Indications

Abdominal paracentesis with appropriate ascitic fluid analysis is probably the most rapid and cost-effective method of diagnosing the cause of ascites. Also, because of the possibility of ascitic fluid infection in a cirrhotic patient admitted to the hospital, a surveillance paracentesis performed on admission may detect unexpected infection.⁹ Not all patients with ascitic fluid infection are symptomatic; many have subtle symptoms, such as mild confusion noticed only by the family. Detection of infection at an early asymptomatic stage may reduce mortality. Therefore, ascitic fluid should be sampled in all inpatients and outpatients with new-onset ascites and in all patients with ascites who are admitted to the hospital. Paracentesis should be repeated in patients (whether hospitalized or not) in whom symptoms, signs, or laboratory abnormalities suggestive of infection develop (e.g., abdominal pain or tenderness, fever, encephalopathy, hypotension, renal failure, acidosis, peripheral leukocytosis).

Contraindications

Few contraindications to paracentesis have been recognized. Coagulopathy is a potential contraindication; however, most patients with cirrhotic ascites have coagulopathy, and if mild to moderate coagulopathy were viewed as a contraindication to paracentesis, few patients with cirrhosis would undergo this procedure.¹⁰ Coagulopathy should preclude paracentesis only when clinically evident fibrinolysis or disseminated intravascular coagulation is present.¹⁰ These conditions occur in fewer than 1 per 1000 paracenteses. No data are available to support cutoff values for coagulation parameters beyond which paracentesis should be avoided. Global coagulation is usually normal in the setting of cirrhosis despite abnormal tests of coagulation because there is a balanced deficiency of procoagulants and anticoagulants.¹¹ Even after multiple paracenteses, bloody ascites usually does not develop in patients with severe prolongation of the prothrombin time. Patients with cirrhosis and without clinically obvious coagulopathy simply do not bleed excessively from needlesticks unless a blood vessel is entered.¹⁰

Studies regarding complications of paracentesis in patients with ascites have documented no deaths or infections caused by paracentesis.^9,10 No episodes of hemoperitoneum or entry of the paracentesis needle into the bowel have been reported in these studies. Complications have included only abdominal wall hematomas in approximately 2% of paracenteses, even though 71% of the patients had an abnormal prothrombin time and 21% had a prothrombin time prolonged by more than five seconds.¹⁰ Complication rates may be higher when paracentesis is performed by an inexperienced operator.

Transfusion of blood products (fresh frozen plasma or platelets) routinely before paracentesis in cirrhotic patients with coagulopathy, presumably to prevent hemorrhagic complications, is not supported by data. Because a hematoma that necessitates blood transfusion develops in only approximately 1% of patients who undergo paracentesis without prophylactic transfusion of plasma or platelets, approximately 100 to 200 units of fresh frozen plasma or platelets would have to be given to prevent the transfusion of approximately 2 units of red blood cells. In a prospective study of 1100 therapeutic paracenteses, no blood products were given prior to the procedure nor were they needed after the procedure despite a platelet count as low as 19,000 cells/mm³ [0.25 × 10⁹/L]) and international normalized ratio (INR) as high as 8.7.¹²

Patient Position and Choice of Needle and Entry Site

The volume of fluid in the abdomen and the thickness of the abdominal wall determine, in part, how the patient should be positioned in preparation for paracentesis. Patients with a large volume of ascites and thin abdominal wall can be “tapped” successfully in the supine position, with the head of the bed or examining table elevated slightly. Patients with less fluid can be placed in the lateral decubitus position and tapped in the midline or in the right or left lower quadrant while supine (see later). Patients with small amounts of fluid may be tapped successfully only in the face-down position or with ultrasound guidance.¹³

The choice of the site for inserting the needle has changed over the years because of the increasing prevalence of obesity and frequency of therapeutic paracentesis. Paracentesis in obese patients poses special challenges. In obese patients, the abdominal wall usually is substantially thicker in the midline than in the lower quadrants on ultrasound examination.¹³ The abdominal wall may be even thicker than the length of a 3.5-inch paracentesis needle. Also, on physical examination, determining whether ascites is present or absent in the obese patient is frequently difficult. Ultrasound examination is helpful in confirming the presence of fluid and in guiding the paracentesis needle. Preferably, the needle is inserted into the left lower quadrant, rather than the right lower quadrant because the cecum may be distended with gas from lactulose therapy. Also, the right lower quadrant is more likely than the left to have a surgical scar (e.g., from an appendectomy). When therapeutic paracentesis is performed, more fluid can be obtained using a lower quadrant needle insertion site than a midline site.

The needle must be placed several centimeters from a surgical scar. The bowel may be adherent to the peritoneal surface of the abdomen near a scar, and a needle inserted there may enter the bowel.⁹ A long midline scar precludes midline paracentesis. An appendectomy scar precludes a right lower quadrant site, in general.

I usually choose a site in the left lower quadrant two fingerbreadths (3 cm) cephalad and two fingerbreadths medial to the anterior superior iliac spine.¹³ In a patient with multiple abdominal scars, ultrasound guidance may be required.

In a patient who is not overweight, I prefer to use a standard metal 1.5-inch, 22-gauge needle. Paracentesis in obese patients requires the use of a longer needle, for example, one that is 3.5 inches and 22 gauge. Steel needles are preferable to plastic-sheathed cannulas because plastic sheaths may shear off into the peritoneal cavity, with the potential to kink and obstruct the flow of fluid after the cannula is removed. Metal needles do not puncture the bowel unless the bowel is adherent to a scar or severe gaseous distention is present.

Technique

Gross Appearance

Non-neutrocytic (i.e., ascitic fluid polymorphonuclear neutrophil [PMN] count less than 250/mm³ [0.25 × 10⁹/L]) ascitic fluid is transparent and usually slightly yellow (Fig. 91-2). Ascitic fluid with a very low protein concentration may have no pigment and look like water. The opacity of many cloudy ascitic fluid specimens is caused by neutrophils. The presence of neutrophils leads to a shimmering effect when a glass tube containing the fluid is rocked back and forth in front of a light. Fluid with an absolute neutrophil count less than 1000/mm³ (1.0 × 10⁹/L) may be nearly clear. Fluid with a count greater than 5000/mm³ (5.0 × 10⁹/L) is quite cloudy, and fluid with a count greater than 50,000/mm³ (50.0 × 10⁹/L) resembles mayonnaise.

Figure 91-2. Algorithm for the approach to the differential diagnosis of ascites. GI, gastrointestinal; LDH, lactate dehydrogenase; PMN, polymorphonuclear neutrophil; RBC, red blood cell; SBP, spontaneous bacterial peritonitis; TP, total protein.

Ascitic fluid specimens frequently are blood-tinged or frankly bloody. A red blood cell count of 10,000/mm³ (10.0 × 10⁹/L) is the threshold for a pink appearance; lower concentrations result in clear or turbid fluid. Ascitic fluid with a red blood cell count greater than 20,000/mm³ (20.0 × 10⁹/L) is distinctly red. Many ascitic fluid specimens are bloody because of a traumatic tap; these specimens are blood-streaked and frequently clot unless the fluid is transferred immediately to the anticoagulant-containing tube for the cell count. By contrast, nontraumatic or remotely traumatic blood-tinged ascitic fluid is homogeneous and does not clot because it has already clotted and the clot has lysed. Some patients with portal hypertension have bloody hepatic lymph, resulting in bloody ascitic fluid—perhaps because of rupture of lymphatics that are under high pressure. Samples from patients with hepatocellular carcinoma are regularly bloody, but only about 10% of samples from patients with peritoneal carcinomatosis are red.² Although many physicians have the impression that tuberculosis results in bloody ascitic fluid, less than 5% of tuberculous samples are hemorrhagic in my experience.

Ascitic fluid frequently is lipid-laden. Lipid opacifies the fluid. The degree of opalescence of ascitic fluid ranges from slightly cloudy to completely opaque and chylous. Most opaque, milky fluid samples have a triglyceride concentration greater than 200 mg/dL (2.26 mmol/L) and usually greater than 1000 mg/dL (11.30 mmol/L). Fluid that has the appearance of dilute skim milk has a triglyceride concentration between 100 mg/dL (1.13 mmol/L) and 200 mg/dL (2.26 mmol/L). A substantial minority of cirrhotic ascitic fluid samples are neither transparent nor frankly milky. These opalescent samples have slightly elevated triglyceride concentrations ranging from 50 mg/dL (0.56 mmol/L) to 200 mg/dL (2.26 mmol/L).¹⁴ The opacity of these fluids does not have the shimmering characteristics of ascitic fluid with an elevated white blood cell count. The lipid usually layers out when a tube of ascitic fluid is placed in the refrigerator for 48 to 72 hours. In contrast with findings in older published reports, most patients with chylous or opalescent ascites have cirrhosis.^14,15

Dark-brown fluid with a bilirubin concentration greater than that of serum usually indicates biliary perforation.¹⁶ Deeply jaundiced patients have bile-stained ascitic fluid, but the bilirubin level and the degree of pigmentation are visually less than those of the corresponding serum. Pancreatic ascites may be pigmented because of the effect of pancreatic enzymes on red blood cells. The red blood cells may have to be centrifuged before the discolored supernatant is revealed. The degree of pigmentation ranges from tea-colored to jet black, as in pancreatic necrosis (formerly hemorrhagic pancreatitis). Black ascitic fluid also may be found in patients with malignant melanoma.

Tests

The practice of ordering every available body fluid test on every ascitic fluid specimen is expensive and can be more confusing than helpful, especially when unexpectedly abnormal results are encountered. An algorithm for the analysis of ascitic fluid is shown in Figure 91-2. The basic concept is that screening tests are performed on the initial specimen; additional testing is performed only when necessary as indicated by the results of the screening tests. Further testing may require another paracentesis, but because most specimens consist of ascitic fluid resulting from uncomplicated cirrhosis, no further testing is needed in a majority of cases. Also, because laboratories frequently store the fluid for a few days, additional testing can often be ordered on the stored fluid.

On the basis of cost analysis, tests can be classified as routine, optional, unusual, and unhelpful (Table 91-2).⁹ The cell count is the single most helpful ascitic fluid test. Only approximately 10 µL of fluid is required for a standard manual hemocytometer count. Therefore, if only one drop of fluid can be obtained, it should be sent for cell count. More fluid is almost always obtainable, however. The fluid should be submitted in an anticoagulant-containing tube (i.e., ethylenediaminetetraacetic acid) to prevent clotting. Because the decision to begin empirical antibiotic treatment of suspected ascitic fluid infection is based largely on the absolute neutrophil count (which should have a turnaround time of a few minutes), rather than the culture (which takes 12 to 48 hours to demonstrate growth), the cell count is more important than the culture in the early detection and treatment of ascitic fluid infection. Even samples from asymptomatic outpatients undergoing therapeutic paracentesis should be sent for a cell and differential count; the information obtained can lead to early, life-saving treatment of bacterial infection.

Total Protein

As noted earlier, the antiquated exudate/transudate system of ascitic fluid classification, which is based on ascitic fluid total protein concentration, is problematic. The protein concentration in ascitic fluid in the setting of cirrhosis is determined almost entirely by the serum protein concentration and portal pressure. A patient with cirrhosis and a relatively high serum protein concentration will have a relatively high ascitic fluid protein concentration. Because of this relationship, almost 20% of ascitic samples in patients with cirrhosis will have a protein concentration greater than 2.5 g/dL (25 g/L). The ascitic fluid total protein concentration does not increase during spontaneous bacterial peritonitis; it remains stable before, during, and after infection.²⁵ In fact, patients with the lowest ascitic protein concentrations are the most susceptible to spontaneous peritonitis.²⁶ During a 10-kg diuresis, the ascitic fluid total protein concentration doubles, and 67% of such patients with cirrhotic ascites have a protein concentration greater than 2.5 g/dL (25 g/L) by the end of diuresis.¹⁷ In almost one third of patients with malignant ascites, the ascites is caused by massive liver metastases or hepatocellular carcinoma, and the ascitic fluid in these patients has a low protein concentration.² In cardiac ascites, the ascitic fluid protein concentration is greater than 2.5 g/dL (25 g/L).²⁷

Therefore, the exudate/transudate method of classification of ascites places many patients with cirrhosis and ascites and all patients with cardiac ascites in the exudate category and many patients with malignant ascites and essentially all patients with spontaneously infected ascites in the transudate category. Clearly, this method of classification is not useful. By contrast, the SAAG classifies fluid by the presence or absence of portal hypertension and is much more physiologic and intuitive in nature.²¹ The albumin gradient classifies cardiac ascites in the high-SAAG category, similar to cirrhotic ascites. The high SAAG of cardiac ascites is presumably the result of high right-sided cardiac pressures. In patients with cardiac ascites, the SAAG may narrow with diuresis; such narrowing does not happen in patients with cirrhosis.

The combination of ascitic fluid total protein, glucose, and LDH is of value in distinguishing spontaneous bacterial peritonitis from intestinal perforation with leakage of gut contents into ascites²⁸ (Fig. 91-3). Patients who have neutrocytic ascitic fluid, in whom the clinical picture suggests bacterial peritonitis (rather than peritoneal carcinomatosis or tuberculous peritonitis) and who meet two of the following three criteria, are likely to have surgical peritonitis and merit immediate radiologic evaluation to determine if intestinal perforation with leakage of intestinal contents into ascites has occurred: total protein greater than 1 g/dL (10 g/L), glucose less than 50 mg/dL (2.8 mmol/L), and LDH greater than the upper limit of normal for serum.²⁸

Figure 91-3. Algorithm for differentiating spontaneous from secondary bacterial peritonitis in patients with neutrocytic ascites (i.e., neutrophil count of 250 cells/mm³ [0.25 × 10⁹/L] or greater) in the absence of hemorrhage into ascitic fluid, tuberculosis, peritoneal carcinomatosis, or pancreatitis. Antibiotic therapy should be started at the time peritonitis (ascitic fluid PMN count ≥250 cells/mm³) is detected. CT, computed tomography; LDH, lactate dehydrogenase; PMN, polymorphonuclear neutrophil; US, ultrasound.

(Reproduced with permission from Akriviadis EA, Runyon BA. The value of an algorithm in differentiating spontaneous from secondary bacterial peritonitis. Gastroenterology 1990; 98:127-33.

Classification

Of the three subtypes of spontaneous ascitic fluid infection, the prototype is spontaneous bacterial peritonitis. The diagnosis of spontaneous bacterial peritonitis is made when there is a positive ascitic fluid culture and an elevated ascitic fluid absolute PMN count (i.e., at least 250 cells/mm³ [0.25 × 10⁹/L]) without evidence of an intra-abdominal surgically treatable source of infection.⁹ When Correia and Conn coined the term “spontaneous bacterial peritonitis” in 1975, their goal was to distinguish this form of infection from surgical peritonitis,⁵⁷ an important distinction. Therefore, although many patients with spontaneous bacterial peritonitis have a focus of infection (e.g., urinary tract infection or pneumonia), the diagnosis of spontaneous bacterial peritonitis is still appropriate unless the focus requires surgical intervention (e.g., a ruptured viscus). I have not encountered a convincing case of polymicrobial spontaneous bacterial peritonitis; all of the patients presumed to have spontaneous bacterial peritonitis in whom ascitic fluid cultures initially grew more than one organism eventually were found to have surgical peritonitis or an erroneous culture result (e.g., a pathogen plus a contaminant or two colony morphologies of one species of bacteria).

The criteria for a diagnosis of monomicrobial non-neutrocytic bacterascites (MNB) include (1) a positive ascitic fluid culture for a single organism, (2) an ascitic fluid PMN count lower than 250 cells/mm³ (0.25 × 10⁹/L), and (3) no evidence of an intra-abdominal surgically treatable source of infection.⁵⁸ In the older literature, MNB was either grouped with spontaneous bacterial peritonitis or labeled “asymptomatic bacterascites.” Because many patients with bacterascites have symptoms, the modifier “asymptomatic” seems inappropriate.

Culture-negative neutrocytic ascites (CNNA) is diagnosed when (1) the ascitic fluid culture grows no bacteria, (2) the ascitic fluid PMN count is 250 cells/mm³ (0.25 × 10⁹/L) or greater, (3) no antibiotics have been given (not even a single dose), and (4) no other explanation for an elevated ascitic PMN count (e.g., hemorrhage into ascites, peritoneal carcinomatosis, tuberculosis, or pancreatitis) can be identified.⁵⁹ This variant of ascitic fluid infection seldom is diagnosed when sensitive culture methods are used.²³

Secondary bacterial peritonitis is diagnosed when (1) the ascitic fluid culture is positive (usually for multiple organisms), (2) the PMN count is 250 cells/mm³ (0.25 × 10⁹/L) or greater, and (3) an intra-abdominal surgically treatable primary source of infection (e.g., perforated intestine, perinephric abscess) has been identified.²⁸ The importance of distinguishing this variant from spontaneous bacterial peritonitis is that secondary peritonitis usually requires emergency surgical intervention (see also Chapter 37).

Polymicrobial bacterascites is diagnosed when (1) multiple organisms are seen on Gram stain or cultured from the ascitic fluid and (2) the PMN count is lower than 250 cells/mm³ (0.25 × 10⁹/L).⁶⁰ This diagnosis should be suspected when the paracentesis is traumatic or unusually difficult because of ileus or when stool or air is aspirated into the paracentesis syringe. Polymicrobial bacterascites is essentially diagnostic of intestinal perforation by the paracentesis needle.

Clinical Setting

The spontaneous variants of ascitic fluid infection—spontaneous bacterial peritonitis, CNNA, and MNB—occur almost exclusively in the setting of severe liver disease. The liver disease usually is chronic (cirrhosis), but may be acute (fulminant hepatic failure) or subacute (alcoholic hepatitis). Cirrhosis of all causes can be complicated by spontaneous ascitic fluid infection. Spontaneous infection of noncirrhotic ascites is rare enough to be the subject of case reports.

Essentially all patients with spontaneous bacterial peritonitis have an elevated serum bilirubin level and abnormal prothrombin time due to advanced cirrhosis.⁹ Ascites appears to be a prerequisite for the development of spontaneous bacterial peritonitis. The peritonitis is unlikely to precede the development of ascites. Usually, the infection develops when the volume of ascites is at its maximum.

Secondary bacterial peritonitis and polymicrobial bacterascites can develop with ascites of any type. The only prerequisite, in addition to the presence of ascites, is an intra-abdominal surgical source of infection.²⁸ Such an infection can result from penetration of a needle into the bowel during attempted paracentesis.⁶⁰

Pathogenesis

Since the 1990s, the elusive cause of spontaneous bacterial peritonitis has become clearer, and the pathogenesis of spontaneous forms of ascitic fluid infection has been partially elucidated (Fig. 91-4). The body of currently available evidence suggests that the spontaneous forms of ascitic fluid infection are the result of overgrowth of a specific organism in the intestine, “translocation” of that microbe from the intestine to mesenteric lymph nodes, and resulting spontaneous bacteremia and subsequent colonization of susceptible ascitic fluid^61–62 (see Fig. 91-4).

Figure 91-4. Proposed pathogenesis of spontaneous ascitic fluid infection. CNNA, culture-negative neutrocytic ascites; SBP, spontaneous bacterial peritonitis.

When bacteria enter the fluid in the abdomen, by whatever route, a battle ensues between the virulence factors of the organism and the immune defenses of the host.⁶³ The ascitic fluid protein concentration does not change with development of spontaneous infection.²⁵ Low-protein ascitic fluid (e.g., protein content less than 1 g/dL [10 g/L]) is particularly susceptible to spontaneous bacterial peritonitis.²⁶ The endogenous antimicrobial (opsonic) activity of human ascitic fluid correlates directly with the protein concentration of the fluid.⁶² Patients with deficient ascitic fluid opsonic activity are predisposed to spontaneous bacterial peritonitis.⁶⁴ Patients with detectable ascitic fluid opsonic activity appear to be protected from spontaneous bacterial peritonitis unless they are exposed to a particularly virulent organism (e.g., Salmonella).^63,64

Studies in both patients and animals with cirrhosis demonstrate that MNB is common.^58,65 Pieces of bacterial DNA are commonly present in serum and ascitic fluid of patients with cirrhosis.⁶⁶ In both humans and rats, most episodes of bacterascites resolve without antibiotic treatment.^58,65 The fluid frequently becomes sterile without an increase in ascitic PMNs. Apparently, the host’s defense mechanisms are able to eradicate the invading bacteria on most occasions. Uncontrolled infection probably develops only when the defenses are weak or the organism is virulent (see Fig. 91-4). Bacterascites probably is more common than spontaneous bacterial peritonitis. Conceivably, ascitic fluid in the setting of cirrhosis is colonized regularly by bacteria, and almost just as regularly, the colonization resolves. The entry of PMNs into the fluid probably signals failure of the peritoneal macrophages to control the infection.⁶⁷ A majority of episodes of MNB appear to resolve in cirrhotic rats and humans, whereas untreated spontaneous bacterial peritonitis is frequently fatal. In summary, MNB probably represents an early stage of ascitic fluid infection, which can resolve or progress to CNNA or to spontaneous bacterial peritonitis.

Most episodes of CNNA are diagnosed by insensitive culture methods for which numbers of bacteria are insufficient to reach the threshold of detectability.²³ Inoculation of ascitic fluid into blood culture bottles can lead to detection of a single organism in the cultured aliquot of fluid, whereas the older method of culture by inoculation of agar plates and broth probably requires at least 100 organisms/mL.²³ Even when optimal culture methods are used, however, a small percentage of specimens of neutrocytic ascitic fluid grow no bacteria. A study of rapid sequential paracenteses (before the initiation of antibiotic treatment) in patients with CNNA demonstrated that, in most cases, the PMN count dropped spontaneously and the culture results remained negative in the second specimen.⁶⁸ When sensitive culture techniques are used, CNNA probably results from (1) previous antibiotic treatment (even one dose), (2) an inadequate volume of fluid inoculated, or (3) spontaneously resolving spontaneous bacterial peritonitis in which the paracentesis is performed after all bacteria have been killed by host defenses but before the PMN count has normalized.

The pathogenesis of secondary bacterial peritonitis is more straightforward than that of spontaneous bacterial peritonitis. When the intestine perforates, billions of bacteria flood into the ascitic fluid. In the absence of a frank perforation, bacteria may cross inflamed tissue planes and enter the fluid. The pathogenesis of polymicrobial bacterascites is also obvious.⁶⁰ A paracentesis needle enters the bowel, and the bowel contents are released into the ascites.

Symptoms and Signs

Although 87% of patients with spontaneous bacterial peritonitis are symptomatic at the time the infection is diagnosed, the symptoms and signs of infection are often subtle, such as a slight change in mental status.⁵⁸ Without prompt paracentesis, the diagnosis and treatment of infected ascites may be delayed, often resulting in the death of the patient. The symptoms and signs manifested in all five variants of ascitic fluid infection are listed in Table 91-6.

Frequency

Since the 1980s, routine paracenteses at the time of hospitalization in patients with ascites have provided data regarding the frequency of ascitic fluid infection. In the 1980s, approximately 10% of patients with ascites were infected at the time of hospital admission; of the subgroup of patients with cirrhosis, about 27% were infected.⁹ At present, because of measures to prevent spontaneous bacterial peritonitis, the frequency has dropped significantly (see later). Of patients with culture-positive ascitic fluid, about two thirds have neutrocytic ascitic fluid (spontaneous bacterial peritonitis), and one third have MNB.⁵⁸ The frequency of CNNA depends largely on the culture technique (see earlier). Polymicrobial bacterascites occurs in only 1 in 1000 paracenteses. Secondary bacterial peritonitis is found in only 0% to 2% of patients with ascites at the time of hospital admission.^9,28

Bacteriology

Escherichia coli, streptococci (mostly pneumococci), and Klebsiella cause most episodes of spontaneous bacterial peritonitis and MNB in patients who are not receiving selective intestinal decontamination (Table 91-7; see later); CNNA is, by definition, culture-negative and polymicrobial bacterascites is, by definition, polymicrobial. The most apparent difference between the spontaneous forms of ascitic fluid infection and the secondary forms (secondary peritonitis and polymicrobial bacterascites) is that the former always are monomicrobial and the latter usually are polymicrobial. Although older papers reported that anaerobic bacteria were present in approximately 6% of cases of spontaneous bacterial peritonitis, the detection of anaerobes probably reflected unrecognized cases of secondary bacterial peritonitis. In more recent series, anaerobes have been found in approximately 1% of cases of spontaneous bacterial peritonitis and MNB.^23,58

Selective intestinal decontamination causes a change in the bacteria isolated from patients in whom an ascitic infection develops. Gram-positive organisms are frequently cultured from the ascitic fluid of these patients (see Table 91-7).⁶⁹

Risk Factors

Patients with cirrhosis are unusually predisposed to bacterial infection because of multiple defects in immune defense. The concept that cirrhosis is a form of acquired immunodeficiency (in the generic sense) is rather new. In a prospective study, a bacterial infection occurred in 34% of 405 patients with cirrhosis at the time of admission to the hospital or during the hospitalization.⁷⁰ Low ascitic fluid total protein concentrations, as well as the phagocytic (both motile and stationary) dysfunction associated with cirrhosis, are risk factors for bacterial infection.

Paracentesis itself has been proposed as a risk factor for ascitic fluid infection. This theoretical risk has not been substantiated in prospective studies of paracentesis-related complications.¹⁰ Spontaneous bacterial peritonitis is statistically more likely to be diagnosed on the first paracentesis than on subsequent taps.¹⁰ Needle-induced ascitic fluid infections do not occur unless the bowel is penetrated by the paracentesis needle^10,60; fortunately, this occurs in only 1 in 1000 taps. One would expect bacteria of the skin flora such as Staphylococcus aureus to be isolated more frequently if poor paracentesis technique were the cause of many cases of spontaneous bacterial peritonitis; yet skin flora microorganisms are seldom isolated from ascitic fluid when sterile technique is used.²³ Iatrogenic peritonitis is most likely to occur when the paracentesis needle enters the bowel during a difficult paracentesis.

Gastrointestinal hemorrhage is an under-recognized risk factor for the development of spontaneous bacteremia and spontaneous bacterial peritonitis. The cumulative probability of infection during a single hospitalization for bleeding is approximately 40%.⁷¹ The risk appears to peak 48 hours after the onset of hemorrhage. The high risk of infection probably is mediated by a shock-induced increase in the translocation of bacteria from the intestine to extraintestinal sites. Urinary tract infections also constitute an under-recognized risk factor for spontaneous bacterial peritonitis.⁷²

Diagnosis

Timely diagnosis of ascitic fluid infection requires a high index of suspicion and a low threshold for performing a paracentesis. Clinical deterioration, especially fever or abdominal pain, in a patient with ascites should raise the suspicion of infection and prompt a paracentesis. If the ascitic fluid PMN count is elevated, the working diagnosis is ascitic fluid infection until proved otherwise. Although peritoneal carcinomatosis, pancreatitis, hemorrhage into ascites, and tuberculosis can lead to an elevated ascitic fluid PMN count, most cases of neutrocytic ascites are caused by bacterial infection. A predominance of PMNs in the WBC differential count lends further support for the diagnosis of infection. In patients with peritoneal carcinomatosis, pancreatitis, and tuberculosis, a predominance of PMNs in the ascites would be an uncommon finding. An elevated absolute ascitic fluid PMN count with a predominance of neutrophils in a clinical setting compatible with infection should prompt empirical antibiotic therapy (Table 91-8; see later).

Table 91-8 Indications for Empirical Antibiotic Therapy of Suspected Spontaneous Ascitic Fluid Infection

Although spontaneous bacterial peritonitis is approximately six times as common as surgical peritonitis in a patient with ascites, secondary peritonitis should be considered in any patient with neutrocytic ascites (see also Chapter 37). Clinical symptoms and signs do not distinguish patients with secondary peritonitis from those with spontaneous bacterial peritonitis (see Fig. 91-3).²⁸ Even with free perforation of the colon into ascitic fluid, a classic surgical abdomen does not develop. Peritoneal signs require contact of inflamed visceral and parietal peritoneal surfaces, and such contact does not occur when there is a large volume of fluid separating these surfaces. Intestinal perforation can be suspected and pursued if a specimen of ascites is neutrocytic and meets two of the following three criteria (see Fig. 91-3): (1) total protein greater than 1 g/dL (10 g/L), (2) glucose less than 50 mg/dL (2.8 mmol/L), and (3) LDH greater than the upper limit of normal for serum.²⁸ In the setting of a perforated viscus, cultures of ascitic fluid nearly always disclose multiple organisms, except in gallbladder rupture, which is usually monomicrobial.¹⁶ Brown ascitic fluid with a bilirubin concentration that is greater than 6 mg/dL (102 µmol/L) and greater than the serum level is indicative of biliary or proximal small intestinal perforation into ascites.¹⁶ An ascitic fluid amylase level that is greater than five-fold that of the serum level also may be indicative of intestinal rupture (but not gallbladder rupture) with the release of luminal amylase.^28,29

The initial ascitic fluid analysis is helpful in delineating which patients are likely to have a ruptured viscus (see Fig. 91-3). Within minutes of the detection of neutrocytic ascitic fluid, these patients should undergo imaging studies to confirm and localize the site of rupture. Plain and upright abdominal films and water-soluble contrast studies of the upper and lower intestines or abdominal computed tomography should be obtained. If perforation is documented, emergency surgical intervention is the next step. Timing is crucial; after septic shock occurs, death is nearly certain. Antibiotic therapy without surgical intervention in the treatment of a ruptured viscus is predictably unsuccessful.

In contrast to patients with peritonitis resulting from perforation of a viscus, patients with secondary peritonitis unrelated to perforation tend not to have a diagnostic initial ascitic fluid analysis.²⁸ The need to make the diagnosis of secondary peritonitis in patients without free perforation is less urgent, and there may be time to evaluate the response of the ascitic PMN count and fluid culture to treatment with antibiotics. It is best to repeat the paracentesis to assess the response to treatment after 48 hours of therapy; by 48 hours, the ascitic PMN count will be lower than the pretreatment value and the ascitic culture will be negative in essentially every patient with spontaneous bacterial peritonitis who has been treated with an appropriate antibiotic.²⁸ Before 48 hours of treatment, the ascitic PMN count may rise to a value higher than baseline in either spontaneous bacterial peritonitis or secondary peritonitis.²⁸ The culture remains positive in secondary peritonitis and becomes rapidly negative in spontaneous bacterial peritonitis (see Fig. 91-3).²⁸ Whereas antibiotics alone cannot control secondary peritonitis, medical therapy cures spontaneous bacterial peritonitis rapidly.²⁸

Treatment

Patients with an ascitic fluid PMN count of 250 cells/mm³ (0.25 × 10⁹/L) or greater and a clinical scenario compatible with ascitic fluid infection should receive empirical antibiotic treatment (Table 91-9; see also Table 91-8).^9,73 Patients with hemorrhage into the ascitic fluid, peritoneal carcinomatosis, pancreatic ascites, or tuberculous peritonitis may have an elevated ascitic PMN count that is unrelated to spontaneous bacterial peritonitis and usually do not require empirical antibiotic treatment. If they do receive antibiotics, the ascitic PMN count usually fluctuates randomly, in contrast to the dramatic reduction in PMN count typical of spontaneous bacterial peritonitis. If the clinical picture is unclear initially, the physician should err on the side of antibiotic treatment (with a non-nephrotoxic antibiotic). If ascitic fluid cultures are negative, the antibiotic can be stopped after 48 hours. In patients with uninfected neutrocytic ascitic fluid (except those with hemorrhage), lymphocytes usually predominate in the ascitic fluid differential count, in contrast to those with spontaneous bacterial peritonitis, in whom PMNs predominate. In patients with bloody ascitic fluid, a “corrected” PMN count should be calculated (as discussed earlier). Antibiotic therapy is not necessary for patients with bloody fluid unless the corrected ascitic fluid PMN count is 250 cells/mm³ (0.25 × 10⁹/L) or greater.

Table 91-9 Treatment of Subtypes of Ascitic Fluid Infection

PMN, polymorphonuclear neutrophil.

* Dose of intravenous metronidazole is 15 mg/kg × 1, then 7.5 mg/kg every 6 hours.

The decision to begin empirical antibiotic treatment in patients with bacterascites must be individualized. Many episodes resolve without treatment⁵⁸; however, the hospital mortality rate of 32% in patients with MNB is attributable, at least, in part, to infection.⁵⁸ Therefore, treatment appears to be warranted in many patients. By definition, the ascitic PMN count is lower than 250 cells/mm³ (0.25 × 10⁹/L) in this variant of ascitic fluid infection, and the PMN count cannot be the only parameter on which to base the decision about empirical therapy. Most patients with MNB in whom the colonization does not resolve progress to spontaneous bacterial peritonitis and have symptoms or signs of infection at the time of the paracentesis that documents bacterascites.⁵⁸ Therefore, patients with cirrhosis and ascites who have convincing symptoms or signs of infection should receive treatment regardless of the ascitic fluid PMN count. Empirical treatment can be discontinued after only two to three days if the culture demonstrates no growth. Asymptomatic patients may not need treatment.⁵⁸ The paracentesis should be repeated for cell count and culture in patients without clinical evidence of infection, as soon as it is known that the initial culture result is positive. If the PMN count has risen to at least 250/mm³ (0.25 × 10⁹/L) or if symptoms or signs of infection have developed, treatment should be started. Culture results usually are negative in patients without a rise in the ascitic fluid PMN count on repeat paracentesis and without clinical evidence of infection, and these persons do not require treatment⁵⁸ because colonization has been eradicated by host immune defenses.

The physician will not know initially that the ascitic fluid culture is destined to be negative in a patient with CNNA; therefore, empirical antibiotic treatment should be started. When the preliminary culture demonstrates no growth, it is helpful to repeat the paracentesis after 48 hours of therapy to assess the response of the PMN count to antibiotics. A dramatic decline in PMN count (always below the baseline pretreatment value and frequently a reduction of more than 80%) confirms a response to treatment.²⁸ In such cases, a few more days of therapy is probably warranted. A stable ascitic fluid PMN count, especially with a predominance of lymphocytes and monocytes, suggests a nonbacterial (or mycobacterial) cause of ascitic fluid neutrocytosis, and the fluid should be sent for cytologic examination and mycobacterial culture. Because a negative culture result may be due to insensitive culture techniques, the prevalence of CNNA in a hospital that still uses conventional methods of culture can be reduced by convincing the microbiology laboratory to accept and process ascitic fluid submitted in blood culture bottles.²³

Gram stain of the ascitic fluid is most helpful in detecting secondary peritonitis, in which multiple different bacterial forms are seen, but is of little value in guiding the choice of empirical antibiotic treatment for spontaneous ascitic infections. I have found that use of the Gram stain did not help narrow the antibiotic coverage in even 1 patient of approximately 500 with spontaneous bacterial peritonitis. Only approximately 10% of Gram stains demonstrate organisms in spontaneous bacterial peritonitis.²³ If a Gram stain indicates secondary peritonitis, coverage of anaerobic flora, in addition to coverage of aerobic and facultative anaerobic flora, is required, as is an emergency search for the source of the infection (see Fig. 91-3; Table 91-9).²⁸ Therefore, a positive Gram stain may lead to broader antibiotic coverage, rather than narrower coverage. Choosing narrow coverage (e.g., penicillin alone) based on a misinterpretation of the significance of the results of the Gram stain may lead to the patient’s death from uncontrolled infection before it becomes apparent that the isolated organism is resistant to the chosen antibiotic.

Until the results of susceptibility testing are available, relatively broad-spectrum antibiotic therapy is warranted in patients with suspected ascitic fluid infection. After sensitivities are known, the spectrum of coverage can usually be narrowed. The antibiotics that have been recommended for empirical treatment have changed over the years. In the late 1970s, the combination of ampicillin and gentamicin was promoted, but this recommendation was not based on susceptibility testing or efficacy data. Subsequently, gentamicin was shown to have an unpredictable volume of distribution in patients with ascites, and the serum creatinine level (and even the creatinine clearance) was found to be a poor index of the glomerular filtration rate in patients with ascites.⁷⁴ Therefore, determining the appropriate loading and maintenance doses of gentamicin for this patient population is difficult, and no evidence-based guidelines are available for the prescribing physician to follow. In my experience, even if high serum levels are avoided, nephrotoxicity still develops in most cirrhotic patients with ascites who receive an aminoglycoside. One study has documented an adjusted odds ratio of 4.0 for aminoglycosides as a risk factor for renal dysfunction in patients with cirrhosis.⁷⁵ Evidence that newer aminoglycosides are less nephrotoxic than gentamicin is lacking.

Several antibiotics are now available for the treatment of ascitic fluid infection. Cefotaxime, a third-generation cephalosporin, has been shown in a controlled trial to be superior to ampicillin plus tobramycin for the treatment of spontaneous bacterial peritonitis.⁷⁶ Fully 98% of causative organisms were susceptible to cefotaxime, which did not result in superinfection or nephrotoxicity.⁷⁶ Cefotaxime or a similar third-generation cephalosporin appears to be the treatment of choice for suspected spontaneous bacterial peritonitis.⁹ Anaerobic coverage is not needed, nor is coverage for Pseudomonas or Staphylococcus.²³ Cefotaxime, 2 g intravenously every eight hours, has been shown to result in excellent ascitic fluid levels (20-fold killing power after one dose).⁷⁷ In patients with a serum creatinine level greater than 3 mg/dL, the dosing interval may be extended to 12 hours.⁷⁷ Neither a loading dose nor an intraperitoneal dose appears to be necessary or appropriate. The clinician should, however, write “first dose STAT” when ordering treatment, to avoid a delay in administration of the life-saving agent.

Prognosis

In the past, 48% to 95% of patients with a spontaneous ascitic fluid infection died during the hospitalization in which the diagnosis was made, despite antibiotic treatment.^9,20 The most recent series report the lowest mortality rates (less than 5% if antibiotics are administered in a timely fashion), probably because of earlier detection and treatment of infection, as well as the avoidance of nephrotoxic antibiotics.⁸⁷ The trial in which cefotaxime plus albumin was studied reported the lowest hospitalization mortality rate yet—10%.⁸¹ Even now, however, some patients are cured of their infection but die of liver failure or gastrointestinal bleeding because of the severity of the underlying liver disease. In fact, spontaneous ascitic fluid infection is a good marker of end-stage liver disease and has been proposed as an indication for liver transplantation in a patient who is otherwise a candidate.

To maximize survival, it is important that paracentesis is performed in all patients with ascites at the time of hospitalization, so that infection can be detected and treated promptly. The ascitic fluid cell count should be reviewed as soon as the results are available (approximately 60 minutes), and appropriate treatment should be instituted if indicated. The first dose of antibiotic should be given immediately. Because the “dipstick” test results are available in 90 to 120 seconds, this new tool may speed treatment of spontaneous bacterial peritonitis and improve survival.¹⁸

Paracentesis should be repeated during the hospitalization if any manifestation of clinical deterioration develops, including abdominal pain, fever, change in mental status, renal failure, acidosis, peripheral leukocytosis, or gastrointestinal bleeding. If the physician waits to perform a paracentesis until convincing symptoms and signs of infection have developed, the infection is likely to be advanced by the time the diagnosis is made. No survivors of spontaneous bacterial peritonitis have been reported when the diagnosis was made after the serum creatinine level had risen above 4 mg/dL (350 µmol/L) or after shock had developed.

Without surgical intervention, the mortality rate for secondary peritonitis in hospitalized patients with ascites approaches 100%. When secondary peritonitis is diagnosed early and treated with emergency laparotomy, the mortality rate is approximately 50%.²⁸

Prevention

The identification of risk factors for spontaneous bacterial peritonitis (including an ascitic fluid protein concentration less than 1.0 g/dL, variceal hemorrhage, and previous episode of spontaneous bacterial peritonitis) has led to controlled trials of prophylactic antibiotics.^26,88–90 Norfloxacin, 400 mg per day orally, has been reported to reduce the risk of spontaneous bacterial peritonitis in inpatients with low-protein ascites and those with previous spontaneous bacterial peritonitis.^88,89 Norfloxacin, 400 mg orally twice daily for seven days, helps prevent infection in patients with variceal hemorrhage⁹⁰ and is cost-effective in preventing recurrent spontaneous bacterial peritonitis.⁹¹ More recently, intravenous ceftriaxone 1 g daily for seven days was found to be even more effective than norfloxacin in the setting of gastrointestinal bleeding; this regimen allows administration of antibiotics to patients who are vomiting blood.⁹² Oral antibiotics select for resistant organisms in the intestinal flora in patients, and in animals these organisms can then cause spontaneous ascitic fluid infection.^86,93 Despite this concern, two randomized trials of primary prevention of ascitic fluid infection with prophylactic norfloxacin or ciprofloxacin have demonstrated a survival advantage for the antibiotic-treated patients (Table 91-10).^94–96

Table 91-10 Prevention of Spontaneous Bacterial Peritonitis (SBP)

Hospitalization

Outpatient treatment of patients with small-volume ascites can be attempted initially. However, patients with large-volume ascites and those who are resistant to outpatient treatment usually require hospitalization for definitive diagnosis and management.⁹ Many of these patients also have gastrointestinal hemorrhage, encephalopathy, infection, or hepatocellular carcinoma. An intensive period of inpatient education and treatment may be required to convince the patient that the prescribed diet and diuretics are actually effective and worth the effort to prevent future hospitalizations.

Precipitating Cause

Determining the immediate precipitant of ascites (e.g., dietary indiscretion or nonadherence to therapy with diuretics) may be of value. Ascites may be precipitated by saline infusions given perioperatively or to treat variceal hemorrhage or by sodium bicarbonate tablets; in such cases the ascites may resolve without the need for long-term treatment.

Diet Education

Fluid loss and weight change are related directly to sodium balance in patients with portal hypertension–related ascites. In the presence of avid renal retention of sodium, dietary sodium restriction is essential. The patient and the food preparer should be educated by a dietitian about a sodium-restricted diet. Severely sodium-restricted diets (e.g., 500 mg, or 22 mmol, of sodium per day) are feasible (but not palatable) in an inpatient setting but unrealistic for outpatients. The dietary sodium restriction that I recommend for both inpatients and outpatients is 2000 mg (88 mmol) per day. Protein is not restricted unless the patient has hepatic encephalopathy refractory to two drugs on a vegetable protein diet.

Fluid Restriction

Indiscriminate restriction of fluid in the treatment of cirrhotic ascites is inappropriate and serves only to alienate patients, nurses, and dietitians; moreover, hypernatremia may result. Sodium restriction, not fluid restriction, results in weight loss; fluid follows sodium passively. The chronic hyponatremia usually seen in patients with cirrhotic ascites is seldom morbid. Attempts to correct hyponatremia rapidly in this setting can lead to more complications than those related to the hyponatremia. Severe hyponatremia (e.g., serum sodium concentration less than 120 mmol/L) does warrant fluid restriction in the patient with cirrhosis and ascites but fortunately occurs in only 1.2% of patients.¹¹² Unless the decline in sodium concentration is rapid, symptoms of hyponatremia usually do not develop in cirrhotic patients until the serum sodium concentration is below 110 mmol/L.

Role of Bed Rest

Although bed rest has traditionally been prescribed, no controlled trials support this practice; bed rest was part of the treatment of heart failure in the past and was extrapolated to the treatment of cirrhosis with ascites without data.¹¹³ An upright posture may aggravate the plasma renin elevation found in most cirrhotic patients with ascites and, theoretically, increase renal sodium retention. In all likelihood, however, strict bed rest is unnecessary and may lead to decubitus ulcer formation in emaciated patients.

Urine Sodium Excretion

The 24-hour urinary sodium excretion is a helpful parameter to follow in patients with portal hypertension–related ascites. The completeness of the urine collection can be assessed by measuring the urinary creatinine excretion: Men with cirrhosis should excrete 15 to 20 mg/kg per day of creatinine, and women should excrete 10 to 15 mg/kg per day⁹; excretion of less creatinine indicates an incomplete collection. Only the 10% to 15% of patients who have significant spontaneous natriuresis can be considered for dietary sodium restriction as sole therapy of ascites (i.e., without diuretics).⁹ When given a choice, however, most patients would prefer to take some diuretics with more liberal intake of sodium than to take no pills with severe restriction of sodium intake. Contrary to popular belief, most patients, including outpatients, can comply with instructions to collect complete 24-hour urine specimens.

Because urine is the most important route of excretion of sodium in the absence of diarrhea or hyperthermia, and because dietary intake is the only source of nonparenteral sodium, dietary intake and urinary excretion of sodium should be roughly equivalent, if the patient’s weight is stable. Nonurinary sodium losses are less than 10 mmol per day in these patients.¹¹⁴ A suboptimal decline in body weight may be the result of inadequate natriuresis, failure to restrict sodium intake, or both. Monitoring 24-hour urinary sodium excretion and daily weight will clarify the issue. Patients who are adherent to an 88 mmol per day sodium diet and who excrete more than 78 mmol per day of sodium in the urine should lose weight. If the weight is increasing despite urinary losses in excess of 78 mmol per day, one can assume that the patient is consuming more sodium than is prescribed in the diet.

Urine Sodium-to-Potassium Ratio

Although 24-hour urine specimens constitute the diagnostic standard, one study has demonstrated that when a random urine specimen has a sodium concentration greater than the potassium concentration, a 24-hour specimen will reveal sodium excretion greater than 78 mmol per day in approximately 90% of cases.¹¹⁵ Therefore, a random urine sodium-to-potassium concentration ratio greater than 1 predicts that the patient should lose weight if a sodium-restricted diet is followed. Patients who do not lose weight despite a random urine sodium-to-potassium ratio greater than 1 probably are not adherent to the diet.

Avoidance of Urinary Bladder Catheters

Many physicians promptly insert a bladder catheter in hospitalized patients with cirrhosis to monitor urine output accurately. Unfortunately, many of these immunocompromised patients have urinary tract infections on hospital admission,⁷² and urethral trauma from insertion of the catheter in the setting of cystitis can lead to bacteremia. Prolonged catheterization predictably leads to cystitis and possibly sepsis in these patients. I insert urinary catheters only briefly and only in the intensive care unit setting; these portals of entry for bacteria should be removed as soon as possible. Twenty-four-hour urine specimens can be collected completely without catheters.

Diuretics

Spironolactone is the mainstay of treatment for patients with cirrhosis and ascites but increases natriuresis slowly. Single-agent diuretic therapy with spironolactone requires several days to induce weight loss. Although spironolactone alone has been shown to be superior to furosemide alone in the treatment of cirrhotic ascites,¹¹⁶ I prefer to start spironolactone and furosemide together on the first hospital day in initial doses of 100 mg and 40 mg, respectively, each taken once in the morning.⁹ Amiloride, 10 mg per day, can be substituted for spironolactone; amiloride is less widely available and more expensive than spironolactone but more rapidly effective, and it does not cause gynecomastia. A new potassium-sparing diuretic, eplerenon, has been used in the treatment of heart failure and does not cause gynecomastia, but studies of its use in cirrhosis are lacking. The half-life of spironolactone is approximately 24 hours in normal control subjects but is markedly prolonged in patients with cirrhosis; almost one month is required to reach a steady state.¹¹⁷ In view of its long half-life, dosing the drug multiple times per day is unnecessary. A loading dose may be appropriate but has not been studied. Single daily doses maximize adherence; 25-, 50-, and 100-mg spironolactone tablets are available generically. Furosemide also should be given once a day.¹¹⁸

If the combination of spironolactone, 100 mg per day (or amiloride, 10 mg per day) and furosemide, 40 mg per day orally, is ineffective in increasing urinary sodium or decreasing body weight, the doses of both drugs should be increased simultaneously, as needed (e.g., spironolactone, 200 mg plus furosemide, 80 mg, then 300 mg plus 120 mg, and finally 400 mg plus 160 mg). In my experience, as well as in a randomized trial, starting both drugs at once speeds the onset of diuresis, whereas slowly increasing the daily dose of spironolactone to 400 mg or even higher before adding furosemide delays diuresis and results in hyperkalemia.¹¹⁹

The 100 : 40 ratio of the daily doses of spironolactone and furosemide usually maintains normokalemia. The ratio of doses can be adjusted to correct abnormal serum potassium levels. Occasionally, an alcoholic patient who has had no recent food intake will have hypokalemia at the time of admission and for a variable interval thereafter. Such a patient should receive spironolactone alone until the serum potassium normalizes; furosemide can then be added. When combined with a sodium-restricted diet in a study of almost 4000 patients, the regimen of spironolactone and furosemide has been demonstrated to achieve successful diuresis in more than 90% of cirrhotic patients.¹²⁰

Intravenous diuretics cause acute decreases in the glomerular filtration rate in patients with cirrhosis and ascites and generally should be avoided.¹²¹ Many patients are given intravenous furosemide when they are hospitalized because of failure of outpatient treatment of ascites in the setting of cirrhosis. The approach of switching from oral to intravenous administration is effective for heart failure, but in patients with cirrhosis, repeated doses of intravenous furosemide regularly lead to azotemia and then to an erroneous diagnosis of hepatorenal syndrome. (The correct diagnosis is diuretic-induced azotemia that resolves when the diuretics are withheld and fluid is administered intravenously.) Some physicians give intravenous albumin with intravenous furosemide, but a randomized crossover study has shown no benefit to albumin in this setting.¹²² Repeated intravenous dosing of furosemide appears to be too “harsh” for the patient with cirrhosis; oral diuretics are better tolerated.

If rapid weight loss is desired, therapeutic paracentesis should be performed (see later). No limit has been identified for acceptable daily weight loss in patients who have massive edema. As soon as the edema has resolved, a reasonable maximum weight loss is probably 0.5 kg per day.¹²³ Encephalopathy, a serum sodium concentration less than 120 mmol/L despite fluid restriction, and a serum creatinine level greater than 2.0 mg/dL (180 mmol/L) are indications to discontinue diuretics and reassess the patient. Abnormalities in potassium levels almost never prohibit diuretic use because the ratio of the two diuretics can be readjusted. Patients with parenchymal renal disease (e.g., diabetic nephropathy) usually require relatively higher doses of furosemide and lower doses of spironolactone; otherwise, they develop hyperkalemia. Patients in whom complications develop despite a careful attempt at diuretic treatment usually require second-line therapy. Prostaglandin inhibitors (e.g., nonsteroidal anti-inflammatory drugs) should be avoided in patients with cirrhosis and ascites because they inhibit diuresis, may promote renal failure, and may cause gastrointestinal bleeding.¹²⁴

Reducing the quantity of fluid in the abdomen can improve the patient’s comfort and prevent hepatic hydrothorax and hernias. Also, by concentrating the ascitic fluid, diuresis increases the opsonic activity of ascitic fluid 10-fold and theoretically may be of value in preventing spontaneous ascitic fluid infection.¹²⁵

An issue that nurses regularly raise is whether diuretics should be withheld when a patient’s blood pressure is low. No data exist to support this practice in the setting of cirrhosis. Baseline blood pressure, mental status, and creatinine must be factored into the decision to continue, hold, or discontinue diuretics. The baseline blood pressure is usually low (e.g., 70 to 100 systolic, in a patient with cirrhotic ascites). Unless it has dropped significantly or the patient has confusion or azotemia, diuretics should be given.

In the past, patients with ascites frequently occupied hospital beds for prolonged durations because of uncertainty regarding the diagnosis and optimal treatment and because of iatrogenic complications. Although a “dry” abdomen is a reasonable ultimate goal, complete resolution of ascites should not be a prerequisite for discharge from the hospital. Patients who are stable, with ascites as their major problem, can be discharged after they are demonstrated to be responding to the medical regimen and are normokalemic, are not azotemic, and have a normal or slightly to moderately reduced serum sodium level. Following discharge from the hospital, a patient should be seen in the outpatient setting within 7 to 14 days.

Role of Sodium Bicarbonate

Mild renal tubular acidosis develops in a substantial minority of patients with cirrhosis and ascites. Although oral sodium bicarbonate administration has been recommended in this setting, such treatment increases sodium intake dramatically and cannot be advocated in the absence of evidence to support its use.

Aquaretics

The aquaretics are a new class of drugs that have been used in animals and preliminarily in patients with cirrhosis to increase urinary water excretion and to increase the serum sodium concentration. Patients with mild hyponatremia (serum sodium less than 130 mmol/L) can respond with an increase in the serum sodium level, although dose reductions were common in a randomized trial.¹²⁶ Whether these drugs will improve severe hyponatremia without causing hypotension awaits further investigation.

Outpatient Management

After discharge from the hospital, the patient’s body weight, orthostatic symptoms, and serum electrolyte, urea, and creatinine levels should be monitored. Twenty-four-hour or random urine specimens for a sodium-to-potassium ratio can be collected to assist with treatment decisions. It is my experience that adherent outpatients can collect complete specimens successfully, when adequate written and oral instructions are provided. The subsequent frequency of follow-up evaluations is determined by the response to treatment and stability of the patient. I usually evaluate these patients every one to four weeks until they clearly are responding to treatment and are not experiencing problems. Intensive outpatient follow-up helps prevent subsequent hospitalizations.

Diuretic doses and dietary sodium intake are adjusted to achieve weight loss and negative sodium balance. Patients who are gaining fluid weight despite diuretic therapy should not be considered to have diuretic-resistant ascites until they are demonstrated to be adherent to the prescribed diet. Monitoring the urine sodium concentration provides insight into adherence. Patients who excrete more than 78 mmol per day of sodium in the urine or have a random urine sodium-to-potassium ratio greater than 1 should be losing weight if they are consuming less than 88 mmol of sodium per day. In my experience, most patients who initially are thought to be diuretic-resistant eventually are found to be nonadherent to the diet; they demonstrate weight gain and urinary sodium excretion as high as 500 mmol per day or more. Diet education is crucial to the successful management of such patients. Patients with truly diuretic-resistant ascites excrete nearly sodium-free urine despite maximal doses of diuretics. During long-term follow-up, abstinent alcoholic patients may become more sensitive to diuretics. In these cases, the dose of diuretics may be tapered and the drugs even discontinued.

Liver Transplantation

Liver transplantation should be considered among the treatment options for patients with cirrhosis and ascites—whether the fluid is diuretic-sensitive or diuretic-refractory (see also Chapter 95). In many areas of the United States, patients with ascites are not offered transplantation until hepatorenal syndrome has developed (see Chapter 92). The 12-month survival rate for patients with ascites refractory to medical therapy is only 32%.¹²⁸ The survival rate for liver transplantation is much higher.

In patients who are candidates for liver transplantation, procedures that could make transplantation difficult should be avoided. Surgery in the right upper quadrant causes adhesions that become vascularized and difficult to remove during transplant surgery. Even peritoneovenous shunting can lead to the formation of a “cocoon” in the right upper quadrant that can involve the bowel and liver.¹²⁹

Serial Paracenteses

Therapeutic abdominal paracentesis is one of the oldest medical procedures. In the 1980s, after 2000 years of use, scientific data regarding large-volume paracentesis were reported, and patients were documented to tolerate large-volume paracentesis well, just as patients had in the 1940s and earlier.¹³⁰ In one large randomized, controlled trial, therapeutic paracentesis plus intravenous infusion of colloid led to fewer minor (asymptomatic) changes in serum electrolyte and creatinine levels than those reported with diuretic therapy; however, no differences in morbidity or mortality rates could be demonstrated.¹³⁰ Therapeutic paracentesis now appears to be first-line therapy for patients in whom ascites is tense and second-line therapy for cirrhotic patients in whom ascites is refractory to diuretics (see Fig. 91-5).⁹ The world record for volume of fluid removed at one time appears to be 41 L.¹³¹

Colloid Replacement

A controversial issue regarding therapeutic paracentesis is the role of colloid replacement. In one study, patients with tense ascites were randomized to receive intravenous albumin (10 g/L of fluid removed) or no albumin after therapeutic paracentesis.¹³² More statistically significant (asymptomatic) changes in serum electrolyte, plasma renin, and serum creatinine levels developed in the patients who did not receive albumin than in those who received albumin, but no greater frequency of clinical morbidity or mortality was seen. Although another study has documented that the patients who have a postparacentesis rise in plasma renin levels have a decreased life expectancy compared with those who have stable renin levels, no study has demonstrated a decreased survival rate in patients not given a plasma expander compared with patients given albumin after paracentesis.¹³³ A new phrase, “paracentesis-induced circulatory dysfunction,” has been coined to describe the rise in plasma renin levels after paracentesis.¹³⁴ Despite the lack of benefit of albumin infusion on survival, the authors of the two studies cited previously recommend routine infusion of albumin after therapeutic paracentesis.^132,134 Albumin infusions markedly increase the degradation of albumin, however, and albumin is expensive.^135,136 In a study performed in the 1960s, 58% of infused albumin was offset by increased degradation, and a 15% increase in the serum albumin level led to a 39% increase in degradation.¹³⁵ Increasing the concentration of albumin in cell culture media has been shown to decrease albumin synthesis.¹³⁷ In view of the cost ($7 to $25/g or $350 to $1250/tap), it is difficult to justify the expense of routine infusions of albumin based on the available data.

The confusion regarding albumin infusion relates, in part, to the design of the relevant studies. In the studies from Barcelona, patients with “tense” ascites could be entered into the trial of albumin versus no albumin, and 31% of these patients were not even receiving diuretics.¹³¹ It seems more appropriate to study the population in which chronic paracenteses are really needed, specifically the diuretic-resistant group, rather than all patients with tense ascites.¹³⁸ Another group of investigators has shown that patients with cirrhosis and diuretic-resistant ascites tolerate a 5-L paracentesis without a change in plasma renin levels.¹³⁹ My approach to patients with tense ascites is to take off enough fluid (4 to 5 L) to relieve intra-abdominal pressure and then to rely on diuretics to eliminate the remainder. To remove all of the fluid by paracentesis when most of it can be removed with diuretics seems inappropriate, partly because paracentesis removes opsonins, whereas diuresis concentrates opsonins.¹²⁵ Patients with early cirrhosis and diuretic-sensitive ascites should be managed with diuretics, not large-volume paracentesis; these patients may be more sensitive to paracentesis-related volume depletion than are patients with advanced cirrhosis.¹⁴⁰ Chronic therapeutic paracenteses should be reserved for the 10% of patients in whom diuretic treatment fails to relieve the ascites.

Other studies have compared less expensive plasma expanders with albumin. No differences in electrolyte imbalance or clinically relevant complications between the groups have been found.¹⁴¹ In addition, some authors advocate giving one half of the plasma expander immediately after the paracentesis and the other half six hours later.^133,141 This approach converts an otherwise simple outpatient procedure into an all-day clinic visit or even a brief hospitalization and seems unwarranted. A colloid that specifically should be avoided is hetastarch, which can accumulate in Kupffer cells and cause portal hypertension in patients without preexisting liver disease.¹⁴²

Consensus statements, a randomized trial of albumin versus saline in 6997 critically ill patients, and systematic reviews have pointed out some of the hazards of albumin infusion and have recommended against its liberal use.^143–145 Until more convincing data involving appropriate groups of patients are available, it seems reasonable to (1) avoid serial large-volume paracenteses in patients with diuretic-sensitive ascites; (2) withhold albumin after taps of 5 L or less; and (3) consider albumin infusion optional after taps of larger volume in patients with diuretic-resistant ascites.⁹

A small, randomized trial has shown that terlipressin may be equivalent to albumin after therapeutic paracentesis in preventing paracentesis-induced circulatory dysfunction; if this drug receives approval for use in the United States and further studies support its efficacy, terlipressin would be an alternative to albumin.¹⁴⁶

Transjugular Intrahepatic Portosystemic Shunt

TIPS is a side-to-side portacaval shunt that is placed by an interventional radiologist (or hepatologist), usually with the use of local anesthesia. TIPS placement was first used for the treatment of refractory variceal bleeding, but it also has been advocated for diuretic-resistant ascites¹⁴⁷ (see Chapter 90). TIPS was received with great enthusiasm in the 1990s, similar to the enthusiasm for the peritoneovenous shunt in the 1970s. Just as with peritoneovenous shunting, TIPS was overused until serious complications and suboptimal efficacy were reported. Four large-scale randomized trials in diuretic-resistant patients have demonstrated consistent superiority of TIPS over repeated paracentesis but no survival advantage.^148–151 Multiple meta-analyses have been published confirming efficacy but with more hepatic encephalopathy in the TIPS group.^152–156 One meta-analysis has demonstrated a trend toward improved survival in the TIPS group.¹⁵³ Another meta-analysis, which analyzed individual patient data, did show improved transplant-free survival with TIPS.¹⁵⁶ Although TIPS dysfunction was common when an uncoated (or uncovered) shunt was used, polytetrafluoroethylene-coated stents have been reported to improve patency and survival when compared with uncoated stents in a nonrandomized study and to improve patency, with no survival advantage, when compared with uncoated stents in a randomized trial.^157,158 Also, the four older TIPS trials preceded development and implementation of the Model for End-stage Liver Disease (MELD) score, which predicts 90-day mortality after TIPS placement (see Chapter 90); new trials using the coated stent and selecting patients according to their MELD scores may demonstrate a survival advantage for TIPS compared with repeated taps.

TIPS also is useful in the treatment of hepatic hydrothorax and umbilical hernia.^111,118 A direct intrahepatic portosystemic shunt connects the portal vein directly to the inferior vena cava and has applicability in patients with Budd-Chiari syndrome (see Chapter 83).¹⁵⁹

Peritoneovenous Shunt

In the mid-1970s, the peritoneovenous shunt was promoted as a new “physiologic” treatment for the management of ascites. Reports of shunt failure, fatal complications following shunt insertion, and randomized trials demonstrating no survival advantage have led to the relegation of this procedure to third-line therapy in patients with cirrhosis and ascites^9,120 (see Fig. 91-5). Patients who are not candidates for liver transplantation and who have a scarred abdomen that is not amenable to repeated paracenteses, who are not candidates for a TIPS, or in whom an attempt at TIPS placement has failed make up the small subset of candidates for a peritoneovenous shunt. A randomized trial has shown that even an uncoated TIPS stent has better “assisted patency” than the peritoneovenous shunt.¹⁶⁰

Novel Treatments

Novel treatment options for patients with refractory ascites include weekly infusions of intravenous albumin, ascites reinfusion, ultrafiltration, terlipressin infusion (not available in the United States), partial splenic artery embolization, peritoneal-urinary drainage of the fluid using a surgically implanted pump, and percutaneous placement of a peritoneovenous shunt by an interventional radiologist.^161–168 More data are needed before these treatments can be advocated.