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THE PREVENTION AND TREATMENT OF ACUTE METABOLIC COMPLICATIONS ASSOCIATED WITH PROLONGED EXTRACORPOREAL CIRCULATION
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VOLUME 45 MAY 1963 NUMBER 5
Thoracic and Cardiovascular Surgery
Original
Communications
THE P R E V E N T I O N A N D T R E A T M E N T OF ACUTE METABOLIC COMPLICATIONS ASSOCIATED W I T H PROLONGED EXTRACORPOREAL CIRCULATION Douglas Moore, M.B.*
and William
F. Bernhard, M.D.**
Boston,
Mass.
P
ERIODS of cardiopulmonary bypass in excess of 2 hours are occasionally necessary to repair complicated intracardiac defects. Although perfusions of this length are often successful, the incidence of hematologic and metabolic complications is far greater than that found with extracorporeal circulation of shorter duration. 1 The most critical physiologic alteration noted under these circumstances is the development of a metabolic acidosis, characterized by precipitous reductions in arterial pH, plasma C0 2 content, and plasma bicarbonate. This increased blood hydrogen ion concentration is the result of inadequate tissue perfusion produced by three related factors: (1) a progressive decrease in perfusion blood flow; (2) the development of an oxygen debt in the skeletal muscle mass, noted primarily in hypothermic perfusions; and (3) the inability of the liver to metabolize an excess load of anaerobic metabolites which accumulate toward the end of perfusion, irrespective of body temperature. 2 " 4 Previous clinical investigations indicate that the maximum alteration in acid-base equilibrium occurs toward the end of extended periods of cardiopulmonary bypass. At this stage, resuscitation of the heart must be effected despite From the Laboratory for Surgical Research, The Children's Hospital Medical Center, and the Department of Surgery, Harvard Medical School, Boston, Mass. These studies "were supported by research grants from the National Heart Institute. National Institutes of Health, U. S. Public Health Service, the American Heart Association, and the Greater Boston Chapter of the Massachusetts Heart Association. Received for publication July 20, 1962. •Research Fellow in Surgery, The Children's Hospital Medical Center, and Research Fellow in Surgery, Harvard Medical School. "Associate Surgeon, The Children's Hospital Medical Center, and Clinical Associate in Surgery, Harvard Medical School.
565
J. Thoracic and Cardiovas. Surg.
MOORE AND BERNHARD
566
the presence of a depleted intrinsic buffering capacity, a low pH, and a myocardium compromised by cardiotomy. In many instances, the restoration of an efficient circulation and preservation of life depend upon prompt and adequate correction of the acidotic state. 5 Recent clinical experience indicates that an organic hydrogen ion acceptor, 2-amino-2-hydroxymethyl-l, 3-propanediol (Tris buffer) is the most efficient buffering agent available. I t is capable of modifying both intracellular and extracellular pH, and is not dependent upon the presence of a normal alveolar exchange for its effectiveness.6 The present investigation involves the use of this agent in selected patients who underwent open repair of a variety of intracardiae defects (Table I ) . Also included in the study are: (1) a biochemical analysis of the heparinized priming blood used to initiate the perfusions; and (2) an evaluation of the effect of Tris buffer on postoperative water and electrolyte excretion. TABLE I.
T Y P E S OF CARDIAC D E F E C T S REPAIRED IN 35 |
Ventricular septal defect (VSD) VSD with pulmonary hypertension VSD with aortic regurgitation VSD with atrial septal defect and pulmonary hypertension Tetralogy of Fallot Tetralogy of Fallot with closure of systemicpulmonary artery anastomosis Atrioventricularis communis Ostium primum defect Aortic stenosis Valvular with pulmonary hypertension Supra valvular Subvalvular Aortic prosthetic valve replacement Coronary arteriovenous fistula Congenital mitral stenosis Mitral regurgitation Total anomalous pulmonary venous drainage Totals
GROUP 1
PATIENTS |
GROUP II
|
TOTALS
1
-
1 1 1
1 5
-
5
1 10
-
2 3
2 4 4
-
1 2 1 1 2 2 1 1 35
-
1 4 1 1
-
1
-
1
-
16
1 1
-
1 1 1 1 2
-
1 19
METHODS AND MATERIAL
Thirty-five patients subjected to open-heart surgery with the use of hypothermic perfusion were included in this investigation. Bach patient was selected on the basis of preoperative evaluation which indicated that repair of the intracardiae abnormality would require an extended period of cardiopulmonary bypass. The cases were divided into two groups for analysis. The 16 patients of Group I received Tris buffer in the pump priming blood (400 mg. per 500 ml. blood), prior to initiation of bypass, to counteract the low pH of this 24-hour-old perfusate. Although the mean duration of perfusion in these 16 cases was 94 minutes (range, 75 to 116 minutes), all patients maintained a normal acid-base equilibrium during perfusion and did not develop a significant degree of acidosis in the postoperative period.
Vol. 45 No. 5
ACUTE METABOLIC COMPLICATIONS
567
Group II was comprised of 19 patients who, despite addition of buffer to the pump priming blood, developed an acute metabolic acidosis during perfusion. Here, the mean duration of bypass was 120 minutes (range, 60 to 184 minutes). All of these patients were treated by the administration of additional Tris buffer* (150 mg. per kilogram of body weight) via the receiving reservoir of the oxygenator 20 minutes prior to termination of perfusion. BIOCHEMICAL DETERMINATIONS
A. Two samples of priming blood were taken from the oxygenator (before and after addition of Tris buffer) approximately 15 minutes prior to initiation of cardiopulmonary bypass. The prime used in each case consisted of heparinized blood collected 24 hours preoperatively (in Fenwal Blood-Pack unitsf), and stored at 4° C. until use. B. During the operation, additional arterial specimens were obtained in all patients according to the following schedule: (1) 5 minutes before start of bypass; (2) 20 minutes prior to expected termination of perfusion; (3) at the termination of perfusion; (4) one hour postoperatively; (5) 3 hours postoperatively; and (6) 6 hours postoperatively. In Group II, Samples No. 2 and No. 3 were obtained before and after the administration of buffer. Blood samples were drawn anaerobically into heparinized, oiled syringes, and the following determinations were performed: (1) arterial pH, (2) plasma C0 2 content, (3) C0 2 combining power, and (4) plasma lactate. The partial pressure of carbon dioxide expressed in millimeters of mercury (pC0 2 ) was calculated at 37° C. using the Henderson-Hasselbalch equation (pK' = 6.10). At reduced body temperatures, pC0 2 was computed from the SeveringhausStupfel nomogram, using values for pK' of 6.10 to 6.30.7 C. In addition to the previous studies, the following determinations were also carried out on each sample: serum sodium, potassium, chloride, calcium, phosphorus, blood glucose, and hematocrit. D. By means of continuous urinary collection, the renal excretion of water and electrolytes was studied in 14 patients (7 from each group), according to the following schedule: (1) 20 minutes prior to expected termination of perfusion; (2) at the end of the first postoperative hour; (3) 2 hours postoperatively; (4) 4 hours postoperatively; and (5) 6 hours postoperatively. At the end of each collection period, total urine volume was recorded, and a representative sample obtained for the determination of pH, carbon dioxide, sodium, potassium, and chloride. Urine and serum osmolarities were also quantitated in each of the five sampling periods. p H determinations were performed on a Beckman (Model G) p H meter with a glass electrode assembly immersed in a water bath. The temperature of the water bath was adjusted to the core! temperature at which the blood speci•The quantity of buffer added to the extracorporeal system to provide a dose of 150 mg. per kilogram of body weight was calculated using the formula: 150 mg. X body i t . /i^ - ~ total blood volume weight (Kg.) x p a t i e n f s blood volume' tFenwal Laboratories Inc., Framingham, Massachusetts. JCore temperature is the estimated mean of rectal and mid-esophageal temperatures.
MOORE AND BEENHARD
568
J. Thoracic and Cardiovas. Surg.
mens were obtained, whereas urine specimens were studied at 37° C. Plasma C0 2 content in all samples was determined by the method of Natelson, C0 2 combining power by a colorimetric technique (Technicon autoanalyzing apparatus), and plasma lactate according to the enzymatic method of Boehringer. 8 ' 9 Blood hematocrit was determined using the Wintrobe method. Serum and urinary sodium and potassium were measured with a Baird flame photometer, chlorides were determined by the method of Schales and Schales, calcium by the method of Sobel, and phosphorus by the Piske technique.10"12 Serum and urinary osmolarities were determined using a Piske osmometer.
PH
LACTATE
C 0 2 CONTENT
UNITS
MUA-
MEQA..
COj COMBINING POWER MEQA..
Pc0* MM.HG.
■
PRE-BUFFER
^
POST-BUFFER
POTASSIUM
HEMOGLOBIN
MEQA.
MOttft
Fig. 1.—Mean data from 240 pints of 24-hour-old heparinized blood used as the perfusate for patients of Groups I and II undergoing prolonged cardiopulmonary bypass. The addition of Tris buffer (400 mg./500 ml.) to this priming blood prior to perfusion restored the H+ ion concentration to normal (pH 7.42), but had no effect on the elevated potassium and lactate contents. RESULTS
A. Biochemical Analysis of Pump-Oxygenator Priming Blood.—The significant mean data derived from an investigation of the priming blood indicated the presence of a low pH (7.22), an elevated plasma lactate content (4.5 mM./L.), and an increased serum K+ (7.3 mEq./L.). The addition of Tris buffer (400 mg. per 500 ml. blood) to this priming volume restored the pH to 7.42, but produced no change in the lactate level, and l'esulted in only minor variations in C0 2 content, C0 2 combining power, and serum potassium (Fig. 1). B. Group I (Prevention of acidosis).—A metabolic acidosis was not detected in the 16 patients of this group in whom bypass was initiated after restoration of the priming blood pH to normal (7.42). In these cases, a normal hydrogen ion concentration was evident throughout perfusion, and the arterial pH at the termination of bypass averaged 7.43 (Fig. 2). One hour postoperatively, the mean pH fell to 7.30, but returned to normal at the end of 6 hours (7.36). The plasma bicarbonate content which had declined to 15 mEq. per liter at the end of perfusion, increased to 17 mEq. per liter one hour postoperatively, and reached 20 mEq. per liter after 6 hours. A progressive increase in plasma lactate concentration occurred throughout
Vol. 45, No. 5 May. 1963
ACUTE METABOLIC COMPLICATIONS
569
the period of bypass, reaching a peak (4.3 mM./L.) at the end of the first postoperative hour. By the sixth hour after operation it had declined to 2.6 mM. per liter. The pC0 2 values dropped slightly during perfusion, and then stabilized in the normal range throughout the postoperative period. C. Group II (Management of acute acidosis).—The metabolic acidosis which developed in this group of 19 patients was controlled by the administration of Tris buffer (150 mg./Kg.) 10 minutes prior to termination of cardiopulmonary bypass. Immediately before treatment, the mean p H of these patients had fallen to 7.18, with an associated sharp increase in plasma lactate (4.4 mM./L.), a decrease in bicarbonate (14 mEq./L.), and a low p C 0 2 (Fig. 3). TRIS BUFFER ADDED TO OXYGENATOR PRIMING BLOOD
IV
PH
PLASMA ?■< HC03 ,„
V
VI
Mini
PCO,
LACTATE MM/L.
a.
JJ
Fig. 2.—Mean data from 16 patients in Group I in whom the duration of bypass was 94 minutes. These patients received no buffer apart from the quantity added to the pump prime prior to bypass. The mean pH a t the termination of psrfusion was 7.43. The timing of all samples (1-6) is recorded in the text.
Following administration of buffer, a prompt rise in pH occurred (7.38), with a corresponding increase in plasma bicarbonate (20 mEq./L.). The maximal lactate concentration was attained one hour postoperatively (6.8 mM./L.) and was accompanied by another fall in arterial pH (7.29). However, the p H increased spontaneously to 7.39 at 3 hours and reached 7.40 6 hours postoperatively, as the lactate concentration declined. Alterations in plasma bicarbonate paralleled the changes in pH, and this too had returned to the normal range (21 mEq./L.) 6 hours after operation. Following the decrease during perfusion, carbon dioxide tension reverted to normal levels in the postoperative period.
MOORE AND BERNHARD
570
J. Thoracic and Cardiovas. Surg.
TRIS BUFFER ADMINISTERED DURING BY-PASS GROUP!
IV
I
VI
750 740 .
PH UNITS
7.30. 720
l-llll
LACTATE" MM/L.
i-
:Q_]_.
Fig. 3.—Data from 19 patients (Group II) who required an extended period of perfusion to effect a satisfactory cardiac repair (mean, 120 minutes). Toward the end of bypass, an acute metabolic acidosis developed (pH 7.18, bicarbonate 14 mEq./L.) and was treated by the administration of Tris buffer (150 mg./Kg.). A prompt rise in pH (7.38) and bicarbonate (20 mEq./L.) occurred (Sample 3), with a transient decline in both parameters after one hour (Sample 4). This coincided with the appearance of maximum plasma lactate levels (6.8 mM./L.) and was rapidly followed by a return to normal levels.
The mean values of serum sodium, potassium, chloride, calcium, phosphorus, glucose, and hematocrit in the patients of this group are presented in Table II. No significant changes were noted during perfusion or in the immediate postoperative period. TABLE II* GROUP i (PREPERFUSION)
Serum electrolytes (mEq./L.) Na + K+
II (PREBUFFER)
in
(POSTBUFFER)
IV ( 1 HR. POSTOP.)
V (3HR. POSTOP.)
VI (6HR. POSTOP.)
139 138 135 138 139 4.7 4.0 4.4 3.7 4.0 97 96 95 95 95 ci- ++ 9.2 9.6 9.7 10.0 9.0 Serum Ca (mg.%) 5.1 6.0 5.6 8.8 6.4 Serum P* + ( m g . % ) 171 239 232 248 229 Blood glucose ( m g . % ) 42 44 41 43 43 Hematocrit ( % ) •Mean data from 19 patients (Group II) undergoing bypass which averaged 120 Prior to perfusion, the oxygenator prime was treated with glucose (12.5 Gm.), gluconate (1.0 Gm.), and Tris buffer (400 mg. per 500 ml. blood). Each patient additional buffer (150 mg./Kg.) toward the end of perfusion.
141 4.2 96 9.6 6.5 177 44 minutes. calcium received
Vol. 45, No. S
May, 1963
ACUTE METABOLIC COMPLICATIONS
u
571 '
DISCUSSION
The most critical alteration in body homeostasis associated with extended periods of extracorporeal circulation is the development of a metabolic acidosis. The progressive increase in blood hydrogen ion concentration which occurs is related to three factors: (1) the addition of significant quantities of lactic acid present in the heparinized blood used to prime the pump-oxygenator system; (2) the development of diffuse cellular hypoxia as a consequence of reductions in perfusion in blood flow; and (3) the presence of an oxygen debt in the lean tissue mass which occurs during prolonged hypothermic perfusions. At normal body temperature, a limited rate exists at which the liver can remove acid metabolites from the circulation. This rate can be exceeded either by an increase in lactate formation or a diminution in hepatocellular activity, which occurs as a physiologic consequence of hypothermia at temperatures below 30° C. Therefore, regardless of the method of perfusion or temperature of the perfusate, an elevated plasma concentration of anaerobic metabolites must be handled by the patient during the terminal stages of prolonged cardiopulmonary bypass and in the immediate postoperative period. Spontaneous compensation of the laeticacidosis will occur if the cardiac output remains at or above a level of 2.5 L. per minute per square meter. However, when the cardiac repair is inadequate or a transient interval of myocardial failure develops, a diminished cardiac output and further tissue hypoxia result. Vigorous treatment with an effective buffering agent must take place at this time if patient survival is to be obtained. Previous experience with Tris buffer lead us to develop a two-stage method for the prevention and treatment of profound metabolic acidosis which may arise under these circumstances. During preoperative evaluation of a large series of cardiac patients, consideration of the type of defect to be repaired and the status of cardiac compensation enabled us to anticipate the possibility of post-perfusion acidosis in 35 cases. In 16 of these, preliminary neutralization of the increased hydrogen ion concentration present in the pump priming blood sufficed to preserve the patient's intrinsic buffers for use in compensation of the lacticacidemia noted at the termination of perfusion (Group I ) . In 19 patients (Group II) the arterial pH and plasma bicarbonate became markedly reduced immediately prior to the end of cardiopulmonary bypass; here, the administration of an additional quantity of buffer to the perfusion system was sufficient to restore acid-base equilibrium. All of the patients included in this investigation received Tris buffer in a concentrated solution (1.5 M ) ; however, the rate of hemolysis during perfusion did not differ from that in a control series of patients who had perfusions of equal duration. Further, in vitro studies indicated that erythrocyte and platelet survival were not altered following incubation with buffer at 37° C.1S Final evidence of the benign character of this agent (when administered in the quantities described) was the total absence of hypoglycemia and respiratory center depression in our patients. An evaluation of renal function in 14 patients of Groups I and I I indicated
MOORE AND B E E N H A R D
572
J. Thoracic and Cardiovas. Surg.
that a significant osmotic diuresis did not follow the administration of buffer despite the presence of an increase in serum and urine osmolarity (noted in Group I I ) . In addition, there was no essential difference between the two groups in the rate of sodium or potassium excretion. However, in agreement with the work of others, a marked rise in rate of bicarbonate loss and an increase in urinary pH were noted in the patients who received additional buffer immediately prior to the end of cardiopulmonary bypass.14 TABLE I I I * PLOW (ML./
M.V
SAMPLE TIME
OSMOLARITY MM./L. URINE SERUM
ELECTROLYTE EXCRETION (MEQ./M.2/HOUR)
24
I 1II 5.9 5.8
278 284 830 635
C0 2 I 1II .08 .02
HOUR) I | II
I Twenty 19 minutes before end of bypass
PH (UNITS)
I
| II
I
| II
NA+ I | ii
K* I
| 11
I
CL| II
1.6 2.0
0.9 1.3
2.1 2.5
I I One hour postoperative
34
34
6.3 7.1
279 296 666 785
.13 .36
1.6 1.5
1.2 0.8
1.7 2.3
I I I Two hours postoperative
31
26
5.9 7.0
277 301 666 790
.09 .30
1.5 0.8
1.4 0.9
1.5 2.5
IV Four hours 35 postoperative
29
5.5 7.1
276 295 711 665
.07 .22
1.9 0.7
1.2 1.0
1.2 2.6
V Six hours 22 28 5.1 7.2 278 284 681 700 .08 .16 0.9 0.6 0.5 2.9 0.3 2.9 postoperative •Mean urine data with corresponding serum osmolarities from 14 patients of Groups I and II. Tris buffer (150 mg./Kg.) was administered to the second group (II) 20 minutes prior to termination of extended bypass (immediately following: the collection of Sample I). In all cases, the initial perfusate contained a small quantity of buffer. SUMMARY
1. Tris buffer was utilized either in the prevention or treatment of profound metabolic acidosis which developed during extended periods of cardiopulmonary bypass. 2. In 16 patients (Group I ) , buffer was added to the 24-hour-old, heparinized, priming blood, prior to initiation of perfusion, to counteract a low pH and high lactic acid concentration. The success of this therapy was manifested by the stability of all acid-base parameters during and following operation. 3. In a second group of 19 patients (Group I I ) , a severe acidosis developed despite preliminary buffering of the priming blood. In these cases the administration of additional Tris buffer toward the end of perfusion successfully restored acid-base equilibrium. 4. An evaluation of renal function following the administration of buffer during bypass disclosed an increased bicarbonate excretion, and a rise in urinary p H ; an osmotic diuresis did not develop although serum osmolarity was transiently elevated.
Vol. 45. No. 5
May, 1963
ACUTE METABOLIC COMPLICATIONS
573
5. It is suggested that Tris buffer is a safe, potent, agent for use in the prevention and treatment of acute hypoxie acidosis from whatever cause. REFERENCES
1. Gans, H., and Krivit, W.: Problems in Hemostasis During Open-Heart Surgery, Ann. Surg. 155: 353-359, 1962. 2. Bemhard, W. F., Schwarz, H. F., Leand, P . M., and Carr, J . Q.: Studies in Balanced Hypothermic Perfusion, Surgery 50: 911-918, 1961. 3. Bemhard, W. F., Cahill, G. F., and Curtis, G. W.: The Rationale of Surgery Under Hypothermia in Certain Patients With Severe Hepatocellular Disease, Ann. Surg. 145: 289-303, 1957. 4. Litwin, M. S., Panico, F . G., Rubini, C , Harken, D. E,, and Moore, F . D . : Acidosis and Lacticacidemia in Extracorporeal Circulation, Ann. Surg. 149: 188-199, 1959. 5. Clowes, G. H., Sabga, G. A., Konitaxis, A., Tomin, R., Hughes, M., and Simeone, F . A . : Effects of Acidosis on Cardiovascular Function in Surgical Patients, Ann. Surg. 154: 524-552, 1961. 6. Moore, A. A. D., and Bemhard, W. F . : The Efficacy of 2-Amino-2-Hydroxymethyl-l, 3-Propanediol (Tris Buffer) in the Management of Metabolic Lacticacidosis Accompanying Prolonged Hypothermic Perfusion, Surgery 52: 905, 1962. 7. Severinghaus, J . W., and Stupfel, M.: Respiratory Physiology During Hypothermia, National Research Council Pub. 431: 52-57, 1956. 8. Natelson, S.: Microtechniques of Clinical Chemistry for the Routine Laboratory, Springfield, 111., 1957, Charles C Thomas, Publisher, pp. 142-147. 9. Boehringer, B . : A Kinetic-Enzymatic Determination of L (±) Lactic Acid in Human Serum and Other Biological Fluids, Biochem. 328: 110, 1956. 10. Schales, D., and Schales, 8. S.: A Simple and Accurate Method for the Determination of Chloride in Biological Fluids, J . Biol. Chem. 140: 879-884, 1941. 11. Sobel, A., and Sobel, S. B . : Microestimation of Calcium in Serum, J . Biol. Chem. 129: 721, 1939. 12. Fiske, C. H., and Subbarow, Y.: The Colorimetric Determination of Phosphorus, J . Biol. Chem. 66: 375, 1925. 13. Moore, A. A. D., Bemhard, W. F., and Kevy, S. V.: The Effects of 2-Amino-2-Hydroxymethyl-1, 3-Propanediol on Fresh and Stored Heparinized Blood. ( I n press.) 14. Samiy, A. H., Oken, D. E., Rees, S. B., Robin, E. D., and Merrill, J . P . : Effect of 2-Amino-2-Hydroxymethyl-l, 3-Propanediol on Electrolyte Excretion, Ann. New York Acad. Sc. 92: 570-578, 1961.
VOLUME 45 MAY 1963 NUMBER 5
Thoracic and Cardiovascular Surgery
Original
Communications
THE P R E V E N T I O N A N D T R E A T M E N T OF ACUTE METABOLIC COMPLICATIONS ASSOCIATED W I T H PROLONGED EXTRACORPOREAL CIRCULATION Douglas Moore, M.B.*
and William
F. Bernhard, M.D.**
Boston,
Mass.
P
ERIODS of cardiopulmonary bypass in excess of 2 hours are occasionally necessary to repair complicated intracardiac defects. Although perfusions of this length are often successful, the incidence of hematologic and metabolic complications is far greater than that found with extracorporeal circulation of shorter duration. 1 The most critical physiologic alteration noted under these circumstances is the development of a metabolic acidosis, characterized by precipitous reductions in arterial pH, plasma C0 2 content, and plasma bicarbonate. This increased blood hydrogen ion concentration is the result of inadequate tissue perfusion produced by three related factors: (1) a progressive decrease in perfusion blood flow; (2) the development of an oxygen debt in the skeletal muscle mass, noted primarily in hypothermic perfusions; and (3) the inability of the liver to metabolize an excess load of anaerobic metabolites which accumulate toward the end of perfusion, irrespective of body temperature. 2 " 4 Previous clinical investigations indicate that the maximum alteration in acid-base equilibrium occurs toward the end of extended periods of cardiopulmonary bypass. At this stage, resuscitation of the heart must be effected despite From the Laboratory for Surgical Research, The Children's Hospital Medical Center, and the Department of Surgery, Harvard Medical School, Boston, Mass. These studies "were supported by research grants from the National Heart Institute. National Institutes of Health, U. S. Public Health Service, the American Heart Association, and the Greater Boston Chapter of the Massachusetts Heart Association. Received for publication July 20, 1962. •Research Fellow in Surgery, The Children's Hospital Medical Center, and Research Fellow in Surgery, Harvard Medical School. "Associate Surgeon, The Children's Hospital Medical Center, and Clinical Associate in Surgery, Harvard Medical School.
565
J. Thoracic and Cardiovas. Surg.
MOORE AND BERNHARD
566
the presence of a depleted intrinsic buffering capacity, a low pH, and a myocardium compromised by cardiotomy. In many instances, the restoration of an efficient circulation and preservation of life depend upon prompt and adequate correction of the acidotic state. 5 Recent clinical experience indicates that an organic hydrogen ion acceptor, 2-amino-2-hydroxymethyl-l, 3-propanediol (Tris buffer) is the most efficient buffering agent available. I t is capable of modifying both intracellular and extracellular pH, and is not dependent upon the presence of a normal alveolar exchange for its effectiveness.6 The present investigation involves the use of this agent in selected patients who underwent open repair of a variety of intracardiae defects (Table I ) . Also included in the study are: (1) a biochemical analysis of the heparinized priming blood used to initiate the perfusions; and (2) an evaluation of the effect of Tris buffer on postoperative water and electrolyte excretion. TABLE I.
T Y P E S OF CARDIAC D E F E C T S REPAIRED IN 35 |
Ventricular septal defect (VSD) VSD with pulmonary hypertension VSD with aortic regurgitation VSD with atrial septal defect and pulmonary hypertension Tetralogy of Fallot Tetralogy of Fallot with closure of systemicpulmonary artery anastomosis Atrioventricularis communis Ostium primum defect Aortic stenosis Valvular with pulmonary hypertension Supra valvular Subvalvular Aortic prosthetic valve replacement Coronary arteriovenous fistula Congenital mitral stenosis Mitral regurgitation Total anomalous pulmonary venous drainage Totals
GROUP 1
PATIENTS |
GROUP II
|
TOTALS
1
-
1 1 1
1 5
-
5
1 10
-
2 3
2 4 4
-
1 2 1 1 2 2 1 1 35
-
1 4 1 1
-
1
-
1
-
16
1 1
-
1 1 1 1 2
-
1 19
METHODS AND MATERIAL
Thirty-five patients subjected to open-heart surgery with the use of hypothermic perfusion were included in this investigation. Bach patient was selected on the basis of preoperative evaluation which indicated that repair of the intracardiae abnormality would require an extended period of cardiopulmonary bypass. The cases were divided into two groups for analysis. The 16 patients of Group I received Tris buffer in the pump priming blood (400 mg. per 500 ml. blood), prior to initiation of bypass, to counteract the low pH of this 24-hour-old perfusate. Although the mean duration of perfusion in these 16 cases was 94 minutes (range, 75 to 116 minutes), all patients maintained a normal acid-base equilibrium during perfusion and did not develop a significant degree of acidosis in the postoperative period.
Vol. 45 No. 5
ACUTE METABOLIC COMPLICATIONS
567
Group II was comprised of 19 patients who, despite addition of buffer to the pump priming blood, developed an acute metabolic acidosis during perfusion. Here, the mean duration of bypass was 120 minutes (range, 60 to 184 minutes). All of these patients were treated by the administration of additional Tris buffer* (150 mg. per kilogram of body weight) via the receiving reservoir of the oxygenator 20 minutes prior to termination of perfusion. BIOCHEMICAL DETERMINATIONS
A. Two samples of priming blood were taken from the oxygenator (before and after addition of Tris buffer) approximately 15 minutes prior to initiation of cardiopulmonary bypass. The prime used in each case consisted of heparinized blood collected 24 hours preoperatively (in Fenwal Blood-Pack unitsf), and stored at 4° C. until use. B. During the operation, additional arterial specimens were obtained in all patients according to the following schedule: (1) 5 minutes before start of bypass; (2) 20 minutes prior to expected termination of perfusion; (3) at the termination of perfusion; (4) one hour postoperatively; (5) 3 hours postoperatively; and (6) 6 hours postoperatively. In Group II, Samples No. 2 and No. 3 were obtained before and after the administration of buffer. Blood samples were drawn anaerobically into heparinized, oiled syringes, and the following determinations were performed: (1) arterial pH, (2) plasma C0 2 content, (3) C0 2 combining power, and (4) plasma lactate. The partial pressure of carbon dioxide expressed in millimeters of mercury (pC0 2 ) was calculated at 37° C. using the Henderson-Hasselbalch equation (pK' = 6.10). At reduced body temperatures, pC0 2 was computed from the SeveringhausStupfel nomogram, using values for pK' of 6.10 to 6.30.7 C. In addition to the previous studies, the following determinations were also carried out on each sample: serum sodium, potassium, chloride, calcium, phosphorus, blood glucose, and hematocrit. D. By means of continuous urinary collection, the renal excretion of water and electrolytes was studied in 14 patients (7 from each group), according to the following schedule: (1) 20 minutes prior to expected termination of perfusion; (2) at the end of the first postoperative hour; (3) 2 hours postoperatively; (4) 4 hours postoperatively; and (5) 6 hours postoperatively. At the end of each collection period, total urine volume was recorded, and a representative sample obtained for the determination of pH, carbon dioxide, sodium, potassium, and chloride. Urine and serum osmolarities were also quantitated in each of the five sampling periods. p H determinations were performed on a Beckman (Model G) p H meter with a glass electrode assembly immersed in a water bath. The temperature of the water bath was adjusted to the core! temperature at which the blood speci•The quantity of buffer added to the extracorporeal system to provide a dose of 150 mg. per kilogram of body weight was calculated using the formula: 150 mg. X body i t . /i^ - ~ total blood volume weight (Kg.) x p a t i e n f s blood volume' tFenwal Laboratories Inc., Framingham, Massachusetts. JCore temperature is the estimated mean of rectal and mid-esophageal temperatures.
MOORE AND BEENHARD
568
J. Thoracic and Cardiovas. Surg.
mens were obtained, whereas urine specimens were studied at 37° C. Plasma C0 2 content in all samples was determined by the method of Natelson, C0 2 combining power by a colorimetric technique (Technicon autoanalyzing apparatus), and plasma lactate according to the enzymatic method of Boehringer. 8 ' 9 Blood hematocrit was determined using the Wintrobe method. Serum and urinary sodium and potassium were measured with a Baird flame photometer, chlorides were determined by the method of Schales and Schales, calcium by the method of Sobel, and phosphorus by the Piske technique.10"12 Serum and urinary osmolarities were determined using a Piske osmometer.
PH
LACTATE
C 0 2 CONTENT
UNITS
MUA-
MEQA..
COj COMBINING POWER MEQA..
Pc0* MM.HG.
■
PRE-BUFFER
^
POST-BUFFER
POTASSIUM
HEMOGLOBIN
MEQA.
MOttft
Fig. 1.—Mean data from 240 pints of 24-hour-old heparinized blood used as the perfusate for patients of Groups I and II undergoing prolonged cardiopulmonary bypass. The addition of Tris buffer (400 mg./500 ml.) to this priming blood prior to perfusion restored the H+ ion concentration to normal (pH 7.42), but had no effect on the elevated potassium and lactate contents. RESULTS
A. Biochemical Analysis of Pump-Oxygenator Priming Blood.—The significant mean data derived from an investigation of the priming blood indicated the presence of a low pH (7.22), an elevated plasma lactate content (4.5 mM./L.), and an increased serum K+ (7.3 mEq./L.). The addition of Tris buffer (400 mg. per 500 ml. blood) to this priming volume restored the pH to 7.42, but produced no change in the lactate level, and l'esulted in only minor variations in C0 2 content, C0 2 combining power, and serum potassium (Fig. 1). B. Group I (Prevention of acidosis).—A metabolic acidosis was not detected in the 16 patients of this group in whom bypass was initiated after restoration of the priming blood pH to normal (7.42). In these cases, a normal hydrogen ion concentration was evident throughout perfusion, and the arterial pH at the termination of bypass averaged 7.43 (Fig. 2). One hour postoperatively, the mean pH fell to 7.30, but returned to normal at the end of 6 hours (7.36). The plasma bicarbonate content which had declined to 15 mEq. per liter at the end of perfusion, increased to 17 mEq. per liter one hour postoperatively, and reached 20 mEq. per liter after 6 hours. A progressive increase in plasma lactate concentration occurred throughout
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the period of bypass, reaching a peak (4.3 mM./L.) at the end of the first postoperative hour. By the sixth hour after operation it had declined to 2.6 mM. per liter. The pC0 2 values dropped slightly during perfusion, and then stabilized in the normal range throughout the postoperative period. C. Group II (Management of acute acidosis).—The metabolic acidosis which developed in this group of 19 patients was controlled by the administration of Tris buffer (150 mg./Kg.) 10 minutes prior to termination of cardiopulmonary bypass. Immediately before treatment, the mean p H of these patients had fallen to 7.18, with an associated sharp increase in plasma lactate (4.4 mM./L.), a decrease in bicarbonate (14 mEq./L.), and a low p C 0 2 (Fig. 3). TRIS BUFFER ADDED TO OXYGENATOR PRIMING BLOOD
IV
PH
PLASMA ?■< HC03 ,„
V
VI
Mini
PCO,
LACTATE MM/L.
a.
JJ
Fig. 2.—Mean data from 16 patients in Group I in whom the duration of bypass was 94 minutes. These patients received no buffer apart from the quantity added to the pump prime prior to bypass. The mean pH a t the termination of psrfusion was 7.43. The timing of all samples (1-6) is recorded in the text.
Following administration of buffer, a prompt rise in pH occurred (7.38), with a corresponding increase in plasma bicarbonate (20 mEq./L.). The maximal lactate concentration was attained one hour postoperatively (6.8 mM./L.) and was accompanied by another fall in arterial pH (7.29). However, the p H increased spontaneously to 7.39 at 3 hours and reached 7.40 6 hours postoperatively, as the lactate concentration declined. Alterations in plasma bicarbonate paralleled the changes in pH, and this too had returned to the normal range (21 mEq./L.) 6 hours after operation. Following the decrease during perfusion, carbon dioxide tension reverted to normal levels in the postoperative period.
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J. Thoracic and Cardiovas. Surg.
TRIS BUFFER ADMINISTERED DURING BY-PASS GROUP!
IV
I
VI
750 740 .
PH UNITS
7.30. 720
l-llll
LACTATE" MM/L.
i-
:Q_]_.
Fig. 3.—Data from 19 patients (Group II) who required an extended period of perfusion to effect a satisfactory cardiac repair (mean, 120 minutes). Toward the end of bypass, an acute metabolic acidosis developed (pH 7.18, bicarbonate 14 mEq./L.) and was treated by the administration of Tris buffer (150 mg./Kg.). A prompt rise in pH (7.38) and bicarbonate (20 mEq./L.) occurred (Sample 3), with a transient decline in both parameters after one hour (Sample 4). This coincided with the appearance of maximum plasma lactate levels (6.8 mM./L.) and was rapidly followed by a return to normal levels.
The mean values of serum sodium, potassium, chloride, calcium, phosphorus, glucose, and hematocrit in the patients of this group are presented in Table II. No significant changes were noted during perfusion or in the immediate postoperative period. TABLE II* GROUP i (PREPERFUSION)
Serum electrolytes (mEq./L.) Na + K+
II (PREBUFFER)
in
(POSTBUFFER)
IV ( 1 HR. POSTOP.)
V (3HR. POSTOP.)
VI (6HR. POSTOP.)
139 138 135 138 139 4.7 4.0 4.4 3.7 4.0 97 96 95 95 95 ci- ++ 9.2 9.6 9.7 10.0 9.0 Serum Ca (mg.%) 5.1 6.0 5.6 8.8 6.4 Serum P* + ( m g . % ) 171 239 232 248 229 Blood glucose ( m g . % ) 42 44 41 43 43 Hematocrit ( % ) •Mean data from 19 patients (Group II) undergoing bypass which averaged 120 Prior to perfusion, the oxygenator prime was treated with glucose (12.5 Gm.), gluconate (1.0 Gm.), and Tris buffer (400 mg. per 500 ml. blood). Each patient additional buffer (150 mg./Kg.) toward the end of perfusion.
141 4.2 96 9.6 6.5 177 44 minutes. calcium received
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DISCUSSION
The most critical alteration in body homeostasis associated with extended periods of extracorporeal circulation is the development of a metabolic acidosis. The progressive increase in blood hydrogen ion concentration which occurs is related to three factors: (1) the addition of significant quantities of lactic acid present in the heparinized blood used to prime the pump-oxygenator system; (2) the development of diffuse cellular hypoxia as a consequence of reductions in perfusion in blood flow; and (3) the presence of an oxygen debt in the lean tissue mass which occurs during prolonged hypothermic perfusions. At normal body temperature, a limited rate exists at which the liver can remove acid metabolites from the circulation. This rate can be exceeded either by an increase in lactate formation or a diminution in hepatocellular activity, which occurs as a physiologic consequence of hypothermia at temperatures below 30° C. Therefore, regardless of the method of perfusion or temperature of the perfusate, an elevated plasma concentration of anaerobic metabolites must be handled by the patient during the terminal stages of prolonged cardiopulmonary bypass and in the immediate postoperative period. Spontaneous compensation of the laeticacidosis will occur if the cardiac output remains at or above a level of 2.5 L. per minute per square meter. However, when the cardiac repair is inadequate or a transient interval of myocardial failure develops, a diminished cardiac output and further tissue hypoxia result. Vigorous treatment with an effective buffering agent must take place at this time if patient survival is to be obtained. Previous experience with Tris buffer lead us to develop a two-stage method for the prevention and treatment of profound metabolic acidosis which may arise under these circumstances. During preoperative evaluation of a large series of cardiac patients, consideration of the type of defect to be repaired and the status of cardiac compensation enabled us to anticipate the possibility of post-perfusion acidosis in 35 cases. In 16 of these, preliminary neutralization of the increased hydrogen ion concentration present in the pump priming blood sufficed to preserve the patient's intrinsic buffers for use in compensation of the lacticacidemia noted at the termination of perfusion (Group I ) . In 19 patients (Group II) the arterial pH and plasma bicarbonate became markedly reduced immediately prior to the end of cardiopulmonary bypass; here, the administration of an additional quantity of buffer to the perfusion system was sufficient to restore acid-base equilibrium. All of the patients included in this investigation received Tris buffer in a concentrated solution (1.5 M ) ; however, the rate of hemolysis during perfusion did not differ from that in a control series of patients who had perfusions of equal duration. Further, in vitro studies indicated that erythrocyte and platelet survival were not altered following incubation with buffer at 37° C.1S Final evidence of the benign character of this agent (when administered in the quantities described) was the total absence of hypoglycemia and respiratory center depression in our patients. An evaluation of renal function in 14 patients of Groups I and I I indicated
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that a significant osmotic diuresis did not follow the administration of buffer despite the presence of an increase in serum and urine osmolarity (noted in Group I I ) . In addition, there was no essential difference between the two groups in the rate of sodium or potassium excretion. However, in agreement with the work of others, a marked rise in rate of bicarbonate loss and an increase in urinary pH were noted in the patients who received additional buffer immediately prior to the end of cardiopulmonary bypass.14 TABLE I I I * PLOW (ML./
M.V
SAMPLE TIME
OSMOLARITY MM./L. URINE SERUM
ELECTROLYTE EXCRETION (MEQ./M.2/HOUR)
24
I 1II 5.9 5.8
278 284 830 635
C0 2 I 1II .08 .02
HOUR) I | II
I Twenty 19 minutes before end of bypass
PH (UNITS)
I
| II
I
| II
NA+ I | ii
K* I
| 11
I
CL| II
1.6 2.0
0.9 1.3
2.1 2.5
I I One hour postoperative
34
34
6.3 7.1
279 296 666 785
.13 .36
1.6 1.5
1.2 0.8
1.7 2.3
I I I Two hours postoperative
31
26
5.9 7.0
277 301 666 790
.09 .30
1.5 0.8
1.4 0.9
1.5 2.5
IV Four hours 35 postoperative
29
5.5 7.1
276 295 711 665
.07 .22
1.9 0.7
1.2 1.0
1.2 2.6
V Six hours 22 28 5.1 7.2 278 284 681 700 .08 .16 0.9 0.6 0.5 2.9 0.3 2.9 postoperative •Mean urine data with corresponding serum osmolarities from 14 patients of Groups I and II. Tris buffer (150 mg./Kg.) was administered to the second group (II) 20 minutes prior to termination of extended bypass (immediately following: the collection of Sample I). In all cases, the initial perfusate contained a small quantity of buffer. SUMMARY
1. Tris buffer was utilized either in the prevention or treatment of profound metabolic acidosis which developed during extended periods of cardiopulmonary bypass. 2. In 16 patients (Group I ) , buffer was added to the 24-hour-old, heparinized, priming blood, prior to initiation of perfusion, to counteract a low pH and high lactic acid concentration. The success of this therapy was manifested by the stability of all acid-base parameters during and following operation. 3. In a second group of 19 patients (Group I I ) , a severe acidosis developed despite preliminary buffering of the priming blood. In these cases the administration of additional Tris buffer toward the end of perfusion successfully restored acid-base equilibrium. 4. An evaluation of renal function following the administration of buffer during bypass disclosed an increased bicarbonate excretion, and a rise in urinary p H ; an osmotic diuresis did not develop although serum osmolarity was transiently elevated.
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5. It is suggested that Tris buffer is a safe, potent, agent for use in the prevention and treatment of acute hypoxie acidosis from whatever cause. REFERENCES
1. Gans, H., and Krivit, W.: Problems in Hemostasis During Open-Heart Surgery, Ann. Surg. 155: 353-359, 1962. 2. Bemhard, W. F., Schwarz, H. F., Leand, P . M., and Carr, J . Q.: Studies in Balanced Hypothermic Perfusion, Surgery 50: 911-918, 1961. 3. Bemhard, W. F., Cahill, G. F., and Curtis, G. W.: The Rationale of Surgery Under Hypothermia in Certain Patients With Severe Hepatocellular Disease, Ann. Surg. 145: 289-303, 1957. 4. Litwin, M. S., Panico, F . G., Rubini, C , Harken, D. E,, and Moore, F . D . : Acidosis and Lacticacidemia in Extracorporeal Circulation, Ann. Surg. 149: 188-199, 1959. 5. Clowes, G. H., Sabga, G. A., Konitaxis, A., Tomin, R., Hughes, M., and Simeone, F . A . : Effects of Acidosis on Cardiovascular Function in Surgical Patients, Ann. Surg. 154: 524-552, 1961. 6. Moore, A. A. D., and Bemhard, W. F . : The Efficacy of 2-Amino-2-Hydroxymethyl-l, 3-Propanediol (Tris Buffer) in the Management of Metabolic Lacticacidosis Accompanying Prolonged Hypothermic Perfusion, Surgery 52: 905, 1962. 7. Severinghaus, J . W., and Stupfel, M.: Respiratory Physiology During Hypothermia, National Research Council Pub. 431: 52-57, 1956. 8. Natelson, S.: Microtechniques of Clinical Chemistry for the Routine Laboratory, Springfield, 111., 1957, Charles C Thomas, Publisher, pp. 142-147. 9. Boehringer, B . : A Kinetic-Enzymatic Determination of L (±) Lactic Acid in Human Serum and Other Biological Fluids, Biochem. 328: 110, 1956. 10. Schales, D., and Schales, 8. S.: A Simple and Accurate Method for the Determination of Chloride in Biological Fluids, J . Biol. Chem. 140: 879-884, 1941. 11. Sobel, A., and Sobel, S. B . : Microestimation of Calcium in Serum, J . Biol. Chem. 129: 721, 1939. 12. Fiske, C. H., and Subbarow, Y.: The Colorimetric Determination of Phosphorus, J . Biol. Chem. 66: 375, 1925. 13. Moore, A. A. D., Bemhard, W. F., and Kevy, S. V.: The Effects of 2-Amino-2-Hydroxymethyl-1, 3-Propanediol on Fresh and Stored Heparinized Blood. ( I n press.) 14. Samiy, A. H., Oken, D. E., Rees, S. B., Robin, E. D., and Merrill, J . P . : Effect of 2-Amino-2-Hydroxymethyl-l, 3-Propanediol on Electrolyte Excretion, Ann. New York Acad. Sc. 92: 570-578, 1961.