The Management of Ascites in Cirrhosis of the Liver

The Management of Ascites in Cirrhosis of the Liver From the Cardiorenal Laboratory, Second (Cornell) Medical Division, Bellevue Hospital, and the Department of MediCine, Cornell University Medical College, New York, N. Y. DA VID A. OGDEN, M.D. Research Fellow of the American College of Physicians

LAWRENCE SCHERR, M.D. Research Fellow of the New York Heart Association

NORTON SPRITZ, M.D. ALBERT L. RUBIN, M.D. Established Investigator, American Heart Association

THE majority of patients with cirrhosis of the liver develop ascites. l This is often a predominant problem in the management of their disease. Intrahepatic vascular obstruction, hypoalbuminemia, and sodium and water retention each have been implicated in ascites formation. 2- 7 No one, but a combination of these factors, is necessary for the production of ascitic fluid, the source of which is most probably lymph from the liver itself.2 Minimal or even moderate ascites produces no untoward effects and therefore does not require therapy directed specifically at the fluid accumulation. Severe, tense ascites causes abdominal discomfort and respiratory embarrassment which may necessitate fluid removal. Reduction in the amount of ascites becomes imperative when it impairs nutrition either by anorexia, nausea or vomiting. In addition, large accumulations of intra-abdominal fluid impair renal blood flow and glomerular filtration rate and may thus contribute to further fluid retention. 8

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DIET AND FLUID INTAKE

A diet adequate in protein and calorie content is of primary importance in hepatocellular disease. Seventy to 80 grams of protein and sufficient carbohydrate and fat to provide a total of 3000 calories a day constitute a diet well suited to most cirrhotics. 9 , 10 In some patients with severe cirrhosis, however, even a restricted protein intake may precipitate hepatic pre-coma or coma. IO , 11 In such patients, the diet must contain as much protein as can be tolerated without producing signs of pre-coma. There is no evidence that vitamin supplements are of additional benefit to the cirrhotic who consumes an adequate diet. It has been repeatedly demonstrated that, if strict dietary sodium restriction can be achieved and maintained for a sufficient period, patients with even the most far-advanced liver disease will eventually lose ascitic fluid. 7 , 12-16 A diet containing 15 mEq. or less of sodium is, however, difficult to achieve if palatability and adequate protein intake are to be maintained. Severe sodium restriction must be sacrificed to attain these goals. In advanced cases, water intake may have to be restricted to prevent dilution and further fluid accumulation. Hyponatremia with excessive body fluid probably reflects the inability of these patients to excrete water.I 6 , 17 'Vhen such a situation is present, attempts to increase sodium concentration with hypertonic saline lead only to further weight gain. The restriction of fluid intake to less than 1500 cc. a day will gradually cause the serum sodium to rise in most instances. ADRENAL STEROIDS

Adrenal steroids inconsistently produce a water, or salt and water diuresis, usually minimal in magnitude, in patients with cirrhosis and ascites. 18 , 19 This, combined with enhanced risk of infection and gastrointestinal hemorrhage-particularly dangerous complications in the cirrhotic-makes these agents of limited value. INTRA VENOUS ALBUMIN

Intravenous salt-poor human albumin has been used to raise serum colloid osmotic pressure in an attempt to mobilize ascitic fluid. Albumin rapidly equilibrates between intravascular and ascitic fluid and would not, therefore, alter the colloid osmotic pressure relationship between the two fluids except for a short time. Mankin and Lowell 21 investigated the role of osmotic factors in ascites formation and concluded that the formation of ascites was primarily dependent on loss of protein into the peritoneal cavity, not a reduction of colloid osmotic pressure. Kunkel et al. report loss of ascites in 14 of 15 cirrhotics treated with intravenous albumin. 20 Their patients, however, were not refractory to the common

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diuretics. Patek et al. were unable to produce a diuresis in three patients with cirrhosis and ascites despite the maintenance of normal serum albumin levels in each for 1:3 to 16 days.22 In most instances, we have also found intravenous albumin to be ineffective in reducing ascites or altering the rate of ascites formation. The high cost of the large amount of albumin required further limits its practicability. PARACENTESIS

Although some patients tolerate repeated paracenteses, the procedure is not without danger. Paracentesis may precipitate peritonitis, hepatic coma, sudden hypovolemia with shock,3 or severe hyponatremia/' 12,23 and produces a loss of 10 to 25 grams of protein for each liter of ascitic fluid removed. It should be employed only when the mechanical effects of excessive intra-abdominal fluid demand relief, more conservative measures having failed. In an attempt to avoid some of the untoward effects of paracentesis, we have recently utilized a small polyethylene catheter introduced into the abdomen through a No. 16 or 18 needle, with the slow removal of ascitic fluid over 24 hours. The intravenous administration of salt-poor albumin during this procedure may prevent hypovolemia in patients who reaccumulate fluid rapidly. Though our experience with this technique is limited, it appears worthy of further trial. SHUNTING SURGERY

Despite the frequently poor correlation between portal hypertension alone and the formation of ascites, the relief of portal hypertension by portal-systemic anastomosis may slow or stop ascites formation when more conservative medical measures have failed. 3, 4 This procedure is indicated when proper medical management can no longer control ascites formation, and there is little other evidence of hepatic insufficiency. The procedure of choice, where technically feasible, is an end-toside porta ca val anastomosis. 3 DIURETICS

Control of ascites can usually be effected by the proper use of diuretics, thereby avoiding the hazards of paracentesis and surgery. It should be emphasized that the use of diuretics in the cirrhotic patient involves certain specific dangers which can be avoided only by the judicious use of these drugs. ACETAzoLEAMIDE; CHLOROTHIAZIDE. These agents have been used with success to control ascites formation,24 Many patients with cirrhosis, however, soon became unresponsive to them. In some patients they

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precipitate hepatic coma,24. 25. 26 a complication which, in the case of chlorothiazide, is sometimes reversible by the administration of potassium chloride. 27 MEASURES TO REDUCE ALDOSTEIWNE EFFECT. The recent discovery of aldosterone and recognition of its role in sodium retention in cirrhosis have led to attempts to eliminate the effects of this adrenal steroid in such patients. Bilateral adrenalectomy has been performed for this purpose in a few carefully selected patients with cirrhosis and ascites, with at least temporarily favorable results. 28 • 29 This form of therapy is not suitable for the usual patient with Laennec's cirrhosis and ascites, and should be considered an experimental procedure at the present time. Reaccumulation of fluid in patients treated with adrenalectomy emphasizes the importance of factors other than aldosterone in fluid retention. Drugs capable of reducing aldosterone effect have recently been developed. The amphenones which inhibit the biosynthesis of adrenal steroids30 . 31 also cause symptoms of adrenal insufficiency and severe gastrointestinal irritation,32 and may precipitate hepatic pre-coma. 19 . 31 They have no place in the therapy of cirrhosis with ascites. The steroidal spirolactones, on the other hand, block the action of aldosterone on the renal tubular cell, probably by competitively inhibiting the natural steroid, resulting in increased sodium and chloride and decreased potassium and hydrogen ion excretion. 33 Satisfactory results with these agents have been reported in two patients treated with different spirolactones after becoming refractory to chlorothiazide, mercurials and acidifying agents. 34 In our experience and that of others, however, aldosterone antagonists alone are usually ineffective when other agents have failed. 30 MERCURIAL COMPOUNDS. Organic mercurial compounds are safe and potent agents in the treatment of ascites. Periodic mercurial injections control accumulation of ascites in most patients, and may be safely given as often as necessary for this purpose as long as diuresis ensues. Patients with far advanced cirrhosis with ascites may have a hypokalemic, hypochloremic alkalosis, even in the absence of any diuretic therapy.36 This metabolic derangement in itself limits the effectiveness of mercurial diuretics. 37 In these patients, restoration of normal serum electrolytes may establish mercurial responsiveness. AMMONIUM OR CALCIUM CHLORIDE. In the cirrhotic with ascites who, despite normal serum electrolyte concentrations, becomes, or is initially, refractory to organic mercurials, the production of a hyperchloremic acidosis will restore responsiveness to these agents. 38 Ammonium or calcium chloride administered orally has been used for this purpose. Both compounds, however, have an unpleasant taste and produce gastrointestinal side effects. Moreover, ammonium chloride may precipitate hepatic coma in patients with cirrhosis.!l. 39 LYSINE MONOHYDROCHLORIDE. We have recently employed lysine

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monohydrochloride to induce hyperchloremic acidosis in cirrhotics with refractory ascites, and have found it extremely effective in restoring responsiveness to organic mercurials. 40 This drug has been much better tolerated than either ammonium or calcium chloride. Diarrhea, the most common side effect, has been easily managed in most patients. Hepatic coma due to this agent has not been observed. In our hands, the production of a controlled hyperchloremic acidosis followed by mercurials has proved the most effective diuretic program. ILL USTRA TIVE CASE

\V.T., a 40 year old white man, was admitted to the Second (Cornell) Medical Division of Bellevue Hospital in July 1958 with a 13-year history of excessive alcohol consumption and inadequate diet. For the 4 months preceding admission he had noticed progressive abdominal swelling, leg edema and mild jaundice. Examination on admission revealed a wasted, icteric man with strikingly distended abdomen and massive edema of the legs, scrotum, penis, abdominal and chest walls. The abdomen was tense, a fluid wave was present, and the liver was ballotable. Liver function studies were compatible with Laennec's cirrhosis. Total serum protein was 6 gm./lOO ml. with 1.8 grams of albumin. Venous blood pH was 7.46, and serum potassium 3.4 mEq./L. prior to therapy. Serum electrolyte concentrations were otherwise normal. The patient's clinical course is illustrated in Figure 1. Aldosterone inhibitor Lysine mone.hyclr·ochl!"ide Mercuhydrin

I

mEq/L

:;:~

12BE 120 mEq/L

:~~f 104

96 mEq/24hrs

Liters 124 hrs 2

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OY''''''''''''''P=ao Pounds

:~

:E Days

50

60

70

Fig. 1. Graph illustrating diuretic therapy, urinary output, weight change, and serum and urinary electrolyte alterations of case reported (W.T.). For details see text.

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The low urinary excretion of sodium and chloride and high excretion of potassium seen initially is typical of cirrhotics accumulating ascites. Therapy was initiated with a spirolactone (SC8109), 0.5 to 1.0 gram intramuscularly each day for 5 days. A transient 10 to I5-fold increase in sodium excretion and a slight decrease in potassium excretion ensued, but there was no water diuresis and no change in weight. Daily intramuscular injections of meralluride for the next 3 days effected a chloruresis and natriuresis of a magnitude similar to that caused by the spirolactone, but in this instance a weight loss of 6}--2 pounds occurred. Following the mercurial diuresis, sodium and chloride excretion again fell to insignificant levels, the patient's weight remained stable, and massive ascites'and edema remained. A controlled hyperchloremic acidosis was then produced with lysine monohydrochloride, 40 grams a day by mouth in divided doses until urinary chloride excretion exceeded 40 mEq. per liter. Daily meralluride injection for 4 days with continued administration of lysine monohydrochloride then produced a remarkable chloruresis, natriuresis and water diuresis with a weight loss of 17 pounds. A second 4-day course of the same aldosterone antagonist then failed to produce either a diuresis or a significant change in urinary electrolyte pattern. Mercurial injection following re-establishment of controlled hyperchloremic acidosis, as described above, again effected a significant diuresis with a loss of 16 pounds of weight. Two subsequent 3-day courses of meralluride alone produced little natriuresis and only slight transient weight loss. Finally, a third program of mercurials in the setting of hyperchloremic acidosis induced with lysine monohydrochloride again produced a dramatic response with a I3-pound weight loss. A total loss of 58 pounds was accomplished in 66 days. SUMMARY

The management of ascites in cirrhosis of the liver has been discussed, and a case presented illustrating the use of certain diuretics in this condition. REFERENCES 1. Ratnoff, O. D. and Patek, A. J. Jr.: Natural History of Laenne("s Cirrhosis of

Liver. Medicine 21: 207, 1942. 2. Volwiler, W., Bollman, J. L. and Gridlay, J. H.: Comparison of Two Types of Experimental Ascites. Proc. of Staff Meet. Mayo Clin. 25: 31, 1950. 3. Wantz, G. E.: Ascites in Liver Disease: Pathogenesis and Treatment. S. Clin. North America 38: 407, 1958. 4. Hyatt, R. E. and Smith, J. R.: Mechanism of Ascites. Am. J. Med. 16: 434, 1954. 5. Post, J. and Patek, A. J. Jr.: Serum Proteins in Cirrhosis of Liver. I. Relation to Prognosis and to Formation of Ascites. Arch. Int. Med. 69: 67, 1942. 6. Shedl, H. P. and Bartter, F. C.: Explanation for and Experimental Correction of Abnormal Water Retention in Cirrhosis. J. Clin. Invest. 37: 928, 1958. 7. Eisenmenger, W. T., Blondheim, S. H., Bongiovanni, A. M. and Kunkel, H. G. Electrolyte Studies on Patients with Cirrhosis of Liver. J. Clin. Invest. 29: 1491, 1950. 8 Bradley, S. E. and Bradley, G. P.: Effect of Increased Intra-abdominal Pressure on Renal Function in Man. J. Clin. Invest. 26: 1010, 1947. 9. Eisenmenger, W. J.: Medical Aspects of Cirrhosis of Liver. Bull. New York Acad. Med. 34: 242, 1958.

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10. Watson, C.: Current Status of Treatment of Cirrhosis of Liver. J.A.M.A. 166. 764,1958. 11. PhilIips, G. B., Schwartz, R, Gabuzda, G. J. Jr. and Davidson, C. S.: Syndrome of Impending Hepatic Coma in Patients with Cirrhosis of Liver Given Certain Nitrogenous Substances. New England J. Med. 247: 239, 1952. 12. Gabuzda, G. J., Traeger, H. S. and Davidson, C. S.: Hepatic Cirrhosis: Effects of Sodium Chloride Administration and Restriction and of Abdominal Paracentesis on Electrolyte and Water Balance. J. Clin. Invest. 33: 780,1954. 13. Faloon, W. W., Eckhardt, R. D., Cooper, A. M. and Davidson, C. S.: Effect of Human Serum Albumin, Mercurial Diuretics and Low Sodium Diet on Sodium Excretion in Patients with Cirrhosis of Liver. J. Clin. Invest. 28: 595,1949. 14. Ricketts, W. E., Eichelberger, L. and Kirsner, J. B.: Observations on Alterat.ions in Electrolytes and Fluid Balance in Patients with Cirrhosis of Liver with and without Ascites. J. Glin. Invest. 30: 1157, 1951. 15. Farnsworth, E. B. and Krakusin, J. S.: Electrolyte Partition in Patients with Edema of Various Origins. J. Lab. & Clin. Med. 33: 1534, 1948. 16. Layne, J. A. and Schemm, F. R.: Use of High Fluid Intake and Low Sodium Acid Ash Diet in Management of Portal Cirrhosis with Ascites. Gastroenterology 9: 705, 1947. 17. Aldersberg, D. and Fox, C. L. Jr.: Changes of Water Tolerance Test in Hepatic Disease. Ann. Int. Med. 19: 642, 1943. 18. Winkler, P. K. and Tygstrup, N.: Prednisone Treatment in Cirrhosis of Liver. Acta med. scandinav. 157: 14!l, 1957. 19. Stormont, J. M., Crabbe, J., Fast, B., Wolfe, S. J. and Davidson, C. S.: Effect of Prednisone and Amphenone on Fluid and Electrolyte Balance and on Aldosterone Excretion of Patients with Cirrhosis and Ascites . .T. Lab. & Clin. Med. 53: 396, 195!l. 20. Kunkel, H. G., Labby, D. H., Ahrens, E. H., Shank, R. E. and Hoagland, C. L.: Use of Concentrated Serum Albumin in Treatment of Cirrhosis of Liver. J. Clin. Invest. 27: 305, 1!l48. 21. Mankin, H. and Lowell, A.: Osmotic Factors Influencing Formation of AS!'ites in Patients with Cirrhosis of Liver. J. Clin. Invest. 27: 145, 1!l48. 22. Patek, A. J. Jr., Mankin, H., Colcher, H., Lowell, A. and Earle, D. P. Jr.: Effects of Intravenous Injection of Concentrated Human Serum Albumin upon Blood Plasma, Ascites and Renal Function in Three Patients with Cirrhosis of Liver. J. Clin. Invest. 27: 135, 1948. 23. Nelson, W. P., Rosenbaum, J. D. and Strauss, M. B.: Hyponatremia in Hepatic Cirrhosis Following Paracentesis. J. Clin. Invest. 30: 738, 1951. 24. Myerson, R. M., Stout, R. E. and Forte, A. L.: Acetazolamide and Chlorothiazide in Treatment of Ascites Due to Cirrhosis of Liver. New England.J. Med. 260: 28, 1!l59. 25. Webster, L. T. Jr. and Davidson, C. S.: Production of Impending Hepatic Coma by the Carbonic Anhydrase Inhibitor, Diamox. Proc. Roc. Exper. BioI. & Med. 91: 27,1956. 26. Mackie, J. E., Stormont, J. M., Hollister, R. M. and Davidson, C. S.: Production of Impending Hepatic Coma by Chlorothiazide and Its Prevention by Antibiotics. New England J. Med. 25.9: 1151, 1958. 27. Sherlock S., Read, A. E., Laidlaw, J. L. and Halsam, R.: Chlorothiazide in Liver Disease. Ann. New York Acad. Sc. 71: 430,1958. 28. Giusefii, J., Werk, E. E., Larson, P. U., Shiff, L. and Elliot, D. W.: Effect of Bilateral Adrenolectomy in Patient with Massive Ascites and Postnecrotic Cirrhosis. New England J. Med. 257: 796, 1957. 29. Marson, F. G. W.: Total Adrenolectomy in Hepatic Cirrhosis with Ascites. Lancet 2: 847, 1954. 30. Peterson, R. E., Hertz, R. and Lubs, H. A.: Suppression of Biosynthesis of Adrenal Cortical Steroid in Man by Amphenone. Proc. Soc. Exper. BioI. & Med. 94: 421, 1957. 31. Sllmmerskill, W. H. and CrabbC, J.: Effect of Amphenone Therapy on Urinary

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Excretion of Aldosterone and Sodium in Hepatic Cirrhosis with Ascites. Lancet 2: 1091, 1957. Hertz, R., Pittman, J. A. and Graff, M. M.: Amphenone Toxicity and Effects on Adrenal and Thyroid Function in Man. J. Clin. Endocrinol. 16: 705, 195(i. Liddle, G. W.: Aldosterone Antagonists. Arch. Int. Med. 102: 998, 1958. Sleisenger, M. H. and others: Effects of Spirolactones on Excretion of Water and Electrolytes, and on Aldosterone Metabolism in Cirrhosis. J. Clin. Invest. 38: 1043, 1959. Kerr, D. N. S., Haslam, R. M., Rcad, A. E. and Sherlock, S.: Use of a Steroidal Spirolactone in Treatment of Ascites in Hepatic Cirrhosis. Lancet 2: 1084,1958. Artman, E. L. and Wise, R. A.: Hypokalemia in Liver Cell Failure. Am. J. Med. 15: 459, 1953. Schwartz, W. B. and Wallace, W. M.: Electrolyte Equilibrium During Mercurial Diuresis. J. Clin. Invest. 31: 171, 1952. Axelrod, D. R., Capps, J. N. and Pitts, R. F.: Potentiation of Diuretic Action on Salyrgan by Ammonium Chloride. Fed. Proc. 9: 6, 1950. Davidson, C. S.: Cirrhosis of Liver. Am. J. Med. 16: 863, 1954. Rubin, A. L., Spritz, N., Mead, A. W., Herrmann, R. and Luckey, E. H.: Use of Lysinemonohydrochloride in Combination with Mercurial Diuretics in Treatment of Refractory Fluid Retention States. Circulation (In press).

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