1. Management of patients with cirrhosis and refractory ascites Treviso 4 Giugno 2009 P. Angeli Dept. of Clinical and Experimental Medicine University of Padova

2. Diuretic-resistant ascites: ascites that cannot be mobilized or he early recurrence of which cannot be prevented because od a lack of response to dietary sodium restriction and intensive diuretic therapy. Diuretic-intractable ascites: ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of the development of diuretic- induced complications that preclude the use of an effective diuretic regimen. Subtypes of refractory ascites MANAGEMENT OF PATIENTS WITH CIRRHOSIS V. Arroyo et al. Hepatology 1996 ; 23 : 165-176.

3. Plasma renin concentration (pg/ml) in cirrhotic patients with responsive or refractory ascites I. Colle et al. Eur. J. Gastroenterol. Hepatol. 2001 ; 13 : 251-256. P < 0.05 MANAGEMENT OF PATIENTS WITH CIRRHOSIS

4. Inadequate sodium intake Excessive physical activity Drugs (NSAIDs, vasodilators) Bacterial infections Factors that may affect the efficacy of diuretics MANAGEMENT OF PATIENTS WITH CIRRHOSIS V. Arroyo et al. Hepatology 1996 ; 23 : 165-176.

5. Prevalence of no compliance to reduced sodium intake among cirrhotic patients with asccites according to the response to diuretic therapy P < 0.05 MANAGEMENT OF PATIENTS WITH CIRRHOSIS P. Angeli et al. 2005 (%)

6. Renal blood flow (ml/min) G. Laffi et al. Gastroenterology 1986 ; 90 : 182-187. N = 5 ; P < 0.05 Acute effects of Ibuprofen on renal blood flow in cirrhotic patients with ascites MANAGEMENT OF PATIENTS WITH CIRRHOSIS

7. Sites of infections in cirrhotic patients M. Borzio et al. Digest. Liver Dis. 2001 ; 33 : 41-48. (%) MANAGEMENT OF PATIENTS WITH CIRRHOSIS

8. % Probability of survival in cirrhotic patients with ascites 2436 Responsive ascites Refractory ascites P < 0.001 months F. Salerno et al. Am. J. Gastroenterol. 1993 ; 88 : 514-519 124860 MANAGEMENT OF PATIENTS WITH CIRRHOSIS

9. Older age Hepatocellular carcinoma Diabetes No abstinence from alcohol beverage Independent predictors of death in patients with refractory ascites MANAGEMENT OF PATIENTS WITH CIRRHOSIS R. Moreau et al. Liver Int. 2004 ; 24 : 457-464.

10. Plasma renin concentration (pg/ml) in cirrhotic patients with responsive or refractory ascites I. Colle et al. Eur. J. Gastroenterol. Hepatol. 2001 ; 13 : 251-256. P < 0.05 MANAGEMENT OF PATIENTS WITH CIRRHOSIS

11. Paracentesis Peritoneovenous shunting TIPS Liver transplantation Therapeutic options for refractory ascites MANAGEMENT OF PATIENTS WITH CIRRHOSIS K. Moore et al. Hepatology 2003 ; 38 : 258-266.

12. Postparacentesis circulatory dysfunction (PPCD): plasma renin activity * = P < 0.05 L. Ruiz-Del-Arbol et al. Gastroenterology 1997 ; 113 : 579-586. * (ng/ml/h) MANAGEMENT OF PATIENTS WITH CIRRHOSIS

13. % Percent decrease in systemic vascular resistance in patients with and without postparacentesis circulatory dysfunction (PPCD) P < 0.05 L. Ruiz-Del-Arbol et al. Gastroenterology 1997 ; 113 : 579-586. with PPCDwithout PPCD MANAGEMENT OF PATIENTS WITH CIRRHOSIS

14. Plasma renin activity in patients without and with postparacentesis circulatory dysfunction (PPCD) * = P < 0.0025; ** = P < 0.001 * ** B48 h1 d1 mo6 mosB48 h1 d1 mo6 mos without PPCDwith PPCD A. Gines et al. Gastroenterology 1996 ; 11 : 1002-1010. (ng/ml/h) MANAGEMENT OF PATIENTS WITH CIRRHOSIS

15. % Probability of survival in patients with and without postparacentesis circulatory dysfunction (PPCD) 24101214 with PPCD without PPCD P = 0.01 68months1618 A. Gines et al. Gastroenterology 1996 ; 11 : 1002-1010. MANAGEMENT OF PATIENTS WITH CIRRHOSIS

16. Postparacentesis circulatory dysfunction: plasma renin activity * = P < 0.001 P. Gines et al. Gastroenterology 1988 ; 94 : 1493-1502. * (ng/ml/h) MANAGEMENT OF PATIENTS WITH CIRRHOSIS

17. Prevalence of postparacentesis circulatory dysfunction A. Gines et al. Gastroenterology 1996 ; 11 : 1002-1010. P < 0.05P < 0.025% MANAGEMENT OF PATIENTS WITH CIRRHOSIS

18. % Probability of survival in patients treated with paracentesis with or without intravenous albumin 510253035 without albumin with albumin P = N.S. P. Gines et al. Gastroenterology 1988 ; 94 : 1493-1502. 1520weeks MANAGEMENT OF PATIENTS WITH CIRRHOSIS

19. Prevalence of postparacentesis circulatory dysfunction: plasma renin activity (ng/ml/h) P = N.S. R. Moreau et al. Gut 2002 ; 50 : 90-94. MANAGEMENT OF PATIENTS WITH CIRRHOSIS

20. G. Fernandez-Esparrach et al. J. Hepatol. 1997 ; 26 : 614-620. Ascites recurrence after therapeutic paracentesis versus diuretics P < 0.001 MANAGEMENT OF PATIENTS WITH CIRRHOSIS (%)

21. Paracentesis should be total. Large volume paracentesis MANAGEMENT OF PATIENTS WITH CIRRHOSIS K. Moore, et al. Hepatology 2003 ; 38 : 258-266. Volume expansion after paracentesis is necessary. Synthetic plasma substitutes may be used if the volume of ascitic fluid removed is 5 l. albumin should be used. Albumin should be used at a dose of 8 gr per liter of ascitic fluid removed. To reduce the frequency of paracentesis patients may continue to receive diuretics as tolerated.

22. % Probability of survival in cirrhotic patients with refractory ascites: paracentesis vs Le Veen shunt 12 Le Veen shunt Paracentesis P = N.S. months A. Ginès et al. Hepatology 1995 ; 22 : 124-131. 618 MANAGEMENT OF PATIENTS WITH CIRRHOSIS

23. % Probability of readmission to the hospital for ascites in cirrhotic patients with refractory ascites: paracentesis vs Le Veen shunt 12 Le Veen shunt Paracentesis P <0.001 months A. Ginès et al. Hepatology 1995 ; 22 : 124-131. 618 MANAGEMENT OF PATIENTS WITH CIRRHOSIS

24. Readmission to the hospital in patients with refractory ascites: paracentesis vs Le Veen shunt MANAGEMENT OF PATIENTS WITH CIRRHOSIS A. Ginès et al. Hepatology 1995 ; 22 : 124-131.

25. Symptomatic disseminated intravascular coagulation Severe bacterial infections Thrombotic obstruction of the venous limb of the prothesis Intraperitoneal fibrosis Potential adverse effects of peritoneovenous shunt MANAGEMENT OF PATIENTS WITH CIRRHOSIS

26. % Probability of developing renal impairment in cirrhotic patients with refractory ascites: paracentesis vs Le Veen shunt 12 Le Veen shunt Paracentesis P = N.S. months A. Ginès et al. Hepatology 1995 ; 22 : 124-131. 618 MANAGEMENT OF PATIENTS WITH CIRRHOSIS

27. In candidates to liver transplantation the first line treatment for refractory ascites is total paracentesis. PVS is contraindicated in candidates to liver transplantation. In non transplant candidates PVS may be considered after failure of paracentesis (need of 3 or more paracentesis per month) in presence of contraindications to TIPS. Conclusions (1) MANAGEMENT OF PATIENTS WITH CIRRHOSIS K. Moore et al. Hepatology 2003 ; 38 : 258-266.

28. Lebrec D.J. et al. Hepatol. 1996 ; 25 : 135 - 144 Rossle M. et al. N. Engl. J. Med. 2000 ; 342 : 1701-1707. Gines P. et al. Gastroenterology 2002 ; 123 : 1839-1847. Sanyal AJ. et al. Gastroenterology 2003 ; 124 : 634-641. Salerno F. et al. Hepatology 2004 ; 40 : 629- 635. Published controlled clinical trials: paracentesis versus TIPS MANAGEMENT OF PATIENTS WITH CIRRHOSIS

29. Mobilization of ascites in patients with refractory ascites: paracentesis vs TIPS MANAGEMENT OF PATIENTS WITH CIRRHOSIS M. Rossle et al. N. Engl. J. Med. 2000 ; 342 : 1701-1707.

30. Changes of urine sodium excretion at 3 months after paracentesis or TIPS P < 0.005 MANAGEMENT OF PATIENTS WITH CIRRHOSIS F. Salerno et al. Hepatology 2004 ; 40 : 629-635.

31. Clinical outcome in patients with refractory ascites according to the assigned treatment EventsTIPS (n° = 35) Paracentesis (n° = 35) P value Hepatic encephalopathy Patients n°27 (77%)23 (66%)N.S. Episodes/patient2.2±0.41.1±0.2<0.01 Moderate (I-II grade) Patients n° 18 (51%)14 (40%)N.S. Moderate (I-II grade) Episodes/patient 1.1±0.30.6±0.1N.S. Severe (III-IV grade) Patient n° 21(60%)12(34%)<0.05 Severe (III-IV grade): epidodes/patient 1.1±0.20.5±0.02<0.025 P. Gines et al. Gastroenterology 2002 ; 123 : 1839-1847. MANAGEMENT OF PATIENTS WITH CIRRHOSIS

32. % Probability of development of de novo HRS or progression from type 2 to type 1 HRS in patients with refractory ascites 121824 With paracentesis plus albumin P < 0.025 mo P. Gines et al. Gastroenterology 2002 ; 123 : 1839-1847. With TIPS 6 MANAGEMENT OF PATIENTS WITH CIRRHOSIS

33. % Probability of survival in patients with refractory or recurrent ascites: paracentesis vs TIPS 5001000 paracentesis TIPS P = N.S. days MANAGEMENT OF PATIENTS WITH CIRRHOSIS AJ. Sanyal et al. Gastroenterology 2003 ; 124 : 634-641. 1500

34. % Probability of survival in patients with refractory or recurrent ascites: paracentesis vs TIPS 123648 paracentesis TIPS P < 0.025 24months MANAGEMENT OF PATIENTS WITH CIRRHOSIS F. Salerno et al. Hepatology 2004 ; 40 : 629-635.

35. Child-Pugh score > 11 serum bilirubin > 6 mg/dl serum creatinine > 3 mg/dl history of recurrent grade  2 hepatic encephalopathy age greater than 72 serious cardiac or pulmonary dysfunction complete portal vein thrombosis HCC recent gastrointestinal bleeding ongoing bacterial infection Contraindications to TIPS MANAGEMENT OF PATIENTS WITH CIRRHOSIS F. Salerno et al. Hepatology 2004 ; 40 : 629-635.

36. A meta-analysis of TIPS versus paracentesis in patients with refractory ascites MANAGEMENT OF PATIENTS WITH CIRRHOSIS A. Albillos et al. J. Hepatol. 2005 ; XX : 1-7. Lebrec 1996 Rossle 2000 Sanyal 2003 Salerno 2004 TOTAL 10.8 Recurrence of ascites Gines 2002 Lower with TIPS 0.60.40.2

37. A meta-analysis of TIPS versus paracentesis in patients with refractory ascites MANAGEMENT OF PATIENTS WITH CIRRHOSIS A. Albillos et al. J. Hepatol. 2005 ; XX : 1-7. Lebrec 1996 Rossle 2000 Sanyal 2003 Salerno 2004 TOTAL 11002040 Encephalopaty Gines 2002 Lower with paracentesis

38. A meta-analysis of TIPS versus paracentesis in patients with refractory ascites MANAGEMENT OF PATIENTS WITH CIRRHOSIS A. Albillos et al. J. Hepatol. 2005 ; XX : 1-7. Lebrec 1996 Rossle 2000 Sanyal 2003 Salerno 2004 TOTAL 1524 Mortality Gines 2002 Lower with paracentesis 30.5 Lower with TIPS

39. Main outcomesTIPS (n=33) Paracentesis (n=33) P Rehospitalization28 (84%)30 (91%)N.S. Rehospitalization per patient 2.1  0.31.6  0.2 N.S. Quality of life in cirrhotic patients after paracentesis or TIPS MANAGEMENT OF PATIENTS WITH CIRRHOSIS F. Salerno et al. Hepatology 2004 ; 40 : 629-635.

40. Baseline6 Months12 MonthsP PCS TIPS 28.4  8.47.0  8.45.0  10.5 N.S. Paracentesis 26.8  9.36.3  9.32.0  11.7 MCS TIPS 44.7  12.63.7  8.33.3  12.6 0.06 Paracentesis 41.0  10.33.4  12.70.5  11.9 Quality of life in cirrhotic patients after paracentesis or TIPS MANAGEMENT OF PATIENTS WITH CIRRHOSIS MS. Campbell et al. Hepatology 2005 ; 42 : 635-640.

41. Main outcomesTIPS (n=33) Paracentesis (n=33) P Treatment failure7 (21%)19 (57%)<0.0025 Ascites recurrence13 (39%)20 (61%)<0.001 Paracentesis per patient per year 1.4  0.45.1  0.7 <0.001 Control of ascites according to the assigned treatment MANAGEMENT OF PATIENTS WITH CIRRHOSIS F. Salerno et al. Hepatology 2004 ; 40 : 629-635.

42. % Probability of remaining free of shunt dysfunction after TIPS procedure 61824 Uncoated Stent Coated Stent P < 0.001 12months MANAGEMENT OF PATIENTS WITH CIRRHOSIS C. Bureau et al. Gastroenterology 2004 ; 126 : 469-475.

43. Peritoneal port for treatment of refractory ascites MANAGEMENT OF PATIENTS WITH CIRRHOSIS MA. Savin et al. J. Vasc. Interv. Radiol. 2005 ; 16 : 363-368.

44. Paracentesis is the first line treatment of refractory ascites in patients with cirrhosis. TIPS is recommended in patients who did not tolerate recurrent total paracentesis, also in those waiting for liver transplantation. TIPS is also indicated if paracentesis fails to adequately remove ascitic fluid (e.g. loculated ascites). Conclusions (2) MANAGEMENT OF PATIENTS WITH CIRRHOSIS K. Moore et al. Hepatology 2003 ; 38 : 258-266.