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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

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

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


Management of ascites in patients with cirrhosis

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


Management of ascites in patients with cirrhosis

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


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Sites of action of diuretics in the nephron

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


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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 ?


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

Comparison between spironolactone alone and spironolactone plus furosemide

Responders (%)

P = N.S.

J. Santos, et al. J. Hepatol. 2003 ; 39 : 187-192.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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


Management of ascites in patients with cirrhosis

MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

Comparison between sequential versus combined diuretic treatment

Responders (%)

P = N.S.

P. Angeli et al. AASLD 2007


Management of ascites in patients with cirrhosis

MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

Comparison between sequential versus combined diuretic treatment

Adverse effects

P. Angeli et al. AASLD 2007


Management of ascites in patients with cirrhosis

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


Management of ascites in patients with cirrhosis

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


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Postparacentesis circulatory dysfunction ppcd plasma renin activity

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Plasma renin activity in patients without and with postparacentesis circulatory dysfunction ppcd

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.


Management of ascites in patients with cirrhosis

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.


Postparacentesis circulatory dysfunction plasma renin activity

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.


Prevalence of postparacentesis circulatory dysfunction

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Prevalence of postparacentesis circulatory dysfunction plasma renin activity ng ml h

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

Probability of one year survival

(%)

Norfloxacin

Placebo

P < 0.01

100

200

300

400

days

J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824.


Management of ascites in patients with cirrhosis

MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

Probability of hepatorenal syndrome

(%)

P < 0.05

Placebo

Norfloxacin

100

200

300

400

days

J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824.


Management of ascites in patients with cirrhosis

Q/A


Management of ascites in patients with cirrhosis

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.


Management of ascites in patients with cirrhosis

MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

Delivery of sodium to the distal tubule in sequential diuretic treatment

P < 0.001

(Eq/min)

P. Angeli et al. AASLD 2007


Management of ascites in patients with cirrhosis

Q/A


Management of ascites in patients with cirrhosis

Hepatorenal syndrome (HRS)

Precipitating events

  • Spontaneous bacterial peritonitis

  • Paracentesis without plasma expansion

  • Gastrointestinal hemorrhage

  • Alcoholic hepatitis

  • Unknown


Management of ascites in patients with cirrhosis

MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS

Probability of hepatorenal syndrome

(%)

P < 0.05

Placebo

Norfloxacin

100

200

300

400

days

J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824.


Management of ascites in patients with cirrhosis

Q/A


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