Management of adult patients with ascites due to cirrhosis
Authors: Bruce A. Runyon
Journal: Hepatology (2004)

SAAG, serum-ascites albumin gradient; PMN, polymorphonuclear leukocyte; TIPS, transjugular intrahepatic portasystemic stent-shunt; SBP, spontaneous bacterial peritonitis. These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recently published world literature on the topic (Medline search); (2) the American College of Physicians' Manual for Assessing Health Practices and Designing Practice Guidelines1; (3) policy guidelines, including the American Association for the Study of Liver Diseases' Policy Statement on Development and Use of Practice Guidelines and the American Gastroenterological Association's Policy Statement on the Use of Medical Practice Guidelines,2, 3; and (4) the author's 22 years of experience in the clinical and laboratory investigation of, and care of patients with, this problem, including 7 years' experience in a liver unit in which approximately 60% of patients have ascites. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventative aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies designed to be followed in every case. Specific recommendations are based on relevant published information. Cost-effectiveness and cost-benefit data should be incorporated in the appropriate setting. In an attempt to characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the American Association for the Study of Liver Diseases requires a grade to be assigned and reported with each recommendation (Table 1). These guidelines were developed for the care of adult patients with clinically detectable ascites. Although the general approach may be applicable to children, the pediatric data base is much smaller and there may be unanticipated differences between adults and children. Patients with ascites that is detected by imaging modalities but is not yet clinically evident are not included because of the lack of published information regarding the natural history of this entity. Cirrhosis was the tenth leading cause of death in the United States, according to a 2000 Vital Statistics Report, in which data was collected through 1998.4 Ascites is the most common of the 3 major complications of cirrhosis; the other complications are hepatic encephalopathy and variceal hemorrhage.5 Approximately 50% of patients with "compensated" cirrhosis, i.e., without having developed one of these complications, develop ascites during 10 years of observation.5 Development of fluid retention in the setting of cirrhosis is an important landmark in the natural history of chronic liver disease: approximately 50% of patients with ascites succumb in 2 years.6 Many patients are referred for liver transplantation after development of ascites. A Medline search from 1966 through 2002 was performed; search terms included ascites, diet therapy, drug therapy, radiotherapy, surgery, and therapy. The search involved only papers published in English and involving humans. A manual search of the author's files was also performed. The search yielded 1,867 papers including 411 published since a similar search was performed in 1997 in preparation for writing the previous guideline on ascites.7 Most patients (approximately 85%) with ascites in the United States have cirrhosis.8 In about 15% of patients with ascites, there is a nonhepatic cause of fluid retention. Successful treatment is dependent on an accurate diagnosis of the cause of ascites; e.g., peritoneal carcinomatosis does not respond to diuretic therapy. Patients with ascites should be questioned about risk factors for liver disease. Those who lack an apparent cause for cirrhosis should also be questioned about lifetime body weight; nonalcoholic steatohepatitis has been concluded to be causative in many of these patients.9 Past history of cancer, heart failure, or tuberculosis is also relevant. Hemophagocytic syndrome can masquerade as cirrhosis with ascites.10 These patients have fever, jaundice, and hepatosplenomegaly, usually in the setting of lymphoma or leukemia.10 The presence of a full, bulging abdomen should lead to percussion of the flanks. If the amount of flank dullness is greater than usual (i.e., if the percussed air-fluid level is higher than normally found on the lateral aspect of the abdomen with the patient supine), one should test for "shifting." Approximately 1,500 mL of fluid must be present before flank dullness is detected.11 If no flank dullness is present, the patient has less than a 10% chance of having ascites.11 The fluid wave and puddle sign are not useful.11 Ascites due to alcoholic cardiomyopathy can mimic that due to alcoholic cirrhosis. Jugular venous distension is present in the former but not in the latter. The physical examination for detecting ascites in the obese patient is problematic. An abdominal ultrasound may be required to determine with certainty if fluid is present. The diagnosis of new-onset ascites is suspected on the basis of the history and physical examinationand usually confirmed by successful abdominal paracentesis and/or ultrasound. The diagnosis of the cause of ascites formation is based on the results of the history, physical, and ascitic fluid analysis. In general, few other tests are required. However, the liver is commonly imaged (usually with ultrasound) to screen for hepatocellular carcinoma, portal vein thrombosis, and hepatic vein thrombosis. Abdominal paracentesis with appropriate ascitic fluid analysis is probably the most rapid and cost-effective method of diagnosing the cause of ascites.12, 13 Fluid due to portal hypertension can be readily differentiated from fluid due to other causes.8 Also, in view of the high prevalence of ascitic fluid infection at the time of admission to the hospital, an admission surveillance tap may detect unexpected infection.14 Although older published series reported a relatively high morbidity, and even mortality, when trocars were used for paracentesis, more recent studies regarding paracentesis complications in patients with ascites documented no deaths or infections caused by the paracentesis.15 Complications were reported in only about 1% of patients (abdominal wall hematomas), despite the fact that 71% of the patients had an abnormal prothrombin time.15 Although more serious complications (hemoperitoneum or bowel entry by the paracentesis needle) occur,16 they are sufficiently unusual (<1/1,000 paracenteses) that they should not deter performance of this procedure. It is the practice of some physicians to give blood products (fresh frozen plasma and/or platelets) routinely before paracentesis in cirrhotic patients with coagulopathy. This policy is not data-supported. The risks and costs of prophylactic transfusions exceed the benefit. In the past, the midline was usually chosen as the site for paracentesis. However, the abdominal wall in the left lower quadrant, 2 finger breadths cephalad and 2 finger breadths medial to the anterior superior iliac spine, has been shown to be thinner and with a larger pool of fluid than the midline.17 If the fluid is difficult to localize by examination because of obesity, ultrasonography can be useful. There are few contraindications to paracentesis. Coagulopathy should preclude paracentesis only when there is clinically evident fibrinolysis or clinically evident disseminated intravascular coagulation.15 These conditions occur in less than 1 per 1,000 procedures. There is no data-supported cutoff of coagulation parameters beyond which paracentesis should be avoided.15 Abdominal paracentesis should be performed and ascitic fluid should be obtained from inpatients and outpatients with clinically apparent new-onset ascites. (Grade II-3) Since bleeding is sufficiently uncommon, the prophylactic use of fresh frozen plasma or platelets before paracentesis is not recommended. (Grade III) Future outcomes studies are required to determine the optimal testing strategy. Meanwhile, an algorithm approach seems preferable to ordering a large number of tests on most specimens. If uncomplicated cirrhotic ascites is suspected, only screening tests (e.g., cell count and differential, albumin and total protein concentration) are performed on the initial specimen. If the results of these tests are unexpectedly abnormal, further testing can be performed on another ascitic fluid sample. Also, many laboratories save an aliquot of fluid for a few days; this fluid can be tested if the specimen has been handled properly. However, since most specimens are consistent with uncomplicated cirrhotic ascites, no further testing will be needed in the majority of patients. If ascitic fluid infection is suspected (fever, abdominal pain, or unexplained encephalopathy), bacterial culture in blood culture bottles should be performed. Use of a urine dipstick to detect neutrophils in ascitic fluid takes only 90 seconds to 2 minutes; if confirmed by other studies, this may become a routine method of providing early suspicion of infection.18, 19 Automated cell counting has been shown to be accurate; the result is rapidly available and thus may replace the manual cell count.20 Additional testing, e.g., total protein, lactate dehydrogenase, and glucose to assist in differentiating spontaneous from secondary bacterial peritonitis, can be performed on the initial specimen based on clinical judgment.21 An ascitic fluid carcinoembryonic antigen greater than 5 ng/mL or ascitic fluid alkaline phosphatase greater than 240 units/L has also been shown to be accurate in detecting gut perforation into ascitic fluid.22 The serum-ascites albumin gradient (SAAG) has been proved in prospective studies to categorize ascites better than the total-protein-based exudate/transudate concept and better than modified pleural fluid exudate/transudate criteria.8, 23 Calculating the SAAG involves measuring the albumin concentration of serum and ascitic fluid specimens obtained on the same day and subtracting the ascitic fluid value from the serum value. If the SAAG is greater than or equal to 1.1 g/dL (11g/L), the patient has portal hypertension, with approximately 97% accuracy.8 Patients who have portal hypertension plus a second cause for ascites formation also have a SAAG greater than or equal to 1.1g/dL. Patients undergoing serial outpatient therapeutic paracenteses probably should be tested only for cell count and differential (the author has detected 8 episodes of spontaneous bacterial peritonitis in approximately 400 paracenteses in a paracentesis clinic in 2 years [Zeid Kayali, Reza Khoshini, B.A.R., outpatient management of refractory ascites, unpublished observations, 2003]). Bacterial culture is not necessary in asymptomatic patients undergoing serial large-volume paracenteses.24, 25 The most expensive tests are the cytology and smear and culture for mycobacteria; these tests should probably be ordered only when there is a high pretest probability of occurrence of the disease under consideration. The ascitic fluid cytology is positive only in the setting of peritoneal carcinomatosis.26 The sensitivity of cytology in detecting peritoneal carcinomatosis is 96.7% if 3 samples are sent and processed promptly; the first sample is positive in 82.8% and at least 1 of 2 samples is positive in 93.3%.26 In this study, 50 mL of fresh warm ascitic fluid were hand-carried to the laboratory for immediate processing. Patients with peritoneal carcinomatosis usually have a history of a breast, colon, gastric, or pancreatic primary carcinoma. The sensitivity of smear for mycobacteria is approximately 0%; the sensitivity of fluid culture for mycobacteria is approximately 50%.27 Only patients at high risk for tuberculous peritonitis (e.g., recent immigration from an endemic area or acquired immunodeficiency syndrome)28 should have testing for mycobacteria on the first ascitic fluid specimen. Laparoscopy with biopsy and mycobacterial culture of tubercles are the most rapid and accurate methods of diagnosing tuberculous peritonitis. Multiple prospective trials have shown that bacterial growth occurs in only about 50% of instances when ascitic fluid with a polymorphonuclear leukocyte (PMN) count greater than or equal to 250cells/mm3 (0.25 × 109/L) is cultured by older methods as compared to approximately 80% if the fluid is inoculated into blood culture bottles at the bedside.29, 30 The initial laboratory investigation of ascitic fluid should include an ascitic fluid cell count and differential, ascitic fluid total protein, and SAAG. (Grade II-2) If ascitic fluid infection is suspected, ascitic fluid should be cultured at the bedside in blood culture bottles. (Grade II-2) Other studies can be ordered based on pretest probability of disease (Table 2). (Grade III) Although cirrhosis is the cause of ascites formation in most patients, approximately 15% have a cause other than liver disease, including cancer, heart failure, tuberculosis, or nephrotic syndrome.8 Approximately 5% of patients with ascites have 2 or more causes of ascites formation, i.e., "mixed" ascites.8 Usually, these patients have cirrhosis plus 1 other cause, e.g., peritoneal carcinomatosis or peritoneal tuberculosis. Many patients with enigmatic ascites are eventually found to have 2 or even 3 causes for ascites formation (e.g., heart failure, diabetic nephropathy, and cirrhosis due to nonalcoholic steatohepatitis). In this setting, the sum of predisposing factors leads to sodium and water retention when each individual factor might not be severe enough to cause fluid overload. Appropriate treatment of patients with ascites depends on the cause of fluid retention. SAAG can be helpful diagnostically as well as in decision-making regarding treatment. Patients with low SAAG ascites usually do not have portal hypertension and, with the exception of nephrotic syndrome, do not respond to salt restriction and diuretics.13 In contrast, patients with a high SAAG have portal hypertension and usually are responsive to these measures.13 The remainder of this guideline is applicable only to patients with cirrhosis as the cause of their ascites. Improvement in the outcome of patients with nonportal-hypertension-related ascites depends on successful treatment of the underlying disorder. Alcohol-induced liver injury is perhaps the most reversible cause of liver disease that leads to high albumin gradient ascites.13 One of the most important steps in treating ascites in this setting is to treat the underlying liver disease by convincing the patient to stop drinking alcohol. In a period of months, abstinence can result in dramatic improvement in the reversible component of alcoholic liver disease. One recent study demonstrates that patients who have Child-Pugh C cirrhosis due to alcohol and who stop drinking have an approximately 75% 3-year survival, but all those who continue to drink die in 3 years.31 Ascites may resolve or become more responsive to medical therapy with abstinence and time. Nonalcoholic liver diseases are less reversible; by the time ascites is present, these patients may be better candidates for liver transplantation than protracted medical therapy. The mainstays of treatment of patients with cirrhosis and ascites include (1) education regarding dietary sodium restriction (2000 mg per day [88 mmol per day]) and (2) oral diuretics.12, 13 More stringent dietary sodium restriction can speed mobilization of ascites. Fluid loss and weight change are directly related to sodium balance in patients with portal-hypertension-related ascites. It is sodium restriction, not fluid restriction, which results in weight loss; fluid follows sodium passively.32 Measurement of urinary sodium excretion is a helpful parameter to follow when rapidity of weight loss is less than desired.12, 13 Random urinary sodium concentrations are of value when they are 0 mmol/L or greater than 100 mmol/L but are much less helpful when they are intermediate because of lack of uniformity of sodium excretion during the day and lack of knowledge of total urine volume, which may vary from 300 mL to greater than 3000 mL. Twenty-four-hour collections of urine for determination of sodium excretion are much more informative than random specimens; however, full-day collections are cumbersome. Providing patients with verbal and written instructions, a container, and a lab order slip to turn in with the completed specimen helps insure compliance. Completeness of collection of the 24-hour specimen can be assessed by measurement of urinary creatinine. Cirrhotic men should excrete more than 15 mg of creatinine per kilogram of body weight per day, and women should excrete more than 10 mg/kg per day.33 Less creatinine is indicative of an incomplete collection. Total nonurinary sodium excretion is less than 10 mmol per day in afebrile cirrhotic patients without diarrhea.34 One of the goals of treatment is to increase urinary excretion of sodium so that it is greater than 78 mmol per day (88 mmol intake per day − 10 mmol nonurinary excretion per day). Only the 10% to 15% of patients who have spontaneous natriuresis greater than 78 mmol per day can be considered for dietary sodium restriction alone (i.e., without diuretics). However, when given a choice, most patients would prefer to take some diuretics and have a more liberal sodium intake than take no pills and have a more severe sodium restriction. A random "spot" urine sodium concentration that is greater than the potassium concentration correlates with a 24-hour sodium excretion greater than 78 mmol per day with approximately 90% accuracy.35 This urine sodium/potassium ratio may replace the cumbersome 24-hour collection. Fluid restriction is not necessary in treating most patients with cirrhosis and ascites. The chronic hyponatremia usually seen in cirrhotic ascites patients is seldom morbid. Attempts to rapidly correct hyponatremia in this setting with hypertonic saline can lead to more complications than the hyponatremia itself.36 Preliminary data suggest that aquaretic drugs have the promise of correcting hyponatremia. However, these agents have been under investigation for more than 10 years in the setting of cirrhosis and are not yet approved in the United States.37 Efficacy without side effects in the subset of patients who are in need of correction of hyponatremia remains unproven. Unfortunately, many drugs that have theoretical promise in treating ascites, e.g., angiotension-converting enzyme inhibitors, have been shown to aggravate hypotension and have not been clinically useful. Severe hyponatremia does warrant fluid restriction in the patient with cirrhosis and ascites; however, there is no data-supported specific threshold for initiating fluid restriction. A serum sodium less than 120–125 mmol/L is a reasonable threshold. Cirrhotic patients do not usually have symptoms from hyponatremia until the sodium is below 110 mmol/L or unless the decline in sodium is very rapid. Although it is traditional to recommend bed rest (based on extrapolation from heart failure), this is impractical and there are no controlled trials to support this practice. Upright posture may aggravate the plasma renin elevation found in cirrhotic patients with ascites. Theoretically, this may increase sodium avidity. This theoretical concern would have to translate into clinically relevant outcomes before bed rest could be advocated. The usual diuretic regimen consists of single morning doses of oral spironolactone and furosemide, beginning with 100 mg of the former and 40 mg of the latter.12, 13 Previously, single-agent spironolactone was advocated, but hyperkalemia and the long half-life of this drug have resulted in its use as a single agent only in patients with minimal fluid overload.38 Single-agent furosemide has been shown in a randomized controlled trial to be less efficacious than spironolactone.39 The good oral bioavailability of furosemide in the cirrhotic patient, together with the acute reductions in glomerular filtration rate associated with intravenous furosemide, favor use of the oral route of administration.40, 41 The doses of both oral diuretics can be increased simultaneously every 3 to 5 days (maintaining the 100 mg:40 mg ratio) if weight loss and natriuresis are inadequate. In general, this ratio maintains normokalemia. Usual maximum doses are 400 mg per day of spironolactone and 160 mg per day of furosemide.12, 13 Furosemide can be temporarily withheld in patients presenting with hypokalemia. Patients with parenchymal renal disease (e.g., diabetic nephropathy or immunoglobulin A nephropathy) may tolerate less spironolactone than usual because of hyperkalemia. Single morning dosing maximizes compliance. Amiloride (10–40 mg per day) can be substituted for spironolactone in patients with tender gynecomastia. However, amiloride is more expensive and has been shown to be less effective than an active metabolite of spironolactone in a randomized controlled trial.42 Newer loop diuretics must be proven to be superior to current drugs before their expense can be justified. Although an intravenous dose of 80 mg of furosemide can cause an acute reduction in renal perfusion and subsequent azotemia in patients with cirrhosis and ascites, this same dose has been shown in one study to separate diuretic-resistant (<50 mmol urine sodium in 8 hours) from diuretic-sensitive patients (>50 mmol).43 This intravenous furosemide "test" may help speed detection of diuretic-resistant patients so that they can more rapidly be given second-line treatment options.43 In the largest, multicenter, randomized controlled trial performed in patients with ascites, this approach (dietary sodium restriction and dual diuretic regimen) has been shown to be effective in more than 90% of patients in achieving a reduction in the volume of ascites to acceptable levels.44 Outpatient treatment can be attempted initially. However, some patients with cirrhosis and ascites also have gastrointestinal hemorrhage, hepatic encephalopathy, bacterial infection, and/or hepatocellular carcinoma, and may require hospitalization for definitive diagnosis and management of their liver disease as well as management of their fluid overload. Frequently, intensive education is required to convince the patient that the diet and diuretics are actually effective and worth the effort. There is no limit to the daily weight loss of patients who have massive edema. Once the edema has resolved, 0.5 kg is probably a reasonable daily maximum.45 Encephalopathy, serum sodium less than 120 mmol/L despite fluid restriction, or serum creatinine greater than 2.0 mg/dL (180 μmol/L) should lead to cessation of diuretics, reassessment of the situation, and consideration of second-line options. In the past, patients with ascites frequently occupied hospital beds for prolonged periods of time because of confusion regarding diagnosis and treatment and because of iatrogenic problems. Although an abdomen without clinically detectable fluid is a reasonable ultimate goal, it should not be a prerequisite for discharge from the hospital. Patients who are stable, with ascites as their major problem, can be discharged to the clinic after it has been determined that they are responding to their medical regimen. However, in order for patients to be discharged early from the hospital, they should be seen in the outpatient setting promptly, ideally within approximately 1 week of discharge. An initial large-volume paracentesis rapidly relieves tense ascites. A prospective study has demonstrated that a single 5-L paracentesis can be performed safely without post-paracentesis colloid infusion in the patient with diuretic-resistant tense ascites.46, 47 Larger volumes of fluid have been safely removed with the administration of intravenous albumin (8 g/L of fluid removed).48 However, large-volume paracentesis does nothing to correct the underlying problem that led to ascites formation, i.e., sodium retention. Large-volume paracentesis predictably removes the fluid more rapidly (minutes) than does careful diuresis (days to weeks).49 A single large-volume paracentesis followed by diet and diuretic therapy is appropriate treatment for patients with tense ascites.46, 49 In the diuretic-sensitive patient, to serially remove fluid by paracentesis when it could be removed with diuretics seems inappropriate. In order to prevent reaccumulation of fluid, sodium intake should be reduced and urinary sodium excretion should be increased with diuretics. Determining the optimal diuretic doses for each patient—titrating the doses upward every 3–5 days until natriuresis and weight loss are achieved—can take some time.. The intravenous furosemide "test" may shorten this time; this should be tested in the context of a randomized trial.43 Although a controlled trial has demonstrated that large-volume paracentesis is faster than diuretic therapy for patients with cirrhosis and tense ascites, it should not be viewed as first-line therapy for all patients with ascites.49 In the outpatient clinic, body weight, orthostatic symptoms, and serum electrolytes, urea, and creatinine are monitored. If weight loss is inadequate, a random spot urine sodium/potassium ratio or 24-hour urine sodium can be measured. Patients who are excreting urine sodium/potassium greater than 1 or 24-hour urine sodium greater than 78 mmol per day and not losing weight should be counseled further about diet sodium restriction. These patients should not be labeled as diuretic-resistant and should not proceed to second-line therapy until it is documented that they are compliant with the diet. Patients who are excreting more than 78 mmol per day of sodium in the urine with unchanged or increasing weight are consuming more sodium in the diet than 88 mmol per day. Patients who do not lose weight and excrete less than 78 mmol per day should receive an attempt at a higher dose of diuretics. Frequency of follow-up is determined by response to treatment and stability of the patient. Some patients warrant evaluation every 2 to 4 weeks until it is clear that they are responding to treatment and not developing problems. Thereafter, evaluation every few months may be appropriate. Intensive outpatient treatment, in particular with regard to diet education, may help prevent subsequent hospitalizations. Development of ascites as a complication of cirrhosis is associated with a poor prognosis, approximately a 50% 2-year survival.6 Liver transplantation should be considered in the treatment options for these patients. Patients with ascites who are thought to have an alcohol component to their liver injury should abstain from alcohol consumption. (Grade II-2) First-line treatment of patients with cirrhosis and ascites consists of sodium restriction (88 mmol per day [2000 mg per day]) and diuretics (oral spironolactone and furosemide). (Grade I) Fluid restriction is not necessary unless serum sodium is less than 120-125 mmol/L. (Grade III) An initial therapeutic abdominal paracentesis should be performed in patients with tense ascites. Sodium restriction and oral diuretics should then be initiated. (Grade II-3) Diuretic-sensitive patients should preferably be treated with sodium restriction and oral diuretics rather than with serial paracenteses. (Grade III) Liver transplantation should be considered in patients with cirrhosis and ascites. (Grade II-3) Refractory ascites is defined as fluid overload that (1) is unresponsive to sodium-restricted diet and high-dose diuretic treatment (400 mg per day of spironolactone and 160 mg per day furosemide), or (2) recurs rapidly after therapeutic paracentesis.50 Prostaglandin inhibitors such as nonsteroidal anti-inflammatory drugs can reduce urinary sodium excretion in patients with cirrhosis and can induce azotemia.51 These drugs can convert patients from diuretic-sensitive to refractory and should be avoided in this setting. Failure of diuretic therapy may be manifested by (1) minimal to no weight loss together with inadequate (<78 mmol per day) urinary sodium excretion despite diuretics, or (2) development of clinically significant complications of diuretics, e.g., encephalopathy, serum creatinine greater than 2.0 mg/dL, serum sodium less than 120 mmol/L, or serum potassium greater than 6.0 mmol/L. Randomized trials have shown that less than 10% of cirrhotic ascites patients are refractory to standard medical therapy.39, 44 Options for patients refractory to routine medical therapy include (1) serial therapeutic paracenteses, (b) liver transplantation, (c) transjugular intrahepatic portasystemic stent-shunt (TIPS), and (d) peritoneovenous shunt.12, 13, 44, 52, 53 Serial therapeutic paracenteses are effective in controlling ascites. This has been known since the time of the ancient Greeks. However, only relatively recently have controlled trials demonstrating the safety of this approach been published.49 Even in patients with no urine sodium excretion, paracenteses performed approximately every 2 weeks control ascites.12, 13 Frequency of paracentesis provides insight into the patient's degree of compliance with the diet. The sodium concentration of ascitic fluid is approximately equivalent to that of plasma in these patients: 130 mmol/L. A 6-L paracentesis removes 780 mmol of sodium (130 mmol/L × 6 L = 780 mmol). A 10-L paracentesis removes 1300 mmol. Patients consuming 88 mmol of sodium per day, excreting approximately 10 mmol per day in nonurinary losses, and excreting no urinary sodium retain a net of 78 mmol per day. Therefore, a 6-L paracentesis removes 10 days (780 mmol /78 mmol per day) of retained sodium and a 10-L paracentesis removes approximately 17 days of retained sodium (1300 mmol /78 mmol per day =16.7 days) in patients with no urinary sodium excretio