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

2. Probability of survival in cirrhotic patients with ascites MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS G. Fattovich et al. Gastroenterology 1997 ; 112 : 463-472 Compensated cirrhosis European Liver Transplant Registry - 2008 LT for cirrhosis 2436months124860 0 0,25 0,5 0,75 1 % F. Salerno et al. Am. J. Gastroenterol. 1993 ; 88 : 514-519 Responsive ascites Refractory ascites

3. FUNCTIONAL RENAL ABNORMALITIES IN CIRRHOSIS AbnormalityClinical consequence Sodium retention Water retention Renal vasoconstriction Ascites and edema Dilutional hyponatremia Hepatorenal syndrome MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

4. Circulatory dysfunction in cirrhosis with ascites Reduction of circulating volume Activation of systemic endogenous vasocontrictors Renal functional abnormalities Splanchnic arterial vasodilation Portal hypertension/liver failure Increased release of NO, CO and other vasodilators MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

5. - Complicated ascites Hyponatremia Spontaneous bacterial peritonitis Hepatorenal syndrome Possible clinical scenario - Uncomplicated ascites K. Moore et al. Hepatology 2003 ; 38 : 258-266. Refractory ascites MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

6. Treatment of uncomplicated ascites GRADE OF ASCITESTYPE OF TREATMENT Grade 1 or minimal ascites Grade 3 or massive ascites No treatment Paracentesis, sodium restriction and diuretics K. Moore, et al. Hepatology 2003 ; 38 : 258-266. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Grade 2 or moderate ascites Sodium restriction an diuretics

7. Effects of different sodium intakes on the response to high dose of spironolactone A. Gauthier, et al. Gut 1986 ; 27 : 705-709. P < 0.05 (%) MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

8. Effects of different sodium intakes on the response to diuretics M. Bernardi, et al. Liver 1993 ; 13 : 156-162. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

9. Dietary sodium intake should be moderately restricted to 90 mmol/day. There is no indication for a more severe salt restriction. The use of salt substitutes that contain potassium is contraindicated. There is no indication for the prophylactic use of salt resctriction in patients who have never had ascites. Dietary sodium restriction K. Moore, et al. Hepatology 2003 ; 38 : 258-266. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

10. Sites of action of diuretics in the nephron MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Thiazides Potassium sparing agents Loop diuretics Distal delivery of Na

11. Delivery of sodium to the distal tubule P. Angeli, et al. Eur. J. Clin. Invest. 1990 ; 20 : 111-117. P < 0.01 (  Eq/min) MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Cirrhotics with renal failure P. Angeli, et al. Hepatology. 1998 ; 28 : 937-943. P < 0.01

12. Fractional distal sodium reabsorption P. Angeli, et al. Eur. J. Clin. Invest. 1990 ; 20 : 111-117. P < 0.005 (%) MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

13. Correlation between aldosteronemia (PA) and hourly urinary sodium excretion (UNa) M. Bernardi, et al. Gut 1983 ; 24 : 761-766. r = 0.78 ; P < 0.001 10.0 5.0 1.0 0.5 10501005001000 r = 0.94 ; P < 0.001 UNa (mmol/hr) PA MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Healthy subjects Cirrhotic patients

14. Enrolled patients n = 40 Furosemide Responders = 11/20 Non-Responders = 10/20 Responders = 0/1 Spironolactone R.M. Perez-Ayuso, et al. Gastroenterology 1983 ; 84 : 961-968. Responders = 18/20 Non-Responders = 1/20 Responders = 9/10 MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

15. Enrolled patients n = 40 Amiloride Responders = 7/20 Non-Responders = 13/20 Responders = 2/6 Potassium canrenoate Responders = 14/20 Non-Responders = 6/20 Responders = 7/13 P. Angeli, et al. Hepatology 1994 ; 19 : 72-79. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

16. The core diuretic should be an aldosterone antagonist and this should be given once per day with food. The aldosterone antagonist should be given at the initial dose of 100-200 mg/day. The diuretic dosage should be increased stepwise to a maximum of 400 mg/day in case of insufficient response. Other potassium sparing diuretic (amiloride) are indicated only in those patients with adverse effects due to the aldosterone antagonist. Diuretics (1) K. Moore, et al. Hepatology 2003 ; 38 : 258-266. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

17. In clinical trials a loop diuretic was added (furosemide 20-40 mg/day) once a patient fails to respond to the aldosterone antagonist (sequential diuretic therapy). The initial dose of furosemide may be increased in a stepwise manner to a maximum of 160 mg/day. Diuretics (2) K. Moore, et al. Hepatology 2003 ; 38 : 258-266. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

18. Enroled patients n = 51 A. Gatta, et al. Hepatology 1991 ; 14 : 231-236. Patients that required diuretic therapy = 45 (88%) Patients with spontaneous diuresis n = 6 (12%) Responders to spironolactone = 55 (56 %) Responders to spironolactone and furosemide= 18 (40 %) Patients with refractory ascites = 2 (4 %) MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

19. Delivery of sodium to the distal tubule in sequential diuretic treatment P < 0.01 (  Eq/min) MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS A. Gatta, et al. Hepatology 1991 ; 14 : 231-236. P < 0.01 Normal value

20. Open question Should we go on with sequential diuretic treatment or introduce combined diuretic treatment (aldosterone antagonist and loop diuretic) from the beginning ? MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

21. Spironolactone 100-200 mg/day Spironolactone 200-300 mg/day Spironolactone 400 mg/day Spironolactone 100-200 mg/day plus furosemide 40-80 mg/day Spironolactone 200-300 mg/day plus furosemide 80-120 mg/day Spironolactone 400 mg/day plus furosemide 120-160 mg/day 4 days Comparison between spironolactone alone and spironolactone plus furosemide J. Santos, et al. J. Hepatol. 2003 ; 39 : 187-192. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

22. Comparison between spironolactone alone and spironolactone plus furosemide P = N.S. Responders (%) J. Santos, et al. J. Hepatol. 2003 ; 39 : 187-192.

23. Comparison between spironolactone alone and spironolactone plus furosemide P = N.S. Time to obtain response (days) J. Santos, et al. J. Hepatol. 2003 ; 39 : 187-192. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

24. Comparison between spironolactone alone and spironolactone plus furosemide P < 0.0025 MANAGEMENT OF PATIENTS WITH CIRRHOSIS Excessive response to diuretics (%) J. Santos, et al. J. Hepatol. 2003 ; 39 : 187-192.

25. Potassium canrenoate 200 mg/day Potassium canrenoate 400 mg/day plus furosemide 50/day Potassium canrenoate 400 mg/day plus furosemide 100 mg/day Potassium canrenoate 200 mg/day plus furosemide 50 mg/day Potassium canrenoate 400 mg/day plus furosemide 100 mg/day Potassium canrenoate 400 mg/day plus furosemide 150 mg/day 4 days Comparison between sequential versus combined diuretic treatment P. Angeli et al. AASLD 2007 MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

26. P = N.S. Comparison between sequential versus combined diuretic treatment Responders (%) P. Angeli et al. AASLD 2007 MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

27. Sequential diuretic treatment (n = 50) Combined diuretic treatment (n = 50) P Pts with adverse effects19 (38%)10 (20%)< 0.05 Pts with hyperkalemia8 (16%)3 (6%)N.S. Pts with hypokalemia1 (2%)--N.S. Pts with hyponatremia7 (14%)2 (4%)N.S. Pts with renal failure6 (12%)7 (14%)N.S. Pts with encephalophaty4 (8%)1 (2%)N.S. Comparison between sequential versus combined diuretic treatment Adverse effects P. Angeli et al. AASLD 2007 MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

28. P < 0.05 Comparison between sequential versus combined diuretic treatment Time to obtain response (days) P. Angeli et al. AASLD 2007 MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

29. P < 0.001 Comparison between sequential versus combined diuretic treatment Time to mobilize ascites (days) P. Angeli et al. AASLD 2007 MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

30. Diuretic dosage should be increased stepwise if there is an insufficient response as defined by a weight loss < 1 Kg in the first week or < 2 Kg every week thereafter until fluid balance is achieved. The safe upper limit of weight loss is contentious. Most experts agree that the diuretic dosage should be adjusted to achieve a maximum rate of weight loss < 500 gr/day in patients without peripheral edema or < 1 Kg in those with peripheral edema. Diuretics (3) K. Moore, et al. Hepatology 2003 ; 38 : 258-266. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

31. Diuretics are contraindicated or should be stopped in patients with: Severe hyponatremia (serum sodium < 125 mmol/l) Progressive renal impairment Worsening hepatic encephalopathy Incapacitating muscle cramps Hypokalemia (serum K < 3.5 mmol/l) stop furosemide Hyperkalemia (serum K > 6.0 mmol/l) stop aldosterone antagonist. Diuretics (4) K. Moore, et al. Hepatology 2003 ; 38 : 258-266. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

32. Treatment of uncomplicated ascites GRADE OF ASCITESTYPE OF TREATMENT Grade 1 or minimal ascites Grade 2 or moderate ascites No treatment Sodium resctriction and diuretics K. Moore, et al. Hepatology 2003 ; 38 : 258-266. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Grade 3 or massive ascitesParacentesis, sodium resctriction and diuretics

33. P. Gines, et al. Gastroenterology 1987 ; 93 : 234-141. % Therapeutic paracentesis versus diuretics in the treatment of massive ascites: efficacy P < 0.05 MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

34. Therapeutic paracentesis versus diuretics in the treatment of massive ascites: complications P. Gines, et al. Gastroenterology 1987 ; 93 : 234-141. ParacentesisDiureticsP Patients with complications 17%61%< 0.001 Patients with hyponatremia 5%30%<0.001 Patients with encephalopathy 10%29%<0.01 Patients with renal impairment 3%27%<0.001 MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

35. P. Gines, et al. Gastroenterology 1987 ; 93 : 234-141. Therapeutic paracentesis versus diuretics in the treatment of massive ascites: duration of hospital stay (days) P < 0.001 MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

36. 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 ASCITES IN PATIENTS WITH CIRRHOSIS

37. % 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 ASCITES IN PATIENTS WITH CIRRHOSIS

38. Percent decrease in systemic vascular resistance in patients with ascites after paracentesis according to intra-abdominal pressure (IAP) J. Cabrera et al. Gut 2001 ; 48 : 384-389. keeping IAP constant after paracentesis allowing IAP go down after paracentesis P < 0.01

39. 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 ASCITES IN PATIENTS WITH CIRRHOSIS

40. % 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 ASCITES IN PATIENTS WITH CIRRHOSIS

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

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

43. Albumin group (n = 30) Polygeline group (n = 38) Absolute difference (95%CI) All liver-related complications 4.33  5.019.61  5.01 -5.3 (-10;-0.6) Ascites episodes 3.31  4.106.98  7.40 -3.7 (-6.7;-0.7) Liver-related complications frequency for a 100-day period after ascites removal by paracentesis R. Moreau, et al. Liver Int. 2006 ; 26 : 46-54. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

44. P < 0.05 Median cost for a 30-day period (Euro) after ascites removal by paracentesis R. Moreau, et al. Liver Int. 2006 ; 26 : 46-54. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

45. 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 ASCITES IN PATIENTS WITH CIRRHOSIS

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

47. patients with cirrhosis and upper gastrointestinal hemorrhage patients with cirrhosis and ascites recovering from an episode of SBP Prevention of spontaneous bacterial peritonitis (SBP) A. Rimola, et al. J. Hepatol. 2000 ; 32 : 142-153. The prevention of SBP is recommended in: MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

48. (%) Probability of recurrence of spontaneous bacterial peritonitis 48 Norfloxacin PlaceboP < 0.01 12months P. Gines et al. Hepatology 1990 ; 12 : 716-724. 1620 MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

49. patients with cirrhosis and low protein ascitic level (15 g/l) Primary prevention of spontaneous bacterial peritonitis (SBP) and one of the following conditions: advanced liver failure (CTP ≥ 9 with total serum bilirubin ≥ 3 mg/dl) or impaired renal function (serum creatinine ≥ 1.2 mg/dl, BUN ≥ 25 mg/dl) or serum sodium level ≤ 130 mmol/l J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

50. (%) Probability of development of spontaneous bacterial peritonitis Norfloxacin PlaceboP < 0.001 J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824. 100200 days300400 MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

51. (%) Probability of one year survival 100 Norfloxacin Placebo P < 0.01 200 days J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824. 300400 MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

52. (%) Probability of hepatorenal syndrome 100 Norfloxacin Placebo P < 0.05 200 days J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824. 300400 MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

53. Q/A

54. Enroled patients n = 51 A. Gatta, et al. Hepatology 1991 ; 14 : 231-236. Patients that required diuretic therapy = 45 (88%) Patients with spontaneous diuresis n = 6 (12%) Responders to spironolactone = 55 (56 %) Responders to spironolactone and furosemide= 18 (40 %) Patients with refractory ascites = 2 (4 %) MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

55. P < 0.001 MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Delivery of sodium to the distal tubule in sequential diuretic treatment P. Angeli et al. AASLD 2007 (  Eq/min)

56. Q/A

57. Precipitating events  Spontaneous bacterial peritonitis  Paracentesis without plasma expansion  Gastrointestinal hemorrhage  Alcoholic hepatitis  Unknown Hepatorenal syndrome (HRS)

58. (%) Probability of hepatorenal syndrome 100 Norfloxacin Placebo P < 0.05 200 days J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824. 300400 MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

59. Q/A