ASCITES. Dr KS Cheung Queen Mary Hospital

Transcription

1 ASCITES Dr KS Cheung Queen Mary Hospital

2 Outline Pathophysiology Differential diagnosis of ascites Diagnostic paracentesis Ascitic fluid analysis Management of Ascites Management of spontaneous bacterial peritonitis Prevention of spontaneous bacterial peritonitis

3 Ascites in cirrhosis Cirrhosis accounts for 75-85% of ascites in Western Europe or the USA 60% of patents with compensated cirrhosis develop ascites within 10 years 15% patients with cirrhotic ascites succumb in 1 year; 44% in 5 years Runyon BA, et al. Ann Intern Med 1992;117: Planas R, et al.. Clin Gastroenterol Hepatol 2006;4:

4 Pathophysiology of ascites Portal hypertension Arterial splanchnic vasodilatation Activation of SNS & RAAS

5 Differential diagnosis of ascites (I) Liver - Cirrhosis - Alcoholic hepatitis - Acute liver failure - Vascular: BCS, SOS, PV thrombosis Heart (CHF, constrictive pericarditis) Kidney (nephrotic syndrome) TB peritonitis, malignancy-related ascites, pancreatic ascites (Chylous ascites, bloody ascites)

6 Differential diagnosis of ascites (II) New onset/worsening of ascites in cirrhosis Non-compliance Progression of underlying liver disease Superimposed acute liver injury (e.g. alcoholic hepatitis, viral hepatitis) HCC

7 Grading of ascites Grade 1: mild ascites (USG only) no Rx Grade 2: moderate ascites (mod abdominal distension) medical therapy Grade 3: gross ascites (marked abdominal distension) large volume paracentesis, then medical therapy Moore KP, et al. Hepatology 2003; 38: 258

8 Diagnostic Paracentesis Abdominal wall hematomas 1% Hemoperitoneum, bowel entry by needle (<0.1%)

9 Is coagulopathy a contraindication? In a study of 4729 paracenteses, 8 out of 9 bleeding complications occurred in patients with renal failure (Cr clearance <50 ml/min) (mean platelet count of 102 ± 37 and a mean INR of 2.0 ± 0.9) Pache I, et al. Aliment Pharmacol Ther 2005;21: In a study of 1100 large-volume paracenteses, no hemorrhagic complications despite platelet <19 (mean platelet count 50.4; 54% <50) & INR as high as 8.7 (mean INR 1.7; 75% >1.5, 26.5% >2) Grabau CM, et al. HEPATOLOGY 2004;40:

10 Is coagulopathy a contraindication? No data-supported cutoff of coagulation parameters beyond which paracentesis should be avoided Routine blood products (FFP or platelet) not data-supported

11 Ascitic fluid analysis Appearance Routine: TCC & D/C, Gm smear, C/ST albumin, total protein Optional: AFB & C/ST, cytology glucose, LDH, amylase Unusual: Tg, CEA, ALP, bilirubin Unhelpful: ph, lactate, cholesterol

12 Appearance Clear Turbid Milky Bloody Brown - Deep jaundice: ascitic bilirubin ~ 40% of serum bilirubin - Rupture GB or perforated DU: ascitic bilirubin > serum bilirubin

13 Fluid biochemistry (I) SAAG >= 11 g/l = portal HT (accuracy 97%) OR portal HT + a second cause Protein <15 g/l increased risk of SBP > 25 to 30 g/l = exduative Runyon BA, et al. Ann Intern Med 1992;117: Rimola A, et al. J Hepatol 2000;32: Triglycerides > 200 mg/dl, usu > 1000 mg/dl (chylous ascites)

14 Fluid biochemistry (II) Glucose: usu similar to serum level; consumed by WBC/bacteria/tumor LDH: larger molecule than glucose, enters ascitic fluid less readily; released in infection/tumor uncomplicated cirrhotic ascites (AF/S ratio 0.4), SBP (1), infection/tumor (>1) Amylase: pancreatic ascites (usu >1000 IU/L, AF/S 6) or gut perforation

15 Fluid biochemistry (III) CEA > 5 ng/ml, ALP >240 U/L: gut perforation (sensitivity 92%, specificity 88% for differentiating secondary peritonitis from SBP) Wu SS, et al. J Hepatol 2001;34: CA 125 should NOT be requested (ascites or pleural effusion of any cause will have raised CA serum 125; level falls when ascites controlled) Zuckerman E, et al. Am J Gastroenterol 1999;94:

16 Spontaneous bacterial infection ANC >= 250 cells/mm^3 (0.25 x 10^9/L) + positive C/ST Gm stain sensitivity: 10% (helpful in ruling in gut perforation enormous bacterial counts) Bacterial C/ST +ve in 40% to 50% Higher yield if blood C/ST bottle used (~ 80%) 10ml fluid

17 Tests for tuberculous peritonitis Cell count: WBC 150 to 4000 /mm^3, usu predominance of mononuclear cells, but can mimic C/ST ve variant of SBP Smear: sensitivity 0 to 6% C/ST: sensitivity 20 to 50% TB PCR Adenosine deaminase Peritoneoscopy with C/ST: sensitivity nearly 100%

18 Adenosine deaminase A meta-analysis of 12 prospective studies encompassing 264 patients: ADA levels had high sensitivity (100%) & specificity (97%) with cut-off values from 36 to 40 IU/L; optimal cut-off value was 39 IU/L Riqueleme A, et al. J Clin Gastroenterol 2006; 40: 705 Sensitivity falls to 30% if underlying cirrhosis (poor humoral and T cell mediated response) Hillebrand DJ, et al. Hepatology 1996; 24:1408

19 Cytology (I) Overall sensitivity for malignancy-related ascites: 58 to 75% Depends upon the cause of the malignancyrelated ascites & amount of fluid Peritoneal carcinomatosis: cytology positive in most cases (In one series, 97% had at least one +ve cytology after testing 3 samples; 83% has 1 st cytology +ve) Runyon BA, et al. Hepatology 1988; 8:1104

20 Cytology (II) Massive liver metastases, chylous ascites due to lymphoma, HCC, or malignant Budd-Chiari syndrome Almost always negative cytologies

21 Treament of cirrhotic ascites Treatment of underlying cause Avoid certain drugs Low salt diet +/- fluid restriction Diuretics Paracentesis TIPS Liver transplantation

22 Treatment of underlying cause Abstinence HBV cirrhosis

23 Low salt diet +/- fluid restriction 2 g/day (88 mmol/d) Usually fluid restriction not necessary (as fluid follows Na passively) No data-supported specific threshold for initiating fluid restriction but serum Na < mmol/l is a reasonable threhold (expert consensus)

24 Drugs contraindicated NSAID ARF, Na & water retention, diuretic resistance (preliminary data show that shortterm COX-2 inhibitors does not impair renal function & response to diuretics) ACEI arterial hypotension, renal failure; (avoid even if low dose) Aminoglycoside renal failure

25 Diuretics (I) Aldactone 100mg + Lasix 40mg Dual agents for rapid natriuresis & normok Single-agent Aldactone if minimal fluid overload or outpatient settings (slower diuresis and lesser need for dose adjustments) most patients require combination therapy eventually

26 Diuretics (II) Simultaneous increase in doses of both drugs q3-5d in a ratio of 100mg:40mg (Aldactone/Lasix) Max dose: Aldactone 400mg/d, Lasix 160mg/d Amiloride (max 40mg/d) if Aldactone-induced tender gynecomastia Triamterene, metolazone, hydrochlorothiazide have also been tried (hydrochlorothiazide can induce rapid hypona in combination with Aldactone/Lasix)

27 Diuretics (III) Single-agent Lasix less efficacious Effect of aldactone is slow Amiloride: expensive, less effective No good evidence as to what is the level of severity of renal impairment & hypona should not be started

28 Targets of treatment Massive edema: - no limit to daily weight loss (AASLD) - 1 kg/d to prevent renal failure/hypona (EASL) Edema resolve: 0.5 kg/d (AASLD, EASL) Dose of diuretics should be reduced and discontinued later whenever possible Cessation of diuretics - uncontrolled/recurrent HE - Na <120 mmol/l - Cr > 180 umol/l - incapacitating muscle cramps

29 Paracentesis for tense ascites An initial therapeutic paracentesis should be performed in patients with tense ascites, followed by low salt diet & diuretics 5-L paracentesis is safe without albumin infusion Peltekian KM, et al. Am J Gastroenterol 1997;92: Larger volume paracentesis require albumin infusion (volume of ascitic fluid removed /- 0.5 L) 8g albumin per litre of ascitic fluid removed Tito L, et al. Gastroenterology 1990;98:

30 Refractory ascites < 10% Fluid overload - despite max dose of diuretics of at least 1 wk (Aldactone 400mg/d & Lasix 160mg/d) & low-salt diet, and not taking NSAID (*NSAID can convert patients from diuretic-sensitive to refractory) - that recurs rapidly after paracentesis Intolerant of diuretics

31 Options for refractory ascites (Exclude non-compliance & NSAID usage) Serial paracenteses TIPS Liver transplantation

32 Serial paracenteses Ascitic fluid Na conc similar to plasma Na conc (130 mmol/l) 6-L paracentesis removes 780 mmol of Na (10 d of retained Na) 10-L paracentesis removes 1300 mmol of Na (17 d of retained Na) Patients with some urinary Na excretion should require paracenteses even less frequently Patients requiring paracenteses of 10L more frequently than q2wk = non-compliance with diet

33 TIPS VS LVP (large volume paracentesis)

34 TIPS VS LVP Better control of ascites (compared with LVP) Converts diuretic-resistant patients into diuretic-sensitive ones More severe HE? Survival benefit Contraindications: bilirubin 105 umol/l, INR >2, Child-Pugh score >11, current HE >= grade 2 or chronic HE, active infection, progressive renal failure, or severe cardiopulmonary disease

35 Liver transplantation 21% of patients with refractory ascites die within 6 months Heuman DM, et al. HEPATOLOGY 2004;40:

36 Spontaneous bacterial peritonitis Asymptomatic Abdominal pain/tenderness Fever, chill, hypothermia Hepatic encephalopathy Hypotension/Shock Blood tests: leukocytosis, worsening of LFT, renal failure, acidosis

37 Spontaneous bacterial peritonitis ANC >=250 cells/mm^3 + positive C/ST Antibiotics only after diagnostic paracentesis (a single dose of broad-spectrum drug cause no growth in 86%, only resistance flora) Akriviadis EA, et al. Gastroenterology 1990;98:

38 Culture-negative neutrocytic ascites PMN >250, C/ST ve Similar S/S, mortality as SBP similar treatment as SBP Majority will have rising PMN & bacterial counts if left untreated; 34.5% become C/ST +ve Runyon BA, et al. HEPATOLOGY 1984;4:

39 Monomicrobial nonneutrocytic bacterascites PMN < 250, C/ST +ve Secondary bacterial colonization of ascites from an extraperitoneal infection (usu have S/S) Spontaneous colonization of ascites (asymptomatic or S/S) Outcome: - spontaneous resolution of colonization (esp if asymptomatic) 62% - progression to SBP S/S Runyon BA, et al. HEPATOLOGY 1990;12:

40 Monomicrobial nonneutrocytic bacterascites Symptomatic start antibiotics Asymptomatic repeat paracentesis - ANC >250 (SBP) start antibiotics - ANC < 250 follow up (repeated C/ST ve = resolution) (repeated C/ST +ve??) EASL clinical practice. Journal of Hepatology 2010 vol. 53 ;

41 Secondary bacterial Peritonitis 2 subsets: - free perforation (e.g. DU) - loculated abscess in the absence of perforation (e.g. perinephric abscess)

42 Secondary bacterial Peritonitis When to suspect? - Localised abdominal S/S - Ascitic ANC count very high (e.g. many thousands) - Fluid biochemistry - Multiple organisms - Inadequate response to treatment

43 Free perforation PMN >=250 (usu many thousands), multiple organisms EITHER at least 2 of the following: - Protein >10 g/dl - LDH > ULN of serum - Glucose < 2.8 mmol/l (* Sensitivity 100%, specificity 45%) OR CEA >5 ng/ml or ALP >240U/L (* Sensitivity 92%, specificity 88% ) Akriviadis EA, et al. Gastroenterology 1990;98: Wu Ss, et al. J Hepatol 2001;34:

44 Nonperforation secondary bacterial peritonitis Protein, LDH, glucose criteria only 50% sensitive Follow-up PMH rises despite 48h after treatment

45 Management of SBP Antibiotics Albumin? Repeat paracentesis Prevention of SBP

46 Trials on antibiotics for SBP

47 Other antibiotics Oral ofloxacin 400mg BD dose adjustment in renal failure (average 8d) as effective as Claforan in SBP In patients without shock, grade 2 HE, Cr > 264 mmol/l, GIB/ileus Navasa M, et al. Gastroenterology 1996; 111:

48 Other antibiotics Ciprofloxacin (200mg q12h IV x 7d or IV x 2d followed by 500mg BD PO x 5d) Terg R, et al. J Hepatol 2000;33: Augmentin (IV then PO) Ricart E, et al. J Hepatol 2000;32:

49 Bacteria in SBP GNB (E. coli, Klebsiella), Gm+ve cocci (streptococcus species) Quinolone prophylaxis more Gm +ve & quinolone-resistant bacteria 70% of quinolone-resistant bacteria also resistant to septrin Cephalosporin-resistant GNB is low regardless of norfloxacin prophylaxis Community-acquired (Gm-ve) VS nosocomial (Gm+ve) Fernandez J, et al. Hepatology 2002;35:

50 Quinolones should not be used Already on quinolone prophylaxis High prevalence of quinolone resistant bacteria Nosocomial SBP

51 Albumin infusion SBP without septic shock deterioration of circulatory function, hepatic insufficiency, hepatic encephalopathy, type 1 HRS 20% hospital mortality rate despite infection resolution

52 Albumin Claforan + Albumin VS Claforan alone: - decrease in mortality from 29% to 10% - decrease in type 1 HRS from 30% to 10% Albumin 1.5g/kg on D1 & 1g/kg on D3 Particularly effective if Cr >88 mmol/l or bilirubin >68 umol/l Sort P, et al. N Engl J Med 1999;341:

53 Prevention of SBP Risk factors: History of SBP Ascitic fluid protein <10-15 g/l Variceal hemorrhage

54 History of SBP (I) Recurrence rate at 1 year: 70% Survival at 1 year: 30 to 50% Survival at 2 year: 25 to 30%

55 Trials on prophylaxis of SBP

56 History of SBP (II) Randomized, double-blind, placebocontrolled trial of norfloxacin (400mg/d) in 80 patients with history of SBP Reduction in SBP recurrence from 68% to 20% at 1 year Reduction of SBP due to GNB from 60% to 3% at 1 year Gines P, et al. Hepatology 1990;12:

57 History of SBP (III) Norfloxacin 400mg/d Septrin 960mg/d, 5x/wk (Ciprofloxacin 750mg/wk) Singh N, et al. Ann Intern Med 1995;122: Rolachon A, et al. HEPATOLOGY 1995;22:

58 Variceal hemorrhage (I) Bacterial infection including SBP occurs in 25% to 65% of patients with cirrhosis and GIB Incidence particularly high in those with advanced cirrhosis or severe hemorrhage Bacterial infection in patients with variceal hemorrhage increased rate of failure to control bleeding, rebleeding, hospital mortality Antibiotic prophylaxis prevents infection, decrease rate of rebleeding and mortality

59 Variceal hemorrhage (II) Norfloxacin 400mg/d x 7d Soriano G, et al. Gastroenterology 1992;103: IV Rocephin 1g q24h x 7d (superior to Norfloxacin) if advanced cirrhosis Fernandez J, et al. Gastroenterology 2006;131: A meta-analysis of 5 trials show a survival benefit of 9.1% in treated group Bernard B, et al. HEPATOLOGY 1999;29:

60 Variceal hemorrhage (III) Rocephin preferred to quinolone in the presence of advanced cirrhosis: - Ascites - Hepatic encephalopathy - Bilirubin 51 umol/l - Severe malnutrition (clear signs of muscle wasting) Fernandez J, et al. Gastroenterology 2006;131:

61 Trials on prophylaxis of SBP

62 68 patients with cirrhosis and low ascitic fluid protein level (< 15 g/l) with advanced liver failure Double-blind, placebo-controlled trial Norfloxacin (400mg/d x 12m VS placebo) Significant difference in 3-month survival (94% VS 62%; p = 0.03) Non-significant difference in 1-year survival (60% VS 48%; p = 0.05) Significant difference in 1-year probability of SBP (7% VS 61%) & HRS (28% VS 41%) Fernandez J, et al. Gastroenterology 2007;133:

63 Low ascitic fluid protein Ascitic fluid protein < 15 g/l Either one of the following (advanced cirrhosis) - Child-Pugh >=9 with bilirubin >=51 umol/l - Cr >106 mmol/l - Serum Na <=130 mmol/l Fernandez J, et al. Gastroenterology 2007;133:

64 ? Continuation of antibiotics prophylaxis without interruption until liver transplantation or death? Discontinuation in patients with improvement of liver disease? Discontinuation of quinolone in those who develop infection due to quinolone-resistant bacteria

65 THE END Thank you