Plasma vasopressin levels and urinary sodium excretion during cardiopulmonary bypass

Plasma vasopressin levels and urinary sodium excretion during cardiopulmonary bypass Comparison of halothane and morphine anesthesia Marked elevations of plasma vasopressin (antidiuretic hormone, ADH) levels have been reported during cardiopulmonary bypass (CPR). This study was undertaken to determine the effects of different anesthetics on ADH level and the changes in urinary flow and electrolyte content during CPR. Twenty-one patients undergoing elective open cardiac surgery were studied in three groups: Group I-halothane anesthesia; Group II-morphine anesthesia, / mg. per kilogram; and Group Ill-morphine anesthesia, 2 mg. per kilogram. In Group I vasopressin levels rose during operation (9.9 ± 4 to 82.4 ± 23 pg. per milliliter, p < 0.01) and bypass (/72.4 ± 23 pg. per milliliter, p < 0.001). During bypass, urine Na: also rose (69 ± 15 to /27 ± 4 mEq. per liter, p < 0.01) and urine K+ declined (64 ± 12 to 31 ± 9 mEq. per liter, p < 0.01). In Group II, vasopressin rose during the surgical procedure (8.5 ± /5 to /7.9 ± 7 pg. per milliliter, p < 0.05) and bypass (82.3 ± 30 pg. per milliliter, p < 0.001). During bypass urine Na: rose (73 ± 37 to 93 ± 25 mEq. per liter, p ± 0.05) and urine K+ declined (96 ± 7 to 5/ ± 16 mEq. per liter, p < 0.05). In Group III vasopressin was not significantly elevated until bypass (7.8 ± 3.6 to 50.1 ± 18 pg. per milliliter, p < 0.01). During bypass, urine K+ declined (73 ± 7 to 40 ± 7 mEq. per liter, p < 0.05). Urine flow rose during bypass in all three groups. The rise in vasopressin was greater in Group I than in Group II or III (p < 0.0/) during CPR. The rise in urine Na" in Group I was greater than that in Group III (p < 0.05) as was the decline in urine K+ (p < 0.05). These data demonstrate that vasopressin levels are not affected by halothane or morphine anesthesia and that the response to surgical stimulation can be attenuated by the depth of anesthesia. They also suggest that there is a stress response to CPR, resulting in high levels of vasopressin and a Na" diuresis, that can also be attenuated by the depth of anesthesia.

Daniel M. Philbin, M.D., Cecil H. Coggins, M.D., Clifton W. Emerson, M.D., Frederick H. Levine, M.D., and Mortimer J. Buckley, M.D., Boston, Mass.

Marked elevations of plasma vasopressin (antidiuretic hormone, ADH) levels in cardiac surgery patients during operation and cardiopulmonary bypass (CPS) have been reported previously. I. 2 These have occurred despite a large fluid load and the noted increase in urine volume. This study was undertaken to determine the effect of different anesthetics on this vaFrom the Cardiac Anesthesia Group, Harvard Anesthesia Research Laboratories, and the Departments of Medicine and Surgery, Harvard Medical School at the Massachusetts General Hospital, Boston, Mass. Presented in part at the American College of Cardiology Scientific Session, Anaheim, Calif., March, 1978. Received for publication Aug. 22, 1978. Accepted for publication Oct. 10, 1978. Address for reprints: Daniel M. Philbin, M.D., Department of Anesthesia, Massachusetts General Hospital, Boston. Mass. 02114.

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sopressin response and the changes in urinary flow and electrolyte content during CPB.

Patients and methods Twenty-one patients scheduled for elective open cardiac operations were studied in three equal groups according to the anesthetic technique: Group I-thiopental, 2 mg. per kilogram, and halothane, 0.5 percent; Group II-morphine, 1 mg. per kilogram; and Group III-morphine, 2 mg. per kilogram. The average age of the three groups was comparable. All patients had normal renal function preoperatively. The patients in Group I underwent coronary artery bypass graft operations, whereas the patients in Groups II and III underwent combinations of coronary artery and/or valvular surgery. All patients received nitrous oxideoxygen, 50 percent each. Premedication consisted of

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Table I. Group I: Renal data (mean ± standard error) Period Control Anesthesia Surgery Bypass, 15 min. Bypass, 30 min. Postbypass, 15 min.

Vasopressin (pg.fml.)

9.9 10.1 82.4* I72At 168.2t 89.3*

± ± ± ± ± ±

9 5 23 23 25 16

Urine Na" (mEq. fL.)

69 69 65 127* 123* 69

± ± ± ± ± ±

15 14 10 4 7 13

Urine K+(mEq.lL.)

64 ± 12 64±13 45 ± 12 31* ± 9 30* ± 8 66 ± 10

Urine flow (ml./min.)

2.1 2.0 3.9 6.9* 4.9

± 0.7 ± 0.6 ± 1.1 ± 2 ± 3

Urine osmolality (mOsm.fKg.)

585 583 456 425:1: 399:1: 380:1:

± 74 ± 76 ± 73 ± 54 ± 44 ± 25

*p < 0.01. tP < 0.001. :j:P < 0.05.

Table II. Group II: Renal data (mean ± standard error) Period Control Anesthesia Surgery Bypass, 15 min. Bypass, 30 min. Postbypass, 15 min.

Vasopressin (pg.lml.)

8.5 8.1 17.9* 82.3t 68.lt 66.3t

± ± ± ± ± ±

5 3 7 30 31 24

Urine Na+ (mEq.

73 70 63 93 99 91

± ± ± ± ± ±

n.,

37 30 17 25* 20* 3

Urine K+(mEq.lL.)

96 97 79 70 51* 72

± ± ± ± ± ±

7 6 27 17 16 14

Urine flow (ml.fmin.)

0.8 0.8 3.3* 4.9* 1.9

± ± ± ± ±

0.2 0.2 1.2 1.6 0.6

Urine osmolality (mOsm.fKg.)

568 571 533 536 445* 376*

± ± ± ± ± ±

75 75 61 42 64 73

*p < 0.05. tP < 0.001.

Table III. Group Ill: Renal data (mean ± standard error) Period Control Anesthesia Surgery Bypass, 15 min. Bypass, 30 min. Postbypass, 15 min.

Vasopressin (pg.fml.)

7.8 8.1 11.9 50.1* 58.3* 34.8t

± ± ± ± ± ±

3.6 3 7 18 16 7

Urine Na+ (mEq.

68 63 62 70 98 69

± ± ± ± ± ±

tt..,

23 23 25 18 14 4

Urine K+(mEq.fL.)

73 72 64 57 40t 57

± ± ± ± ± ±

7 7 12 12 7 10

Urine flow (ml./min.)

0.8 0.5 2.9 12.2* 6.9* 4.9*

± ± ± ± ± ±

0.3 0.2 1.2 7 3 3

Urine osmolality (mOsm.lKg.)

542 547 526 465 328* 350*

± ± ± ± ± ±

44 43 68 52 17 30

*p < 0.01. tP < 0.05.

0.4 mg. of scopolamine and 0.1 mg. of morphine per kilogram administered intramuscularly approximately 90 minutes prior to arrival in the induction room. Informed consent was obtained from all patients and the protocol was approved by the Human Studies Committee of the Massachusetts General Hospital. Monitoring electrocardiograph (ECG) leads were placed and percutaneous radial artery, central venous pressure, and 16 gauge intravenous catheters were introduced after induction of local anesthesia. Arterial and central venous pressure values and an ECG were recorded continuously on an eight-channel monitor with oscilloscope. An indwelling urinary catheter was placed after induction of anesthesia and connected to a collecting bag.

The study was divided into five periods: (1) control-after placement of monitoring lines and prior to induction of anesthesia; (2) anesthesia-15 minutes after induction of anesthesia; (3) surgery-15 minutes after surgical incision; (4) bypass-15 and 30 minutes after start of bypass; and (5) postbypass-at 15 minutes. In the respective periods, the following variables were measured or recorded: (1) mean arterial and central venous pressures; (2) heart rate and ECG; (3) arterial blood gases, electrolytes, and osmolality; (4) urine flow, osmolality, and electrolytes; and (5) plasma vasopressin levels. Serum and urine osmolalities were determined by freezing point depression with a 3-W Advanced osmometer. Plasma vasopressin (ADH) levels were de-

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termined by a radioimmunoassay reported previously, utilizing 1251-labeled arginine vasopressin and rabbit antibodies." Intragroup data were analyzed for correlated t test and intergroup data for uncorrelated t test. After control measurements were obtained, anesthesia was induced as previously described. During this period, the patients were intubated, catheterized, and prepared for operation. The heart was approached by a median sternotomy. Cannulation for bypass utilized the ascending aorta and both venae cavae via the right atrium. A Bentley disposable bubble oxygenator was used with 3 L. of lactated Ringer's prime. All patients were cooled to 28° C. and the heart was fibrillated by the standard technique. Results Group I. Table I summarizes the major data obtained in Group I (Pentothal-halothane anesthesia). There were no significant changes in serum electrolytes or osmolality. The decline in urine osmolality and K+ content and the rise in urinary Na" did achieve significance during bypass. Plasma vasopressin levels became significantly elevated during operation and rose further during bypass, as did urinary flow. Group II. Table II summarizes the major data forGroup II (morphine anesthesia, I mg. per kilogram). Again, there were no significant changes in serum osmolality or electrolytes. The rise in urinary Na" and flow and the fall in urinary K+ and osmolality were statistically significant during bypass. Plasma vasopressin levels were significantly elevated during operation and bypass-more so in the latter period. Group III. Table III summarizes the data for Group III (morphine anesthesia, 2 mg. per kilogram). In this group, the significant changes occurred only in periods 4 and 5 (during and after bypass). Urine osmolality and K+ content declined and urine Na" and flow rose. Plasma vasopressin levels became significantly elevated with the institution of CPB. The rise in plasma vasopressin levels in Group I was significantly higher than in Group II or III (p < 0.01). The rise in urinary Na" in Group I was greater than that in Group III (p < 0.05), as was the decline in urinary K+ (p < 0.05). Discussion The indwelling catheter was inserted after the patient had been anesthetized; and for this reason control urine flows could not be determined and control values for urinary electrolytes and osmolality are reported on the initial bladder sample. The control values for vasopressin are slightly higher

Thoracic and Cardiovascular

Surgery

than normal. However, these values were obtained following placement of monitoring lines in patients who had been without fluids overnight and who were awaiting major operations; therefore, they are reasonable .': 4. 5 In previous work, two of us have demonstrated that the vasopressin levels in cardiac surgery patients are not significantly affected by the induction of anesthesia with either Pentothal-halothane or morphine." These data confirm this observation and suggest that stimulation can be attenuated by the depth of anesthesia. Thus, in Group III, the plasma vasopressin levels did not become significantly elevated during operation, prior to the institution of bypass. It may well be that this response to surgical stress, as previously reported in the literature,": 7. 8 might be interpreted more correctly as a response to comparatively light anesthesia. It should also be noted that prior to the advent of the radioimmunoassays for vasopressin, the biological assay utilized was tedious, time consuming, and nonspecific." Thus many of the previous studies used indirect evidence for vasopressin (ADH) levels, i.e., urine flow. Under these circumstances, the relationship of urine flow and vasopressin is not exact. All three groups of patients demonstrated significant elevation of vasopressin during CPB. This occurred despite the fluid load and the decline in urine osmolality. The smallest rise occurred in Group III, again supporting the speculation that this is indeed a "stress" response to the institution of the unphysiological state of CPB, with the loss of pulsatile flow and the rapid decline in left atrial pressure perhaps being significant factors. Hemodilution is probably not a significant factor since previous work has demonstrated that the addition of whole blood to the prime does not alter the vasopressin rise during CPB.10 It appears more likely that this outpouring of vasopressin is a physiological response in an attempt to maintain homeostasis. The levels reported in all three groups are well beyond the physiological range for an antidiuretic effect on the kidney and in fact occurred when urinary flows were at their highest. The maximum antidiuretic effect of vasopressin is exerted at concentrations below 20 pg. per milliliter. 11 Once this has been exceeded, higher vasopressin levels will either have no effect or possibly even exert some inhibitory action on urine concentration secondary to a hemodynamic effect. In high concentrations such as reported here, the vasoconstrictor effect of vasopressin may become significant. It is an extremely potent endogenous vasoconstrictor in man, more so than angiotensin," because of its direct action on the smooth muscle of vascular beds.": 14 At these levels of vasopressin, urine

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flow is independent and may be reflecting the status of hemodynamic events.' It should be noted that in all these groups, urinary Na" excretion increased during bypass, paralleling to some extent the vasopressin response. The greatest increase in Na" occurred in Group I, which also demonstrated the greatest vasopressin rise, while the smallest changes occurred in Group III. At these concentrations, a sodium diuresis can possibly be produced in man. At high concentrations, vasopressin is known to increase renal excretion of sodium in rats and dogS. 15 - 17 This can occur if there is no detectable pressor response" or if pressor response is ablated by the administration of sodium nitroprusside." The site of action for this natri uretic effect of vasopressin is unknown since there is evidence for inhibition of distal sodium reabsorption'? as well as inhibition in the proximal tubule. 20 Thus it is possible that the increased plasma vasopressin concentrations are responsible, at least in part, for the increased urinary sodium excretion observed during CPB. It is also possible that the sodium diuresis is merely a reflection of local pressure changes in the kidney with a redistribution of renal blood flOW 2 1 or a secondary effect mediated by an unknown factor. 22 In conclusion, we feel that these data support the concept that the vasopressin response to surgical stimulation is a nonspecific stress response, which can be attenuated by deeper levels of anesthesia. They also again demonstrate that the anesthetics used, under these conditions, do not significantly affect plasma vasopressin levels. The marked elevation of vasopressin during CPB is probably a physiological response to maintain pressure and resistance. This too can be attenuated by deeper anesthesia. These high levels may contribute to a sodium diuresis and increased urinary flow, and not an antidiuresis. REFERENCES I Philbin DM, Coggins CH, Wilson N, Sokoloski J: Antidiuretic hormone levels during cardiopulmonary bypass. J THORAC CARDIOVASC SURG 73:145-148, 1977 2 Wu W, Zbuzkora V: Plasma vasopressin levels during cardiac surgery. American Society of Anesthesiologists, Abstracts of Scientific Papers, 1977, pp 585-586 3 Philbin DM, Wilson N, Sokoloski J, Coggins CH: Radioimmunoassay of antidiuretic hormone during morphine anesthesia. Can Anaesth Soc J 23:290-295, 1976 4 Moran WH Jr, Mittenberger FW, Shuayb WA, Zimmerman B: The relationship of antidiuretic hormone secretion to surgical stress. Surgery 56:99-108, 1964 5 Moran WH Jr, Zimmerman B: Mechanisms of antidiuretic hormone control of importance to the surgical patient. Surgery 62:639-644, 1967

6 Philbin DM, Coggins CH: Plasmic antidiuretic hormone levels in cardiac surgical patients during morphine and halothane anesthesia. Anesthesiology 49:95-98, 1978 7 Ukai M, Moran WH Jr, Zimmerman B: The role of visceral afferent pathways on vasopressin secretion and urinary excretory patterns during surgical stress. Ann Surg 168:16-28, 1968 8 Oyama T, Kimura K: Plasma levels of antidiuretic hormone in man during ethyl ether anaesthesia and surgery. Can Anaesth Soc J 17:495-503, 1970 9 Yoshida S, Motohasi K, Ibayashi H, et al: Method forthe assay of antidiuretic hormone in plasma with a note on the antidiuretic titer of human plasma. J Lab Clin Med 62:279-285, 1963 10 Philbin DM, Coggins CH: Plasma vasopressin levels during cardiopulmonary bypass with and without profound haemodilution. Can Anaesth Soc J 25:282-285, 1978 II Robertson GL: Vasopressin in osmotic regulation in man. Annu Rev Med 25:315-322, 1974 12 Moran WH Jr: CPPB and vasopressin secretion (editorial). Anesthesiology 34:501-504, 1971 13 Corliss RJ, McKenna DH, Sialer S, et al.: Systemic and coronary hemodynamic effects of vasopressin. Am J Med Sci 256:293-299, 1968 14 Edmunds R, West JB: A study on the effect of vasopressin on portal and systemic blood pressure. Surg Gynecol Obstet 114:458-462, 1962 15 Buckalew VM Jr, Dimond KA: Effect of vasopressin on sodium excretion and plasma antinatriferic activity in the dog. Am J Physiol 231:28-33, 1976 16 Grinnel GH, Kramer JL, Duff WM, Lydon TE: Further studies on the diuretic activity of antidiuretic hormone. Endocrinology 83:199-206, 1968 17 Kurtzman NA, Rogers PW, Boonjarern S, Arruda JAL: Effect of infusion of pharmacologic amounts of vasopressin on renal electrolyte excretion. Am J Physiol 228:890-894, 1975 18 Martinez-Maldonado M, Eknoyan G, Suki WN: Natriuretic effects of vasopressin and cyclic AMP? Possible site factor in the nephron. Am J Physiol 220:2013-2020, 1971 19 Wen SF: The effect of vasopressin on phosphate transport in the proximal tubule of the dog. J Clin Invest 53:660664, 1974 20 Knight T, Weinman EJ: Effect of pharmacologic doses of vasopressin on sodium and water reabsorption in the rat kidney. Clin Res 25:404A, 1976 21 Johnson MD, Park CS, Malvin RL: Antidiuretic hormone and the redistribution of renal cortical blood flow. Am J Physiol 232:FIII-116, 1977 22 Walter R, Smith CW, Mehta PK, Boonjarern S, Arruda JAL, Kurtzman NA: Conformational considerations of vasopressin as a guide to development of biological probes and therapeutic agents, Disturbance in Body Fluid Osmolality, TE Andreoli, TJ Grantham, FC Rector Jr, eds., Bethesda, 1977, American Physiological Society, pp 1-36