Management of ascites in patients with cirrhosis

Treviso 4 Giugno 2009

P. AngeliDept. of Clinical and Experimental Medicine University of Padova

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

24 36 months12 48 600

F. Salerno et al. Am. J. Gastroenterol. 1993 ; 88 : 514-519

Responsive ascites

Refractory ascites

FUNCTIONAL RENAL ABNORMALITIES IN CIRRHOSIS

Abnormality Clinical consequence

• Sodium retention• Water retention• Renal vasoconstriction

• Ascites and edema• Dilutional hyponatremia• Hepatorenal syndrome

Circulatory dysfunction in cirrhosis with ascites

Reduction of circulating volume

Activation of systemicendogenous vasocontrictors

Renal functional abnormalities

Splanchnic arterial vasodilation

Portal hypertension/liver failureIncreased release of NO, CO and other vasodilators

- Complicated ascites

• Hyponatremia• Spontaneous bacterial peritonitis• Hepatorenal syndrome

Possible clinical scenario

- Uncomplicated ascites

K. Moore et al. Hepatology 2003 ; 38 : 258-266.

• Refractory ascites

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

K. Moore, et al. Hepatology 2003 ; 38 : 258-266.

Grade 2 or moderate ascites Sodium restriction an diuretics

Salt restriction No salt restriction

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

40 mmol/day 120 mmol/day

No diuretics 9.7 % 7.5 %

Response to potassiumcanrenoate (200 mg/day)

40,4 % 41,5 %

Response to potassiumcanrenoate (400 or 600mg/day)

25,8 % 30,2 %

Response to potassiumcanrenoate (400 mg/day)plus furosemide (up to 100mg/day)

17,7 % 13,2 %

No response to diuretics 4,8 % 5,7 %

Effects of different sodium intakes on the response to diuretics

M. Bernardi, et al. Liver 1993 ; 13 : 156-162.

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

Sites of action of diuretics in the nephronSites of action of diuretics in the nephron

ThiazidesThiazides Potassium sparing Potassium sparing agentsagents

Loop diureticsLoop diuretics

Distal delivery of Na

Controls Cirrhotics withoutrenal failure

Delivery of sodium to the distal tubule

P. Angeli, et al. Eur. J. Clin. Invest. 1990 ; 20 : 111-117.

P < 0.01

(Eq/min)

Cirrhotics with renal failure

P. Angeli, et al. Hepatology. 1998 ; 28 : 937-943.

P < 0.01

Controls Cirrhotics

Fractional distal sodium reabsorption

P. Angeli, et al. Eur. J. Clin. Invest. 1990 ; 20 : 111-117.

P < 0.005

Correlation between aldosteronemia (PA) and hourly urinary sodium excretion (UNa)

M. Bernardi, et al. Gut 1983 ; 24 : 761-766.

r = 0.78 ; P < 0.00110.0

1.00.5

10 50 100 500 1000

r = 0.94 ; P < 0.001

Healthy subjects

Cirrhotic patients

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

Responders = 9/10

Enrolled patients n = 40

Amiloride

Responders = 7/20

Responders = 2/6

Potassium canrenoate

Responders = 14/20

Responders = 7/13

P. Angeli, et al. Hepatology 1994 ; 19 : 72-79.

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)

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)

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 %)

Responders tospironolactone

Responders tospironolactone plus

furosemide

Refractory ascites

Delivery of sodium to the distal tubule in sequential diuretic treatment

P < 0.01

Normal value

Open question

Should we go on with sequential diuretic treatment or introduce combined diuretic treatment (aldosterone antagonist and loop diuretic) from the beginning ?

Spironolactone 100-200 mg/day

Spironolactone 200-300 mg/day

Spironolactone 400 mg/day

Spironolactone 100-200 mg/dayplus furosemide 40-80 mg/day

Spironolactone 200-300 mg/dayplus furosemide 80-120 mg/day

Spironolactone 400 mg/dayplus 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.

Spironolactone Spironolactone plusFurosemide

P = N.S.

Responders (%)

P = N.S.

Time to obtain response (days)

P < 0.0025

MANAGEMENT OF PATIENTS WITH CIRRHOSIS

Excessive response to diuretics (%)

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

Potassium canrenoate 200 mg/dayplus furosemide 50 mg/day

Potassium canrenoate 400 mg/dayplus furosemide 100 mg/day

Potassium canrenoate 400 mg/day plus furosemide 150 mg/day

4 days

4 days4 days

Comparison between sequential versus combined diuretic treatment

P. Angeli et al. AASLD 2007

P = N.S.

Responders (%)

Sequential diuretic treatment Combined diuretic treatment

Sequential diuretic treatment

(n = 50)

Combined diuretic treatment(n = 50)

Pts with adverse effects 19 (38%) 10 (20%) < 0.05

Pts with hyperkalemia 8 (16%) 3 (6%) N.S.

Pts with hypokalemia 1 (2%) -- N.S.

Pts with hyponatremia 7 (14%) 2 (4%) N.S.

Pts with renal failure 6 (12%) 7 (14%) N.S.

Pts with encephalophaty 4 (8%) 1 (2%) N.S.

Adverse effects

P < 0.05

Time to obtain response (days)

P < 0.001

Time to mobilize ascites (days)

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)

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)

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

Paracentesis Diuretics

P. Gines, et al. Gastroenterology 1987 ; 93 : 234-141.

Therapeutic paracentesis versus diuretics in the treatment of massive ascites: efficacy

P < 0.05

Therapeutic paracentesis versus diuretics in the treatment of massive ascites: complications

Paracentesis Diuretics P

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

Paracentesis Diuretics

Therapeutic paracentesis versus diuretics in the treatment of massive ascites: duration of

hospital stay (days)

P < 0.001

Postparacentesis circulatory dysfunction (PPCD): plasma renin activity

Before paracentesis 1 hour afterparacentesis

6th day afterparacentesis

With PPCD Without PPCD

* = P < 0.05

L. Ruiz-Del-Arbol et al. Gastroenterology 1997 ; 113 : 579-586.

(ng/ml/h)

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 PPCD without PPCD

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

Plasma renin activity in patients without and with postparacentesis circulatory dysfunction (PPCD)

* = P < 0.0025; ** = P < 0.001*

B 48 h 1 d 1 mo 6 mos B 48 h 1 d 1 mo 6 mos

without PPCD with PPCD

A. Gines et al. Gastroenterology 1996 ; 11 : 1002-1010.

(ng/ml/h)

Probability of survival in patients with and without postparacentesis circulatory dysfunction (PPCD)

2 4 10 12 14

with PPCD

without PPCD

P = 0.01

6 8 months16 18

Postparacentesis circulatory dysfunction: plasma renin activity

Before paracentesis After paracentesis

With Albumin Without Albumin

* = P < 0.001

P. Gines et al. Gastroenterology 1988 ; 94 : 1493-1502.

(ng/ml/h)

Prevalence of postparacentesis circulatory dysfunction

< 5 liters 5-9 liters > 9 liters

Albumin Dextran 70 and polygeline

P < 0.05 P < 0.025%

Albumin group(n = 30)

Polygeline group (n = 38)

Absolute difference (95%CI)

All liver-related complications 4.335.01 9.615.01 -5.3 (-10;-0.6)

Ascites episodes 3.314.10 6.987.40 -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.

Albumin group Polygeline group

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.

Prevalence of postparacentesis circulatory dysfunction: plasma renin activity (ng/ml/h)

Before paracentesis After paracentesis

With Albumin With Terlipressin

P = N.S.

R. Moreau et al. Gut 2002 ; 50 : 90-94.

Diuretics No Diuretics

G. Fernandez-Esparrach et al. J. Hepatol. 1997 ; 26 : 614-620.

Ascites recurrence after therapeutic paracentesis versus diuretics

P < 0.001

• 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:

100(%)

Probability of recurrence of spontaneous bacterial peritonitis

Norfloxacin

PlaceboP < 0.01

12 months

P. Gines et al. Hepatology 1990 ; 12 : 716-724.

• 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)

• impaired renal function (serum creatinine ≥ 1.2 mg/dl, BUN ≥ 25 mg/dl)

• serum sodium level ≤ 130 mmol/l

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

100(%)

Probability of development of spontaneous bacterial peritonitis

Norfloxacin

PlaceboP < 0.001

100 200 days300 400

100(%)

Probability of one year survival

Norfloxacin

Placebo

P < 0.01

200 days

300 400

100(%)

Probability of hepatorenal syndrome

Norfloxacin

Placebo

P < 0.05

200 days

300 400

Enroled patients n = 51

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 %)

Responders Non responders

P < 0.001

Delivery of sodium to the distal tubule in sequential diuretic treatment

Precipitating events

Spontaneous bacterial peritonitis

Paracentesis without plasma expansion

Gastrointestinal hemorrhage

Alcoholic hepatitis

Unknown

Hepatorenal syndrome (HRS)

100(%)

Probability of hepatorenal syndrome

Norfloxacin

Placebo

P < 0.05

200 days

300 400

Management of ascites in patients with cirrhosis

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