese N, Kirsch U, Lutz G, Pokar H, Rodewald G: Kombination von Kardioplegie und Coronarperfusion bei Herzoperationen in Normothermie, Thoraxchirurgie 20:427, 1972