Ascites

I. Problem/Condition.

Ascites is the accumulation of fluid in the peritoneal cavity, usually resulting from cirrhosis. Only cirrhotic patients with portal hypertension (HTN) develop ascites, and portal HTN can also lead to the development of ascites in patients with conditions other than cirrhosis. Portal HTN results in activation of the renin-angiotensin-aldosterone system, sympathetic nervous system, and antidiuretic hormone, culminating in renal vasoconstriction and salt and water retention. This complicated pathophysiology ultimately leads to the development of ascites.

Ascites may also accumulate due to reasons other than portal HTN, discussed in the next section.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

There are various diseases that can lead to the accumulation of fluid in the peritoneal cavity. It is due to cirrhosis 85% of the time.

Other causes of ascites related to portal HTN include heart failure, acute liver failure or alcoholic hepatitis, hepatic veno-occlusive disease (Budd-Chiari syndrome), constrictive pericarditis, and end-stage renal disease (ESRD).

Cancer and infections may lead to ascites because of the increased fluid production in the peritoneal cavity exceeding resorptive capacity. The most common cancers that lead to ascites are pancreatic and ovarian followed by colon and other abdominal cancers, lymphoma, uterine, and breast cancer.

Hypoalbuminemia, with resultant decrease in oncotic pressure, may lead to ascites in protein-losing enteropathy, malnutrition, and nephrotic syndrome. Hypoalbuminemia is often a contributing factor in the development of ascites in cirrhosis as well.

Pancreatic ascites can occur with acute or chronic pancreatitis, from a leaking pseudocyst, or after pancreatic trauma.

Approximately 5% of the time, ascites is caused by more than two causes and is termed “mixed” ascites.

Finally, the patient may have increased abdominal girth for reasons other than ascites, such as obesity, tumor, large intra-abdominal cysts, or bowel obstruction.

B. Describe a diagnostic approach/method to the patient with this problem

The initial diagnostic approach to a patient with ascites requires the combination of a thorough history and physical examination followed by abdominal paracentesis with lab analysis of the fluid. Imaging, usually with ultrasound, may be useful in detecting ascites that is not readily apparent on physical exam and in quantifying the amount of ascites. Ultrasound is also helpful in determining if a patient has chronic liver disease, primary liver tumor or metastases, or (if Doppler flow is used) portal or hepatic vein thrombosis. Abdominal computed tomography (CT) or magnetic resonance imaging (MRI) may be useful to better characterize suspected tumor or thrombosis.

1. Historical information important in the diagnosis of this problem.

As ascites progresses, patients may complain of compressive symptoms such as abdominal discomfort, early satiety, or nausea. Weight gain and increasing abdominal girth are commonly reported. Patients with concurrent hernias will have bulging of the hernia. Patients may also report shortness of breath due to pressure on the diaphragm.

Patients with cirrhosis may complain of muscle wasting, gynecomastia, testicular atrophy, jaundice, or generalized weakness. Symptoms related to other complications of cirrhosis, such as confusion (hepatic encephalopathy), or hematemesis or melena (variceal bleeding) should also be queried. Patients should be questioned regarding alcohol use, risk factors for hepatitis (sexual history, intravenous (IV) drug abuse, blood transfusions, tattoos), family history of autoimmune disease, medications, and travel history.

Malignancy is the second leading cause of ascites. Symptoms that may suggest malignancy are recent weight loss, night sweats, fevers, or a personal or family history of malignancy. Patients with heart failure usually report paroxysmal nocturnal dyspnea, orthopnea and peripheral edema. Any history of infectious exposures, including tuberculosis, should be queried.

Patients with known ascites should be questioned regarding compliance with salt restriction and diuretic therapy, and for any past complications related to the ascites such as spontaneous bacterial peritonitis (SBP). Symptoms of SBP include fever, abdominal pain, and confusion.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Unfortunately, it can be difficult to diagnose the presence and quantify of ascites in many patients. Tense ascites is generally obvious on physical examination, with impressive bulging of the abdominal wall and prominence of abdominal collateral veins. In patients with less tense ascites, the presence of flank dullness and/or bulging is generally the most sensitive physical exam finding. Other physical exam maneuvers used to detect ascites include palpating a fluid wave or assessing for shifting dullness by percussing the abdomen as the patient repositions from supine to lying on one side. However, these findings have poor specificity and lower sensitivity than flank dullness.

Many patients will have stigmata of chronic liver disease such as jaundice, spider angiomata, abdominal wall collateral veins, and palmar erythema. Patients with congestive heart failure or constrictive pericarditis may have elevated jugular venous pressure, crackles on lung exam, and a positive hepatojugular reflux. A palpable abdominal mass or umbilical nodule is suggestive of malignancy.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Abdominal paracentesis is vital in determining the cause of ascites and in ruling out infection. A large volume paracentesis (LVP) may also be performed to alleviate compressive symptoms. Abdominal paracentesis is a generally safe procedure, best performed in the left lower quadrant or right lower quadrant. Paracentesis at these sites precludes puncture of the liver, spleen, or inferior epigastric arteries which course midway between the umbilicus and the anterior superior iliac spine. Insertion near scars or abdominal wall collaterals should also be avoided.

There is no agreed upon “cut-off” value for thrombocytopenia or coagulopathy. The American Association for the Study of Liver Diseases (AASLD) practice guidelines state: “Coagulopathy should preclude paracentesis only when there is clinically evident hyperfibrinolysis (three-dimensional ecchymosis/hematoma) or clinically evident disseminated intravascular coagulation.” In a study of more than 1100 large-volume paracenteses (LVP), there were no bleeding complications despite a cohort that consisted of platelet counts as low as 19,000 cells/mm³ (54% less than 50,000), and international normalized ratio (INR) as high as 8.7 (75% more than 1.5 and 26% more than 2.0). Thus, prophylactic blood products are rarely needed prior to a paracentesis.

Ascitic fluid analysis

Ascitic fluid is classified by subtracting the ascitic fluid albumin from that of the serum – the serum-ascites albumin gradient (SAAG). A value > 1.1 is consistent with portal HTN with 97% accuracy. Conversely, a value < 1.1 suggests an etiology other than portal HTN. Thus, when first evaluating ascites, ascitic fluid and serum albumin levels should always be obtained. There is little utility in repeating fluid albumin levels after the etiology of ascites has been established.

An ascitic fluid protein level is helpful in distinguishing portal HTN due to cirrhosis or heart failure; a total protein level of < 2.5 g/dL is consistent with cirrhosis. In cirrhosis, a protein level of < 1 gram/deciliter (g/d)L portends a higher risk of spontaneous bacterial peritonitis (SBP) and primary antibiotic prophylaxis should be considered. A cell count with differential should generally be ordered, even in asymptomatic patients, to rule-out SBP. Gram stain and culture should be sent if the suspicion for infection is relatively high.

Other tests to consider

Amylaseis elevated above its typical 40 international units/liter (IU/L) value in the setting of pancreatitis or bowel perforation.
Cytology should be ordered if malignancy is suspected. The sensitivity of cytology varies depending on the malignancy but is greatest in those with peritoneal carcinomatosis. The sensitivity can be increased by sending serial samples from separate paracenteses.
Glucose and LDH levels, in addition to total protein, may be helpful in distinguishing secondary peritonitis from SBP. This is discussed in further detail below.
Tuberculous (TB) peritonitis can be difficult to diagnose, as direct smears are very insensitive and fluid cultures are usually negative. Sending a larger volume of fluid for culture may improve sensitivity. Increased adenonise deaminase activity (ADA) has high sensitivity and specificity in non-cirrhotics with peritoneal TB, but the fact that ADA is falsely lowered in patients with cirrhosis limits the sensitivity of ADA in these patients. Mycobacterial polymerase chain reaction (PCR) testing and enzyme-linked immunospot assays of T-cell mediated immune response are promising as non-invasive means of diagnosing tuberculous peritonitis, though their use is currently limited. Ultimately, many patients require laparoscopy with peritoneal biopsy to confirm the diagnosis.

Serum studies

A complete blood count, comprehensive metabolic panel, and coagulation studies should be sent on all patients with a new diagnosis of ascites, or in those with suspicion for infection or decompensation of their liver disease. A brain natriuretic peptide (BNP) may be helpful in distinguishing cirrhosis from heart failure. Blood cultures may be obtained in ill-appearing patients with suspicion for SBP or other infection.

Imaging

Ultrasonography of the abdomen allows for quantification of the fluid and evaluation of the liver parenchyma. Ultrasound may also be used in radiology or at the bedside to “mark” the best site for paracentesis. One study demonstrated increased success at obtaining peritoneal fluid when comparing ultrasound-marking of the fluid to a “blind” approach. Ultrasound with Doppler flow is used if portal or hepatic vein thrombosis is suspected. Ultrasound may also be used to screen for hepatocellular carcinoma in high-risk patients.

Computed tomography (CT) or magnetic resonance imaging of the liver is sometimes necessary to better characterize a mass or thrombosis seen on ultrasound. Lastly, urgent imaging initially with plain films and often with CT scan is needed in patients with suspected secondary peritonitis.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Spontaneous bacterial peritonitis

SBP is defined as an ascitic fluid polymorphonuclear (PMN) cell count of > 250 cells/mm³ (cells/cubic millimetre) in conjunction with a positive gram stain and/or culture. If red blood cells are present on the tap, subtract 1 PMN for every 250 red blood cells/mm³.

See chapter on Spontaneous Bacterial Peritonitis for further details.

Culture-negative neutrocytic ascites

PMN count >250 cells/mm³ with negative gram stain and culture.

Secondary peritonitis

Secondary peritonitis refers to infection due to a surgically-treatable cause, such as abscess or perforation. Secondary peritonitis may be suspected clinically, or when a gram stain and/or culture reveals multiple organisms. Two or more of the following ascitic lab findings (Runyon’s criteria) also supports a diagnosis of secondary peritonitis:

Protein > 1 g/dL
Glucose < 50 mg/dL (milligrams/deciliter)
LDH > the upper limit of normal for serum

In all cases of suspected secondary peritonitis, urgent abdominal imaging and surgical consultation is warranted.

Portal hypertension-related

SAAG > 1.1. Total protein in the ascites can be used to distinguish cirrhosis (protein < 2.5 g/dL) from cardiac causes (protein > 2.5 g/dL).

Non-portal hypertension

SAAG <1.1.

Other tests

Pancreatitis: elevated amylase
Chylous ascites: elevated triglycerides
Malignancy: appropriate clinical picture, malignant or atypical cells on cytology
PMN > 250 cells/mm³ (but usually not with a PMN predominance) can be seen in TB and malignancy.

Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

None

III. Management while the Diagnostic Process is Proceeding

A. Management of ascites.

For all patients with ascites and a serum-to-ascites albumin gradient of more than 1.1 g/dL

Sodium should be restricted to < 2000 mg/day. Patients may benefit from a dietary consult to avoid hidden salt in most food products. Be careful not to be too strict regarding sodium restriction, as cirrhotic patients are generally malnourished and a very low sodium diet may be unpalatable.
Fluid restriction seems less important than sodium restriction, but is necessary in the setting of more moderate to severe hyponatremia. Certainly patients should be instructed to not consume an inordinate amount of fluid.
Diuretics increase urinary sodium (and thus free water) excretion and are necessary in most patients with ascites. Spironolactone and furosemide are generally prescribed in a ratio of 5:2, starting at a low-dose of each and uptitrating as necessary, and as renal function allows. This ratio generally achieves good natriuresis while maintaining normokalemia. Intravenous loop diuretics are sometimes necessary but are associated with an increased risk of renal failure. In patients with painful gynecomastia, amiloride may be substituted for spironolactone, though it is more expensive and less effective. The AASLD recommends increasing diuretics every 3-5 days as tolerated to achieve effective weight loss and natriuresis.
Finally, attempt to treat or control the underlying cause of ascites if possible. For example, patients with alcoholic liver disease should completely abstain from alcohol. Those with ESRD can be dialyzed more aggressively. Patients with a cardiac cause of ascites may respond to heart failure treatments.

For patients with tense ascites with a serum-to-ascites albumin gradient of more than 1.1 g/dL that are diuretic sensitive

A large-volume paracentesis (LVP) may be needed in the patient with tense ascites, especially while waiting on the full effects of diuresis and salt restriction. In diuretic-sensitive patients, repeat LVP will not be necessary, or will at least be infrequent.

There is no agreed-upon upper limit to the amount of fluid that can be safely removed. Removal of 5 or fewer liters is generally regarded as safe, without the need for a subsequent albumin infusion. The administration of albumin after LVP of > 5 liters remains somewhat controversial, though it is generally recommended in the AASLD guidelines. One meta-analysis reported a mortality benefit after LVP when albumin was given as compared to a variety of other plasma expanders. However, this meta-analysis did not include any placebo-controlled trials, so albumin showed superiority over other treatments of questionable benefit. Many clinicians are more likely to prescribe albumin after LVP in patients with underlying hypotension or renal dysfunction, as these patients theoretically have the greatest benefit. If given, albumin is generally infused at 6-8 grams per liter of fluid removed.

For patients with tense ascites with a serum-to-ascites albumin gradient of more than 1.1 g/dL that are diuretic resistant or have refractory ascites

Refractory ascites is defined as lack of response to high dose diuretic therapy with a strict diet or ascites that quickly recurs following an LVP. Patients may also develop side effects to high dose diuretic therapy such as kidney failure, hepatic encephalopathy, hyperkalemia, or hyponatremia. Patients with a poor response to diuresis should again be questioned and educated regarding a low sodium diet. The adequacy of natriuresis can also be assessed via a 24-hour urine collection or a spot urine sodium:potassium ratio. Drugs which may hinder natriuresis and worsen renal function, such as non-steroidal inflammatory agents (NSAIDS) should be avoided if at all possible.

For patients who are truly refractory to or intolerant of diuretics, serial LVP is necessary to control the ascites. LVP may be needed every 2 weeks or even more frequently depending on the patient’s degree of discomfort. Transjugular intrahepatic portosystemic shunt (TIPS), generally performed by an Interventional Radiologist, is another effective means of controlling ascites in selected patients.

Additionally, the AASLD recommends consideration of liver transplantation in all patients with cirrhosis and ascites.

Except for patients with nephrotic syndrome, patients with a SAAG of < 1.1 g/dL do not respond to diuretics and salt restriction. Treatment of ascites for this patient population will depend on the etiology.

Spontaneous bacterial peritonitis and culture-negative neutrocytic ascites

Initiate antibiotic therapy promptly after diagnostic paracentesis if the patient has signs and symptoms consistent with infection (fever, abdominal pain, encephalopathy, serum leucocytosis). Antibiotics can be discontinued if ascitic fluid analysis is not consistent with infection. Best outcomes have been achieved with an IV 3^rd-generation cephalosporin such as cefotaxime 2 g (grams) every 8 hours, or ceftriaxone at 2 g daily or 1 g every 12 hrs. One study demonstrated superiority of cefotaxime over the combination of ampicillin plus tobramycin. Cephalosporins have consistently shown cure rates of ~ 90-95%. Treatment is generally for 5 days provided the patient has clinically improved; likewise with clinical improvement a repeat paracentesis to document a decrease in the PMN count is not required. Repeat paracentesis to look for a rising PMN count and to resend cultures is necessary for persistent fever or other signs of clinical deterioration.

Outpatient treatment of SBP, usually after a brief hospitalization, is effective provided the patient is not vomiting, is not encephalopathic, and does not have renal failure. An oral quinolone is generally used.

One study showed a significant reduction in renal failure and mortality (absolute risk reduction 19%) in patients with SBP who were given albumin versus placebo. Albumin was given at 1.5 g/kg (grams/kilogram) of body weight on day one followed by 1 g/kg on day three. This and another study showed that low-risk patients (bilirubin < 4 mg/dL, BUN < 30 mg/dL, and creatinine < 1 mg/dL) did well without albumin.

SBP is more common in the setting of variceal haemorrhage. IV ceftriaxone 1 g daily was shown to reduce this risk more than oral norfloxacin.

Lastly, patients with a history of SBP, or those with an ascitic fluid protein < 1 g/dL, benefit from antibiotic prophylaxis. Possible regimens include norfloxacin 400 mg once daily, trimethoprim/sulfamethoxazole (TMP/SMX) 160 mg/800 mg given 5 times/week, or ciprofloxacin 750 mg once per week. TMP/SMX and ciprofloxacin can also be given daily as intermittent dosing may increase bacterial resistance. Proton pump inhibitors may increase the risk of SBP and should only be given if there is a clear indication to do so.

Secondary bacterial peritonitis due to abscess or perforation

Patients should have an urgent pain film to evaluate for perforation, and a prompt surgical consultation. A CT scan is often necessary to evaluate for abscess or perforation in the event of a negative plain film, or as requested by surgery. Antibiotic coverage should include a 3^rd-generation cephalosporin in addition to anaerobic coverage, usually with metronidazole.

Other important information

All patients with ascites due to cirrhosis should be referred and considered for transplantation. The presence of ascites in a patient with cirrhosis is associated with a mortality of 15% at 1 year and 44% at 5 years.

For ascites in patients with alcohol induced liver injury, the most important first step is to abstain from alcohol. This type of ascites is often reversible once the offending agent is removed. In this patient population, cessation from alcohol can also over time lead to an improved response to diuretics and sodium restriction.

Patients with hepatitis B and/or C will also have an improved response to medical therapy for ascites after initiating antiviral therapy.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

It is important to always rule out infection in patients presenting with new ascites or in those with cirrhosis requiring serial LVP.

Perform a diagnostic paracentesis prior to initiating antibiotics. You may start antibiotics immediately following paracentesis while fluid results are pending.

TREATMENT

Ascites due to portal hypertension

Diuretics:

Initial dosing: Spironolactone 50 or 100 mg by mouth daily and furosemide 20 or 40 mg by mouth daily
Remember to keep spironolactone and furosemide dosing at a ratio of 5:2 to maintain normokalemia

Spontaneous bacterial peritonitis or culture-negative neutrocytic ascites

Third generation cephalosporin such as cefotaxime 2 g IV every 8 hours or ceftriaxone 1 g IV twice a day or 2 g daily for 5 days
IV albumin to prevent hepatorenal syndrome and death at a dose of 1.5 g/kg of body weight at time of diagnosis followed by 1 g/kg on day 3. Low risk patients (normal renal function and bilirubin < 4 mg/dL) do well without albumin.

Secondary bacterial peritonitis with or without perforation

Third generation cephalosporin as above
Anaerobic coverage with metronidazole
Abdominal imaging and surgical consultation

Prevention of spontaneous bacterial peritonitis after surviving first episode

TMP/SMX160 mg/800 mg daily or norfloxacin 400 mg daily
Intermittent dosing of TMP/SMX or ciprofloxacin is less ideal given possible induction of bacterial resistance

Patients with ascites and gastrointestinal bleed

Ceftriaxone 1 g IV daily for a total of 7 days
May use oral quinolone as well, especially if patient is otherwise ready for discharge

IV. What’s the evidence?

Gines, P,, Cardenas, A,, Arroyo, V. “Management of Cirrhosis and Ascites.”. . vol. 350. 2004. pp. 1646-54.

Runyon, B.. “Management of Adult Patients with Ascites Due to Cirrhosis: Update 2012.”. AASLD Guidelines,. 2013.

Grabau, CM,, Crago, SF,, Hoff, LK,, Simon, JA,, Melton, CA,, Ott, BJ. “Performance standards for therapeutic abdominal paracentesis.”. . 2004. pp. 484-88.

Runyon, BA,, Hoefs, JC,, Morgan, TR.. “Ascitic fluid analysis in malignancy-related ascites.”. . vol. 8. 1988. pp. 1104-09.

Akriviadis, EA,, Runyon, BA:. “Utility of an algorithm in differentiating spontaneous from secondary bacterial peritonitis.”. . vol. 98. 1990. pp. 127-133.

Felisart, J,, Rimola, A,, Arroyo, V. “Randomized comparative study of efficacy and nephrotoxicity of ampicillin plus tobramycin versus cefotaxime in cirrhotics with severe infections.”. . vol. 5. 1985. pp. 457-62.

Sort, P,, Navasa, M,, Arroyo, V. “Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.”. . vol. 341. 1999. pp. 403-9.

Gines, P,, Arroyo, V,, Gines, P,, Rodes, J,, Schrier, RW. “Hernandez-Esperrach G: Prognosis of cirrhosis with ascites.”. Malden Mass., Blackwell Science,. 1999. pp. 431-41.

D Amico, G,, Morabito, A,, Pagliaro, L,, Marubini, E. “Survival and prognostic indicators in compensated and decompensated cirrhosis.”. . vol. 31. 1986. pp. 468-75.

Runyon, BA,, Montano, AA,, Akriviadis, EA. “The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites.”. . vol. 117. 1992. pp. 215-20.

Bernardi, M,, Carceni, P,, Navickis, RJ,, Wilkes, MM. “Albumin infusion in patients undergoing large-volume paracentesis: a meta-analysis of randomized trials.”. . vol. 55. 2012. pp. 1172-81.

Cattau, EI,, Benjamin, SB,, Knuff, TE,, Castell, DO.. “The accuracy of the physical exam in the diagnosis of suspected ascites.”. . vol. 247. 1982. pp. 1164-6.

Runyon, BA. “Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis.”. . vol. 91. 1986. pp. 1343-6.

Hillebrand, DJ,, Runyon, BA,, Yasmineh, WG,, Rynders, GP. “Ascitic fluid adenosine deaminase insensitivity in detecting tuberculous peritonitis in the United States.”. . vol. 24. 1996. pp. 1408-12.

Riquelme, A,, Calvo, M,, Salech, F. “Value of adenosine deaminase (ADA) in ascitic fluid for the diagnosis of tuberculous peritonitis: a meta-analysis.”. . vol. 40. 2006. pp. 705-10.

Nazeer, SR,, Dewbre, H,, Miller, AH. “Ultrasound-assisted paracentesis performed by emergency physicians vs the traditional technique: a prospective, randomized study.”. .. vol. 23. 2005. pp. 363-7.

Fernandez, J,, Ruiz del Arbol, L,, Gomez, C. “Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and haemorrhage.”. . vol. 131. 2006. pp. 1049-56.

Saab, S,, Hernandez, JC,, Chi, AC,, Tong, MJ. “Oral antibiotic prophylaxis reduces spontaneous bacterial peritonitis occurrence and improves short-term survival in cirrhosis: a meta-analysis.”. . vol. 104. 2009. pp. 993-1001.

Sigal, SH,, Stanca, CM,, Fernandez, J. “Restricted use of albumin for spontaneous bacterial peritonitis.”. . vol. 56. 2007. pp. 597-9.

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