Easl clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal
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2y : 0.07,
p = 0.4 D’Amico et al., 2005 [95] 5 330
Yes Lower in TIPS group. OR 0.14 (0.7– 0.27) Higher in TIPS group. OR 2.26 (1.35–3.76) No difference between groups A trend towards better survival in TIPS group OR 0.74 (0.40–1.37) Saab et al., 2006 [96] 5 330
? Lower after 3 months in TIPS group. OR 0.07 (0.03–0.18, p <0.01) 12 months OR 0.14 (0.06–0.28, p <0.01) Higher in TIPS group. OR 2.24 (1.39–3.6) p <0.01 30-days OR 1.0 (0.10–0.06, p = 1) 24 months OR 1.29 (0.65–2.56, p = 0.5) Salerno et al., 2007 [97] 4 305
No Lower in TIPS group. 42 versus 89% in LVP group (p <0.0001) Higher in TIPS group. (1.13 versus 0.63 (p = 0.006)). Transplant-free survival better in TIPS group (p = 0.035) DifE
4M and DifE
12M : Difference in effects at 4 and 12 months. DifE 1y and DifE
2y OR, odds ratio. RR, relative risk. JOURNAL OF HEPATOLOGY Journal of Hepatology 2010 vol. 53 j 397–417
403 blood cell count, tachycardia, and/or tachypnea; (3) worsening of liver function; (4) hepatic encephalopathy; (5) shock; (6) renal failure; and (7) gastrointestinal bleeding. However, it is impor- tant to point out that SBP may be asymptomatic, particularly in outpatients [109,110]. 3.1.2. Ascitic fluid cell analysis Peritoneal infection causes an inflammatory reaction resulting in an increased number of neutrophils in ascitic fluid. Despite the use of sensitive methods, ascites culture is negative in as many as 60% of patients with clinical manifestations suggestive of SBP and increased ascites neutrophil count [10,106–108]. Ascitic fluid neutrophil count is obtained as follows: ascitic fluid is centrifuged, then a smear is stained with Giemsa and total and differential cell counts are made with an optical microscope. This can be done in less than 4 h [10,107,108,112]. Historically, manual counts were recommended, as coulter counter determinations of neutrophil counts were inaccurate at the relatively low levels of neutrophils in ascitic fluid [10]. However, a recent study found excellent corre- lation between these two techniques, even at low counts, suggest- ing that automated counting may replace manual counts [113]. The greatest sensitivity for the diagnosis of SBP is reached with a cutoff neutrophil count of 250/mm 3 , although the greatest specificity is reached with a cutoff of 500 neutrophils/mm 3 [10,66,107]. Since there may be some delay in obtaining an ascitic fluid cell count, the use of reagent strips (RSs) has been proposed for a rapid diag- nosis of SBP (reviewed in [114]). These reagent strips, designed for use in urine, identify leukocytes by detecting their esterase activity via a colorimetric reaction [114]. However, a large, multi- center prospective study has shown that the Multistix 8 SG Ò RS
ical review of 19 studies comparing RSs (i.e., either Multistix 8 SG Ò , Nephur Ò , Combur Ò , UriScan Ò , or Aution Ò ) to cytobacteriological methods has shown that RSs have low sensitivity and a high risk of false negative results, in particular in patients with SBP and low neutrophil count [114]. Thus, the use of reagent strips cannot be recommended for the rapid diagnosis of SBP. 3.1.3. Ascitic fluid culture When culture is positive ($40% of cases), the most common pathogens include Gram-negative bacteria (GNB), usually Esche- richia coli and Gram-positive cocci (mainly streptococcus species and enterococci) [10,105–108]. A recent study has shown that 30% of isolated GNB are resistant to quinolones and 30% are resis- tant to trimethoprim–sulfamethoxazole [106]. Seventy percent of quinolone-resistant GNB are also resistant to trimethoprim–sul- famethoxazole [106]. The incidence of SBP due to quinolone- resistant GNB is higher in patients on norfloxacin therapy than in patients ‘naïve’ for this treatment [106]. The rate of cephalo- sporin-resistant GNB is low in patients with SBP regardless of norfloxacin prophylaxis [106]. Patients on norfloxacin prophy- laxis may develop SBP caused by Gram-positive cocci [10,106– 108]. Finally, the epidemiology of bacterial infections differs between community-acquired (in which GNB infections predom- inate) and nosocomial infections (in which Gram-positive infec- tions predominate) [106]. Patients with an ascitic fluid neutrophil count P250 cells/ mm 3 and negative culture have culture-negative SBP [10,115]. Their clinical presentation is similar to that of patients with cul- ture-positive SBP [10,116] and should be treated in a similar manner.
Some patients have ‘bacterascites’ in which cultures are posi- tive but there is normal ascitic neutrophil count (<250/mm 3 )
terial colonization of ascites from an extraperitoneal infection. These patients usually have general symptoms and signs of infec- tion. In other patients, ‘bacterascites’ is due to the spontaneous col- onization of ascites, and they can either be clinically asymptomatic or have abdominal pain or fever. While in some patients, particu- larly in those who are asymptomatic, bacterascites represents a transient and spontaneously reversible colonization of ascites, in other patients, mainly those who are symptomatic, bacterascites may represent the first step in the development of SBP [10]. 3.1.4. Spontaneous bacterial pleural empyema Infection of a pre-existing hydrothorax, known as spontaneous bacterial pleural empyema, is uncommon although the exact prevalence is unknown [112]. The diagnosis is based on pleural fluid analysis obtained by diagnostic thoracocentesis. In the larg- est observational study reported so far, the diagnosis of sponta- neous bacterial empyema was established when the pleural fluid analysis showed a positive culture and more than 250 neu- trophils/mm 3 or a negative culture and more than 500 neutro- phils/mm 3 , in the absence of lung infection [117]. Pleural fluid culture in blood culture bottles was positive in 75% of cases [117]. Spontaneous bacterial pleural empyema was associated with SBP in $50% of cases [117]. 3.1.5. Secondary bacterial peritonitis A small proportion of patients with cirrhosis may develop perito- nitis due to perforation or inflammation of an intra-abdominal organ, a condition known as secondary bacterial peritonitis. The differentiation of this condition from SBP is important. Secondary bacterial peritonitis should be suspected in patients who have localized abdominal symptoms or signs, presence of multiple organisms on ascitic culture, very high ascitic neutrophil count and/or high ascitic protein concentration, or in those patients with an inadequate response to therapy [112]. Patients with sus- pected secondary bacterial peritonitis should undergo appropri- ate radiological investigation such as CT scanning [112]. The use of other tests such as measurement of glucose or lactate dehydrogenase in ascitic fluid has been suggested to help with the diagnosis of secondary bacterial peritonitis [112]. However, there are very limited data on the specificity and sensitivity of these tests in this setting. Recommendations A diagnostic paracentesis should be carried out in all patients with cirrhosis and ascites at hospital admission to rule out SBP. A diagnostic paracentesis should also be performed in patients with gastrointestinal bleeding, shock, fever, or other signs of systemic inflammation, gastroin- testinal symptoms, as well as in patients with worsening liver and/or renal function, and hepatic encephalopathy (Level A1). The diagnosis of SBP is based on neutrophil count in ascitic fluid of >250/mm 3 as determined by microscopy (Level A1). At present there are insufficient data to recommend the use of automated cell counters or reagent strips for the rapid diagno- sis of SBP. Ascitic fluid culture is frequently negative even if per- formed in blood culture bottles and is not necessary for the Clinical Practice Guidelines 404 Journal of Hepatology 2010 vol. 53 j 397–417
diagnosis of SBP, but it is important to guide antibiotic ther- apy (Level A1). Blood cultures should be performed in all patients with suspected SBP before starting antibiotic treat- ment (Level A1). Some patients may have an ascitic neutrophil count less than 250/mm 3 but with a positive ascitic fluid culture. This condition is known as bacterascites. If the patient exhibits signs of systemic inflammation or infection, the patient should be treated with antibiotics (Level A1). Otherwise, the patient should undergo a second paracentesis when culture results come back positive. Patients in whom the repeat ascit- ic neutrophil count is >250/mm 3 should be treated for SBP, and the remaining patients (i.e., neutrophils <250/mm 3 ) should be followed up (Level B1). Spontaneous bacterial pleural empyema may complicate hepatic hydrothorax. Diagnostic thoracocentesis should be performed in patients with pleural effusion and suspected infection with inoculation of fluid into blood culture bottles (Level A1). The diagnosis is based on positive pleural fluid cul- ture and increased neutrophil count of >250/mm 3 or negative pleural fluid culture and >500 neutrophils/mm 3 in the absence of pneumonia (Level B1). Patients with suspected secondary bacterial peritonitis should undergo appropriate radiological investigation such as CT scanning (Level A1). The use of other tests such as mea- surement of glucose or lactate dehydrogenase in ascitic fluid cannot be recommended for the diagnosis of secondary bacte- rial peritonitis (Level B1). 3.2. Management of spontaneous bacterial peritonitis 3.2.1. Empirical antibiotic therapy Empirical antibiotic therapy must be initiated immediately after the diagnosis of SBP, without the results of ascitic fluid culture [10,107]. Potentially nephrotoxic antibiotics (i.e., aminoglyco- sides) should not be used as empirical therapy [10]. Cefotaxime, a third-generation cephalosporin, has been extensively investi- gated in patients with SBP because it covers most causative organisms and because of its high ascitic fluid concentrations during therapy [118–122]. Infection resolution is obtained in 77–98% of patients. A dose of 4 g/day is as effective as a dose of 8 g/day [119]. A 5-day therapy is as effective as a 10-day treat- ment [123] (Table 6). Alternatively, amoxicillin/clavulanic acid, first given intrave- nously then orally, has similar results with respect to SBP res- olution and mortality, compared with cefotaxime [122] and with a much lower cost. However, there is only one compara- tive study with a small sample size and results should be confirmed in larger trials. Ciprofloxacin, given either for 7 days intravenously or for 2 days intravenously followed by 5 days orally, results in a similar SBP resolution rate and hospital sur- vival compared with cefotaxime, but with a significantly higher cost [124]. However, switch therapy (i.e., use of intravenous antibiotic initially, followed by oral step-down administration) with ciprofloxacin is more cost-effective than intravenous cefotaxime [125]. Oral ofloxacin has given similar results as intravenous cefotaxime in uncomplicated SBP, without renal failure, hepatic encephalopathy, gastrointestinal bleeding, ileus, or shock [120]. Cefotaxime or amoxicillin/clavulanic acid are effective in patients who develop SBP while on norfloxacin prophylaxis [10]. If ascitic fluid neutrophil count fails to decrease to less than 25% of the pre-treatment value after 2 days of antibiotic treat- ment, there is a high likelihood of failure to respond to therapy [10,112]. This should raise the suspicion of an infection caused by bacteria resistant to antibiotic therapy, indicating the need for modification of antibiotic treatment according to in vitro sensi- tivity or on empiric basis or the presence of ‘secondary peritonitis’. Recommendations. Empirical antibiotics should be started immediately following the diagnosis of SBP (Level A1). Since the most common causative organisms of SBP are Gram-negative aerobic bacteria, such as E. coli, the first line antibiotic treatment are third-generation cephalosporins (Level A1). Alternative options include amoxycillin/clavulanic acid and quinolones such as ciprofloxacin or ofloxacin. How- ever, the use of quinolones should not be considered in patients who are taking these drugs for prophylaxis against SBP, in areas where there is a high prevalence of quinolone- resistant bacteria or in nosocomial SBP (Level B1). Table 6. Antibiotic therapy for spontaneous bacterial peritonitis in patients with cirrhosis. Reference Treatments Number of patients Infection resolution (%) In-hospital survival (%) Felisart, 1985 [118] Tobramycin (1.75 mg/kg/8h IV) plus ampicillin (2 g/4h IV) versus cefotaxime (2 g/4h IV) 36 56 61 37 85 * 73 Rimola, 1995 [119] Cefotaxime (2 g/6h IV) versus cefotaxime (2 g/12h IV) 71 77
72 79 79 Navasa, 1996 [120] Ofloxacin (400 mg/12h PO) versus cefotaxime (2 g/6h IV) 64 84 81 59 85 81 Sort, 1999 [121] Cefotaxime (2 g/6h IV) versus cefotaxime (2 g/6h IV) plus IV albumin 63 94
63 98 90 ** Ricart, 2000 [122] Amoxicillin/clavulanic acid (1/0.2 g/8h) IV followed by 0.5/0.125 g/8h PO versus cefotaxime (1 g/6h IV) 24 87 87 24 83 79 Terg, 2000 [124] Ciprofloxacin (200 mg/12h IV for 7 days) versus ciprofloxacin (200 mg/12h for 2 days, followed by 500 mg/12h PO for 5 days) 40 76 77 40 78 77 * p <0.02 versus tobramycin plus ampicillin. ** p = 0.01 versus cefotaxime alone. JOURNAL OF HEPATOLOGY Journal of Hepatology 2010 vol. 53 j 397–417
405 SBP resolves with antibiotic therapy in approximately 90% of patients. Resolution of SBP should be proven by demon- strating a decrease of ascitic neutrophil count to <250/mm 3 and sterile cultures of ascitic fluid, if positive at diagnosis (Level A1). A second paracentesis after 48 h of start of treat- ment may help guide the effect of antibiotic therapy. Failure of antibiotic therapy should be suspected if there is worsening of clinical signs and symptoms and/or no marked reduction or increase in ascitic fluid neutrophil count com- pared to levels at diagnosis. Failure of antibiotic therapy is usually due to resistant bacteria or secondary bacterial perito- nitis. Once secondary bacterial peritonitis has been excluded, antibiotics should be changed according to in vitro suscepti- bility of isolated organisms, or modified to alternative empiric broad spectrum agents (Level A1). Spontaneous bacterial empyema should be managed similarly as SBP 3.2.2. Intravenous albumin in patients with spontaneous bacterial peritonitis without septic shock SBP without septic shock may precipitate deterioration of circu- latory function with severe hepatic insufficiency, hepatic enceph- alopathy, and type 1 hepatorenal syndrome (HRS) [121,126,127] and has approximately a 20% hospital mortality rate despite infection resolution [121,126]. A randomized, controlled study in patients with SBP treated with cefotaxime showed that albumin (1.5 g/kg body weight at diagnosis, followed by 1 g/kg on day 3) significantly decreased the incidence of type 1 HRS (from 30% to 10%) and reduced mortality from 29% to 10% compared with cefotaxime alone. Treatment with albumin was particularly effective in patients with baseline serum bilirubin P68 l mol/L (4 mg/dl) or serum creatinine P88 l mol/L (1 mg/dl). It is unclear whether intrave- nous albumin is useful in patients with baseline bilirubin <68 l mol/L and creatinine <88 l mol/L, as the incidence of type 1 HRS was very low in the two treatment groups (7% without albumin and 0% with albumin) [121]. Non-randomized studies in patients with SBP also show that the incidence of renal failure and death are very low in patients with moderate liver failure and without renal dysfunction at diagnosis of SBP [128–130]. It is not known whether crystalloids or artificial col- loids could replace albumin in the prevention of HRS in patients with SBP. Albumin improves circulatory function in patients with SBP while equivalent doses of hydroxyethyl starch have no such beneficial effect [131]. Clearly, further studies are needed to assess the efficacy of albumin as well as other expanders in the management of SBP. Until further trials are completed, albumin infusion appears a valuable adjunction to the treatment of SBP.
Recommendations HRS occurs in approximately 30% of patients with SBP treated with antibiotics alone, and is associ- ated with a poor survival. The administration of albumin (1.5 g/ kg at diagnosis and 1g/kg on day 3) decreases the frequency of HRS and improves survival (Level A1). It is unclear whether albumin is useful in the subgroup of patients with baseline serum bilirubin <68 l mol/L and creatinine <88 l mol/L (Level B2). Until more information is available, we recommend that all patients who develop SBP should be treated with broad spectrum antibiotics and intravenous albumin (Level A2). 3.3. Prophylaxis of spontaneous bacterial peritonitis Since most episodes of SBP are thought to result from the trans- location of enteric GNB, the ideal prophylactic agent should be safe, affordable, and effective at decreasing the amounts of these organisms from the gut while preserving the protective anaerobic flora (selective intestinal decontamination) [108]. Given the high cost and inevitable risk of developing resistant organisms, the use of prophylactic antibiotics must be strictly restricted to patients at high risk of SBP. Three high-risk patient populations have been identified: (1) patients with acute gastrointestinal hemorrhage; (2) patients with low total protein content in ascitic fluid and no prior history of SBP (primary prophylaxis); and (3) patients with a previous history of SBP (secondary prophylaxis). 3.3.1. Patients with acute gastrointestinal hemorrhage Bacterial infection, including SBP, is a major problem in patients with cirrhosis and acute gastrointestinal hemorrhage, occurring in between 25% and 65% of patients with gastrointestinal bleed- ing [132–141]. The incidence of bacterial infection is particularly high in patients with advanced cirrhosis and/or severe hemor- rhage [138,139]. In addition, the presence of bacterial infection in patients with variceal hemorrhage is associated with an increased rate of failure to control bleeding [142,143], rebleeding [136,138], and hospital mortality [139,143–145]. Antibiotic pro- phylaxis has been shown to prevent infection in patients with gastrointestinal bleeding [10,107,108] and decrease the rate of rebleeding [144]. A meta-analysis [139] of five studies performed in patients with gastrointestinal bleeding [132,134,135,137,140] has shown that antibiotic prophylaxis significantly decreased both the incidence of severe infections (SBP and/or septicemia) and mortality. Selective intestinal decontamination with norfloxacin (400 mg/12 h orally for 7 days), a quinolone with relatively poor gastrointestinal absorption, and which has antibacterial activity against GNB but not against Gram-positive cocci or anaerobic bacteria, is the most commonly used approach for the prophy- laxis of bacterial infections in patients with gastrointestinal hem- orrhage [10,107,134]. In recent years, the epidemiology of bacterial infections in cirrhosis has changed, with an increasing incidence of SBP and other infections caused by quinolone-resis- tant bacteria (see above) [106,146,147]. In addition, a substantial number of infections in patients with gastrointestinal hemor- rhage are caused by Gram-positive bacteria likely related to inva- sive procedures used in these patients [106]. A recent study comparing oral norfloxacin to intravenous cef- triaxone for the prophylaxis of bacterial infection in patients with gastrointestinal bleeding and advanced cirrhosis (at least 2 of the following: ascites, severe malnutrition, encephalopathy, or biliru- bin >3 mg/dl) showed that ceftriaxone was more effective than norfloxacin in the prevention of infections [148]. Recommendations In patients with gastrointestinal bleed- ing and severe liver disease (see text) ceftriaxone is the prophy- lactic antibiotic of choice, whilst patients with less severe liver disease may be given oral norfloxacin or an alternative oral Yüklə 2,55 Mb. Dostları ilə paylaş:
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