Ascites

Ascites refers to the accumulation of excessive volumes of fluid within the peritoneal cavity. Cirrhosis is the most common cause of ascites. The other main causes are infection (acute and chronic, including tuberculosis), malignancy, pancreatitis, heart failure, hepatic venous obstruction, nephrotic syndrome, and myxedema.

Pathogenesis

Ascites forms because of an imbalance between the formation and resorption of peritoneal fluid. Distribution of fluid between vascular and tissue spaces is determined by the equilibrium of hydrostatic and oncotic pressures in the two compartments. The accumulation of fluid in the peritoneal cavity of patients with cirrhosis results from an interaction of a number of factors:

• Portal hypertension with increased total splanchnic plasma volume.
• Renal changes favoring increased sodium and water resorption and retention include the following:
• Stimulation of the renin-aldosterone system.
• Increased antidiuretic hormone release.
• Decreased release of «natriuretic» hormone or third factor.
• Imbalance in the formation and removal of hepatic and gut lymph. Lymphatic drainage (removal) fails to compensate for the increased lymph leakage, mainly due to elevated hepatic sinusoidal pressure, leading to formation of ascites.
• Hypoalbuminemia from decreased hepatic synthesis, which results in decreased intravascular oncotic pressure. The leakage of albumin through lymph into the peritoneal cavity increases the intraperitoneal oncotic pressure, favoring ascites formation.
• Elevated plasma vasopressin and epinephrine levels. These hormonal responses to a volume-depleted state further accentuate renal and vascular factors.

Diagnosis

Clinical presentation. The physical findings of ascites include the puddle sign, bulging flanks, flank and shifting dullness, and fluid wave. Abdominal or umbilical herniation, penile or scrotal edema, or right-sided pleural effusion may be present.

Detection of more than 2 L of ascites is not difficult, but less than this amount is not always ascertained by physical examination. The percussion maneuvers require the presence of at least 500 mL of fluid. The diagnostic accuracy of all the maneuvers described is only about 50%. The maneuver to determine flank and shifting dullness is probably the most reliable.

Radiologic studies

Plain abdominal x-ray films may reveal general haziness of the abdomen with loss of the psoas shadow. Usually, there is centralization and separation of bowel loops.

Ultrasonography can detect as little as 30 mL of ascitic fluid with the patient in the right lateral decubitus position. Free and loculated collections can be identified.

Computed tomography scans of the abdomen may detect small amounts of ascites and at the same time evaluate intraabdominal anatomy, giving important information on the size and state of the liver and spleen and on the presence or absence of varices and tumors.

Characterization of ascitic fluid

Paracentesis. A diagnostic paracentesis should be performed for new onset ascites or when a complication is suspected. The procedure is performed under sterile conditions using a 20- to 23-gauge angiocatheter. The most frequent site of puncture is on the linea alba slightly below the umbilicus. The iliac fossa also may be used. Paracentesis rarely leads to serious complications (< 1%), which include bowel perforation, hemorrhage, and persistent ascitic fluid leakage. It is much safer to perform the paracentesis under ultrasound guidance with proper localization of ascitic fluid away from bowel loops.

Laboratory studies

Approximately 50 mL of ascitic fluid is withdrawn for diagnostic purposes. The ascitic fluid is analyzed for appearance, color, red and white blood cell counts, and percentage of neutrophils, total protein, albumin, glucose, triglycerides, and amylase determination. The fluid should be inoculated into blood culture bottles at the bedside for aerobic and anaerobic organisms. Samples should be sent for Gram’s and acid-fast bacillus stains, tuberculin and fungal cultures, and cytologic study to look for malignant cells. Gram’s stain is helpful only in the setting of gut perforation. A concomitant serum sample is also analyzed for the preceding chemical parameters.

A serum ascites albumin gradient equal to or greater than 1.1 g/dL is consistent with ascites secondary to portal hypertension and cirrhosis. The cell count in cirrhotic ascites is usually less than 500 white cells/ВµL with less than 25% neutrophils (polymorphonuclear cells). polymorphonuclear counts greater than 250/Вµl/L strongly suggest bacterial infection either from spontaneous bacterial peritonitis or from perforation of a viscus. Patients with bloody ascites should have a corrected polymorphonuclear count calculated, as one polymorphonuclear is subtracted from the total absolute polymorphonuclear count for every 250 red blood cells. Ascitic fluid, lactate, and pH values are not helpful in diagnosing infection.

The presence of blood in the ascitic fluid suggests infection with tuberculosis, fungi, or, more commonly, malignancy. Pancreatic ascites has a high protein concentration, increased number of neutrophils, and elevated amylase levels. Increased triglycerides in the ascitic fluid indicate chylous ascites and suggest the presence of lymphatic obstruction and disruption by trauma, lymphoma, tumor, or infection.

Spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis seems to occur in 8% to 10% of patients with alcoholic cirrhosis. The patient may be totally asymptomatic or present with signs and symptoms of peritonitis or increased liver failure and encephalopathy or both. When

Spontaneous bacterial peritonitis is suspected, ascitic fluid and blood cultures should be obtained, and the patient should be treated promptly with broad-spectrum antibiotics (e.g., a third-generation cephalosporin). Because untreated Spontaneous bacterial peritonitis results in high mortality, overtreatment rather than delayed treatment is recommended. The antibiotic coverage may be altered following culture results. Five days of intravenous antibiotic therapy is sufficient even for patients with bacteremia.

The organisms most commonly found in the infected ascitic fluid belong to the gut flora such as Escherichia coli, pneumococcus, and Klebsiella organisms. Anaerobic infection is rare. In 70% of patients, the blood cultures are also positive for bacteria. The pathogenesis of Spontaneous bacterial peritonitis is multifactorial. The decreased hepatic reticuloendothelial filtration of gut bacteria and the decreased antimicrobial activity of ascitic fluid with low opsonic activity due to low complement and antibody levels and neutrophil dysfunction are thought to play a large role.

Possible routes of entry for the bacteria are transmurally from the gastrointestinal tract, from the lymphatics, or, in women, from the genital tract and fallopian tubes. Recurrent Spontaneous bacterial peritonitis may be seen in a high percentage of patients. An ascitic fluid protein concentration less than 1.0 g/dL is the best predictor of recurrence. Oral quinolone therapy (e.g., norfloxacin) has been shown to be effective in decreasing the rate of recurrence of infection. Diuresis also may help in Spontaneous bacterial peritonitis by increasing ascitic fluid opsonic and total protein concentrations.

Spontaneous bacterial peritonitis is sometimes difficult to distinguish from secondary peritonitis resulting from rupture of an abscess or bowel perforation. The number and type of infecting organisms may be helpful in distinguishing spontaneous from secondary peritonitis. Unlike secondary peritonitis, in which there are always multiple organisms, a single organism is cultured in 78% to 88% of Spontaneous bacterial peritonitis cases. If present, pneumoperitoneum strongly suggests secondary bacterial peritonitis. The treatment of secondary peritonitis is surgical. However, all patients require proper broad-spectrum antibiotic coverage.

Complications of ascites

Most of the complications of ascites result from increased intraabdominal pressure and are proportional to the volume and rate of fluid accumulation. The most common complications are dyspnea, decreased cardiac input, anorexia, reflux esophagitis, vomiting, ventral hernia, and escape of the ascitic fluid along tissue planes to the chest (hydrothorax) and the scrotum. By increasing the portal hypertension, the risk of upper gastrointestinal bleeding may also be increased.

Treatment of ascites

The treatment of uncomplicated ascites should start with attempts to improve the hepatic function. Patients should abstain from alcohol and other hepatotoxic drugs and should receive good nutrition to promote hepatic regeneration. When drug therapy may be helpful in decreasing hepatic inflammation, patients should be treated appropriately. Hepatic healing and regeneration have resulted in decrease of ascites.

Most patients, especially those with urine sodium concentrations less than 10 mEq/L, respond to moderate periods of bed rest and restriction of dietary sodium to 0.5 to 1.0 g per day and fluid intake to less than 1 L per day with spontaneous diuresis.

• Diuretics. If the preceding measures do not induce spontaneous diuresis, diuretics may be used. Optimally, diuresis should result in loss of 1 L or 1 to 2 lb (0.4-0.9 kg) per day. Peripheral edema is more easily mobilized by diuretics than ascites and serves as a safety valve for fluid loss. Excessive diuresis may result in azotemia, hyponatremia, hepatorenal syndrome, and encephalopathy.
• Spironolactone (Aldactone) is usually the diuretic of choice at 100 to 200 mg per day given in a single dose. If the urinary sodium concentration remains less than 10 mEq/liter and the diuresis is suboptimal, doses up to 600 mg per day may be used. The effect of the drug (inhibition of the effect of aldosterone at the distal tube) is slow, and initial diuresis begins after 2 to 3 days. The possible side effects are gynecomastia, lactation, and hyperkalemia.
• Furosemide. In patients in whom diuresis is not successful with spironolactone, furosemide (Lasix) may be added, starting at 40 mg per day. The dosage may be increased to 240 mg per day, especially in patients with peripheral edema.

Combination therapy

Although single-agent spironolactone has been shown to be superior to single-agent furosemide, it is usually preferable to start spironolactone and furosemide together, beginning with 100 mg and 40 mg, respectively, given as a single dose.

Single daily doses of medications are most appropriate and enhance compliance. Amiloride hydrochloride 10 mg per day can be substituted for spironolactone; amiloride hydrochloride is less available and more expensive than spironolactone, but it is more rapidly effective and does not cause gynecomastia. If the combination of 100 mg per day of spironolactone (or 10 mg of amiloride hydrochloride) and 40 mg per day of furosemide is ineffective in increasing urinary sodium or decreasing body weight, the dosages of both drugs should be simultaneously increased as needed (e.g., 200 plus 80, then 300 plus 120, and finally 400 mg per day of spironolactone [or 40 mg per day of amiloride hydrochloride] plus 160 mg per day of furosemide).

Doses higher than 400 mg per day plus 160 mg per day can be given, but additional increments in urine sodium are marginal. Addition of a third diuretic such as hydrochlorothiazide can lead to a natriuresis in such a patient but may result in hyponatremia. Although the preceding ratios of spironolactone and furosemide usually maintain normokalemia, the doses of these two drugs can be adjusted to correct serum potassium imbalance.

Treatment of refractory ascites

In 10% to 20% of patients with ascites, the standard medical therapy is ineffective or causes serious side effects. Ascites that is resistant to mobilization with the usual therapy is not always the result of refractory hepatorenal failure. The conditions that may contribute to refractory ascites include worsening of the primary liver disease, such as active inflammation, portal or hepatic vein thrombosis, gastrointestinal bleeding, infection, Spontaneous bacterial peritonitis, malnutrition, hepatocellular carcinoma, superimposed cardiac or renal disease, and hepatotoxic (e.g., alcohol and acetaminophen) and nephrotoxic substances.

Nonsteroidal antiinflammatory drugs (nonsteroidal antiinflammatory drugs) reduce renal blood flow by reducing renal vasodilating prostaglandins, glomerular filtration rate, and response to diuretics. Angiotensin-converting enzyme inhibitors and some calcium channel blockers decrease peripheral vascular resistance, effective vascular volume, and renal perfusion. Aminoglycoside nephrotoxicity is more prevalent in patients with cirrhosis and may result in renal failure.

Current options for the 10% of patients whose condition is refractory to routine medical therapy include therapeutic paracentesis, peritoneovenous shunt, and liver transplantation. Side-to-side portacaval shunts have been used in the treatment of refractory ascites, but operative hemorrhagic complications and portosystemic encephalopathy have led to the abandonment of this approach. Whether TIPS will be of value in the treatment of patients with diuretic resistant ascites remains to be seen.

Therapeutic paracentesis

The safety and efficacy of large-volume paracentesis have been confirmed. The procedure involves the daily removal of 4 to 6 L of ascitic fluid until the abdomen is completely evacuated. After paracentesis, adjunctive therapy with diuretics and dietary sodium restriction should be continued to prevent rapid reaccumulation of ascitic fluid. The procedure may be repeated at intervals of 2 to 4 weeks.

In view of the ease and efficacy of diuretic therapy in more than 90% of patients, therapeutic paracentesis should be reserved for treatment of tense ascites and ascites that is refractory to diuretic therapy. In addition to being time-consuming for both the physician and the patient, the procedure leads to protein and opsonin depletion; diuresis, on the other hand, conserves proteins and opsonins. Depletion of opsonins could predispose to spontaneous bacterial peritonitis.

Colloid replacement after large-volume paracentesis remains controversial. The cost of albumin infusion ranges from $120 to $1,250 per tap. The changes noted in plasma renin and serum electrolytes and creatinine in patients who receive no colloid replacement do not seem to be clinically significant and have not resulted in increases in morbidity or mortality.

Shunts

In about 5% of patients, ascites do not respond to the usual dosages of diuretics, and increases in diuretic dosages result in the deterioration of renal function. In these patients, a shunting procedure may be considered. A side-to-side portosystemic shunt has been used in some patients, but the procedure is associated with high mortality.

Peritoneovenous shunts

The reinfusion of ascitic fluid by a peritoneovenous shunt (e.g., LeVeen or Denver shunt) may be therapeutic in selected patients. The peritoneovenous shunt routes the ascitic fluid subcutaneously from the peritoneal cavity into the internal jugular vein through a pressure activated one-way valve. Most patients still require diuretics but at reduced doses. There is also a concomitant improvement in renal blood flow. Serious complications of the peritoneovenous shunt occur in more than 10% of the patients and may lead to death.

The complications include peritoneal infection and sepsis, disseminated intravascular coagulation, congestive heart failure, and ruptured esophageal varices. The shunt may clot in about 30% of the recipients and require replacement. The procedure is contraindicated in patients with sepsis, heart failure, malignancy, and history of variceal bleeding. The morbidity and survival rates of patients with cirrhosis treated with peritoneovenous shunts correlate with the degree of impairment of liver and renal functions. The best results are obtained in the few patients with diuretic-resistant ascites and relatively preserved hepatic function.

At the present time, peritoneovenous shunting is reserved for a very small group of patients who fail to improve with both diuretic and paracentesis therapy or patients in whom diuretic therapy has failed, who live too far from medical care to receive large-volume paracentesis every other week.

Liver transplantation

Orthotopic liver transplantation should be considered among the treatment options of a patient with refractory ascites who is otherwise a transplant candidate. The 12-month survival of patients with ascites refractory to medical therapy is only 25%. With liver transplantation, however, the 12-month survival is 70% to 75%.