Current Medical Management of Cirrhotic Ascites

Current Medical Management of Cirrhotic Ascites JORGE

L.

HERRERA,

MD,

FACP,

FACG

ABSTRACT: The presence of ascites may indicate a number of hepatic and extra-hepatic disorders. This situation requires comprehensive evaluation to determine the underlying cause. The evaluation and management of ascites in patients with known cirrhosis is very important since this manifestation of portal hypertensicm has a detrimental effect on the prognosis for such patients. KEY INDEXING TERMS: Ascites; Cirrhosis; Portal hypertension; Spontaneous bacterial peritonitis; Paracentesis. [Am J Med Sci 1991; 302(1):31-37.]

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scites refers to the accumulation of fluid within the peritoneal cavity. Ascites cannot be considered a specific disease entity; rather, it is a physical sign that indicates the presence of disease. This is emphasized by the numerous diseases associated with ascites formation (table 1). This review will discuss ascites resulting from advanced liver disease and cirrhosis. The pathophysiology of ascites formation and its diagnosis and management will be discussed. Pathophysiology

With liver disease, ascites forms as a consequence of portal hypertension. Sodium retention is universally present in patients with cirrhosis and ascites. 1 The pathogenesis of sodium and water retention in cirrhosis has been extensively researched for many years. Traditionally, two main theories have explained excessive sodium retention in cirrhosis. The first is the classical "underfill" theory,2 which proposes that the hepatic venous block and portal hypertension in cirrhosis lead to fluid transudation into the abdominal cavity, resulting in ascites formation. This results in a decreased effective plasma volume ("underfill"), leadDivision of Gastroenterology, Department of Medicine University of South Alabama, Mobile, Alabama. The author wishes to thank Ms. Susan Williams for her assistance in preparing this manuscript. Reprint Requests: Jorge L. Herrera MD, Division of Gastroenter· ology, University of South Alabama Medical Center, 2451 Fillingim St., Mobile, AL 36617. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

ing to secondary urinary sodium and water retention as a compensatory mechanism. The second theory is the "overflow theory".3 This proposes that ascites formation is a secondary phenomenon that results from primary renal sodium and water retention, without a preceding decrease in effective plasma volume. The cause of the primary sodium retention has not been delineated but presumably results from a hepatorenal reflex. The sodium and water retention then leads to "overflow" ascites formation secondary to the hypervolemia and the increased pressure in the portal system. Studies involving head-out water immersion of humans4 and animal models of cirrhosis5 •6 have provided data supporting both theories. A third theory, the "integrated" theory of ascites formation, has been proposed by Schrier et a1. 7 This theory proposes that cirrhosis leads to peripheral arterial vasodilation as the initial event. Consequently, there is decreased "effective" plasma volume and activation of compensatory hormonal system with resulting renal sodium retention. This theory is based on prior findings that demonstrate, in experimental cirrhosis8 •9 and in patients with compensated cirrhoSiS,10 systemic hemodynamic changes characterized by primary peripheral vasodilation and a secondary increase in cardiac output occur prior to ascites formation. A recent studyll has confirmed that patients with cirrhosis are unable to maintain a normal central blood volume. Therefore, central circulatory underfilling is an integral part of the hemodynamic and homeostatic derangements in cirrhosis. Thus, despite intense study, the basis of the abnormalities of renal sodium handling in cirrhosis is incompletely defined. When managing a patient with advanced liver disease, however, understanding that the clinical course is frequently complicated by derangements in renal function is important. Among the renal complications of liver disease that require therapeutic intervention is the progressive impairment of renal sodium handling that lead to the formation of ascites and peripheral edema. 12 Clinical Diagnosis of Ascites

The first step in assessing a patient thought to have ascites is to determine whether the abdominal distention is actually ascites. Conditions that can mimic as31

Management of Ascites

Table 1. Causes of Ascites Portal Hypertension Cirrhosis Hepatic congestion Congestive heart failure Constrictive pericarditis Budd-Chiari Syndrome Infections Bacterial peritonitis Tuberculous peritonitis Fungal Chlamydia Parasitic Malignancy Peritoneal carcinomatosis Mesothelioma Metastatic liver disease Other Malnutrition Nephrotic syndrome Protein-losing enteropathy Chylous Pancreatic Myxedema Nephrogenic

cites include exogenous obesity, pregnancy, and large pancreatic or ovarian cystS. 13 Accumulation of over one liter of ascitic fluid is required for detection during routine physical exam using the signs of shifting dullness and positive fluid wave. 14 Routine radiographic techniques, such as a flat plate of the abdomen, may suggest the presence of ascites through blurring of the psoas shadow and medial displacement of colonic air. However, this requires over 2.5 liters of fluid. IS During physical examination, the "puddle sign," elicited with the patient assuming the knee-elbow position, may detect as little as 200 cc of ascites. 16 The reliability of these physical findings has been questioned. Several studies have shown that the clinical diagnosis of ascites is incorrect 33%-50% of the time,17.18 with the overall diagnostic accuracy of the physical findings at 56%.19 The most sensitive way to detect ascites is ultrasonography.20 CT scan is equally sensitive, but more expensive. 21 Ultrasound can detect as little as 150 cc of fluid with the patient in the right lateral decubitus or in the hand-knee position. 20 In addition, both of these techniques can differentiate between free or loculated fluid22 and detect other potential etiologies for the ascites, such as liver masses, other abdominal/pelvic masses, or the presence of retroperitoneal adenopathy.21 Abdominal ultrasound should be obtained in any patient in whom the diagnosis of ascites is equivocal, prior to attempting a diagnostic paracentesis. Evaluation of the Ascitic Fluid

All patients with new onset ascites, or patients with known ascites whose clinical condition changes, require a diagnostic paracentesis. This applies even to patients

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with known pre-existing cirrhosis. Cirrhotic ascites may be complicated by superimposed spontaneous bacterial peritonitis,23 hepatocellular carcinoma, peritoneal carcinomatosis, or, less likely, abdominal tuberculosis. 24 Paracentesis is a safe procedure that can be performed with low morbidity and virtually no mortality.2s The procedure is performed under sterile conditions using a narrow (21-22 gauge) needle. 26 The patient is placed in a semi-recumbent position, and the area of dullness is percussed. A site caudad to the umbilicus and caudad to the level of perc ussed dullness is selected. The avascular linea alba (midline) and the iliac fossae are most commonly selected. The area selected should be away from visible vessels and surgical scars. If multiple scars are present, or obesity precludes reliable percussion, ascitic fluid should be located by ultrasonography and a guided paracentesis performed. 25 Approximately 50 cc of fluid is withdrawn for diagnostic purposes. Removal of larger quantities of fluid may be indicated when tuberculosis or malignancy is suspected. Centrifugation of the larger volume with isolation of malignant cells or the causative organism from the centrifuged deposit may increase the diagnostic yield. 27.28 Paracentesis is not contraindicated in the presence of coagulopathy. Prophylactic transfusion of fresh frozen plasma should not be administered to these patients prior to paracentesis. 29 The risk of bleeding from a paracentesis is 1 %, and the majority of these episodes do not require transfusion. 25 On the other hand, the risk of acquiring hepatitis after transfusion of fresh frozen plasma exceeds the risk of bleeding from the paracentesis needle puncture. 30 The ascitic fluid should be analyzed using the tests listed in Table 2. The gross appearance of the fluid may help in the differential diagnosis. Bloody ascitic fluid is most often found in patients with malignant Table 2. Evaluation of Ascitic Fluid Routine tests Gross appearance White cell count and differential Total protein Albumin· Gram's and Ziehl-Neelsen stains Aerobic and anaerobic cultures Mycobacterial cultures Cytology Optional tests Amylase pH Lactate Glucose· Red cell count Lactate dehydrogenase· Triglyceride Carcinoembryonic antigen

• Simultaneous pla.~ma levels should be obtained. July 1991 Volume 302 Number 1

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ascites, primary liver cancer or a ruptured mesenteric varixY Even when no specific cause for bloody ascites is found, these patients appear to have a significantly poorer prognosis than those with clear ascites. 31 The possibility of a traumatic tap should be considered and a different paracentesis site on the opposite side of the abdomen should be selected and another sample should be obtained promptly. Measuring the hematocrit in both samples can determine whether the initial tap was traumatic and led to localized bleeding. Milky fluid suggests chylous ascites. This can be confirmed by determining its triglyceride content. 32 Turbid or cloudy fluid may indicate infection,:!3 though infected ascitic fluid is usually clear. Determining the ascitic fluid total protein and albumin content will help differentiate transudative from exudative ascites. Traditionally, ascitic fluid with a total protein >2.5 gm/dl is classified as an exudate. Exudative ascites is more commonly seen in tuberculous peritonitis, peritoneal carcinomatosis, hepatic vein thrombosis, constrictive pericarditis, right-sided heart failure, pancreatic ascites and myxedema. 24 Transudative ascites, on the other hand, is most commonly seen in cirrhotic ascites, even when complicated by hepatoma or spontaneous bacterial peritonitis. 34 Up to 19% of hospitalized patients with hepatic cirrhosis and ascites, however, have a high protein concentration in the ascitic fluid. 35 In addition, diuresis of cirrhotic ascites may lead to an increase in the protein concentration of the ascitic fluid to levels higher than 2.5 gm/ d1. 36 On the other hand, approximately 30% of patients with malignant ascites will have an ascitic fluid protein content of <2.0 gm/d1.37 Thus, classification of ascites using the total protein concentration is fraught with problems. The serum-ascites albumin concentration gradient (this is a difference rather than a ratio) has been shown to be superior to the "exudate/transudate" method of classification.38,39 This method is based on the concept of oncotic-hydrostatic balance. Patients with portal hypertension have a large difference (~1.1 gm/dl) between their serum and ascitic fluid albumin concentrations. Those with a low gradient «1.1 gm/dl) usually have a non-cirrhotic cause of ascites.:J8,39 The serum and ascitic fluid albumin determination should be obtained simultaneously to make this classification method accurate. In addition, the patient should be stable, not in shock or receiving large amounts of intravenous fluids, and the assay used to measure the albumin concentration should be accurate at low range. 40 Infected VS. Sterile Ascites

The ascitic fluid total white blood cell count (WBC) and differential is important in suspecting infection. Routine paracentesis has documented a 10%-27% -prevalence of spontaneous bacterial peritonitis (SBP)' in patients with ascites as they are admitted to the THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

hospita1. 2:1,41,42 Spontaneous bacterial peritonitis appears to result from episodes of bacteremia seeding the ascitic fluid. 4:l Patients with chronic liver disease have several host defense abnormalities, including complement deficiency,44 defects in neutrophil function,45 and deficiencies in reticuloendothelial system function:16 These defects in host defense favor the development of SBP during episodes of transient bacteremia. A low ascitic fluid protein concentration selects patients likely to develop SBP. 41 Ascites that is relatively resistant to SBP-seen in heart failure or peritoneal carcinomatosis-usually has a high protein concentration. 47 Spontaneous bacterial peritonitis should be suspected in any patient with an ascitic fluid neutrophil (PMN) count ~250 cells/mm3. Physical findings do not aid the differential diagnosis. 48 The ascitic fluid of a patient with SBP usually has a total protein of less than 1 gm/dl, glucose similar to the serum glucose, and lactate dehydrogenase level less than serum. 48 Ascitic fluid pH is not more sensitive or specific that PMN count and does not become abnormal until the ascitic fluid PMN count is already ~250 cells per ILL.29 Thus, determination of ascitic fluid pH does not add much to the evaluation of suspected SBP. Culture and gram stain of the ascitic fluid should always be obtained when performing diagnostic paracentesis. Unfortunately, the majority of cases of suspected SBP are "culture negative." This is probably a result of the conventional culture method recommended by the American Society for Microbiology.49 This method recommends culturing three drops of ascitic fluid on three different culture plates and infusing 1 cc of ascitic fluid in 5 cc of brain-heart infusion broth. Recently, this conventional method has been compared to a blood culture bottle method, with bedside inoculation of 10 ml of ascitic fluid into blood culture bottles. 50 Using this new method, bacterial growth was seen in 93% of patients with ascitic fluid PMN ~250, whereas only 43% of these patients had positive cultures when the conventional method was used. 50 Thus, therapy of suspected SBP should be based on PMN count and continued even if ascitic fluid cultures from the conventional method are negative. Management of Ascites

The presence of a small amount of ascites does not require treatment. However, significant fluid accumulation should be treated to reduce the risk of complications related to ascites and to improve the patient's overall appearance and sense of well being. Major complications that would be prevented by successful therapy of ascites in'clude SBP and rupture of umbilical hernia. 51 Respiratory distress, anorexia, and abdominal discomfort also can be prevented. Medical management of ascites involves bed rest, restriction of sodium, and in some cases, water intake and use of diuretics to effect salt and water loss. Re-

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Management of Ascites

centiy, the use of large volume paracentesis has been resurrected as an effective and safe method of treating ascites. Although patients can be treated on an outpatient basis, patients with new onset or massive ascites are initially best managed in the hospital. Daily weight, measurement of abdominal girth, and intake and output balance should be followed. A baseline urine sample for sodium and potassium may be of prognostic significance. 52 Patients with urinary sodium excretion of > 10 meqJdl have a significantly better prognosis than those with urine sodium <10 meqJdl. 52 The urine sodium/potassium ratio can also guide diuretic therapy. Most cirrhotics initially have a sodium/potassium ratio of <1 in the first morning urine specimen. Reversal of this ratio to > 1 signals a therapeutic dose of diuretic and usually results in effective diuresis. 53 Sodium intake should be initially restricted to 500 mg per day. While patients with congestive heart failure may do well with 1500-2000 mg of sodium a day, patients with ascites require a much more severe curtailment of sodium intake to initiate diuresis. 54 While the patient will rarely comply with this degree of sodium restriction after discharge, such severe restriction after diuresis is initiated may not be necessary for most patients55 and may be liberalized to 1500-2000 mg/day sodium intake. Water restriction should be prescribed if hyponatremia «130 meg/dl) develops.56 The goal of diuretic therapy should be to mobilize one-half to one-pound of fluid daily without doubling the blood urea nitrogen (BUN) or raising it to >20 mg/ dl, or raising the creatinine to > 1.5 mg/dl. 24 In patients with peripheral edema, a greater daily weight loss (>2 kg/day) may be allowed without deleterious effects in renal function. 57 The initial diuretic of choice is spironolactone, since potassium stores are frequently depleted in cirrhotic patients, the diuretic action is mild, and is relatively free of side effects.58 In addition, a high aldosterone state exists in up to two-thirds ofpatients with cirrhosis and ascites. 58 Spironolactone, by competing with aldosterone for intracellular receptors in the renal tubule, is ideally suited for these patients. An initial dose of 50 mg twice a day is used and increments of 50-to-100 mg are made no sooner than every four days. Because the half-life of spironolactone is approximately two days, the maximal onset of action is delayed. 59 With this regimen, substantial diuresis is achieved in 40%-75% of patients,53,58,6o with the best results obtained when strict sodium restriction is also maintained. Avid proximal salt and water retention may explain the lack of response in the remaining patients, since the site of spironolactone's action is in the distal convoluted tubule. In general, the maximum dose should be 400 mg/d, although some authorities recommend up to 600 mg/d. 61 The most common side effects of this drug are hyperkalemia, volume depletion, and gynecomastia. Hyperchloremic metabolic acidosis has been described in patients taking as little as 200 mg/d of spironolactone. 62 34

If spironolactone in a dose of 400 mg/d is not effective, Gabow et al62 recommend adding furosemide in an initial oral dose of 40 mg/d. If significant diuresis or volume depletion does not exist, increments of 40 mg a day or every other day up to a maximum of 160 mg/d may be necessary. The use of more potent diuretics such as furosemide or ethacrynic acid is more likely to lead to complications, the most common being volume depletion, hypokalemia, hyponatremia and encephalopathy.24 Metolazone in combination with furosemide has been advocated by some authors,63 but this regimen causes many complications in cirrhotics with ascites. Approximately 95% of cirrhotic patients will respond to diuretic therapy.24 In some patients, lack ofresponse to diuretics may reflect the development of renal insufficiency during diuretic therapy, as shown by a significant decrease in glomerular filtration rate.64 Once the patient responds, and diuresis is achieved, diuretic dose should be reduced and the patient maintained on a salt-restricted diet. Only through trial and error can the ideal regimen for each patient be tailored. The patient must be assessed frequently on an outpatient basis for evidence of volume depletion, electrolyte imbalance, or renal impairment. Large volume paracentesis as primary therapy for ascites was discarded in the 1950s as unsafe after di- · uretics became available. More recently, well-designed studies primarily from Spain65 have demonstrated that large volume paracentesis is safe and may be useful in the primary management of ascites. Removal of 4-6 liters of ascitic fluid a day until the disappearance of ascites resulted in elimination of ascites in 96% of patients, compared to only 73% of patients receiving standard diuretic therapy.65 Also, more patients in the diuretic group developed renal and electrolyte complications than those in the large paracentesis group. Duration of hospital stay was significantly longer in the diuretic group than in the paracentesis group. The use of intravenous albumin (40 gm after each 4-6 liter paracentesis) appears to help decrease the likelihood of renal and electrolyte disturbances induced by largevolume paracentesis.66 However, not all physicians agree with this recommendation. Some physicians advocate large-volume paracentesis as first-line therapy for patients with tense cirrhotic ascites, but this is highly controversial. Recurrence of ascites requiring multiple, frequent, and time-consuming paracentesis is not uncommon, even when patients are discharged on diuretics. In addition, patients treated with large volume paracentesis develop immunologic changes that theoretically may increase the risk of SBP.67 A significant reduction in ~erum and ascitic complement concentrations was noted in the large-volume paracentesis group. While the ascitic fluid opsonic activity remained stable in the paracentesis group, it occurred at the expense of reduced serum complement. Moreover, in the diuretic-treated paJuly 1991 Volume 302 Number 1

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tients, the opsonic activity of the ascitic fluid significantly increased with diuresis. 67 Thus, long-term studies to determine the safety of large-volume paracentesis are needed before we embrace this method as the firstline therapy of ascites. Refractory Ascites Refractory ascites is ascites which has resisted the therapeutic maneuvers previously discussed. Several factors may render a patient refractory to diuretics (Table 3). Before considering a patient refractory, the patient's compliance with his diet and medications must be verified. Inadvertent sodium administration in the form of diet, medications, or intravenous fluids must be avoided. Inadequate diuretic therapy is one of the most common causes of "refractory ascites." A urine sodium-topotassium ratio of> 1 should be present when adequate doses of diuretics have been used. 53 Electrolyte imbalance, particularly hypokalemia, often associated with hypomagnesemia, may render a patient "diuretic resistant." Concomitant use of nonsteroidal anti-inflammatory drugs may also render the patient diuretic-resistant. Nonsteroidal anti-inflammatory agents decrease the renal production of prostaglandins and, in the presence of cirrhosis, may induce water retention and renal failure. 68 Such drugs should be avoided in these patients. Finally, deterioration of liver function secondary to progression of the underlying liver disease may manifest itself as refractory ascites. A series of factors may precipitate refractory ascites69 (Table 3). The development of primary hepatocellular carcinoma or internal malignancy may present with worsening ascites. Spontaneous bacterial peritonitis, or the occurrence of chylous ascites by rupture of a dilated lymphatic, may render the ascites refractory to usual therapy. Finally, the development of Budd-Chiari syndrome should always be suspected in a patient with worsening ascites, right upper quadrant pain or hepatomegaly. Consequently, worsening ascites on a patient previously under good control should prompt a search for underlying complicating conditions. Peritoneovenous Shunts In 1974, LeVeen and his associates introduced the peritoneovenous shunt (PVS).70 This device consists of a fenestrated intra-abdominal tube connected through a one-way pressure-sensitive valve to a silicone tube that traverses the subcutaneous tissue up to the neck, where it enters the internal jugular vein. This system establishes a sustained circulating blood volume expansion through the continuous passage of ascites from the peritoneal cavity to the general circulation. Whenever a pressure gradient of 3 cm or more exists between the abdominal cavity and the superior vena cava, the device opens and ascitic fluid flows into the central venous system. THE

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Table 3. Refractory Ascites: Potential Causes Excessive sodium intake Dietary indiscretion Inadvertent administration Inadequate diuretic dose Hypokalemia Nonsteroidal anti-inflammatory drugs Worsening hepatocellular disease Primary hepatocellular carcinoma Peritoneal carcinomatosis Spontaneous bacterial peritonitis Development of chylous ascites New onset of Budd-Chiari syndrome

The Le Veen shunt can be inserted under local anesthesia. 71 There are two other devices in the market: the Denver Shunt72 and the Cordis-Hakim shunt. 73 These prostheses have a valvular system that open at a lower pressure gradient (1-3 cm H20), or when the pumping chamber is externally pressed, respectively. They were designed to reduce the high incidence of shunt obstruction seen with the Le Veen shunt. However, a randomized study revealed a higher probability of obstruction with the Denver Shunt compared to the LeVeen shunt. 74 The LeVeen shunt can reverse most of the abnormalities thought to be involved in the pathogenesis of ascites formation. It increases the circulating blood volume and cardiac output,75 and it suppresses the plasma levels of renin, aldosterone,76 and norepinephrine. 77 It is associated with a significant increase in urine volume, sodium excretion, and free water clearance, as well as initial disappearance of ascites in most patients. 78 Unfortunately, peritoneovenous shunting is associated with a high rate of complications, which may occur early in the post-op period, or at any time during follow up. Acute bacterial infection, usually caused by Staphylococcus aureus, is the most serious early complication and requires removal of the shunt. 79 Practically every patient develops laboratory abnormalities consistent with disseminated intravascular coagulopathy. However, the incidence of symptomatic coagulopathy is low.80 Other complications related to the sudden expansion of the intravascular system include gastrointestinal variceal hemorrhage, acute pulmonary edema, and acute myocardial infarction.81 The postoperative mortality within one month after surgery is reportedly between 10 and 26%.78 On randomized, prospective studies, PVS has not been shown to prolong survival in cirrhotics82 and there is a high rate of shunt occlusion.83 The morbidity and mortality correlate with the degree of hepatic or renal impairment rather than with the use of the PVS. Therefore, the best results with this shunt should be expected in those few patients with diuretic resistant ascites and preserved hepatic function. 84 In clinical practice, PVS has a very limited roll in the therapy of ascites.

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Management of Ascites

Conclusions

New onset ascites, or sudden change in the condition of any patient with ascites, warrants further investigation that includes diagnostic paracentesis. The cornerstone of ascites management is salt restriction and the judicious use of diuretics. Patients who are resistant to diuretic therapy should be evaluated carefully to exclude potential causes of their refractory nature. The 5% or less of patients who are truly unresponsive to diuretics may be candidates for large-volume paracentesis and, in rare cases, peritoneovenous shunting if repeated paracenteses are required. References 1. Goodyer AVN, ReIman AS, Lawrason FD, Epstein FH: Salt retention in cirrhosis of liver. J Clin Invest 29:973-981, 1950. 2. Atkinson M, Losowsky MS: The mechanism of ascites formation in chronic liver disease. Quart J Med 30:153-166, 1961. 3. Lieberman FL, Denison EK, Reynolds TB: The relationship of plasma volume, portal hypertension, ascites and renal sodium retention in cirrhosis: The "overflow" theory of ascites formation. Ann NY Acad Sci 170:202-208, 1970. 4. Epstein M: Renal effects of head-out water immersion in man: Implications for an understanding of volume homeostasis. Physiol Rev 58:529-581, 1978. 5. Lopez Novoa JM, Rengel MA, Hernando L: Dynamics of ascites formation in rats with experimental cirrhosis. Am J Physiol238: F353-F357, 1980. 6. Jimenez W, Martinez-Pardo A, Arroyo V, Bruix J, Rimola A, Gaya J, Francisca Rivera F, Rodes J: Temporal relationship between hyperaldosteronism, sodium retention and ascites formation in rats with experimental cirrhosis. Hepatology 5:245250,1985. 7. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodes J: Peripheral arterial vasodilation hypothesis: A proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 8:1151-1157,1988. 8. Fernandez-Munoz 0, Caramelo C, Santons JC, Blanchart A, Hernando L, Lopez-Novoa JM: Systemic and splanchnic hemodynamic disturbances in conscious rats with experimental liver cirrhosis without ascites. Am J Physiol 249:G316-G320, 1985. 9. Vorobioff J, Bredfeldt JE, Groszman RJ: Increased blood flow through the portal system in cirrhotic rats. Gastroenterology 87: 1120-1126,1984. 10. Bosch J, Arroyo V, Betriu A, Mas A, Carrilho F, Rivera F, Navarro-Lopez F, Rodes J: Hepatic hemodynamics and the reninangiotensin-aldosterone system in cirrhosis. Gastroenterology 78: 92-99, 1980. 11. Henriksen JH, Brendtsen F, Sorensen T, Stadeager C and RingLarsen H: Reduced central blood volume in cirrhosis. Gastroenterology 97:1506-1513, 1989. 12. Epstein M: Renal function abnormalities in cirrhosis: Pathophysiology and management, in Zakim 0, Boyer TO (eds): Hepatology. A Textbook of Liver Disease. Philadelphia, W.B. Saunders Co., 1982, pp 446-464. 13. Grobe JL, Kozarek RA, Sanowski RA and Earnest DL: Pseudoascites associated with giant ovarian cysts and elevated cystic fluid amylase. Am J Gastroenterol 78:421-424, 1983. 14. Bender MD, Ockner RK: Ascites, in Fordtran JS, Sleisinger MH (eds): Gastrointestinal Disease. Philadelphia, W.B. Saunders, Co., 1989,pp.428-454. 15. Jorulf H: Roentgen diagnosis of intraperitoneal fluid. A physical, anatomic and clinical investigation. Acta Radiol [Diagn] (Stockh) 343(suppl):1-124, 1975. 16. Lawson JD, Weissbein AS: The puddle sign: An aid in the diagnosis of minimal ascites. New Engl J Med 260:652-654,1959.

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17. Goldberg BB: Ultrasonic evaluation of intraperitoneal fluid JAMA, 235:2427-2430, 1976. 18. Black M, Friedman AC: Ultrasound examination in the patient with ascites, editorial. Ann Int Med 110:253-255,1989. 19. Cattau EL, Benjamin SB, Knuff TE, Castell DO: The accuracy of the physical examination in the diagnosis of suspected ascites. JAMA 247:1164-1166, 1982. 20. Goldberg BB, Goodman GA, Clearfield HR: Evaluation of ascites by ultrasound. Radiology 96:15-22, 1970. 21. Jolles H, Coulam CM: CT of ascites: Differential diagnosis. AJR 135:315-322, 1985. 22. Yeh HC, Wolf BS: Ultrasonography in ascites. Radiology 124: 783-790,1977. 23. Almdal TP, Skinhoj P: Spontaneous bacterial peritonitis in cirrhosis: Incidence, diagnosis and prognosis. Scand J Gastroenterol 22:295-300,1987. 24. Schiff ER: Treatment of ascites. Ala J Med Sci 22:44-49, 1985. 25. Runyon BA: Paracentesis of ascitic fluid: A safe procedure. Arch Intern Med 146:2259-2261, 1986. 26. Ryan E, Neale G: Tapping ascites. Br Med J 281:499-500, 550551,1980. 27. Singh MM, Bhargava AN, Jain KP: Tuberculous peritonitis: An evaluation of pathogenic mechanisms, diagnostic procedures and therapeutic measures. New Engl J Med 281:1091-1094, 1969. 28. McGrew EA, Nanos S: The cytology of serous effusions, in Keebler PM, Reagan JW (eds): A Manual of Cytotechnology. Chicago, American Society of Clinical Pathologists Press, 1984, pp 228237. 29. Runyon BA: Spontaneous bacterial peritonitis: An explosion of information, editorial. Hepatology 8:171-175,1988. 30. Dienstag JL, Alter HJ. Non-A, Non-B Hepatitis: Evolving epidemiologic and clinical perspective. Sem Liver Dis 6:67-78, 1986. 31. DeSitter L, Rector WG: The significance of bloody ascites in patients with cirrhosis. Am J Gastroenterol 79:136-138, 1984. 32. Press OW, Press NO, Kaufman SO: Evaluation and management of chylous ascites. Ann Intern Med 96:358-364, 1982. 33. Bar-Mier S, Lerner E, Conn HO: Analysis of ascitic fluid in cirrhosis. Dig Dis Sci 24:136-144, 1979. 34. Rocco VK, Ware AJ: Cirrhotic ascites: Pathophysiology, diagnosis and management. Ann Intern Med 105:573-585, 1986. 35. Sampliner RE, !ber FL: High protein ascites in patients with uncomplicated hepatic cirrhosis. Am J Med Sci 267:275-279, 1974. 36. Hoefs JC: Increase in ascites white blood cell and protein concentrations during diuresis in patients with chronic liver disease. Hepatology 1:249-254, 1981. 37. Boyer TO, Kahn AM, Reynolds TB: Diagnostic value of ascitic fluid lactic dehydrogenase, protein and WBC levels. Arch Intern Med 138:1103-1105, 1978. 38. Pare P, Talbot J, Hoefs JC: Serum-ascites albumin concentration gradient: A physiologic approach to the differential diagnosis of ascites. Gastroenterology 85:240-244, 1983. 39. Rector WG, Reynolds TB: Superiority of serum-ascites albumin difference over the ascites total protein concentration in separation of "transudative" and·"exudative" ascites. Amer J Med 77:83-85, 1984. 40. Hoefs JC: Serum protein concentration and portal pressure determine the ascitic fluid protein concentration in patients with chronic liver disease. J Lab Clin Med 102:260-273, 1983. 41. Runyon BA: Low-protein concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis. Gastroenterology 91: 1343-1346, 1986. 42. Pinzello G, Simonetti RG, Craxi A, Di Piazza S, Spano C, Pagliaro L: Spontaneous bacterial peritonitis: A prospective investigation in predominantly nonalcoholic cirrhotic patients. Hepatology 3:545-549, 1983. 43. Hoefs JC, Runyon BA: Spontaneous bacterial peritonitis. DM 31:1-48, 1985. July 1991 Volume 302 Number 1

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