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Effect of temperature of cardioplegic solution
Effect of temperature of cardioplegic solution This study tests the hypothesis that the efficacy of cardioplegic solution depends upon its chemical constituents rather than on its temperature alone. A standard preparation of right heart bypass in the dog was utilized. Left ventricular function curves were inscribed before and after I hour of aortic cross-clamping. No deterioration in function was observed in nonischemic control hearts or in hearts protected with cardioplegic solution consisting of potassium chloride (25 mEq. per liter) and mannitol (12.5 Gm. per liter in 5 percent dextrose and 0.2 percent saline at either 4° C or 28° C. Severe myocardial depression was observed in hearts rendered ischemic for I hour at 28° C. without protection and also in hearts perfused with 5 percent dextrose and 0.2 percent saline at 28° C. without the potassium chloride and mannitol. The evidence from this study indicates that cardioplegic solution exerts a protective effect beyond that which is afforded by hypothermia.
Douglas M. Behrendt, M.D.,* and Kenneth E. Jochim,, Ph.D.,** Ann Arbor, Mich.
H ow best to protect the myocardium from ischemic damage during aortic cross-clamping remains an unresolved problem in cardiac surgery. Recent reports suggest that cardioplegic solutions offer major advantages over previously utilized techniques, and the clinical results with cardioplegia have been excellent. The ideal composition and method of administration of these cardioplegic solutions remain unknown, and a variety of recipes has been advocated. Common to most is the recommendation that the solution be cold, generally about 4° C. Some believe that it is the temperature rather than the chemical composition which is the important protective factor. However, the studies of Hearse and associates1, 2 show that in the isolated perfused rat heart preparation hyperkalemia exerts a protective effect in addition to the protection afforded by hypothermia during short periods of ischemia. The present study was designed to test the hypothesis that the efficacy of cardioplegic solution depends upon its chemical constituents rather than just on its temperature when used in a blood-perfused large animal preparation designed to resemble the patient undergoing From the Section of Thoracic Surgery, Department of Surgery, and the Department of Physiology, University of Michigan, Ann Arbor, Mich. 48109. Received for publication Nov. 29, 1977. Accepted for publication June 12, 1978. Address for reprints: Dr. D. M. Behrendt, C7069 Out-Patient Building, University Hospital, Ann Arbor, Mich. 48109. * Department of Surgery. "Department of Physiology. 0022-5223/78/0376-0353$00.50/0 © 1978 The C. V. Mosby Co.
heart surgery more closely than the isolated rat heart preparation. An ischemic period of I hour was chosen, since many open-heart procedures can be carried out during that interval. Methods Five groups of dogs were studied: Group I. In five dogs continuous coronary perfusion was maintained with the heart beating at 34° C to establish that the preparation itself was stable for the required 3 to 4 hours. Group II. In six dogs the aorta was clamped at a myocardial temperature of 28° C. for 1 hour. Group III. In 12 dogs the myocardial temperature was reduced to 28° C. Then the aorta was clamped and the coronary arteries were rapidly perfused through the aortic root with one of the following: a. In four dogs 200 ml. of cardioplegic solution at 4° C. was used. This solution consisted of 5 percent dextrose in 0.2 percent saline containing 25 mEq. of potassium chloride and 25 Gm. of mannitol in each liter. The pH was 6.8 and the osmolarity 380 mOsm. per liter. b. In four other dogs 200 ml. of the same cardioplegic solution at 28° C. was used. c. In the last four dogs 200 ml. of 5 percent dextrose in 0.2 percent saline, without potassium chloride or mannitol, was perfused. The conditioned mongrel dogs were premedicated with morphine sulfate (2 mg. per kilogram), anesthetized with Chloralose (40 mg. per kilogram) and urethane (400 mg. per kilogram), intubated, and ventilated. Blood gases and body temperatures were 353
The Journal of Thoracic and Cardiovascular Surgery
3 5 4 Behrendt and Jochim
flow meter
oxygenator pump
Fig. 1. Right heart preparation in the dog. LA, Left atrium. RA, Right atrium. LV, Left ventricle. RV, Right ventricle. PA, Pulmonary artery. SVC, Superior vena cava. IVC, Inferior vena cava. monitored. Right heart bypass (Fig. 1) was established through cannulation of the venae cavae and perfusion of oxygenated, temperature-controlled blood into the pulmonary artery. The sinoatrial node was surgically excluded and the heart rate was controlled by atrial pacing. Afterload was maintained at a constant level by a combination of a tourniquet about the descending thoracic aorta and a peripheral arteriovenous fistula. Preload was determined by the flow of blood delivered into the pulmonary artery. The extracorporeal pump and Harvey oxygenator were primed with fresh, homologous, whole heparinized blood, mildly diluted (20 percent) with Rheomacrodex. Temperature was maintained at 36° to 37° C. during ventricular function recordings. Left ventricular stroke volume (SV) was recorded from a previously calibrated Carolina square-wave electromagnetic fiowmeter probe encircling the aortic root (Fig. 2). Measurement of coronary blood flow was assumed to be unnecessary for this experiment. Left ventricular pressure (LVP), its first derivative (LV dp/dt), and its end-diastolic pressure (LVEDP) were recorded from a short, large-bore metal cannula placed in the left ventricle through its apex and connected to a Statham P 23 strain gauge and an operational amplifier differentiating circuit having a time constant of 20 msec. Left ventricular stroke work (SW) was computed by on-line integration of the product of LVP and aortic flow over each beat. After the preparation was completed and stabilized, measurements of left ventricular SV, SW, dp/dt, and LVEDP were made over a range of cardiac outputs.
Fig. 2. Data obtained from right heart preparation in the dog. SV, Stroke volume (ml.). SW, Stroke work (Gm.-M.). AF, Aortic f\ow. dP/dt, First derivative of left ventricular pressure (mm. Hg/sec). MAP, Mean aortic pressure (mm. Hg). LVEDP, Left ventricular end-diastolic pressure (mm. Hg). LVP, Left ventricular pressure (mm. Hg). Plots were made of SW and dp/dt versus LVEDP for each dog in the control state. Total cardiopulmonary bypass was then begun by switching the arterial input from the pulmonary artery to the femoral artery. The body temperature was reduced to 28° C. The left ventricle was vented and the aorta was clamped for 1 hour during which the myocardium was protected by one of the several methods described. Following this the aorta was undamped, the animals were rewarmed to 37° C , and the heart was defibrillated. Right heart bypass was reinstituted, and after a half hour stabilization period ventricular function was again assessed to determine the degree of functional myocardial damage sustained. The "before" and "after" curves of SW and dp/dt max versus LVEDP were compared for each dog. For statistical analysis, values of SW and dp/dt max at 5 and 8 mm. Hg were compared (Tables I and II) by means of the Students t test for paired data. These values were chosen because they lay within the observed control ranges of all the animals. Results Group I: Control animals. No dog had any change in ventricular function curves. Group II: Ischemic arrest. These hearts fibrillated for 10 to 15 minutes following clamping and then be-
Volume 76 Number 3 September, 1978
35 5
Temperature of cardioplegic solution
Table II. Left ventricular dp/dt max (millimeters per second)
Table I. Left ventricular stroke work (gram-meters) LVED of 5 mm. Hg
LVED of 5 mm. Hg
LVED of 8 mm. Hg
Group
Before
After
p Value
Before
After
p Value
Group I Group II Group Ilia Group Illb Group IIIc
32.2 17.5 8.4 11.5 18.4
30.0 2.0 12.8 14.8 2.9
NS <0.05 NS NS <0.05
46.8 43.2 26.4 28.3 36.8
42.0 6.7 29.4 28.8 8.5
NS <0.01 NS NS <0.02
Group Group Group Group Group Group
I II Ilia Illb IIIc
Before
After
2,640 3,250 1,980 2,300 2,500
2,630 1,280 2,230 2,300 1,400
LVED of 8 mm. Hg
p Value
Before
After
p Value
NS <0.05 NS NS <0.01
3,130 3,740 2,900 2,760 3,000
3,000 1,430 2,800 2,480 1,430
NS <0.025 NS NS <0.001
Legend: The stroke work values (gram-meters) represent the combined average values for each group measured before and after the ischemic period at a preload of either 5 or 8 mm. Hg (see text). Significance of differences was determined by Student's t test for paired data and are expressed as a p value.
Legend: The dp/dt max values (millimeters per second) represent the combined average values for each group measured before and after the ischemic period at a preload of either 5 or 8 mm. Hg (see text). Significance of differences was determined by Student's t test for paired data.
came quiescent. All required defibrillation after resumption of perfusion and rewarming. This was often accomplished with difficulty, and a 30 to 60 minute "rest" with coronary perfusion was needed before function curves could be inscribed. Each had a significant shift of the SW and dp/dt curve to the right, indicating depressed contractility. In four dogs this was a dramatic shift, indicating profound depression. Contractility in one dog was so poor that no recordings could be made. Group Ilia: 4° C. cardioplegia. These hearts became flaccid promptly upon administration of the cardioplegic solution and did not fibrillate. Measurement of myocardial temperature revealed that it quickly fell below 10° C. during the perfusion, thereafter rose gradually over a 30 minute interval, and stabilized at 20° to 25° C. during the balance of the ischemic period. Upon removal of the aortic clamp at the end of 1 hour and rewarming, all resumed spontaneous contractions, but three subsequently fibrillated and required one low-energy shock for defibrillation. There were no statistically significant shifts in either the SW or dp/dt versus LVEDP curves in three dogs. One showed initial depression followed by complete recovery within 30 minutes. Group IHb: 28° C cardioplegia. These hearts behaved like those in Group Ilia, promptly becoming flaccid and defibrillating easily after the aorta was undamped. Two had slightly depressed contractility initially but recovered to control levels or better within 30 minutes. The other two were not depressed. Group IIIc: 5 percent dextrose in 0.2 percent saline at 28° C. The 5 percent dextrose in 0.2 percent saline had no cardioplegic effect; the hearts fibrillated for a short period following administration. Defibrillation was difficult and could not be accomplished in one dog following resumption of coronary flow and rewarming. Contractility was severely de-
pressed in all of the others, as evidenced by significantly shifted curves of SW and dp/dt versus LVEDP. These dogs behaved like the animals in Group II, in which the aorta was clamped and no intracoronary perfusion was done. These data show that cardioplegic solution exerts a protective effect even when administered into the coronary arteries at 28° C. Administration of 5 percent dextrose in 0.2 percent saline at 28° C. without the active ingredients was not protective. Discussion Cardiac asystole, produced by administration of high-potassium solutions, was employed briefly in the 1950's. The technique, as advocated by Melrose,3 involved injection of a small volume of highly concentrated potassium citrate (230 mEq per liter) into the aortic root. Myocardial injury resulted, probably either from the high concentration of potassium or citrate or from the extreme hyperosmolarity (about 500 mOsm. per liter) of these solutions.4, 5 Thus the method was abandoned in favor of other techniques for myocardial protection during aortic cross-clamping. It is fair to say that, although generally satisfactory, these methods have not always achieved ideal myocardial protection, and they are sometimes technically cumbersome. Gay and Ebert6 reintroduced the concept of potassium-induced arrest experimentally in 1973 using a solution containing 25 mEq. of potassium chloride per liter at an osmolarity of 275 mOsm. per liter. This seemed to preserve myocardial function and histologic appearance during 60 minutes of normothermic ischemia. Additional laboratory work and several clinical series have subsequently demonstrated the considerable technical advantages and apparent safety of this technique.7-11 The composition of the ideal cardioplegic solution remains undetermined. Most solutions currently in use
The Journal of Thoracic and Cardiovascular Surgery
3 5 6 Behrendt and Jochim
contain potassium (15 to 30 mEq. per liter), sometimes with a variety of additional agents thought to be beneficial. The rationale of employing hyperkalemia appears sound. Elevation of extracellular potassium reduces myocardial transmembrane potential, which prevents cell excitation and thereby contraction. Myocardial stores of high-energy phosphates are consequently conserved during the ischemic period. 9 ' 12, 13 Also, because cardiac standstill is virtually immediate, and because resumption of spontaneous beating promptly follows removal of the aortic clamp, prolonged periods of ventricular fibrillation are avoided. Ventricular fibrillation itself has been shown by Buckberg and associates 14 to produce maldistribution of coronary blood flow and subendocardial ischemia. Studies of long-term cardiac preservation suggest that potassium concentrations approaching intracellular levels (100 to 150 mEq. per liter) may provide even better results at low temperatures. 15 ' 16 Cellular swelling appears to be concomitant with myocardial ischemia and to cause increased coronary vascular resistance, reduced ventricular compliance, and additional cell damage. Mannitol has been shown to inhibit cell swelling and thus to promote improved myocardial performance and histologic appearance. 1 7 - 2 0 The rationale for the use of some of the other agents currently employed appears less clear. It has been suggested that steroids 21 or procaine hydrochloride 22 also be employed for membrane stabilization, and some current investigation is directed at evaluating these agents. Some investigators have added glucose with or without insulin in an attempt to provide substrate for anaerobic metabolism. The ideal pH and osmolarity of these solutions remain speculative. There are data to suggest that lactate should be excluded 12 ' 13 and that calcium should be included. 23 Common to all these solutions is the fact that they are chilled to approximately 4° C. when administered. Goldstein, Buckberg, and associates 24 have stressed the need for administering a sufficient initial volume to reduce myocardial temperature to 10 to 15° C. and then giving additional doses during the ischemic period. Because of collateral coronary flow, myocardial temperature drifts up to 20° to 25° C. within 30 minutes. The cardioplegic agent may be washed out, and undesirable myocardial electrical activity may be resumed. We have observed these phenomena in both our laboratory and clinical work. The ideal myocardial temperature for preservation is uncertain. We and others have evidence that profound cooling, i.e., below 15° to 20° C , may be in itself detrimental, particularly to subsequent myocardial
compliance. Tyers' 2 5 data suggest that a myocardial temperature of 10° to 15° C may be ideal. This, in fact, is the temperature we have achieved by rapid infusion of 1 liter of 4° C. cardioplegic solution in patients. The myocardial temperature in these patients then drifts upward in a variable fashion to 20° to 25° C. Thus we repeat the cardioplegic perfusion every 30 minutes in our clinical practice. Some 26 suggest that it is the hypothermia per se rather than the cardioplegic chemicals which provides the myocardial protection in these techniques. The present study demonstrates that this is not the case. Hearts rendered cardioplegic at 28° C. with potassium (25 mEq. per liter) and mannitol (12.5 Gm. per liter) performed nearly normally following 1 hour's ischemia and just as well as hearts rendered ischemic with 4 8 C cardioplegic solution. Hearts perfused with the same solution at 28° C. lacking the potassium and mannitol were severely damaged. This is not to suggest that cardioplegic solution should not be cold, for hypothermia itself is clearly at least partially protective 27 and the two effects are probably additive. 1, 2- 24 ' 2 8 _ 3 ° REFERENCES 1 Hearse DJ, Stewart DA, Braimbridge MV: The additive effects of potassium ions and hypothermia for the induction of elective cardiac arrest. Biochem Soc Trans 3:417, 1975 2 Hearse DJ, Steward DA, Braimbridge MV: Hypothermic arrest and potassium arrest. Circ Res 36:481-489, 1975 3 Melrose DG, DreyerB, Bentall HH, Baker JB: Elective cardiac arrest. Lancet 2:21-22, 1955 4 McFarland JA, Thomas LB, Gilbert JW, Morrow AG: Myocardial necrosis following elective cardiac arrest induced with potassium citrate J THORAC CARDIOVASC SURG 40:200-208, 1960
5 Kusumoki T, Cheng HC, McGuire HH Jr, Bosher LH Jr: Myocardial dysfunction after cardioplegia. J THORAC CARDIOVASC SURG 40:813-822, 1960
6 Gay WA Jr, Ebert PA: Functional, metabolic, and morphologic effects of potassium-induced cardioplegia. Surgery 74:284-289, 1973 7 Molina JE, Feiber W, Sisk A, Polen T, Collins B: Cardioplegia without fibrillation or defibrillation in cardiac surgery. Surgery 81:619-626, 1977 8 Roe BB, Hutchinson JC, Fishman NH, Ullyot DJ, Smith DL: Myocardial protection with cold, ischemic, potassium-induced cardioplegia. J THORAC CARDIOVASC SURG 73:366-373, 1977
9. Adams PX, Cunningham JN Jr, Brazier J, Pappis M, Trehan N, Spencer FC: Technique and experience using potassium cardioplegia during myocardial revascularization for preinfarction angina. Surgery 83:12-19, 1978 10 Tyers GFO, Manley NJ, Williams EH, Schaffer CW,
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Williams DR, Kurusz M: Preliminary clinical experience with isotonic hypothermic potassium-induced arrest. J THORAC CARDIOVASC SURG 74:674-681, 1977
11 Cankovic-Darracott S, Braimbridge MV, Williams BT, Bitensky L, Chayen J: Myocardial preservation during aortic valve surgery. J THORAC CARDIOVASC SURG
73:699-706, 1977 12 Todd GJ, Tyers GFO: Amelioration of the effects of ischemic cardiac arrest by the intracoronary administration of cardioplegic solution. Circulation 52:1111-1117, 1975 13 Hearse DJ, Stewart DA, Chain EB: Recovery from cardiac bypass and elective cardiac arrest. Cir Res 35:448457, 1974 14 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 66:742-751, 1973
15 Reitz BA: Potassium-induced cardioplegia (discussion). Ann Thorac Surg 20:99, 1975 16 Berkoff H: Optimal combinations of hypothermia and cardioplegic solutions for organ preservation. Presented before the Association for Academic Surgery. November, 1977. 17 Powell WJ Jr, DiBona DR, Flores J, Leaf A: The protective effect of hyperosmotic mannitol in myocardial ischemia and necrosis. Circulation 54:603-615, 1976 18 Belie N, Singer D, Elson J, Bonnar J: Protection of ischemic myocardium by hyperosmolal mannitol. Circulation 51:Suppl 2:158, 1975 19 Willerson JT: Investigation of the mechanism of the inotropic effect of hypertonic mannitol in isolated cardiac muscle and of mannitol's influence on regional myocardial blood flow in dogs with myocardial ischemia. Am J Cardiol 33:450, 1974 20 Allen WB, Blackstone EH, Kouchoukos NT: Effects of cardiopulmonary bypass and ischemic cardioplegia on the diastolic pressure-volume relationship and water content of the canine left ventricle. Circulation 49,50:Suppl 3: 19, 1974
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solution
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21 Busuttil RW, George WJ, Hewitt RL: Protective effect of methylprednisolone on the heart during ischemic arrest. J THORAC CARDIOVASC SURG 20:955-965, 1975
22 Follette D, Fey K, Mulder D, Maloney JV Jr, Buckberg GD: Prolonged safe aortic clamping by combining membrane stabilization, multidose cardioplegia, and appropriate pH reperfusion. J THORAC CARDIOVASC SURG
74:682-694, 1977 23 Hearse DJ, Stewart DA, Braimbridge MV: Myocardial protection during ischemic arrest. J THORAC CARDIOVASC SURG 72:880-884, 1976
24 Goldstein SM, Nelson RL, McConnell DH, Buckberg GD: Effects of conventional hypothermic ischemic arrest and pharmacological arrest on myocardial supply/demand balance during aortic cross clamping. Ann Thorac Surg 23:520-528, 1977 25 Tyers GFO, Williams EH, Hughes HC, Todd GJ: Effect of perfusate temperature on myocardial protection from ischemia. J THORAC CARDIOVASC SURG 73:766-771,
1977 26 Ellis RJ, Pyror W, Ebert PA: Advantages of potassium cardioplegia and perfusion hypothermia in left ventricular hypertrophy. Ann Thorac Surg 24:299-306, 1977 27 Bamer HB, Standeven JW, Jellinek M, Menz LJ, Hahn JW: Topical cardiac hypothermia for myocardial preservation. J THORAC
CARDIOVASC
SURG
73:856-866,
1977 28 Nelson RL, Goldstein SM, McConnell DH, Maloney JV Jr, Buckberg GD: Improved myocardial performance after aortic cross clamping by combining pharmacologic arrest with topical hypthermia. Circulation 54:Suppl 3:11-15, 1976 29 Gott VL, Bartlett M, Long DM, Lillehei CW, Johnson JA: Myocardial energy substances in the dog heart during potassium and hypothermic arrest. J Appl Physiol 17:815-818, 1962 30 Jynge P, Hearse DJ, Braimbridge MV: Myocardial protection during ischemic cardiac arrest. J THORAC CARDIOVASC SURG 73:848-854, 1977
Douglas M. Behrendt, M.D.,* and Kenneth E. Jochim,, Ph.D.,** Ann Arbor, Mich.
H ow best to protect the myocardium from ischemic damage during aortic cross-clamping remains an unresolved problem in cardiac surgery. Recent reports suggest that cardioplegic solutions offer major advantages over previously utilized techniques, and the clinical results with cardioplegia have been excellent. The ideal composition and method of administration of these cardioplegic solutions remain unknown, and a variety of recipes has been advocated. Common to most is the recommendation that the solution be cold, generally about 4° C. Some believe that it is the temperature rather than the chemical composition which is the important protective factor. However, the studies of Hearse and associates1, 2 show that in the isolated perfused rat heart preparation hyperkalemia exerts a protective effect in addition to the protection afforded by hypothermia during short periods of ischemia. The present study was designed to test the hypothesis that the efficacy of cardioplegic solution depends upon its chemical constituents rather than just on its temperature when used in a blood-perfused large animal preparation designed to resemble the patient undergoing From the Section of Thoracic Surgery, Department of Surgery, and the Department of Physiology, University of Michigan, Ann Arbor, Mich. 48109. Received for publication Nov. 29, 1977. Accepted for publication June 12, 1978. Address for reprints: Dr. D. M. Behrendt, C7069 Out-Patient Building, University Hospital, Ann Arbor, Mich. 48109. * Department of Surgery. "Department of Physiology. 0022-5223/78/0376-0353$00.50/0 © 1978 The C. V. Mosby Co.
heart surgery more closely than the isolated rat heart preparation. An ischemic period of I hour was chosen, since many open-heart procedures can be carried out during that interval. Methods Five groups of dogs were studied: Group I. In five dogs continuous coronary perfusion was maintained with the heart beating at 34° C to establish that the preparation itself was stable for the required 3 to 4 hours. Group II. In six dogs the aorta was clamped at a myocardial temperature of 28° C. for 1 hour. Group III. In 12 dogs the myocardial temperature was reduced to 28° C. Then the aorta was clamped and the coronary arteries were rapidly perfused through the aortic root with one of the following: a. In four dogs 200 ml. of cardioplegic solution at 4° C. was used. This solution consisted of 5 percent dextrose in 0.2 percent saline containing 25 mEq. of potassium chloride and 25 Gm. of mannitol in each liter. The pH was 6.8 and the osmolarity 380 mOsm. per liter. b. In four other dogs 200 ml. of the same cardioplegic solution at 28° C. was used. c. In the last four dogs 200 ml. of 5 percent dextrose in 0.2 percent saline, without potassium chloride or mannitol, was perfused. The conditioned mongrel dogs were premedicated with morphine sulfate (2 mg. per kilogram), anesthetized with Chloralose (40 mg. per kilogram) and urethane (400 mg. per kilogram), intubated, and ventilated. Blood gases and body temperatures were 353
The Journal of Thoracic and Cardiovascular Surgery
3 5 4 Behrendt and Jochim
flow meter
oxygenator pump
Fig. 1. Right heart preparation in the dog. LA, Left atrium. RA, Right atrium. LV, Left ventricle. RV, Right ventricle. PA, Pulmonary artery. SVC, Superior vena cava. IVC, Inferior vena cava. monitored. Right heart bypass (Fig. 1) was established through cannulation of the venae cavae and perfusion of oxygenated, temperature-controlled blood into the pulmonary artery. The sinoatrial node was surgically excluded and the heart rate was controlled by atrial pacing. Afterload was maintained at a constant level by a combination of a tourniquet about the descending thoracic aorta and a peripheral arteriovenous fistula. Preload was determined by the flow of blood delivered into the pulmonary artery. The extracorporeal pump and Harvey oxygenator were primed with fresh, homologous, whole heparinized blood, mildly diluted (20 percent) with Rheomacrodex. Temperature was maintained at 36° to 37° C. during ventricular function recordings. Left ventricular stroke volume (SV) was recorded from a previously calibrated Carolina square-wave electromagnetic fiowmeter probe encircling the aortic root (Fig. 2). Measurement of coronary blood flow was assumed to be unnecessary for this experiment. Left ventricular pressure (LVP), its first derivative (LV dp/dt), and its end-diastolic pressure (LVEDP) were recorded from a short, large-bore metal cannula placed in the left ventricle through its apex and connected to a Statham P 23 strain gauge and an operational amplifier differentiating circuit having a time constant of 20 msec. Left ventricular stroke work (SW) was computed by on-line integration of the product of LVP and aortic flow over each beat. After the preparation was completed and stabilized, measurements of left ventricular SV, SW, dp/dt, and LVEDP were made over a range of cardiac outputs.
Fig. 2. Data obtained from right heart preparation in the dog. SV, Stroke volume (ml.). SW, Stroke work (Gm.-M.). AF, Aortic f\ow. dP/dt, First derivative of left ventricular pressure (mm. Hg/sec). MAP, Mean aortic pressure (mm. Hg). LVEDP, Left ventricular end-diastolic pressure (mm. Hg). LVP, Left ventricular pressure (mm. Hg). Plots were made of SW and dp/dt versus LVEDP for each dog in the control state. Total cardiopulmonary bypass was then begun by switching the arterial input from the pulmonary artery to the femoral artery. The body temperature was reduced to 28° C. The left ventricle was vented and the aorta was clamped for 1 hour during which the myocardium was protected by one of the several methods described. Following this the aorta was undamped, the animals were rewarmed to 37° C , and the heart was defibrillated. Right heart bypass was reinstituted, and after a half hour stabilization period ventricular function was again assessed to determine the degree of functional myocardial damage sustained. The "before" and "after" curves of SW and dp/dt max versus LVEDP were compared for each dog. For statistical analysis, values of SW and dp/dt max at 5 and 8 mm. Hg were compared (Tables I and II) by means of the Students t test for paired data. These values were chosen because they lay within the observed control ranges of all the animals. Results Group I: Control animals. No dog had any change in ventricular function curves. Group II: Ischemic arrest. These hearts fibrillated for 10 to 15 minutes following clamping and then be-
Volume 76 Number 3 September, 1978
35 5
Temperature of cardioplegic solution
Table II. Left ventricular dp/dt max (millimeters per second)
Table I. Left ventricular stroke work (gram-meters) LVED of 5 mm. Hg
LVED of 5 mm. Hg
LVED of 8 mm. Hg
Group
Before
After
p Value
Before
After
p Value
Group I Group II Group Ilia Group Illb Group IIIc
32.2 17.5 8.4 11.5 18.4
30.0 2.0 12.8 14.8 2.9
NS <0.05 NS NS <0.05
46.8 43.2 26.4 28.3 36.8
42.0 6.7 29.4 28.8 8.5
NS <0.01 NS NS <0.02
Group Group Group Group Group Group
I II Ilia Illb IIIc
Before
After
2,640 3,250 1,980 2,300 2,500
2,630 1,280 2,230 2,300 1,400
LVED of 8 mm. Hg
p Value
Before
After
p Value
NS <0.05 NS NS <0.01
3,130 3,740 2,900 2,760 3,000
3,000 1,430 2,800 2,480 1,430
NS <0.025 NS NS <0.001
Legend: The stroke work values (gram-meters) represent the combined average values for each group measured before and after the ischemic period at a preload of either 5 or 8 mm. Hg (see text). Significance of differences was determined by Student's t test for paired data and are expressed as a p value.
Legend: The dp/dt max values (millimeters per second) represent the combined average values for each group measured before and after the ischemic period at a preload of either 5 or 8 mm. Hg (see text). Significance of differences was determined by Student's t test for paired data.
came quiescent. All required defibrillation after resumption of perfusion and rewarming. This was often accomplished with difficulty, and a 30 to 60 minute "rest" with coronary perfusion was needed before function curves could be inscribed. Each had a significant shift of the SW and dp/dt curve to the right, indicating depressed contractility. In four dogs this was a dramatic shift, indicating profound depression. Contractility in one dog was so poor that no recordings could be made. Group Ilia: 4° C. cardioplegia. These hearts became flaccid promptly upon administration of the cardioplegic solution and did not fibrillate. Measurement of myocardial temperature revealed that it quickly fell below 10° C. during the perfusion, thereafter rose gradually over a 30 minute interval, and stabilized at 20° to 25° C. during the balance of the ischemic period. Upon removal of the aortic clamp at the end of 1 hour and rewarming, all resumed spontaneous contractions, but three subsequently fibrillated and required one low-energy shock for defibrillation. There were no statistically significant shifts in either the SW or dp/dt versus LVEDP curves in three dogs. One showed initial depression followed by complete recovery within 30 minutes. Group IHb: 28° C cardioplegia. These hearts behaved like those in Group Ilia, promptly becoming flaccid and defibrillating easily after the aorta was undamped. Two had slightly depressed contractility initially but recovered to control levels or better within 30 minutes. The other two were not depressed. Group IIIc: 5 percent dextrose in 0.2 percent saline at 28° C. The 5 percent dextrose in 0.2 percent saline had no cardioplegic effect; the hearts fibrillated for a short period following administration. Defibrillation was difficult and could not be accomplished in one dog following resumption of coronary flow and rewarming. Contractility was severely de-
pressed in all of the others, as evidenced by significantly shifted curves of SW and dp/dt versus LVEDP. These dogs behaved like the animals in Group II, in which the aorta was clamped and no intracoronary perfusion was done. These data show that cardioplegic solution exerts a protective effect even when administered into the coronary arteries at 28° C. Administration of 5 percent dextrose in 0.2 percent saline at 28° C. without the active ingredients was not protective. Discussion Cardiac asystole, produced by administration of high-potassium solutions, was employed briefly in the 1950's. The technique, as advocated by Melrose,3 involved injection of a small volume of highly concentrated potassium citrate (230 mEq per liter) into the aortic root. Myocardial injury resulted, probably either from the high concentration of potassium or citrate or from the extreme hyperosmolarity (about 500 mOsm. per liter) of these solutions.4, 5 Thus the method was abandoned in favor of other techniques for myocardial protection during aortic cross-clamping. It is fair to say that, although generally satisfactory, these methods have not always achieved ideal myocardial protection, and they are sometimes technically cumbersome. Gay and Ebert6 reintroduced the concept of potassium-induced arrest experimentally in 1973 using a solution containing 25 mEq. of potassium chloride per liter at an osmolarity of 275 mOsm. per liter. This seemed to preserve myocardial function and histologic appearance during 60 minutes of normothermic ischemia. Additional laboratory work and several clinical series have subsequently demonstrated the considerable technical advantages and apparent safety of this technique.7-11 The composition of the ideal cardioplegic solution remains undetermined. Most solutions currently in use
The Journal of Thoracic and Cardiovascular Surgery
3 5 6 Behrendt and Jochim
contain potassium (15 to 30 mEq. per liter), sometimes with a variety of additional agents thought to be beneficial. The rationale of employing hyperkalemia appears sound. Elevation of extracellular potassium reduces myocardial transmembrane potential, which prevents cell excitation and thereby contraction. Myocardial stores of high-energy phosphates are consequently conserved during the ischemic period. 9 ' 12, 13 Also, because cardiac standstill is virtually immediate, and because resumption of spontaneous beating promptly follows removal of the aortic clamp, prolonged periods of ventricular fibrillation are avoided. Ventricular fibrillation itself has been shown by Buckberg and associates 14 to produce maldistribution of coronary blood flow and subendocardial ischemia. Studies of long-term cardiac preservation suggest that potassium concentrations approaching intracellular levels (100 to 150 mEq. per liter) may provide even better results at low temperatures. 15 ' 16 Cellular swelling appears to be concomitant with myocardial ischemia and to cause increased coronary vascular resistance, reduced ventricular compliance, and additional cell damage. Mannitol has been shown to inhibit cell swelling and thus to promote improved myocardial performance and histologic appearance. 1 7 - 2 0 The rationale for the use of some of the other agents currently employed appears less clear. It has been suggested that steroids 21 or procaine hydrochloride 22 also be employed for membrane stabilization, and some current investigation is directed at evaluating these agents. Some investigators have added glucose with or without insulin in an attempt to provide substrate for anaerobic metabolism. The ideal pH and osmolarity of these solutions remain speculative. There are data to suggest that lactate should be excluded 12 ' 13 and that calcium should be included. 23 Common to all these solutions is the fact that they are chilled to approximately 4° C. when administered. Goldstein, Buckberg, and associates 24 have stressed the need for administering a sufficient initial volume to reduce myocardial temperature to 10 to 15° C. and then giving additional doses during the ischemic period. Because of collateral coronary flow, myocardial temperature drifts up to 20° to 25° C. within 30 minutes. The cardioplegic agent may be washed out, and undesirable myocardial electrical activity may be resumed. We have observed these phenomena in both our laboratory and clinical work. The ideal myocardial temperature for preservation is uncertain. We and others have evidence that profound cooling, i.e., below 15° to 20° C , may be in itself detrimental, particularly to subsequent myocardial
compliance. Tyers' 2 5 data suggest that a myocardial temperature of 10° to 15° C may be ideal. This, in fact, is the temperature we have achieved by rapid infusion of 1 liter of 4° C. cardioplegic solution in patients. The myocardial temperature in these patients then drifts upward in a variable fashion to 20° to 25° C. Thus we repeat the cardioplegic perfusion every 30 minutes in our clinical practice. Some 26 suggest that it is the hypothermia per se rather than the cardioplegic chemicals which provides the myocardial protection in these techniques. The present study demonstrates that this is not the case. Hearts rendered cardioplegic at 28° C. with potassium (25 mEq. per liter) and mannitol (12.5 Gm. per liter) performed nearly normally following 1 hour's ischemia and just as well as hearts rendered ischemic with 4 8 C cardioplegic solution. Hearts perfused with the same solution at 28° C. lacking the potassium and mannitol were severely damaged. This is not to suggest that cardioplegic solution should not be cold, for hypothermia itself is clearly at least partially protective 27 and the two effects are probably additive. 1, 2- 24 ' 2 8 _ 3 ° REFERENCES 1 Hearse DJ, Stewart DA, Braimbridge MV: The additive effects of potassium ions and hypothermia for the induction of elective cardiac arrest. Biochem Soc Trans 3:417, 1975 2 Hearse DJ, Steward DA, Braimbridge MV: Hypothermic arrest and potassium arrest. Circ Res 36:481-489, 1975 3 Melrose DG, DreyerB, Bentall HH, Baker JB: Elective cardiac arrest. Lancet 2:21-22, 1955 4 McFarland JA, Thomas LB, Gilbert JW, Morrow AG: Myocardial necrosis following elective cardiac arrest induced with potassium citrate J THORAC CARDIOVASC SURG 40:200-208, 1960
5 Kusumoki T, Cheng HC, McGuire HH Jr, Bosher LH Jr: Myocardial dysfunction after cardioplegia. J THORAC CARDIOVASC SURG 40:813-822, 1960
6 Gay WA Jr, Ebert PA: Functional, metabolic, and morphologic effects of potassium-induced cardioplegia. Surgery 74:284-289, 1973 7 Molina JE, Feiber W, Sisk A, Polen T, Collins B: Cardioplegia without fibrillation or defibrillation in cardiac surgery. Surgery 81:619-626, 1977 8 Roe BB, Hutchinson JC, Fishman NH, Ullyot DJ, Smith DL: Myocardial protection with cold, ischemic, potassium-induced cardioplegia. J THORAC CARDIOVASC SURG 73:366-373, 1977
9. Adams PX, Cunningham JN Jr, Brazier J, Pappis M, Trehan N, Spencer FC: Technique and experience using potassium cardioplegia during myocardial revascularization for preinfarction angina. Surgery 83:12-19, 1978 10 Tyers GFO, Manley NJ, Williams EH, Schaffer CW,
Volume 76 Number 3 September, 1978
Williams DR, Kurusz M: Preliminary clinical experience with isotonic hypothermic potassium-induced arrest. J THORAC CARDIOVASC SURG 74:674-681, 1977
11 Cankovic-Darracott S, Braimbridge MV, Williams BT, Bitensky L, Chayen J: Myocardial preservation during aortic valve surgery. J THORAC CARDIOVASC SURG
73:699-706, 1977 12 Todd GJ, Tyers GFO: Amelioration of the effects of ischemic cardiac arrest by the intracoronary administration of cardioplegic solution. Circulation 52:1111-1117, 1975 13 Hearse DJ, Stewart DA, Chain EB: Recovery from cardiac bypass and elective cardiac arrest. Cir Res 35:448457, 1974 14 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 66:742-751, 1973
15 Reitz BA: Potassium-induced cardioplegia (discussion). Ann Thorac Surg 20:99, 1975 16 Berkoff H: Optimal combinations of hypothermia and cardioplegic solutions for organ preservation. Presented before the Association for Academic Surgery. November, 1977. 17 Powell WJ Jr, DiBona DR, Flores J, Leaf A: The protective effect of hyperosmotic mannitol in myocardial ischemia and necrosis. Circulation 54:603-615, 1976 18 Belie N, Singer D, Elson J, Bonnar J: Protection of ischemic myocardium by hyperosmolal mannitol. Circulation 51:Suppl 2:158, 1975 19 Willerson JT: Investigation of the mechanism of the inotropic effect of hypertonic mannitol in isolated cardiac muscle and of mannitol's influence on regional myocardial blood flow in dogs with myocardial ischemia. Am J Cardiol 33:450, 1974 20 Allen WB, Blackstone EH, Kouchoukos NT: Effects of cardiopulmonary bypass and ischemic cardioplegia on the diastolic pressure-volume relationship and water content of the canine left ventricle. Circulation 49,50:Suppl 3: 19, 1974
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21 Busuttil RW, George WJ, Hewitt RL: Protective effect of methylprednisolone on the heart during ischemic arrest. J THORAC CARDIOVASC SURG 20:955-965, 1975
22 Follette D, Fey K, Mulder D, Maloney JV Jr, Buckberg GD: Prolonged safe aortic clamping by combining membrane stabilization, multidose cardioplegia, and appropriate pH reperfusion. J THORAC CARDIOVASC SURG
74:682-694, 1977 23 Hearse DJ, Stewart DA, Braimbridge MV: Myocardial protection during ischemic arrest. J THORAC CARDIOVASC SURG 72:880-884, 1976
24 Goldstein SM, Nelson RL, McConnell DH, Buckberg GD: Effects of conventional hypothermic ischemic arrest and pharmacological arrest on myocardial supply/demand balance during aortic cross clamping. Ann Thorac Surg 23:520-528, 1977 25 Tyers GFO, Williams EH, Hughes HC, Todd GJ: Effect of perfusate temperature on myocardial protection from ischemia. J THORAC CARDIOVASC SURG 73:766-771,
1977 26 Ellis RJ, Pyror W, Ebert PA: Advantages of potassium cardioplegia and perfusion hypothermia in left ventricular hypertrophy. Ann Thorac Surg 24:299-306, 1977 27 Bamer HB, Standeven JW, Jellinek M, Menz LJ, Hahn JW: Topical cardiac hypothermia for myocardial preservation. J THORAC
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1977 28 Nelson RL, Goldstein SM, McConnell DH, Maloney JV Jr, Buckberg GD: Improved myocardial performance after aortic cross clamping by combining pharmacologic arrest with topical hypthermia. Circulation 54:Suppl 3:11-15, 1976 29 Gott VL, Bartlett M, Long DM, Lillehei CW, Johnson JA: Myocardial energy substances in the dog heart during potassium and hypothermic arrest. J Appl Physiol 17:815-818, 1962 30 Jynge P, Hearse DJ, Braimbridge MV: Myocardial protection during ischemic cardiac arrest. J THORAC CARDIOVASC SURG 73:848-854, 1977