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Management of ascites in patients with cirrhosis

Management of ascites in patients with cirrhosis. P. Angeli Dept. of Clinical and Experimental Medicine University of Padova. Treviso 4 Giugno 2009. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS. 1. Compensated cirrhosis. %. 0,75. LT for cirrhosis. Responsive ascites. 0,5.

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Management of ascites in patients with cirrhosis

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

  2. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS 1 Compensated cirrhosis % 0,75 LT for cirrhosis Responsive ascites 0,5 0,25 Refractory ascites 0 12 24 36 48 60 months G. Fattovich et al. Gastroenterology 1997 ; 112 : 463-472 F. Salerno et al. Am. J. Gastroenterol. 1993 ; 88 : 514-519 European Liver Transplant Registry - 2008 Probability of survival in cirrhotic patients with ascites

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

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

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

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

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

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

  9. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Dietary sodium restriction • 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. K. Moore, et al. Hepatology 2003 ; 38 : 258-266.

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

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

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

  13. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Correlation between aldosteronemia (PA) and hourly urinary sodium excretion (UNa) 10.0 r = 0.78 ; P < 0.001 Healthy subjects 5.0 UNa (mmol/hr) Cirrhotic patients 1.0 0.5 r = 0.94 ; P < 0.001 10 50 100 500 1000 PA M. Bernardi, et al. Gut 1983 ; 24 : 761-766.

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

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

  16. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Diuretics (1) • 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. K. Moore, et al. Hepatology 2003 ; 38 : 258-266.

  17. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Diuretics (2) • 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. K. Moore, et al. Hepatology 2003 ; 38 : 258-266.

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

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

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

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

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

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

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

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

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

  27. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Comparison between sequential versus combined diuretic treatment Adverse effects P. Angeli et al. AASLD 2007

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

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

  30. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Diuretics (3) • 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. K. Moore, et al. Hepatology 2003 ; 38 : 258-266.

  31. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Diuretics (4) • 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. K. Moore, et al. Hepatology 2003 ; 38 : 258-266.

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

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

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

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

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

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

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

  39. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS B 48 h 1 d 1 mo 6 mos Plasma renin activity in patients without and with postparacentesis circulatory dysfunction (PPCD) (ng/ml/h) * = P < 0.0025; ** = P < 0.001 ** ** * B 48 h 1 d 1 mo 6 mos without PPCD with PPCD A. Gines et al. Gastroenterology 1996 ; 11 : 1002-1010.

  40. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Probability of survival in patients with and without postparacentesis circulatory dysfunction (PPCD) % without PPCD P = 0.01 with PPCD 2 4 6 8 10 12 14 16 18 months A. Gines et al. Gastroenterology 1996 ; 11 : 1002-1010.

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

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

  43. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Liver-related complications frequency for a 100-day period after ascites removal by paracentesis R. Moreau, et al. Liver Int. 2006 ; 26 : 46-54.

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

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

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

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

  48. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Probability of recurrence of spontaneous bacterial peritonitis (%) P < 0.01 Placebo Norfloxacin 4 8 12 16 20 months P. Gines et al. Hepatology 1990 ; 12 : 716-724.

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

  50. MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS Probability of development of spontaneous bacterial peritonitis (%) P < 0.001 Placebo Norfloxacin 100 200 300 400 days J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824.

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