CATECHOLAMINE AND SEROTONIN RESPONSE TO CARDIOPULMONARY BYPASS

CATECHOLAMINE A N D S E R O T O N I N RESPONSE T O C A R D I O P U L M O N A R Y BYPASS Robert Replogle,

M.D*

(by invitation),

Richard A. DeWall, M.D.** (by invitation), (Sponsored

Minneapolis,

Morris Levy, M.D. (by

(by invitation),

and Richard C. Lillehei,

invitation), M.D.***

Minn.

by Robert E. Gross, M.D.,

Boston,

Mass.)

P

ROLONGED periods of cardiopulmonary bypass are necessary to repair the more complicated congenital and acquired cardiac lesions. Perhaps for this reason, the popularity of high flow, normothermic perfusions has deferred somewhat to renewed interest in perfusions at low or moderate flow rates in combination with low or moderate hypothermia. Continued investigation of the effects of cardiopulmonary bypass (with and without hypothermia) on human physiology and metabolism may define technical changes that will allow longer and safer periods of bypass. This study represents our efforts to measure (a) the sympathomimetic response to bypass at different flow rates and temperatures, (b) serotonin release by the principal circulating source, the platelet, and (c) the correlation between the measurable changes in these agents and circulatory dynamics as evidenced by effective renal plasma flow arid glomerular filtration rate measurements. METHODS

Fourteen adult and pediatric patients with a variety of congenital and acquired cardiac lesions were studied. Cardiopulmonary bypass was carried out with a bubble oxygenator, 12 primed with a combination of low molecular weight dextran and whole blood,26 for periods of 30 minutes to Sy2 hours. There were 9 normothermic (33° to 37° C ) , moderate to low flow (1.6 to 2.4 L./M. 2 /min.), and 5 hypothermia (25° to 31° C ) , low flow (0.85 to 1.9 L./M. 2 /min.) perfusions. All the operations were done under Pentothal, Flaxedil, and nitrous oxide anesthesia. From the Department of Surgery, University of Minnesota Medical School, Minneapolis 14, Minn. Supported by U. S. Public Health Service Grant No. H-2941 and a grant from the Minnesota Heart Association. Read a t the Porty-second Annual Meeting of The American Association for Thoracic Surgery a t St. Louis, Mo., April 16-18, 1962. •Present address: Department of Surgery, Children's Hospital Medical Center, Boston, Mass. * 'Established Investigator, American Heart Association. ***John and Mary R. Markle Scholar. 638

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Plasma epinephrine, norepinephrine, and serum serotonin concentrations were measured every 30 minutes during bypass. At least two measurements of these substances were made after the onset of operation but before bypass was instituted; these measurements served as controls. Two further measurements were made 30 minutes and 60 minutes following the termination of bypass. The technical details of the catecholamine and serotonin (5-hydroxytryptamine) determinations for this study are fully described elsewhere 33 ; the susceptibility of these measurements to technical errors makes comparisons between catecholamine concentrations of 2 fig per liter of plasma, or less, tenuous at best, and we emphasize that only qualitative differences can be inferred. Effective renal plasma flow was measured using I 131 labeled Diodrast, 32 and glomerular filtration rate was measured with inulin, 36 using the direct resorcinol method without alkali technique. Blood samples were drawn from a polyethylene catheter in the superficial femoral vein. Serial platelet counts were made throughout the experimental period. Electroencephalograms were monitored during the perfusion, and arterial blood pressures were recorded by means of a polyethylene catheter in the internal mammary artery. Preand postoperative blood volumes were measured using the I 131 labeled albumin technique. 1 Esophageal and rectal temperatures were recorded from appropriately placed thermistor probes. RESULTS

Epinephrine and Norepinephrine.—Table I shows the relationships of the catecholamine and serotonin concentrations to cardiopulmonary bypass at normothermic and moderate hypothermic temperatures at low and moderate perfusion rates. Pre-bypass plasma epinephrine measurements averaged 0.26 /*g per liter, and norepinephrine, 1.33 ^.g per liter; these values are similar to those of Hamelberg and associates 16 who found plasma epinephrine averaged 0.34 /xg per liter, and norepinephrine, 1.5 fig per liter, after one hour of nitrous oxide anesthesia at light surgical levels. An increase in circulating epinephrine and norepinephrine during normothermic bypass is seen. A less marked, but readily apparent, increase is seen during hypothermic cardiopulmonary bypass, even though the perfusion rate averaged only 1.3 L. per square meter per minute during these bypass periods. One patient underwent bypass at a rectal temperature below 27° C , and the catecholamine measurements during this bypass period are also recorded in Table I. Very low values for epinephrine and norepinephrine were observed during this period, although the perfusion rate was only 0.9 L. per square meter per minute. However, during the latter part of this bypass this patient was warmed to 30° C. and the perfusion rate increased to 1.3 L. per square meter per minute. An increased epinephrine level resulted. After the completion of cardiopulmonary bypass, determinations of epinephrine, norepinephrine, and serotonin values were continued at intervals of 30 minutes for 60 to 90 minutes. Plasma epinephrine values were persistently

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elevated, but the relatively high average value for the group as a whole was, in large measure, due to the very high levels observed in the patients who succumbed in the postoperative period. The magnitude of the difference in plasma epinephrine levels between the surviving patients and those who failed to recover is striking. Serotonin.—Serum serotonin values were averaged for the whole group in Fig. 1. The control values recorded here are quite similar to the value of 21 yu.g per 100 ml. of serum previously recorded in the normal adult volunteer with the technique for serotonin measurement used in the present study. 10 A distinct fall in serum serotonin during bypass was observed, although a wide range of values in individual patients was noted. As virtually all the serotonin found in the blood is platelet bound, 35 Fig. 1 illustrates the relationship between changes in platelet count and serotonin values. To relate platelet change to mechanical trauma, the abscissa of the graph represents total perfusion volume, that is, perfusion rate times duration of bypass. The similarity of the platelet and serotonin changes, we believe, indicates that the decrease in serum serotonin during cardiopulmonary bypass is probably due to mechanical platelet destruction and release of platelot-bound serotonin. The picture of falling serum serotonin concentration, however, is not unlike that reported during hemorrhagic shock in the dog. 42 Renal Hemodynamics.—The effective renal plasma flow and glomerular filtration rate, as measured by our clearance techniques, were markedly depressed in all the patients studied save one. The single exception was an adult undergoing excision of a left atrial myxoma. Bypass during this procedure, which TABLE

I*

EPINEPHRINE t

NOREPINEPHRINEt

SEROTONIN t

0.26 (0.00- 0.83)

1.33 (0.16- 4.06)

21.5 (10.0-33.0)

4.0 (0.40-12.3 )

4.9

(0.91-12.06)

11.3 ( 4.0-24.0)

2.0

(0.00- 3.05)

2.7

(1.17- 4.87)

10.1 ( 3.0-20.0)

0.33 (0.00- 0.70)

2.5

(2.07- 2.75)

6.0 ( 5.7- 8.3)

6.35 (5.08- 8.05)

4.25 (3.11- 5.42)

QoA-)

Pre-Bypass

Controls

Bypass Studies 1. Normothermia Perfusion rate, 1.7-2.4 L./M.2/min. Temp., 33° C.-370 C. (r) 2. Moderate Hypothermia Perfusion rate 0.85-1.9 L./M.s /min. Temp., 25° 0.-31° C. (r) 3. Deep Hypothermia Perfusion rate 0.9 L./M.2/min. Temp. 25° C.-27° C. (r) Increase in temp, to 30° C. (r)

OA-)

Post Bypass Studies 2.07 (0.00-30.97) 3.26 (1.13- 9.05) 8.0 ( 0.0-17.0) Entire Group 1.20 (0.00- 5.02) 2.0 (0.00- 3.36) 8.7 ( 0.0-17.0) a. Survivors (10) 10.9 (2.35-30.97) 6.9 (2.58-13.98) 5.5 ( 5.0- 7.0) b. Nonsurvivors (4) •Average values for epinephrine, norepinephrine, and serotonin before, during, and following bypass are recorded. The low epinephrine concentration observed during low temperature perfusion, and the subsequent elevation, as the patient is warmed, is recorded. tMean with range.

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was done at normal body temperature at a perfusion rate of 2.7 L. per square meter per minute for only 15 minutes, was unassociated with any change in epinephrine, norepinephrine, or serotonin concentrations. Clearance values in this patient also remained near control levels. Effective renal plasma flow (RPF) and glomerular nitration rate (GFR) as measured by clearance techniques are, of course, inaccurate at the depressed SERUM SEROTONIN vs. PERFUSION RATE x LENGTH OF BYPASS 100

90-

80

70

»

60 50-

40-

t\

30

20

"-oO

O Serotonin

X

x

• -o

Platelets

10

50 100 150 200 250 300 Total Perfusion Volume (liters /min./min. of bypass)

Fig. 1.—Relationship between total perfusion volume and serum serotonin concentrations. The similarity of the platelet and serotonin curves suggest platelet destruction with serotonin release during bypass.

levels measured here 2 ; P A H extraction, however, has been shown to remain normal until the R P F is reduced to 3 per cent or less of control values. 31 Failure of the urinary output to be maintained by the stimulus of a large load of low molecular weight dextran, an effective osmotic diuretic, indicates almost totally absent glomerular filtration. Illustrative Protocols.—Table II details the data from a patient who had an operation for correction of tetralogy of Fallot. Although plasma catecholamine levels showed little change during the bypass period, the R P F and GFR

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were severely diminished. The diuresis which followed bypass is a product of the osmotic diuretic effect of low molecular weight dextran (LMD), and persisted in the immediate postoperative period as evidenced by the urinary output of 800 c.c. in the first 8 hours after operation. No blood urea nitrogen (BUN) elevation was noted in this patient. TABLE EPINEPHRINE

TIME (MIN.)

EPF (C.C./ MIN.)

GFR (C.C./ MIN.)

30 60

420 430

73 95

0.00 0.05

30 55 75

18 9 61

3 <1 13

0.39 0.26 0.73

30 60

543 450

55 42

0.78 0.01

0<5/ L.)

NOREPINEPHRINE

ilia/ L.)

II*

ARTERIAL PRESSURE (MM. HG)

PERFUSION RATE (C.C./ M.2/ MIN.)

0.77 100 1.49 110 Begin Bypass 2.78 65 950 8.01 70 875 2.12 105 875 End Bypass 1.99 120 3.76 108

RECTAL TEMP.

URINE VOLUME (C.C.)

SEROTONIN

(W 100

PLATELETS

36.0 36.0

10 8

19.0 21.0

103 240 240

32.0 30.5 32.0

4 1 2

12.8 12.8 12.8

180 200 130

34.5 36.5

125 180

3.9 9.0

150 150

(°c.)

ML.)

Plasma H g b = 80 mg.% Recovery Boom Total Urine Volume—8 hr. postop. = 800 c.c. (700 c.c. L M D ) . Blood Volume—Preop. — 4,175 c . c ; 1 hr. postop. = 3,500 c.c. BUN—Preop. = 12 m g . % ; 1st postop. day = 22 mg.%. Legend: RPF—Renal plasma flow. GFR—Glomerular filtration rate. •Perfusion data from bypass for correction of tetralogy of Pallot in a 26-year-old woman (M. T.). The low renal blood flow and persistent hypotension are not associated with a significant elevation in plasma epinephrine values, although norepinephrine did increase significantly. (Pump prime: 1.000 c.c. whole blood; 1,500 c.c. low molecular weight dextran.)

Table I I I illustrates a more representative study in this series. The pump oxygenator was again primed with whole blood and LMD. Renal blood flow and urinary output were markedly reduced during bypass, and elevation of plasma epinephrine values were also observed as the perfusion rate fell from 1.9 to 1.7 L. per square meter per minute. Diminished renal plasma flow persisted in the post-bypass period, although a small diuresis was seen immediately after bypass. This diuresis persisted in the postoperative period, the urine volume being 600 c.c. over the first 6 hours following operation. Some element of transient renal damage in this patient was indicated by the elevation of the BUN to 50 mg. per cent on the second postoperative day with a return to a more normal value of 28 mg. per cent on the sixth postoperative day. Another study is depicted in Table IV. This adult male with severe calcific aortic valvular insufficiency required cardiopulmonary bypass for 3 hours at normothermia and low to moderate flow rates. The low control values for R P F and GFR probably indicate the inability of the patient's failing heart to maintain an adequate circulation. Elevation of plasma epinephrine (and, later, norepinephrine) occurred shortly after the onset of bypass and, toward the end of the run, reached a level characteristic of experimental hemorrhagic shock.33 These high catecholamine values persisted after the completion of the period of

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TABLE I I I * EPINEPHRINE

RPF (C.C./ MIN.)

TIME (MIN.)

(MG/ L.)

NOREPINEPHEINE (AlG/L.)

PERFUSION RATE (C.C./ M.2/ MIN.)

ARTERIAL PRESSURE (MM. HG)

30 60 90

755 520 670

0.20 0.00

0.50 1.23

120 120 120

20 40 60 90 120

42 385 175 120 10

0.40 0.38 0.74 4.11 2.61

2.16 1.83 2.44 1.99 3.80

100 100 100 100 100

30 60

150 160

2.12 1.74

End Bypass 2.09 130 2.08 150

Begin

RECTAL TEMP.

(°C.) 37 37 37

Bypass 1,900 1,900 1,710 1,500 1,700

34 32 32 32 32

URINE VOLUME (C.C.)

15 5 10 3 5 5 1

SEROTONIN

(AC/ 100

PLATELETS

18 27

103 200 210

24 13 22 6

150 170 180 140

ML.)

Plasma Hgb = ZOO mg.% 35 7 50 12 36

160 180

Recovery Boom 6 h r . postop. 140 37 800 total Blood Volume—30 min. postop. = 2,800 c . c ; 4 hr. postop. = 4,500 c.c. BUN—Preop. = 12 m g . % ; 2nd postop. day = 50 m g . % ; 6th postop. day = 28 mg.%. Legend: RPF—Renal plasma flow. •Low flow, normothermic perfusion in a 30-year-old man (H. S.) who underwent total aortic valve replacement. TABLE

TIME (MIN.)

30 60

RPF (C.C./ MIN.)

110 105

L.)

NOREPINEPHRINE (jBG/L.)

ARTERIAL PRESSURE (MM. HG)

35 30

0.39 0.51

4.06 3.61

190 190

<1 <1 3 <1 <1 <1

1.87 2.21 2.06 3.42 4.67 6.75 12.06

3.75 3.75 4.43 6.33 8.71 5.84 12.30

GFR (C.C./ MIN.)

EPINEPHRINE

(*»/

Begin 5 30 60 90 120 150 180

30 60

7 11 15 9 10 6

10 7

IV*

<1 <1

4.64 2.35

Bypass 110 110 150 170 180 180 110

End Bypass 8.25 160 9.05 160

PERFUSION RATE (C.C./

M.V

MIN.)

1770 1870 1870 1870 1770 1570 1400

RECTAL TEMP.

URINE VOLUME (C.C.)

37.0 37.0

22 21

35.5 34.0 34.0 34.0 35.0 38.0 38.0

5 3 6 3 1 1

38.0 38.0

2 1

(°c)

Aramine 2 mg Plasma Hgb. = 250 mg.%

Recovery Boom Total Urine Volume—4 hr. postop. = 400 c.c. (LMD 200 c.c. infused). Blood Volume—Preop. 4,930 c . c ; 1 hr. postop. = 4,500 c.c. BUN—Preop. = 20 m g . % ; 1st postop. day = 48 m g . % ; 7th postop. day = 210 m g . % ; 8th postop. day—Died. Legend: RPF—Renal plasma flow. GFR—Glomerular filtration rate. *A 3 hour bypass for aortic valve replacement in a 5 2-year-old man (M. K.). The circulatory stress during bypass is apparent from the high levels of plasma epinephrlne and norepinephrine. The prolonged period of renal ischemia may have contributed to the postoperative renal failure.

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bypass. E P P and GFR were reduced to almost immeasurable levels during the bypass period, and this depression of renal circulation and function also continued after bypass. Only briefly, at the very termination of the period of bypass, was there any evidence of hypotension, and this fall in blood pressure responded readily to a single injection of 2 mg. of Aramine (metaraminol). Although this patient also received a quantity of LMD used to prime the pump oxygenator, no evidence of post-bypass diuresis was observed. An initially adequate volume of urine flow postoperatively followed the infusion of additional LMD. However, elevation of the BUN to 48 mg. per cent on the first postoperative day gave warning of renal damage, and the severity of the renal insult was indicated by the BUN of 210 mg. per cent on the seventh postoperative day. The patient died in uremia on the eighth postoperative day. DISCUSSION

The importance of adequate post-bypass cardiac function for the successful conclusion of cardiopulmonary bypass is obvious; persistence of a diminished post-bypass cardiac output, and the association of this state with postoperative failure has been clearly demonstrated by Boyd and co-workers.5 It is perhaps being too optimistic to expect a return of near normal cardiac function in a diseased heart, following prolonged bypass with attendant myocardial trauma and ischemia. Clowes7 has pointed out the normal pattern of cardiac response to operation. In his studies, the cardiac output fell an average of 33 per cent during the course of an intrathoracic operative procedure; postoperatively it rose to 130 per cent of resting values, and this change was associated with a gradual correction of the metabolic acidosis acquired during the operative and immediate postoperative periods. Three patients in this series who recovered from open-heart operations responded similarly with a postoperative increase in cardiac output. However, 2 patients who died postoperatively failed to demonstrate any increase in cardiac output; this failure to respond resulted in an increasing metabolic acidosis, further circulatory deterioration, 8 and death. Clowes thought that epinephrine and norepinephrine might be responsible for the observed increase in cardiac output at the termination of the operation. However, this plausible explanation is not supported by the studies of Hammond, Aronow, and Moore17 who failed to demonstrate any predictable response of plasma epinephrine and norepinephrine to surgical trauma. We observed that the highest post-bypass epinephrine levels occurred in those patients in whom evidence of circulatory inadequacy was most apparent. Whatever support the heart and circulation might be given by elevated plasma epinephrine concentrations may be offset by the metabolic acidosis that is regularly associated with inadequate tissue perfusion. Thrower and his colleagues39 have reported on the adverse effect of acidosis on myocardial contractility, and Snyder and coworkers 37 have shown a decreased response in cardiac output to the stimulus of epinephrine during a state of metabolic acidosis. Since it is known that catecholamines may cause or accentuate an already existing acidotic state, 28 it is reasonable to expect that correction of the underlying metabolic derangement

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UrIlJ

of metabolic acidosis in those patients whose post-bypass cardiac function is depressed would be more helpful than attempts to flail the circulatory system with intravenous infusions of pressor agents. Moreover, the untoward effects of norepinephrine on renal hemodynamics during periods of circulatory crisis have been recorded. 6 ' 9 Therefore, the perpetuation of metabolic acidosis by endogenous catecholamines impairs their own effectiveness and further aggravation follows the administration of any exogenous pressor agents. The observation of diminished plasma epinephrine values in the patient cooled to 25° C. is an interesting correlation with the report of Hume and Egdahl. 22 They noted marked adrenal medullary depression in the anesthetized, traumatized dog cooled to 27° C. and, concomitantly, a striking fall in plasma epinephrine and norepinephrine concentrations. They did not find any significant differences in adrenal secretion of epinephrine and norepinephrine between normothermic patients during operation and a single patient cooled to 30° C.22 The persistence of moderate concentrations of circulating norepinephrine in our patients may indicate the continued secretion of this substance by peripheral nervous sources in response to the stimulus of a drastically reduced cardiac output, since it is known that plasma norepinephrine may remain unchanged even after total bilateral adrenalectomy. 17 The significance of serotonin release is unclear. Various coagulation abnormalities attributed to changes in serotonin concentration 14 have not been supported by experimental evidence, 34 ' 40 although in vivo observations in man 23 have shown serotonin to be a potent agent in stimulating the production of fibrinolytic activity in veins, provided rapid removal from the site of injection is prevented. It has also been theorized that serotonin plays a major role in renal vasoconstriction during cardiopulmonary bypass, 15 and this theory receives support from the observation by Hollander and associates20 that the intravenous injection of serotonin in man is associated with a significant decrease in P A H and inulin clearances. Experimental studies, in contrast, failed to show any effect of a constant infusion of serotonin on renal hemodynamics in the dog.19 Acute renal failure following cardiopulmonary bypass is a significant cause of postoperative mortality. 13 Severe depression of renal circulation is common in our studies, and it is tempting to speculate that renal ischemia during bypass results in acute tubular necrosis in the post-bypass period. However, the kidney is known to tolerate 2 hours of complete ischemia without subsequent acute tubular necrosis,30 and protection of the kidney against renal arterial occlusion of up to 4 hours has been reported during whole body hypothermia at 22° to 24° C. in the dog.18 Yet we should emphasize that the dog kidney is more resistant to ischemia than the human kidney. Severely depressed renal blood flow in several patients not exhibiting significant elevations of plasma epinephrine and norepinephrine was unexpected and suggests a nervous component or some other circulating factor. I t is possible that central nervous stimulation of renal vasoconstriction is responsible for such changes observed in these patients. Support for this comes from the studies of Balint and his co-workers3 who found that while the innervated kidney of the dog responded to hemorrhagic hypotension by renal vasoconstriction, the

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vascular tone of the denervated kidney remained unchanged. Houck 21 has shown that unilateral stimulation of renal nerves in the dog produced marked depression of PAH clearance, resulting, after prolonged stimulation, in regions of ischemia and infarcts involving both cortex and medulla. Hoff and colleagues19 demonstrated striking reductions in renal blood flow and pathologic changes characteristic of acute tubular necrosis in cats subjected to electrical stimulation of areas in the anterior sigmoid gyrus. These changes were abolished by denervation of the kidneys. In this regard, the association of acute tubular necrosis with brain lesions has recently been emphasized.38 The most critical studies are those of McGiff and Aviado, 29 who found in the dog that the greatest increase in vascular resistance in both the femoral and renal arterial systems was induced by increasing the intracranial pressure. The renal circulation was capable of responding to this nervous stimulus almost to the point of complete cessation of blood flow and consistently responded with a greater degree of vasoconstriction than the femoral vascular bed. Intense renal vasoconstriction in the dog has been reported following infusion of lysed homologous red blood cells,11 although initial passage of the lysed cells through the liver by direct portal vein infusion reportedly removed whatever renal vasoactive principle was responsible. Infusion of hemoglobin from autologous lysed red blood cells in the human being, of sufficient quantity to attain a mean plasma hemoglobin concentration of 178 mg. per cent, was associated with a mean decrease of 56 per cent in P A H clearance and 37 per cent in inulin clearance.27 The likelihood that increased plasma hemoglobin concentrations may be responsible for the changes observed in renal blood flow seems untenable in view of previous studies demonstrating adequate renal perfusion during cardiopulmonary bypass at high flow rates despite hemoglobinuria.32 Support for this view comes from the work of Ladd, 24 who used mannitol diuresis (500 to 2,000 6m. intravenously) in Korean war casualties in an attempt to prevent tubular hemoglobin cast formation. He states, " t h e prevention of urinary stasis and precipitation did not measurably improve renal function. Two of the five patients never recovered from post-traumatic renal failure and the three others showed clearance patterns comparable to untreated casualties with equivalent trauma. In view of these findings, the role of heme pigment must be relegated to a position of secondary importance insofar as the genesis of post-traumatic renal insufficiency is concerned." Ladd also noted that the development of acute tubular necrosis in Korean war casualties did not appear to reflect directly the injury received during shock, but rather resulted secondarily from continued interference with renal blood flow during convalescence. This concept seems pertinent in this discussion of renal failure following cardiopulmonary bypass, for, although renal blood flow may be impaired during the course of bypass, the injury sustained by that brief period of ischemia will be repaired subsequently if adequate cardiovascular function is regained. If, on the other hand, the postoperative cardiac function is depressed as well, the period of renal ischemia is prolonged and may result in acute tubular necrosis.

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SUMMARY

An investigation of plasma epinephrine, norepinephrine, and serum serotonin concentrations was undertaken before, during, and after cardiopulmonary bypass. Marked increases in circulating epinephrine were seen during normothermic, moderate flow perfusions, whereas smaller but still significant increases were seen during low flow, hypothermic perfusions. Evidence for serotonin release from platelets during extracorporeal circulation was obtained. The significance of these findings with regard to post-bypass circulatory function was discussed. REFERENCES 1. Ausman, R. K., Gemmill, S. J., Aust, J . B., and Lillehei, C. W.: Use of Blood Volume Determinations in Open Heart Surgery, Tr. Am. Soc. Artificial Organs 7: 216, 1961. 2. Balint, P., and Fekete, A . : Circulation and Renal Function in the Dehydrated Dog, Acta Physiol. Acad. Sc. Hung. 17: 278, 1960. 3. Balint, P., Fekete, A., and Syalay, Z.: The Nervous Regulation of Renal Adaptation, Acta phvsiol. Hung. 10: 263, 1956. 4. Belisle, C. A., Woods, E. F., Nunn, D. B., P a r k e r , E. F., Lee, W. H., Jr., and Richardson, J. A: The Role of Epinephrine and Norepinephrine in Rebound Cardiovascular Phenomenon in Azygos Flow Studies and Cardiopulmonary Bypass in Dogs, J . THORACIC SURG. 39:

815,

1960.

5. Boyd, A. D., Tremblay, R. E., Spencer, F . C , and Bahnson, H. T.: Estimation of Cardiac Output Soon After I n t r a c a r d i a c Surgery, Ann. Surg. 150: 613, 1959. 6. Chung, W., and 8ima, V.: Renal Tubular Necrosis: I t s Relation to Norepinephrine Administration, Surgery 50: 328, 1961. 7. Clowes, G. H. A., and Del Guercio, L. R.: Circulatory Response to T r a u m a of Surgical Operations, Metabolism 9: 67, 1960. 8. Clowes, G. H. A., Sabga, G. A., Konitaxis, A., Tomin, R., Hughes, M., and Simeone, F . A.: Effects of Acidosis on Cardiovascular Function in Surgical P a t i e n t s , Ann. Surg. 154: 524, 1961. 9. Corday, E., and Williams, J . H . : Effect of Shock and of Vasopressor Drugs on the Regional Circulation of the Brain, Heart, Kidney and Liver, Am. J. Med. 29: 228, 1960. 10. Davis, R. B . : The Concentration of Serotonin in Normal Human Serum as Determined by an Improved Method, J . L a b . & Clin. Med. 54: 344, 1959. 11. DeMaria, W. J . A.: Effect of Homologous Blood Components and Heterologous Lysed Red Blood Cells on Dog Renal Dynamics, Proc. Soc. Exper. Biol. & Med. 108: 122, 1961. 12. DeWall, R. A., Warden, H. E., Varco, R. L., and Lillehei, C. W.: The Helix Reservoir P u m p Oxygenator, Surg. Gynec. & Obst. 104: 699, 1957. 13. Doberneck, R. C., Reiser, M. P., and Lillehei, C. W.: Acute Renal Failure After OpenH e a r t Surgery Utilizing Extracorporeal Circulation and Total Body Perfusion, J . THORACIC SURG. 4 3 :

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14. Erspamer, V.: Pharmacology of Indolalkylamines, Pharmacol. Rev. 6: 425, 1954. 15. Frick, M. H . : Influence of 5 H y d r o x y t r y p t a m i n e on Renal Function in Extracorporeal Circulation, N a t u r e 187: 609, I960. 16. Hamelberg, W., Sprouse, J. H., Mahaffay, J. E., and Richardson, J . A.: Catecholamine Levels During Light and Deep Anesthesia, Anesthesiology 2 1 : 297, 1960. 17. Hammond, W. G., Aronow, L., and Moore, F . D . : Studies in Surgical Endocrinology. I I I . Plasma Concentrations of Epinephrine and Norepinephrine in Anesthesia, Trauma and Surgery, as Measured by a Modification of the Method of WeilMalherbe and Bone, Ann. Surg. 144: 715, 1956. 18. Harsing, L., Jellinek, S., Kover, G., Lasylo, K., Veghelyi, P., and Fonyody, S.: The Effect of Hypothermia on Ischaemic Changes in the Kidney, A c t a physiol. Hung. 10: 429, 1956. 19. Hoff, E . C , Kell, J . F., Hastings, N., Sholes, D. M., and Gray, E. H . : Vasomotor, Cellular and Functional Changes Produced in Kidney by Brain Stimulation, J . Neurophysiol. 14: 317, 1951. 20. Hollander, W., Miehelson, A. L., and Wilkins, R. W.: Serotonin and Antiserotonins. I. Their Circulatory, Respiratory and Renal Effects in Man, Circulation 16: 246, 1957.

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