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Iatrogenic myocardial edema with potassium cardioplegia
Iatrogenic myocardial edema with potassium cardioplegia Postischemic myocardial edema depresses left ventricular function and coronary perfusion. Pharmacologic cardioplegia is being used increasingly to enhance myocardial protection during cardiac operations. In the present study we varied the colloid osmotic and osmotic pressures and the infusion pressures offour cardioplegic solutions to determine their respective roles in producing or preventing myocardial edema in a nonischemic setting. We found that myocardial edema during potassium cardioplegia (I) is independent of infusion pressures. (2) is caused by isosmotic crystalloid solutions. (3) is worsened by hyposmolar crystalloid solutions. (4) is avoided by the addition of colloid. and (5) is avoided if the solution is made hyperosmotic with the addition of mannitol.
Robert P. Foglia, M.D., David L. Steed, M.D., David M. Follette, M.D., Edward DeLand, Ph.D., and Gerald D. Buckberg, M.D., Los Angeles, Calif.
Myocardial edema is a regular consequence of anoxic damage during aortic clamping. 1, 2 Postischemic edema reduces ventricular performance and compliance" and limits coronary perfusion during reoxygenation.v 5 In an effort to avoid ischemic damage, pharmacologic cardioplegia is increasingly being used. The effectiveness of a properly designed and administered cardioplegic solution in providing myocardial protection is borne out by our experimental studies" showing the complete recovery of left ventricular (L V) function as well as compliance after 2 hours of aortic clamping when such a cardioplegic solution was used. In the present study, we tested the effect of different clinically used cardioplegic solutions of varying colloid osmotic and osmotic pressures, and we administered them at different infusion pressures and volumes. We did this to determine if these cardioplegic solutions would cause myocardial edema, even without ischemia, and whether this iatrogenic edema was avoidable by attending to the determinants of capillary filtration and absorption, i.e., Starling forces. Methods Preparation. Seventeen adult mongrel dogs, weighing 17 to 24 kg, were premedicated with morphine
sulfate (2 mg/kg) and anesthetized with phamytol (10 mg/kg) and alpha chloralose (75 mg/kg). After intubation, ventilation was controlled with a positivepressure respirator and we performed a median sternotomy. Polyethylene catheters were placed into the aorta, left atrium, and vena cava for measuring pressures and withdrawing blood samples. Two additional Teflon catheters* were placed into the proximal aorta for infusion of the cardioplegic solution and measuring infusion pressure. Pressure catheters were connected to Statham p23db transducers, and measurements were recorded on a Honeywell multichannel recorder. A thermistor probet was placed into the intraventricular septum to measure temperature. Normothermic total cardiopulmonary bypass was instituted with an Optiflo oxygenatort primed with 2,000 ml of whole blood, 375 ml of 0.9% sodium chloride, 44 mEq of sodium bicarbonate, and 2 gm of ascorbic acid. Systemic arterial pressure was kept at 100 mm Hg; hematocrit value was 31% ± 1%, pH 7.46 ± 0.02, and Pco, 32 ± 1 mm Hg. Serum colloid osmotic pressure was 10.2 ± 0.5 torr§ and serum osmolarity was 311 ± 2 rnOsm." Measurements. LV water content was measured by taking transmural biopsies of the free wall with a high-
From the Department of Surgery. Thoracic, UCLA School of Medicine, Los Angeles, Calif. 90024.
*Deseret Corporation, Sandy, Utah.
Received for publication Jan. 31, 1979. Accepted for publication April 24, 1979.
tYeliow Springs Instrument Corporation, Yellow Springs, Ohio. :j:Galen Laboratories, Santa Ana, Calif.
Address for reprints: Robert P. Foglia, M.D., Department of Surgery, UCLA School of Medicine, Los Angeles, Calif. 90024.
§Membrane oncometer designed and tested at UCLA Hospital. "Wescor Corporation, Santa Monica, Calif.
0022-5223/79/0802IH06$OO.60/0 © 1979 The C. V. Mosby Co.
217
The Journal of
2 I 8 Foglia et al.
Thoracic and Cardiovascular Surgery
82
oN
1.4
80 E
1.2
<, Ol
I
I
E
78
76/ _
'------
C.OP (rnrnl-lq) 0 Osmolarity 271
(mOsrnl
o
310
E 1.0
DO o
0.8
21 356
370
I
Fig. I. Effects of varying colloid osmotic pressure and osmolarity on myocardial water content. Stippled area shows range of control values ± standard error of the mean. C.O.P., Colloid osmotic pressure. Osmolarity is expressed in milliosmoles. 82
Colloid
Osmolarity
0
310
21
356
(mmHg)
~
o
80
(mOsm)
CO.P(mmHg) 0 Osmolarity: 271
21 356
Fig. 3. Left ventricular compliance during aortic clamping with different cardioplegic solutions (25 ml left ventricular volume). C.O.P., Colloid osmotic pressure. Osmolarity is expressed in milliosmoles.
Table I. Cardioplegic solution composition * Solution
I
o~
II III IV
78
o
370
(rnOsm)
oN
I
o
310
COP (torr)
o o
o
21 ± I (albumin)
Osmolarity (mOsm) 271 ± 3 310 ± 3
370 ± 3 (mannitol) 356 ± 6 (glucose)
Legend: COP, Colloid osmotic pressure.
*Na+ = II 0 ± 4 .mEq/L. K+ = 28. mEq/L. pH 8° C. Values are mean ± SEM.
76 30mmHg
80mmHg
Infusion Pressure
Fig. 2. Effects of varying infusion pressure on myocardial water content. Stippled area shows range of control values ± standard error of the mean. Osmolarity is expressed in milliosmoles. speed drill. The samples averaged 15 to 25 mg and were dried to a constant weight during 48 hours in an oven at 80° C. After the tissue was reweighed, the water content was expressed as a percent water per tissue sample. L V compliance and performance were determined by recording pressure from an intraventricular balloon surrounding a pressure catheter that was placed in the left ventricle through an apical stab wound. The balloon was surrounded by a second balloon to prevent herniation through the mitral valve. Both balloons were totally compliant to a 50 ml volume. LV function and compliance were measured by inflating the inner bal-
= 7.70.
Temperature
=
loon with 5 ml aliquots of normal saline and simultaneously recording LV systolic and diastolic pressures. LV dP/dt was measured by differentiating the L V signal. Compliance was expressed as end-diastolic pressure/balloon volume. Solution composition. Each cardioplegic solution had comparable electrolyte composition and was 8° C when given (Table I). The cardioplegic additive was 30 mEq/L of potassium chloride, and pH was adjusted to 7.70. 7 The solutions differed only in colloid osmotic and osmotic pressures: Solution I, hyposmolar (271 mOsm), no protein; Solution II, isosmolar (310 mOsm), no protein; Solution lll, hyperosmolar (370 mOsm with mannitol), no protein; Solution IV, hyperosmolar (356 mOsm, with glucose) and hypercolloid (21 torr, with albumin). Procedure. A transmural biopsy was taken for measurement of myocardial water content and an isovolumetric LV function curve was inscribed before each pharmacologic arrest and 10 minutes after the resump-
Volume 78
2I9
Myocardial edema with potassium cardioplegia
Number 2 August, 1979
Table II Infusion Volume Solution
No.
(ml )
Pressure (mmHg)
I
7 5 5 6 7 5 4 5
250 250 250 1,000 250 250 250 1,000
80 30 80 80 30 30 80 80
II II II III
IV IV IV
LV function (% recovery) *
Percent water
Control
78.1 78.7 78.8 78.3 78.8 78.3 78.8 78.6
± ± ± ± ± ± ± ±
0.2 0.2 0.3 0.3 0.3 0.3 0.4 0.5
Arrest (control)
80.4 79.5 79.5 79.3 75.5 76.5 77.1 76.0
Peak developed pressure
Reperfusion
± 0.3 ± 0.2 ± 0.3 ± 0.2 ± 0.4 ± 0.3 ±0.5 ± 0.3
78.4 79.1 78.8 78.7 78.8 78.6 78.9 78.5
± ± ± ± ± ± ± ±
0.3 0.3 0.3 0.5 0.2 0.2 0.2 0.5
91 90 94 93 94 95 104 102
± ± ± ± ± ± ± ±
4 2 4 3 6 3 3 6
+dPldt
91.5 91.6 100.0 83.3 100.2 91.4 105.0 98.1
± ± ± ± ± ± ± ±
Compliance
7.7 3.8 7.5 6.6 5.6 1.9 3.2 7.2
96 87 94 93 91 91 !OI 93
± ± ± ± ± ± ± ±
2 4 3 5 3 5 7 9
Legend: LV, Left ventricular.
'At 25 cc balloon volume.
tion of sinus rhythm. Pharmacologic arrest was accomplished by clamping the aorta and infusing either 250 or 1,000 ml of cardioplegic solution into the proximal aorta at an infusion pressure of either 30 or 80 mm Hg. During arrest, we obtained transmural biopsies for measurement of myocardial water content and inflated the intraventricular balloon to assess ventricular compliance. We limited periods of arrest to 10 min to avoid ischemic damage so that we could separate the effects of cardioplegic solution composition from those of ischemia.
Results The results are summarized in Tables II and III and Figs. I through 3. Cardioplegic composition. All hearts stopped within I minute after beginning the cardioplegic infusion. Despite rapid cardioplegia, significant myocardial water accumulation (2.3% water gain, p < 0.05) occurred when arrest was achieved with the hyposmotic crystalloid solution (Fig. I, Table II). Less severe but significant myocardial edema (0.8% water gain, p < 0.05) also occurred when the osmolarity of the crystalloid cardioplegic solution was made normal. In contrast, the hyperosmotic, hypercolloid cardioplegic solution produced significant myocardial water loss (1.8% dehydration, p < 0.05). A comparable degree of cardiac dehydration (2.3% water loss, p < 0.05) was produced by the hyperosmotic mannitol-containing solution with no added colloid. Infusion pressure. Arrest occurred within 19 seconds when the cardioplegic solution was infused at 80 mm Hg, but it was delayed until 53 seconds when an infusion pressure of 30 mm Hg was used. The myocardial edema produced by the isosmolar crystalloid solution without protein was comparable at both 30 and
Table III. Left ventricular compliance*: Beating versus arrested heart Infusion Solution
I II II II III
IV IV IV
No.
Pressure (mm Hg)
7 5 7 6 7 5 4 5
80 30 80 80 30 30 80 80
I
Volume (ml)
250 250 250 1,000 250 250 250 1,000
Compliance Beating (mm Hg)
0.58 0.56 0.55 0.57 0.57 0.53 0.56 0.61
± ± ± ± ± ± ± ±
0.06 0.06 0.06 0.04 0.06 0.03 0.04 0.05
I
Arrest (mm Hg)
1.31 ± 0.12 0.98 ± 0.09 1.00 ± 0.14 1.93±0.31 0.94 ± 0.09 0.84 ± 0.05 0.91 ± 0.07 1.52 ± 0.08
'Mean ± SEM at 25 cc balloon volume.
80 mm Hg infusion pressures (0.8% versus 0.7% water gain). Similarly, the myocardial dehydration (1. 8% versus 1.7% water loss) produced by the hyperosmotic colloid solution was comparable at high and low infusion pressures (Fig. 2). Cardioplegia volume. The principal effect of the large volume of go C cardioplegic infusate was the production of more profound myocardial cooling. When 250 rnl was given myocardial temperature fell to 20° C, whereas 1,000 ml lowered myocardial temperature to 12° C (p < 0.05). The larger volume infusions accentuated the direction of myocardial water movement but, owing to variability in the data, this difference was not significant. For example, there was a 0.8% ± 0.2% water gain with 250 ml infusions, compared with a 1.0% ± 0.3% gain with 1,000 ml of the isosmolar crystalloid solution; there was a 1.7% ± 0,5% water loss with 250 rnl infusions of the hyperosmotic protein-containing solution, compared with a 2.6% ± 0.4% water loss with 1,000 rnl infusions (Table II).
The Journal of Thoracic and Cardiovascular Surgery
220 Foglia et al.
Ventricular compliance. In all instances, cold arrested hearts were less compliant than warm beating hearts (Table III). The lowered compliance occurred when the cardioplegic solutions reduced intramyocardial temperature to 12 C. At comparable myocardial temperatures (20 C) and infusion volumes (250 ml), the hyposmotic crystalloid solution caused the greatest depression in compliance (126%), whereas the hyperosmotic protein-containing solution produced the least depression (58%) of compliance (Fig. 3). Water content and function after reperfusion. In all instances, myocardial water content, compliance, and cardiac performance returned to prearrest levels when these variables were measured 10 minutes after the aortic clamp was released (Table II). 0
0
Discussion Leaf" has shown that myocardial edema is one of the earliest results of ischemic cellular damage and reflects the limitation of cellular capacity to regulate its volume after ischemia. As a result, marked cellular swelling may occur after blood supply is restored. 9. 10 In all instances, myocardial edema results from an alteration of the determinants of capillary fluid flux. These determinants, described by Starling;'! include the hydrostatic and colloid osmotic pressures on either side of the capillary and the state of capillary membrane, as shown by the equation: H2 0 movement = K (P, - Pi -
1Tc
+ 1Tj)
where P, = capillary hydrostatic pressure, Pi = interstitial hydrostatic pressure, 7Tc = capillary colloid osmotic pressure, 7Tj = interstitial colloid osmotic pressure, and K = filtration constant of the capillary membrane. When Starling proposed this theory, he dealt with steady-state circumstances where fluid osmolarity was normal and the cell membrane was intact. With myocardial ischemia, however, the capillary membrane often is damaged. Consequently, myocardial edema can develop at perfusion and colloid osmotic pressures that would not cause swelling of the normal heart. To a large extent, each of the factors regulating myocardial fluid flux is under our control when we give cardioplegic solutions. Although we could not assure a steady state in our study, we limited periods of myocardial anoxia to 10 minutes to avoid cellular damage. The return of all measured variables (performance, compliance, and water content) to control levels indicated that detectable ischemic injury was not produced. This avoidance of ischemic cellular damage allowed us to evaluate the effect on myocardial water content of vary-
ing the composition (crystalloid and colloid) as well as the infusion pressure and volume of the cardioplegic solutions. Cardioplegic composition. Our studies demonstrate that cardioplegic solutions can cause significant changes in myocardial water content even while avoiding ischemic injury. The importance of maintaining the colloid osmotic pressure of the blood perfusing the heart is emphasized by reports showing the production of marked myocardial edema when crystalloid hemodilution is used in priming the extracorporeal circuit, even under conditions where aortic clamping is not practiced. 12. 13 In our study, all cardioplegic solutions produced prompt arrest, but hearts gained 1% water when as little as 250 rnl of an isosmotic solution without protein was employed as the vehicle for the cardioplegic solution. This effect was accentuated when we reduced the osmolarity of the cardioplegic solution. Heart receiving a hyposmolar crystalloid solution gained as much water (2.3%) as did hearts we" studied previously, which were subjected to 60 minutes of topical hypothermic ischemic arrest (2.4% water gain). The myocardial edema caused by the cardioplegic solutions resolved promptly when these hearts were reperfused with blood containing appropriate osmotic and colloid osmotic pressures after 10 minutes of ischemia. Such reversal was not possible in our previous studies when ischemic edema was produced by longer periods of aortic clamping. 3 In contrast, hypercolloidal hyperosmotic cardioplegic solution caused moderate myocardial dehydration. We added the colloid to maintain the colloid osmotic forces necessary to prevent edema. To our surprise, comparable dehydration occurred without adding protein when we raised osmolarity from 310 mOsm to 370 mOsm with hyperosmotic mannitol. This observation has clinical implications in that protein, a costly additive to the cardioplegic solution, does not appear necessary if sufficient hyperosmolarity is used. Infusion pressure. Our initial hypothesis was that edema would develop if high hydrostatic pressures were used while delivering asanguineous anoxic cardioplegic solutions. We anticipated that the hydrostatic gradient would force fluid out of the capillary bed. Such edema at high perfusion pressures was recently reported by Engelman and associates '" when they studied reperfusion of postischemic hearts. Our experimental observations did not support this hypothesis. We found tissue water content to be determined by the cardioplegic solution composition, but not by the perfusion pressure (30 or 80 mm Hg). Our study, however, was carried out in hearts with normal
Volume 78 Number 2
Myocardial edema with potassium cardioplegia
22 I
August. 1979
capillary membranes. In contrast, Engelman observed edema development in hearts that had undergone severe ischemic injury. It is possible also that the arterial pressure recorded in the aorta becomes dissipated as fluid (blood or cardioplegic solution) proceeds down the branched coronary arteries to the capillaries. Such attenuation of perfusion pressure would explain why beating hearts, whose arteries are maximally dilated, do not become edematous at perfusion pressures of 100 mm Hg. Inasmuch as our biopsies were taken approximately 8 minutes after stopping the cardioplegic infusion, it is possible also that we failed to detect a transient water gain when a high pressure was used; re-equilibration during the time between the end of the infusion and the time of the biopsy may have occurred. The principal difference between delivery of cardioplegic solutions at high and low perfusion pressures was in the rapidity of pharmacologic arrest; at an infusion pressure of 80 mm Hg hearts stopped within 19 seconds, as compared with 53 seconds at an infusion pressure of 30 mm Hg. Rapid cardioplegia provides the practical advantages of reducing the duration of ischemic electromechanical work occurring when nonblood-containing cardioplegic vehicles are used. A recent study by Wright and associates." shows that the transient electromechanical activity preceding arrest with crystalloid cardioplegic solutions produces a substantial reduction of high-energy phosphates. Inducing pharmacologic arrest by delivery of a cardioplegic solution containing appropriate osmolarity and colloid osmolarity at an infusion pressure of 80 mm Hg will produce rapid cardioplegia and may circumvent this potential problem. This may be of special importance in patients with obstructive coronary lesions. It will be necessary, however, to test whether repeated infusions of cardioplegic solutions have the same result, especially under high pressures, before using such pressures when clinically administering multidose cardioplegia. Infusion volume. The volume of cardioplegic infusate did not affect the myocardial water content, but larger volume infusions did produce more profound cardiac hypothermia; 1,000 ml infusates lowered myocardial temperature to 12° C, whereas 250 ml infusates reduced myocardial temperature to only 200 C. This ability to achieve more profound levels of hypothermia may be one potential advantage of increased cardioplegic volumes. We measured ventricular compliance during arrest in an effort to quantitate the effects of myocardial edema. We observed that arrested hearts developed higher LV diastolic pressures than normothermic beating hearts at comparable LV volumes. The lowest compliance al-
ways occurred with the most profound levels of hypothermia. However, arrested hearts do continue to metabolize, since arrest is essentially a prolonged diastole. Diastole is an active metabolic state related directly to the cell's ability to sequester calcium, and therefore it is possible that the decreased compliance during arrest reflects the progressive reduction in the rate of myocardial calcium flux with hypothermia. At comparable levels of hypothermia, however, hearts made edematous with crystalloid cardioplegia were always less compliant than those with normal or decreased water content. The reversible nature of the iatrogenic changes in myocardial water content was evident from post-reperfusion measurements of myocardial compliance, performance, and wet: dry weights. All variables returned to control levels after blood containing appropriate colloid osmotic and osmotic pressures was reintroduced by removing the aortic clamp. Consequently, little or no ischemic damage or alteration of the heart's capacity to regulate its cellular volume was produced by these brief periods of pharmacologic arrest in normal hearts. In contrast, in most patients undergoing cardiac operations, the heart evidences varying degrees of hypertrophy and ischemia and must undergo longer periods of aortic clamping. We suspect that in such cases the edema produced by any cardioplegic solution may be less reversible and will add to the edema stemming from ischemia itself.
2
3
4 5
6
REFERENCES Utley JR, Michalsky GB, Bryant LR, Mobin-Uddin K, McKean HE: Determinants of myocardial water content during cardiopulmonary bypass. J THoRAc CARDIOVASC SURG 68:8-16, 1974 Follette DM, Steed DL, Foglia RP, Fey KH, Buckberg GD: Reduction of postischemic myocardial damage by maintaining arrest during initial reperfusion. Surg Forum 28:281-283, 1977 Nelson RL, Goldstein M, McConnell DH, Maloney JV, Buckberg GD: Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. J THoRAc CARDIOVASC SURG 73:201-207, 1977 Frame LH, Powell WJ: Progressive resistanceto coronary blood flow in the low flow ischemic state. Circulation 52:Suppl 2:183, 1975 Willerson JT, Watson JT, Hutton I, Templeton GH, Fixler DE: Reduced myocardial reflowand increased coronary vascularresistancefollowing prolonged myocardial ischemia in the dog. Circ Res 36:771-781, 1975 FolletteDM, Fey K, Mulder DG, Maloney JV, Buckberg GD: Prolonged safe aortic clamping by combining membrane stabilization, multidose cardioplegia, and appro-
222 Foglia et al.
7
8 9
10
II 12
priate pH reperfusion. J THoRAc CARDIOVASC SURG 74:682-694, 1977 McConnell DH, White F, Nelson RL, Goldstein SM, Maloney JV, Deland EC, Buckberg GD: Importance of alkalosis in maintenance of "ideal" blood pH during hypothermia. Surg Forum 26:263-265, 1975 Leaf A: Cell swelling. A factor in ischemic tissue injury. Editorial. Circulation 48:455-458, 1973 Whalen DA, Hamilton DG, Ganote CE, Jennings RB: Effect of a transient period of ischemia on myocardial cells. I. Effects on cell volume regulation. Am J Pathol 74:381-398, 1974 Kloner RA, Ganote CE, Whalen DA, Jennings RB: Effect of a transient period of ischemia on myocardial cells. II. Fine structure during the first few minutes of reflow. Am J Pathol 74:399-422, 1974 Starling EH: On the absorption of fluids from the connective tissue spaces. J Physiol (London) 19:312-326, 1896 Lowenstein E, Cooper JD, Erdman AJ, Geffin G, Laver
The Journal of Thoracic and Cardiovascular Surgery
MB, Yoshikakawa H: Lung and heart water accumulation associated with hemodilution. Intentional Hemodilution, K Messmer, H Schmid-Schonbein, eds. (Bibliotheca haematologica, No. 41), Basel, 1975, S. Karger, A. G., pp. 190-202 13 Laks H, Standeven J, Blair 0, Hahn J, Jellinek M, Willman VL: The effects of cardiopulmonary bypass with crystalloid and colloid hemodilution on myocardial extravascular water. J THoRAc CARDIOVASC SURG 73: 129138, 1977 14 Engelman RM, Spencer FC, Adler A, George TH, Chandra R, Body SD: Effects of normothermic anoxic arrest on coronary blood flow distribution of pigs. Surg Forum 25: 176-179, 1974 15 Wright RM, Levitsky S, Holland C, Feinberg H: Beneficial effects of potassium cardioplegia during intermittent aortic cross clamping and reperfusion. J Surg Res 24:201-209, 1978
Information for authors Most of the provisions of the Copyright Act of 1976 became effective on January I, 1978. Therefore, all manuscripts must be accompanied by the following written statement, signed by one author: "The undersigned author transfers all copyright ownership of the manuscript (title of article) to The C. V. Mosby Company in the event the work is published. The undersigned author warrants that the article is original, is not under consideration by another journal, and has not been previously published. I sign for and accept responsibility for releasing this material on behalf of any and all co-authors." Authors will be consulted, when possible, regarding republication of their material.
Robert P. Foglia, M.D., David L. Steed, M.D., David M. Follette, M.D., Edward DeLand, Ph.D., and Gerald D. Buckberg, M.D., Los Angeles, Calif.
Myocardial edema is a regular consequence of anoxic damage during aortic clamping. 1, 2 Postischemic edema reduces ventricular performance and compliance" and limits coronary perfusion during reoxygenation.v 5 In an effort to avoid ischemic damage, pharmacologic cardioplegia is increasingly being used. The effectiveness of a properly designed and administered cardioplegic solution in providing myocardial protection is borne out by our experimental studies" showing the complete recovery of left ventricular (L V) function as well as compliance after 2 hours of aortic clamping when such a cardioplegic solution was used. In the present study, we tested the effect of different clinically used cardioplegic solutions of varying colloid osmotic and osmotic pressures, and we administered them at different infusion pressures and volumes. We did this to determine if these cardioplegic solutions would cause myocardial edema, even without ischemia, and whether this iatrogenic edema was avoidable by attending to the determinants of capillary filtration and absorption, i.e., Starling forces. Methods Preparation. Seventeen adult mongrel dogs, weighing 17 to 24 kg, were premedicated with morphine
sulfate (2 mg/kg) and anesthetized with phamytol (10 mg/kg) and alpha chloralose (75 mg/kg). After intubation, ventilation was controlled with a positivepressure respirator and we performed a median sternotomy. Polyethylene catheters were placed into the aorta, left atrium, and vena cava for measuring pressures and withdrawing blood samples. Two additional Teflon catheters* were placed into the proximal aorta for infusion of the cardioplegic solution and measuring infusion pressure. Pressure catheters were connected to Statham p23db transducers, and measurements were recorded on a Honeywell multichannel recorder. A thermistor probet was placed into the intraventricular septum to measure temperature. Normothermic total cardiopulmonary bypass was instituted with an Optiflo oxygenatort primed with 2,000 ml of whole blood, 375 ml of 0.9% sodium chloride, 44 mEq of sodium bicarbonate, and 2 gm of ascorbic acid. Systemic arterial pressure was kept at 100 mm Hg; hematocrit value was 31% ± 1%, pH 7.46 ± 0.02, and Pco, 32 ± 1 mm Hg. Serum colloid osmotic pressure was 10.2 ± 0.5 torr§ and serum osmolarity was 311 ± 2 rnOsm." Measurements. LV water content was measured by taking transmural biopsies of the free wall with a high-
From the Department of Surgery. Thoracic, UCLA School of Medicine, Los Angeles, Calif. 90024.
*Deseret Corporation, Sandy, Utah.
Received for publication Jan. 31, 1979. Accepted for publication April 24, 1979.
tYeliow Springs Instrument Corporation, Yellow Springs, Ohio. :j:Galen Laboratories, Santa Ana, Calif.
Address for reprints: Robert P. Foglia, M.D., Department of Surgery, UCLA School of Medicine, Los Angeles, Calif. 90024.
§Membrane oncometer designed and tested at UCLA Hospital. "Wescor Corporation, Santa Monica, Calif.
0022-5223/79/0802IH06$OO.60/0 © 1979 The C. V. Mosby Co.
217
The Journal of
2 I 8 Foglia et al.
Thoracic and Cardiovascular Surgery
82
oN
1.4
80 E
1.2
<, Ol
I
I
E
78
76/ _
'------
C.OP (rnrnl-lq) 0 Osmolarity 271
(mOsrnl
o
310
E 1.0
DO o
0.8
21 356
370
I
Fig. I. Effects of varying colloid osmotic pressure and osmolarity on myocardial water content. Stippled area shows range of control values ± standard error of the mean. C.O.P., Colloid osmotic pressure. Osmolarity is expressed in milliosmoles. 82
Colloid
Osmolarity
0
310
21
356
(mmHg)
~
o
80
(mOsm)
CO.P(mmHg) 0 Osmolarity: 271
21 356
Fig. 3. Left ventricular compliance during aortic clamping with different cardioplegic solutions (25 ml left ventricular volume). C.O.P., Colloid osmotic pressure. Osmolarity is expressed in milliosmoles.
Table I. Cardioplegic solution composition * Solution
I
o~
II III IV
78
o
370
(rnOsm)
oN
I
o
310
COP (torr)
o o
o
21 ± I (albumin)
Osmolarity (mOsm) 271 ± 3 310 ± 3
370 ± 3 (mannitol) 356 ± 6 (glucose)
Legend: COP, Colloid osmotic pressure.
*Na+ = II 0 ± 4 .mEq/L. K+ = 28. mEq/L. pH 8° C. Values are mean ± SEM.
76 30mmHg
80mmHg
Infusion Pressure
Fig. 2. Effects of varying infusion pressure on myocardial water content. Stippled area shows range of control values ± standard error of the mean. Osmolarity is expressed in milliosmoles. speed drill. The samples averaged 15 to 25 mg and were dried to a constant weight during 48 hours in an oven at 80° C. After the tissue was reweighed, the water content was expressed as a percent water per tissue sample. L V compliance and performance were determined by recording pressure from an intraventricular balloon surrounding a pressure catheter that was placed in the left ventricle through an apical stab wound. The balloon was surrounded by a second balloon to prevent herniation through the mitral valve. Both balloons were totally compliant to a 50 ml volume. LV function and compliance were measured by inflating the inner bal-
= 7.70.
Temperature
=
loon with 5 ml aliquots of normal saline and simultaneously recording LV systolic and diastolic pressures. LV dP/dt was measured by differentiating the L V signal. Compliance was expressed as end-diastolic pressure/balloon volume. Solution composition. Each cardioplegic solution had comparable electrolyte composition and was 8° C when given (Table I). The cardioplegic additive was 30 mEq/L of potassium chloride, and pH was adjusted to 7.70. 7 The solutions differed only in colloid osmotic and osmotic pressures: Solution I, hyposmolar (271 mOsm), no protein; Solution II, isosmolar (310 mOsm), no protein; Solution lll, hyperosmolar (370 mOsm with mannitol), no protein; Solution IV, hyperosmolar (356 mOsm, with glucose) and hypercolloid (21 torr, with albumin). Procedure. A transmural biopsy was taken for measurement of myocardial water content and an isovolumetric LV function curve was inscribed before each pharmacologic arrest and 10 minutes after the resump-
Volume 78
2I9
Myocardial edema with potassium cardioplegia
Number 2 August, 1979
Table II Infusion Volume Solution
No.
(ml )
Pressure (mmHg)
I
7 5 5 6 7 5 4 5
250 250 250 1,000 250 250 250 1,000
80 30 80 80 30 30 80 80
II II II III
IV IV IV
LV function (% recovery) *
Percent water
Control
78.1 78.7 78.8 78.3 78.8 78.3 78.8 78.6
± ± ± ± ± ± ± ±
0.2 0.2 0.3 0.3 0.3 0.3 0.4 0.5
Arrest (control)
80.4 79.5 79.5 79.3 75.5 76.5 77.1 76.0
Peak developed pressure
Reperfusion
± 0.3 ± 0.2 ± 0.3 ± 0.2 ± 0.4 ± 0.3 ±0.5 ± 0.3
78.4 79.1 78.8 78.7 78.8 78.6 78.9 78.5
± ± ± ± ± ± ± ±
0.3 0.3 0.3 0.5 0.2 0.2 0.2 0.5
91 90 94 93 94 95 104 102
± ± ± ± ± ± ± ±
4 2 4 3 6 3 3 6
+dPldt
91.5 91.6 100.0 83.3 100.2 91.4 105.0 98.1
± ± ± ± ± ± ± ±
Compliance
7.7 3.8 7.5 6.6 5.6 1.9 3.2 7.2
96 87 94 93 91 91 !OI 93
± ± ± ± ± ± ± ±
2 4 3 5 3 5 7 9
Legend: LV, Left ventricular.
'At 25 cc balloon volume.
tion of sinus rhythm. Pharmacologic arrest was accomplished by clamping the aorta and infusing either 250 or 1,000 ml of cardioplegic solution into the proximal aorta at an infusion pressure of either 30 or 80 mm Hg. During arrest, we obtained transmural biopsies for measurement of myocardial water content and inflated the intraventricular balloon to assess ventricular compliance. We limited periods of arrest to 10 min to avoid ischemic damage so that we could separate the effects of cardioplegic solution composition from those of ischemia.
Results The results are summarized in Tables II and III and Figs. I through 3. Cardioplegic composition. All hearts stopped within I minute after beginning the cardioplegic infusion. Despite rapid cardioplegia, significant myocardial water accumulation (2.3% water gain, p < 0.05) occurred when arrest was achieved with the hyposmotic crystalloid solution (Fig. I, Table II). Less severe but significant myocardial edema (0.8% water gain, p < 0.05) also occurred when the osmolarity of the crystalloid cardioplegic solution was made normal. In contrast, the hyperosmotic, hypercolloid cardioplegic solution produced significant myocardial water loss (1.8% dehydration, p < 0.05). A comparable degree of cardiac dehydration (2.3% water loss, p < 0.05) was produced by the hyperosmotic mannitol-containing solution with no added colloid. Infusion pressure. Arrest occurred within 19 seconds when the cardioplegic solution was infused at 80 mm Hg, but it was delayed until 53 seconds when an infusion pressure of 30 mm Hg was used. The myocardial edema produced by the isosmolar crystalloid solution without protein was comparable at both 30 and
Table III. Left ventricular compliance*: Beating versus arrested heart Infusion Solution
I II II II III
IV IV IV
No.
Pressure (mm Hg)
7 5 7 6 7 5 4 5
80 30 80 80 30 30 80 80
I
Volume (ml)
250 250 250 1,000 250 250 250 1,000
Compliance Beating (mm Hg)
0.58 0.56 0.55 0.57 0.57 0.53 0.56 0.61
± ± ± ± ± ± ± ±
0.06 0.06 0.06 0.04 0.06 0.03 0.04 0.05
I
Arrest (mm Hg)
1.31 ± 0.12 0.98 ± 0.09 1.00 ± 0.14 1.93±0.31 0.94 ± 0.09 0.84 ± 0.05 0.91 ± 0.07 1.52 ± 0.08
'Mean ± SEM at 25 cc balloon volume.
80 mm Hg infusion pressures (0.8% versus 0.7% water gain). Similarly, the myocardial dehydration (1. 8% versus 1.7% water loss) produced by the hyperosmotic colloid solution was comparable at high and low infusion pressures (Fig. 2). Cardioplegia volume. The principal effect of the large volume of go C cardioplegic infusate was the production of more profound myocardial cooling. When 250 rnl was given myocardial temperature fell to 20° C, whereas 1,000 ml lowered myocardial temperature to 12° C (p < 0.05). The larger volume infusions accentuated the direction of myocardial water movement but, owing to variability in the data, this difference was not significant. For example, there was a 0.8% ± 0.2% water gain with 250 ml infusions, compared with a 1.0% ± 0.3% gain with 1,000 ml of the isosmolar crystalloid solution; there was a 1.7% ± 0,5% water loss with 250 rnl infusions of the hyperosmotic protein-containing solution, compared with a 2.6% ± 0.4% water loss with 1,000 rnl infusions (Table II).
The Journal of Thoracic and Cardiovascular Surgery
220 Foglia et al.
Ventricular compliance. In all instances, cold arrested hearts were less compliant than warm beating hearts (Table III). The lowered compliance occurred when the cardioplegic solutions reduced intramyocardial temperature to 12 C. At comparable myocardial temperatures (20 C) and infusion volumes (250 ml), the hyposmotic crystalloid solution caused the greatest depression in compliance (126%), whereas the hyperosmotic protein-containing solution produced the least depression (58%) of compliance (Fig. 3). Water content and function after reperfusion. In all instances, myocardial water content, compliance, and cardiac performance returned to prearrest levels when these variables were measured 10 minutes after the aortic clamp was released (Table II). 0
0
Discussion Leaf" has shown that myocardial edema is one of the earliest results of ischemic cellular damage and reflects the limitation of cellular capacity to regulate its volume after ischemia. As a result, marked cellular swelling may occur after blood supply is restored. 9. 10 In all instances, myocardial edema results from an alteration of the determinants of capillary fluid flux. These determinants, described by Starling;'! include the hydrostatic and colloid osmotic pressures on either side of the capillary and the state of capillary membrane, as shown by the equation: H2 0 movement = K (P, - Pi -
1Tc
+ 1Tj)
where P, = capillary hydrostatic pressure, Pi = interstitial hydrostatic pressure, 7Tc = capillary colloid osmotic pressure, 7Tj = interstitial colloid osmotic pressure, and K = filtration constant of the capillary membrane. When Starling proposed this theory, he dealt with steady-state circumstances where fluid osmolarity was normal and the cell membrane was intact. With myocardial ischemia, however, the capillary membrane often is damaged. Consequently, myocardial edema can develop at perfusion and colloid osmotic pressures that would not cause swelling of the normal heart. To a large extent, each of the factors regulating myocardial fluid flux is under our control when we give cardioplegic solutions. Although we could not assure a steady state in our study, we limited periods of myocardial anoxia to 10 minutes to avoid cellular damage. The return of all measured variables (performance, compliance, and water content) to control levels indicated that detectable ischemic injury was not produced. This avoidance of ischemic cellular damage allowed us to evaluate the effect on myocardial water content of vary-
ing the composition (crystalloid and colloid) as well as the infusion pressure and volume of the cardioplegic solutions. Cardioplegic composition. Our studies demonstrate that cardioplegic solutions can cause significant changes in myocardial water content even while avoiding ischemic injury. The importance of maintaining the colloid osmotic pressure of the blood perfusing the heart is emphasized by reports showing the production of marked myocardial edema when crystalloid hemodilution is used in priming the extracorporeal circuit, even under conditions where aortic clamping is not practiced. 12. 13 In our study, all cardioplegic solutions produced prompt arrest, but hearts gained 1% water when as little as 250 rnl of an isosmotic solution without protein was employed as the vehicle for the cardioplegic solution. This effect was accentuated when we reduced the osmolarity of the cardioplegic solution. Heart receiving a hyposmolar crystalloid solution gained as much water (2.3%) as did hearts we" studied previously, which were subjected to 60 minutes of topical hypothermic ischemic arrest (2.4% water gain). The myocardial edema caused by the cardioplegic solutions resolved promptly when these hearts were reperfused with blood containing appropriate osmotic and colloid osmotic pressures after 10 minutes of ischemia. Such reversal was not possible in our previous studies when ischemic edema was produced by longer periods of aortic clamping. 3 In contrast, hypercolloidal hyperosmotic cardioplegic solution caused moderate myocardial dehydration. We added the colloid to maintain the colloid osmotic forces necessary to prevent edema. To our surprise, comparable dehydration occurred without adding protein when we raised osmolarity from 310 mOsm to 370 mOsm with hyperosmotic mannitol. This observation has clinical implications in that protein, a costly additive to the cardioplegic solution, does not appear necessary if sufficient hyperosmolarity is used. Infusion pressure. Our initial hypothesis was that edema would develop if high hydrostatic pressures were used while delivering asanguineous anoxic cardioplegic solutions. We anticipated that the hydrostatic gradient would force fluid out of the capillary bed. Such edema at high perfusion pressures was recently reported by Engelman and associates '" when they studied reperfusion of postischemic hearts. Our experimental observations did not support this hypothesis. We found tissue water content to be determined by the cardioplegic solution composition, but not by the perfusion pressure (30 or 80 mm Hg). Our study, however, was carried out in hearts with normal
Volume 78 Number 2
Myocardial edema with potassium cardioplegia
22 I
August. 1979
capillary membranes. In contrast, Engelman observed edema development in hearts that had undergone severe ischemic injury. It is possible also that the arterial pressure recorded in the aorta becomes dissipated as fluid (blood or cardioplegic solution) proceeds down the branched coronary arteries to the capillaries. Such attenuation of perfusion pressure would explain why beating hearts, whose arteries are maximally dilated, do not become edematous at perfusion pressures of 100 mm Hg. Inasmuch as our biopsies were taken approximately 8 minutes after stopping the cardioplegic infusion, it is possible also that we failed to detect a transient water gain when a high pressure was used; re-equilibration during the time between the end of the infusion and the time of the biopsy may have occurred. The principal difference between delivery of cardioplegic solutions at high and low perfusion pressures was in the rapidity of pharmacologic arrest; at an infusion pressure of 80 mm Hg hearts stopped within 19 seconds, as compared with 53 seconds at an infusion pressure of 30 mm Hg. Rapid cardioplegia provides the practical advantages of reducing the duration of ischemic electromechanical work occurring when nonblood-containing cardioplegic vehicles are used. A recent study by Wright and associates." shows that the transient electromechanical activity preceding arrest with crystalloid cardioplegic solutions produces a substantial reduction of high-energy phosphates. Inducing pharmacologic arrest by delivery of a cardioplegic solution containing appropriate osmolarity and colloid osmolarity at an infusion pressure of 80 mm Hg will produce rapid cardioplegia and may circumvent this potential problem. This may be of special importance in patients with obstructive coronary lesions. It will be necessary, however, to test whether repeated infusions of cardioplegic solutions have the same result, especially under high pressures, before using such pressures when clinically administering multidose cardioplegia. Infusion volume. The volume of cardioplegic infusate did not affect the myocardial water content, but larger volume infusions did produce more profound cardiac hypothermia; 1,000 ml infusates lowered myocardial temperature to 12° C, whereas 250 ml infusates reduced myocardial temperature to only 200 C. This ability to achieve more profound levels of hypothermia may be one potential advantage of increased cardioplegic volumes. We measured ventricular compliance during arrest in an effort to quantitate the effects of myocardial edema. We observed that arrested hearts developed higher LV diastolic pressures than normothermic beating hearts at comparable LV volumes. The lowest compliance al-
ways occurred with the most profound levels of hypothermia. However, arrested hearts do continue to metabolize, since arrest is essentially a prolonged diastole. Diastole is an active metabolic state related directly to the cell's ability to sequester calcium, and therefore it is possible that the decreased compliance during arrest reflects the progressive reduction in the rate of myocardial calcium flux with hypothermia. At comparable levels of hypothermia, however, hearts made edematous with crystalloid cardioplegia were always less compliant than those with normal or decreased water content. The reversible nature of the iatrogenic changes in myocardial water content was evident from post-reperfusion measurements of myocardial compliance, performance, and wet: dry weights. All variables returned to control levels after blood containing appropriate colloid osmotic and osmotic pressures was reintroduced by removing the aortic clamp. Consequently, little or no ischemic damage or alteration of the heart's capacity to regulate its cellular volume was produced by these brief periods of pharmacologic arrest in normal hearts. In contrast, in most patients undergoing cardiac operations, the heart evidences varying degrees of hypertrophy and ischemia and must undergo longer periods of aortic clamping. We suspect that in such cases the edema produced by any cardioplegic solution may be less reversible and will add to the edema stemming from ischemia itself.
2
3
4 5
6
REFERENCES Utley JR, Michalsky GB, Bryant LR, Mobin-Uddin K, McKean HE: Determinants of myocardial water content during cardiopulmonary bypass. J THoRAc CARDIOVASC SURG 68:8-16, 1974 Follette DM, Steed DL, Foglia RP, Fey KH, Buckberg GD: Reduction of postischemic myocardial damage by maintaining arrest during initial reperfusion. Surg Forum 28:281-283, 1977 Nelson RL, Goldstein M, McConnell DH, Maloney JV, Buckberg GD: Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. J THoRAc CARDIOVASC SURG 73:201-207, 1977 Frame LH, Powell WJ: Progressive resistanceto coronary blood flow in the low flow ischemic state. Circulation 52:Suppl 2:183, 1975 Willerson JT, Watson JT, Hutton I, Templeton GH, Fixler DE: Reduced myocardial reflowand increased coronary vascularresistancefollowing prolonged myocardial ischemia in the dog. Circ Res 36:771-781, 1975 FolletteDM, Fey K, Mulder DG, Maloney JV, Buckberg GD: Prolonged safe aortic clamping by combining membrane stabilization, multidose cardioplegia, and appro-
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8 9
10
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priate pH reperfusion. J THoRAc CARDIOVASC SURG 74:682-694, 1977 McConnell DH, White F, Nelson RL, Goldstein SM, Maloney JV, Deland EC, Buckberg GD: Importance of alkalosis in maintenance of "ideal" blood pH during hypothermia. Surg Forum 26:263-265, 1975 Leaf A: Cell swelling. A factor in ischemic tissue injury. Editorial. Circulation 48:455-458, 1973 Whalen DA, Hamilton DG, Ganote CE, Jennings RB: Effect of a transient period of ischemia on myocardial cells. I. Effects on cell volume regulation. Am J Pathol 74:381-398, 1974 Kloner RA, Ganote CE, Whalen DA, Jennings RB: Effect of a transient period of ischemia on myocardial cells. II. Fine structure during the first few minutes of reflow. Am J Pathol 74:399-422, 1974 Starling EH: On the absorption of fluids from the connective tissue spaces. J Physiol (London) 19:312-326, 1896 Lowenstein E, Cooper JD, Erdman AJ, Geffin G, Laver
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MB, Yoshikakawa H: Lung and heart water accumulation associated with hemodilution. Intentional Hemodilution, K Messmer, H Schmid-Schonbein, eds. (Bibliotheca haematologica, No. 41), Basel, 1975, S. Karger, A. G., pp. 190-202 13 Laks H, Standeven J, Blair 0, Hahn J, Jellinek M, Willman VL: The effects of cardiopulmonary bypass with crystalloid and colloid hemodilution on myocardial extravascular water. J THoRAc CARDIOVASC SURG 73: 129138, 1977 14 Engelman RM, Spencer FC, Adler A, George TH, Chandra R, Body SD: Effects of normothermic anoxic arrest on coronary blood flow distribution of pigs. Surg Forum 25: 176-179, 1974 15 Wright RM, Levitsky S, Holland C, Feinberg H: Beneficial effects of potassium cardioplegia during intermittent aortic cross clamping and reperfusion. J Surg Res 24:201-209, 1978
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