management of ascites in patients with cirrhosis treviso 4 giugno 2009 p. angeli dept. of clinical...
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Management of ascites in patients with cirrhosis
Treviso 4 Giugno 2009
P. AngeliDept. of Clinical and Experimental Medicine University of Padova
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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
0,25
0,5
0,75
1
%
F. Salerno et al. Am. J. Gastroenterol. 1993 ; 88 : 514-519
Responsive ascites
Refractory ascites
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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
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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
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
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- 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
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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.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Grade 2 or moderate ascites Sodium restriction an diuretics
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0
25
50
75
100
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
(%)
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
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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.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
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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
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Sites of action of diuretics in the nephronSites of action of diuretics in the nephron
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
ThiazidesThiazides Potassium sparing Potassium sparing agentsagents
Loop diureticsLoop diuretics
Distal delivery of Na
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0
1000
2000
3000
4000
5000
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)
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Cirrhotics with renal failure
P. Angeli, et al. Hepatology. 1998 ; 28 : 937-943.
P < 0.01
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80
85
90
95
100
Controls Cirrhotics
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
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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
5.0
1.0
0.5
10 50 100 500 1000
r = 0.94 ; P < 0.001
UN
a (m
mo l
/hr)
PA
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Healthy subjects
Cirrhotic patients
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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
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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
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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
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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
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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
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0
1000
2000
3000
4000
5000
Responders tospironolactone
Responders tospironolactone plus
furosemide
Refractory ascites
Delivery of sodium to the distal tubule in sequential diuretic treatment
P < 0.01
(E
q/m
in)
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
A. Gatta, et al. Hepatology 1991 ; 14 : 231-236.
P < 0.01
Normal value
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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
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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
4 days
4 days
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
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80
85
90
95
100
Spironolactone Spironolactone plusFurosemide
Comparison between spironolactone alone and spironolactone plus furosemide
P = N.S.
Responders (%)
J. Santos, et al. J. Hepatol. 2003 ; 39 : 187-192.
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0
4
8
12
16
20
Spironolactone Spironolactone plusFurosemide
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
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0
20
40
60
80
100
Spironolactone Spironolactone plusFurosemide
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.
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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/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
4 days
4 days
4 days
4 days4 days
Comparison between sequential versus combined diuretic treatment
P. Angeli et al. AASLD 2007
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
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P = N.S.
Comparison between sequential versus combined diuretic treatment
Responders (%)
0
20
40
60
80
100
Sequential diuretic treatment Combined diuretic treatment
P. Angeli et al. AASLD 2007
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
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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.
Comparison between sequential versus combined diuretic treatment
Adverse effects
P. Angeli et al. AASLD 2007
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
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0
2
4
6
8
10
Sequential diuretic treatment Combined diuretic treatment
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
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0
5
10
15
20
25
Sequential diuretic treatment Combined diuretic treatment
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
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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
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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
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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
•
K. Moore, et al. Hepatology 2003 ; 38 : 258-266.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
Grade 3 or massive ascites Paracentesis, sodium resctriction and diuretics
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50
60
70
80
90
100
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
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
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Therapeutic paracentesis versus diuretics in the
treatment of massive ascites: complications
P. Gines, et al. Gastroenterology 1987 ; 93 : 234-141.
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
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
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0
10
20
30
40
50
Paracentesis Diuretics
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
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Postparacentesis circulatory dysfunction (PPCD): plasma renin activity
0
10
20
30
40
50
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)
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
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-20
-15
-10
-5
0
%
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
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
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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)
-300
-250
-200
-150
-100
-50
0
J. Cabrera et al. Gut 2001 ; 48 : 384-389.
keeping IAP constant after paracentesis
allowing IAP go down after paracentesis
P < 0.01
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Plasma renin activity in patients without and with postparacentesis circulatory dysfunction (PPCD)
0
4
8
12
16
20
* = 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)
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
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0
0,2
0,4
0,6
0,8
1
%
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
A. Gines et al. Gastroenterology 1996 ; 11 : 1002-1010.
MANAGEMENT OF ASCITES IN PATIENTS WITH CIRRHOSIS
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Postparacentesis circulatory dysfunction: plasma renin activity
0
3
6
9
12
15
Before paracentesis After paracentesis
With Albumin Without Albumin
* = P < 0.001
P. Gines et al. Gastroenterology 1988 ; 94 : 1493-1502.
*
(ng/ml/h)
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Prevalence of postparacentesis circulatory dysfunction
0
20
40
60
< 5 liters 5-9 liters > 9 liters
Albumin Dextran 70 and polygeline
A. Gines et al. Gastroenterology 1996 ; 11 : 1002-1010.
P < 0.05 P < 0.025%
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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.
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0
1000
2000
3000
4000
5000
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.
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Prevalence of postparacentesis circulatory dysfunction: plasma renin activity (ng/ml/h)
0
3
6
9
12
15
Before paracentesis After paracentesis
With Albumin With Terlipressin
P = N.S.
R. Moreau et al. Gut 2002 ; 50 : 90-94.
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0
20
40
60
80
100
Diuretics No Diuretics
G. Fernandez-Esparrach et al. J. Hepatol. 1997 ; 26 : 614-620.
Ascites recurrence after therapeutic paracentesis versus diuretics
P < 0.001
(%)
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• 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:
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0
20
40
60
80
100
(%)
Probability of recurrence of spontaneous bacterial peritonitis
4 8
Norfloxacin
PlaceboP < 0.01
12 months
P. Gines et al. Hepatology 1990 ; 12 : 716-724.
16 20
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• 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.
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0
20
40
60
80
100
(%)
Probability of development of spontaneous bacterial peritonitis
Norfloxacin
PlaceboP < 0.001
J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824.
100 200 days300 400
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0
20
40
60
80
100(%)
Probability of one year survival
100
Norfloxacin
Placebo
P < 0.01
200 days
J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824.
300 400
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0
20
40
60
80
100(%)
Probability of hepatorenal syndrome
100
Norfloxacin
Placebo
P < 0.05
200 days
J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824.
300 400
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Q/A
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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 %)
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0
1000
2000
3000
4000
5000
Responders Non responders
P < 0.001
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Delivery of sodium to the distal tubule in sequential diuretic treatment
P. Angeli et al. AASLD 2007
(E
q/m
in)
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Q/A
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Precipitating events
Spontaneous bacterial peritonitis
Paracentesis without plasma expansion
Gastrointestinal hemorrhage
Alcoholic hepatitis
Unknown
Hepatorenal syndrome (HRS)
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0
20
40
60
80
100(%)
Probability of hepatorenal syndrome
100
Norfloxacin
Placebo
P < 0.05
200 days
J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824.
300 400
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Q/A