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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
Probability of survival in cirrhotic patients
with ascites
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
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
FUNCTIONAL RENAL ABNORMALITIES IN
CIRRHOSIS
Abnormality
Clinical consequence
• Sodium retention
• Ascites and edema
• Water retention
• Dilutional hyponatremia
• Renal vasoconstriction
• Hepatorenal syndrome
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
Possible clinical scenario
- Uncomplicated ascites
- Complicated ascites
•
•
•
•
Refractory ascites
Hyponatremia
Spontaneous bacterial peritonitis
Hepatorenal syndrome
K. Moore et al. Hepatology 2003 ; 38 : 258-266.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Treatment of uncomplicated ascites
GRADE OF ASCITES
TYPE OF TREATMENT
• Grade 1 or minimal ascites
• No treatment
• Grade 2 or moderate ascites
• Sodium restriction an
diuretics
• Grade 3 or massive ascites
• Paracentesis, sodium
restriction and diuretics
K. Moore, et al. Hepatology 2003 ; 38 : 258-266.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Effects of different sodium intakes on the response to
high dose of spironolactone
(%)
100
P < 0.05
75
50
25
0
Salt restriction
No salt restriction
A. Gauthier, et al. Gut 1986 ; 27 : 705-709.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Effects of different sodium intakes on the response to
diuretics
40 mmol/day
120 mmol/day
No diuretics
9.7 %
7.5 %
Response to potassium
canrenoate (200 mg/day)
Response to potassium
canrenoate (400 or 600
mg/day)
Response to potassium
canrenoate (400 mg/day)
plus furosemide (up to 100
mg/day)
No response to diuretics
40,4 %
41,5 %
25,8 %
30,2 %
17,7 %
13,2 %
4,8 %
5,7 %
M. Bernardi, et al. Liver 1993 ; 13 : 156-162.
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.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Sites of action of diuretics in the nephron
Thiazides
Potassium sparing
agents
Distal
delivery of Na
Loop diuretics
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Delivery of sodium to the distal tubule
(Eq/min)
5000
P < 0.01
4000
P < 0.01
3000
2000
1000
0
Controls
Cirrhotics without
renal failure
Cirrhotics with
renal failure
P. Angeli, et al. Eur. J. Clin. Invest. 1990 ; 20 : 111-117.
P. Angeli, et al. Hepatology. 1998 ; 28 : 937-943.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Fractional distal sodium reabsorption
(%)
100
P < 0.005
95
90
85
80
Controls
Cirrhotics
P. Angeli, et al. Eur. J. Clin. Invest. 1990 ; 20 : 111-117.
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
5.0
Healthy
subjects
Cirrhotic
patients
1.0
0.5
r = 0.94 ; P < 0.001
10
50
100
500
M. Bernardi, et al. Gut 1983 ; 24 : 761-766.
1000
PA
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Enrolled patients n = 40
Furosemide
Spironolactone
Responders = 11/20
Responders = 18/20
Non-Responders = 10/20
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
Enrolled patients n = 40
Amiloride
Potassium canrenoate
Responders = 7/20
Responders = 14/20
Non-Responders = 13/20
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
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
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
Enroled patients n = 51
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 %)
A. Gatta, et al. Hepatology 1991 ; 14 : 231-236.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Delivery of sodium to the distal tubule in
sequential diuretic treatment
5000
(Eq/min)
4000
Normal value
3000
2000
P < 0.01
P < 0.01
1000
0
Responders to
spironolactone
Responders to
Refractory ascites
spironolactone plus
furosemide
A. Gatta, et al. Hepatology 1991 ; 14 : 231-236.
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
Comparison between spironolactone alone and
spironolactone plus furosemide
Spironolactone 100-200 mg/day
4 days
Spironolactone 100-200 mg/day
plus furosemide 40-80 mg/day
4 days
Spironolactone 200-300 mg/day
4 days
Spironolactone 200-300 mg/day
plus furosemide 80-120 mg/day
4 days
Spironolactone 400 mg/day
Spironolactone 400 mg/day
plus furosemide 120-160 mg/day
J. Santos, et al. J. Hepatol. 2003 ; 39 : 187-192.
Comparison between spironolactone alone and
spironolactone plus furosemide
Responders (%)
100
P = N.S.
95
90
85
80
Spironolactone
Spironolactone plus
Furosemide
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
Time to obtain response (days)
20
P = N.S.
16
12
8
4
0
Spironolactone
Spironolactone plus
Furosemide
J. Santos, et al. J. Hepatol. 2003 ; 39 : 187-192.
MANAGEMENT OF PATIENTS WITH CIRRHOSIS
Comparison between spironolactone alone and
spironolactone plus furosemide
Excessive response to diuretics (%)
100
P < 0.0025
80
60
40
20
0
Spironolactone
Spironolactone plus
Furosemide
J. Santos, et al. J. Hepatol. 2003 ; 39 : 187-192.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Comparison between sequential versus combined
diuretic treatment
Potassium canrenoate 200 mg/day
4 days
Potassium canrenoate 200 mg/day
plus furosemide 50 mg/day
Potassium canrenoate 400 mg/day
4 days
4 days
Potassium canrenoate 400 mg/day
plus furosemide 50/day
4 days
Potassium canrenoate 400 mg/day
plus furosemide 100 mg/day
Potassium canrenoate 400 mg/day
plus furosemide 100 mg/day
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
Comparison between sequential versus combined
diuretic treatment
Responders (%)
100
P = N.S.
80
60
40
20
0
Sequential diuretic treatment
Combined diuretic treatment
P. Angeli et al. AASLD 2007
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Comparison between sequential versus combined
diuretic treatment
Adverse effects
Sequential
diuretic treatment
(n = 50)
Combined diuretic
treatment
(n = 50)
P
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.
P. Angeli et al. AASLD 2007
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Comparison between sequential versus combined
diuretic treatment
Time to obtain response (days)
10
P < 0.05
8
6
4
2
0
Sequential diuretic treatment
Combined diuretic treatment
P. Angeli et al. AASLD 2007
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Comparison between sequential versus combined
diuretic treatment
Time to mobilize ascites (days)
25
20
P < 0.001
15
10
5
0
Sequential diuretic treatment
Combined diuretic treatment
P. Angeli et al. AASLD 2007
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
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
Treatment of uncomplicated ascites
GRADE OF ASCITES
TYPE OF TREATMENT
• Grade 1 or minimal ascites
• No treatment
• Grade 2 or moderate ascites
• 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
Therapeutic paracentesis versus diuretics in the
treatment of massive ascites: efficacy
100
P < 0.05
%
90
80
70
60
50
Paracentesis
Diuretics
P. Gines, et al. Gastroenterology 1987 ; 93 : 234-141.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
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
P. Gines, et al. Gastroenterology 1987 ; 93 : 234-141.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Therapeutic paracentesis versus diuretics in the
treatment of massive ascites: duration of
hospital stay (days)
50
40
P < 0.001
30
20
10
0
Paracentesis
Diuretics
P. Gines, et al. Gastroenterology 1987 ; 93 : 234-141.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Postparacentesis circulatory dysfunction (PPCD):
plasma renin activity
(ng/ml/h)
50
* = P < 0.05
40
*
30
20
10
0
Before paracentesis
1 hour after
paracentesis
With PPCD
6th day after
paracentesis
Without PPCD
L. Ruiz-Del-Arbol et al. Gastroenterology 1997 ; 113 : 579-586.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Percent decrease in systemic vascular resistance in
patients with and without postparacentesis circulatory
dysfunction (PPCD)
0
%
-5
-10
-15
-20
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
Percent decrease in systemic vascular resistance in
patients with ascites after paracentesis according to
intra-abdominal pressure (IAP)
0
-50
-100
-150
P < 0.01
-200
-250
-300
keeping IAP constant
after paracentesis
allowing IAP go down
after paracentesis
J. Cabrera et al. Gut 2001 ; 48 : 384-389.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Plasma renin activity in patients without and with
postparacentesis circulatory dysfunction (PPCD)
(ng/ml/h)
20
16
* = P < 0.0025; ** = P < 0.001
**
**
*
12
8
4
0
B 48 h 1 d 1 mo 6 mos
without PPCD
B 48 h 1 d 1 mo 6 mos
with PPCD
A. Gines et al. Gastroenterology 1996 ; 11 : 1002-1010.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Probability of survival in patients with and without
postparacentesis circulatory dysfunction (PPCD)
1
%
without PPCD
0,8
0,6
0,4
P = 0.01
with PPCD
0,2
0
2
4
6
8
10
12
14
16
18
A. Gines et al. Gastroenterology 1996 ; 11 : 1002-1010.
months
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Postparacentesis circulatory dysfunction: plasma
renin activity
(ng/ml/h)
15
*
12
* = P < 0.001
9
6
3
0
Before paracentesis
With Albumin
After paracentesis
Without Albumin
P. Gines et al. Gastroenterology 1988 ; 94 : 1493-1502.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Prevalence of postparacentesis circulatory
dysfunction
60
%
P < 0.05
P < 0.025
40
20
0
< 5 liters
Albumin
5-9 liters
> 9 liters
Dextran 70 and polygeline
A. Gines et al. Gastroenterology 1996 ; 11 : 1002-1010.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Liver-related complications frequency for a 100-day
period after ascites removal by paracentesis
Albumin group
(n = 30)
Polygeline
group (n = 38)
Absolute
difference
(95%CI)
All liver-related
complications
4.335.01
9.615.01
-5.3 (-10;-0.6)
Ascites episodes
3.314.10
6.987.40
-3.7 (-6.7;-0.7)
R. Moreau, et al. Liver Int. 2006 ; 26 : 46-54.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Median cost for a 30-day period (Euro) after ascites
removal by paracentesis
5000
P < 0.05
4000
3000
2000
1000
0
Albumin group
Polygeline group
R. Moreau, et al. Liver Int. 2006 ; 26 : 46-54.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Prevalence of postparacentesis circulatory
dysfunction: plasma renin activity (ng/ml/h)
15
12
P = N.S.
9
6
3
0
Before paracentesis
With Albumin
After paracentesis
With Terlipressin
R. Moreau et al. Gut 2002 ; 50 : 90-94.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Ascites recurrence after therapeutic
paracentesis versus diuretics
(%)
100
80
P < 0.001
60
40
20
0
Diuretics
No Diuretics
G. Fernandez-Esparrach et al. J. Hepatol. 1997 ; 26 : 614-620.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Prevention of spontaneous bacterial peritonitis (SBP)
The prevention of SBP is recommended in:
• patients with cirrhosis and upper gastrointestinal
hemorrhage
• patients with cirrhosis and ascites recovering
from an episode of SBP
A. Rimola, et al. J. Hepatol. 2000 ; 32 : 142-153.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Probability of recurrence of spontaneous bacterial
peritonitis
(%)
100
80
P < 0.01
Placebo
60
40
Norfloxacin
20
0
4
8
12
16
P. Gines et al. Hepatology 1990 ; 12 : 716-724.
20 months
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)
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
Probability of development of spontaneous bacterial
peritonitis
100
(%)
80
P < 0.001
Placebo
60
40
Norfloxacin
20
0
100
200
300
400
J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824.
days
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Probability of one year survival
100
(%)
80
Norfloxacin
60
Placebo
40
P < 0.01
20
0
100
200
300
400
J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824.
days
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Probability of hepatorenal syndrome
100
(%)
P < 0.05
80
60
Placebo
40
20
Norfloxacin
0
100
200
300
400
J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824.
days
Q/A
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Enroled patients n = 51
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 %)
A. Gatta, et al. Hepatology 1991 ; 14 : 231-236.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Delivery of sodium to the distal tubule in
sequential diuretic treatment
5000
(Eq/min)
P < 0.001
4000
3000
2000
1000
0
Responders
Non responders
P. Angeli et al. AASLD 2007
Q/A
Hepatorenal syndrome (HRS)
Precipitating events

Spontaneous bacterial peritonitis

Paracentesis without plasma expansion

Gastrointestinal hemorrhage

Alcoholic hepatitis

Unknown
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Probability of hepatorenal syndrome
100
(%)
P < 0.05
80
60
Placebo
40
20
Norfloxacin
0
100
200
300
400
J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824.
days
Q/A