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Management of Cirrhotic
Complications
“Uncontrolled Ascites”
Siwaporn Chainuvati, MD
Siriraj Hospital
Mahidol University
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Topic
Definition, pathogenesis
Current therapeutic options
Experimental treatments
Clinical approach
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Probability of Survival in
Patients with Cirrhosis and
Refractory Ascites
Gines P et al. NEJM 2004:1646-54
Non-refractory
ascites
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Diagnostic Criteria
Lack of response to maximal doses of diuretic for at least 1 week
Persistent ascites despite sodium restriction
Mean weight loss < 0.8 kg over 4 days
Urinary sodium excretion less than sodium intake
Early recurrence of ascites within 4 weeks of fluid mobilization
Diuretic-induced complications in the absence of other precipitating factors
Runyon B et al. Hepatology 2009:2087-2107, EASL Journal of Hepatology 2010:397-417
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Conditions Leading to Transient
Refractoriness to Diuretic
Therapy
Inappropriate dose of diuretics
Iatrogenic causes of renal failure: NSAIDs, ACEI, aminoglycosides
Pre-renal failure precipitated by diarrhea, vomiting, SBP
Non-compliance with low sodium diet
Salerno F et al. Liver Int 2010:937-947
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Refractory Ascites
Diuretic-resistant ascites (20%)
• Lack of response to sodium restriction and high-dose diuretic (furosemide 160 mg, spironolactone 400 mg)
Diuretic-intractable ascites (80%)
• Development of diuretic-induced complications
Runyon B et al. Hepatology 2009:20872107
EASL Journal of Hepatology 2010:397-417
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Clinical Impact of
Refractory Ascites
Dilutional Hyponatremia
Hepatorenal Syndrome
Hepatic Hydrothorax
Spontaneous Bacterial
Peritonitis
Spontaneous Bacterial Empyema
Umbilical Hernia
Siqueira F et al Gastroenterol Hepatol 2009
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Dilutional Hyponatremia
• 30% of patients with
ascites
• Increase mortality if
Na< 125 mEq/L
• Fluid restriction if Na<
120mEq
Umbilical Hernia
• 20% of patients with
ascites
• At risk of inguinal
hernia development
• Paracentesis
• Avoid surgery due to
high risk of fluid
leakage, infection,
bleeding
• Incarceration,
strangulation, SBP
Siqueira F et al Gastroenterol Hepatol 2009
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CIRRHOSIS
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Treatment of Refractory Ascites
Liver transplantation
Large volume paracentesis (LVP) + albumin
Transjugular intrahepatic portosystemic shunt (TIPS)
Continue diuretics if no complication and Ur Na excretion > 30 mEq/L
Wong F Journal of Gastroenterol and Hapatol 2012:11-20
Runyon B et al. Hepatology 2004:1-16
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Complications of Paracentesis
Bleeding < 1%
Leakage of ascitic fluid
Paracentesis-induced circulatory dysfunction (PICD) or post-paracentesis circulatory dysfunction (PPCD)
• Increase cardiac output, decline of peripheral and splanchnic vascular resistance, activation of RAAS, increase HVPG
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PICD
70% occurs after LVP with no expander
15-50% after LVP with plasma expander
Shorter time to ascites recurrence
20% HRS and/or hyponatremia
Reduced survival
PRA level> 50% of pretreatment value to > 4 ng/ml*hr at 6th d
PRA
Ruiz-Del-Arbol L et al.
Gastroenterology 1997:579-586
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PICD Depends on the Type of Plasma Volume Expander and the Amount of Ascites Removed
De
ve
lop
me
nt
of
PC
D
%
Ascites removed
Overall <5-6 L >5-6 L
70
60
50
40
30
20
10
0
No expander
Saline
Synthetic expander
Albumin
Gines et al., Gastroenterology 1988; 94:1493;
Gines et al., Gastroenterology 1996; 111:1002;
Sola-Vera et al., Hepatology 2003; 37:1147
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Albumin Infusion in Patients Undergoing
Large-Volume Paracentesis: A Meta-Analysis of Randomized Trials
Trials (1988-2010) 1225 patients
Albumin
(6-8 g/L)
Control
(Dextran-70,
3.5% gelatin, 6% HES,
3.5% saline,
Norepinephrine, Midodrine, Terlipressin)
PICD (13 Trials:N= 857)
15% 30%
Mortality (11 trials:N= 927)
12% 14.4%
Bernardi M et al. Hepatology 2012:1172-1181
Albumin reduces morbidity and mortality among cirrhotic patients, tense ascites, LVP
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Transjugular Intrahepatic
Portosystemic Shunt (TIPS)
Side-side porto caval shunt
Decrease portal pressure
Improvement of circulatory dysfunction
Improvement on renal blood flow, urine Na-excretion, serum Cr
Colombo L J Clin gastroenterol 2007:S344-351
Rosle M et al. Gut 2010:988-1000
Bhogal H et al. Clin Gastroenterol Hepatol 2011:936-946
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Contraindications for TIPS
Absolute
Contraindication
Relative
Contraindication
• Congestive heart failure • Age > 70
• Severe pulmonary
hypertension > 50
mmHg
• Portal vein thrombosis
• Child-Pugh > 12 • HCC
• Multiple hepatic cysts • INR > 5
• Uncontrolled
encephalopathy
• Platelets < 20,000 mm3
• Unrelieved biliary
obstruction
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Meta-Analyses of TIPS and LVP
on Refractory Ascites
n TIPS,
%
LVP,% P TIPS,
%
LVP,% P TIPS,
%
LVP,% P
Lebrec
1996
25 38 0 - 23 0 - 29 56 <.05
Rossle
2000
60 84 43 - 58 48 NS 69 52 NS
Gines
2002
70 51 17 .003 77 66 NS* 41 35 NS
Sanyal
2003
109 58 16 <.001 42 23 NS* 19 mo 12 mo NS
Salerno
2004
66 79 42 .012 61 39 NS* 77 52 .021
Narahara
2011
60 87 20 <.001 67 17 <.001 80 49 <.005
Ascites control Encephalopathy Survival at 1 yr
Bhogal H et al. Clin Gastroenterol Hepatol 2011:936-946
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TIPS in Refractory Ascites
Improved transplant-free survival, better control of ascites
Lower PHTN related complications (GIB, SBP, HRS)
HE (30%) more severe HE in TIPS group (OR 2.26)
(Age, CPT >11, MELD >18)
Can cause cardiac failure, liver failure, endotipsitis, intravascular hemolysis
Patient’s selection: Age, bilirubin level < 5 mg/dl, Na > 130 mEq/L
Salerno et al. Liver Int 2010:1137-1342
Rosle M et al. Gut 2010:988-1000
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Vasoconstrictors, Albumin Control PCD% Ascites control
Terlipressin
(2006)
Albumin 23 vs 10
Midodrine (2006) Albumin 60 vs 30
Octreotide+
Midodrine (2012)
Albumin 25 vs 18 Time to LVP 10 d
vs 8 d
Albumin 4 g
(2011)
Albumin 8 g 14 vs 20 Time to LVP 98 d
vs 112 d
SMT+ Midodrine
SMT+ Clonidine
SMT+Midodrine+
Clonidine
Diuretic+ LVP
(SMT)
Better control of
ascites in
SMT+ midodrine,
SMT+M+C
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Future options
• No recommendation
to use Vasopressin
V2 receptor
antagonists
• Automated Low-
Flow Ascites pump
system (peritoneo-
vesical)
Wong F Journal of Gastroenterol and Hapatol 2012:11-20
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Automated Low Flow Pump
System for the Treatment of
Refractory Ascites
Bellot P et al. Journal of Hepatology 2013 in press
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Nutritional Support in Patients with
Refractory Ascites Main outcome Parenteral-
nutrition-
support,
balanced diet
and BCAA
(n=40)
Balanced diet
and BCAA (n=40)
Low sodium diet
(n=40) P- value
Death at 12 mo 18 (45%) 24 (60%) 33 (82.5%) A:B=0.048
A:C=<0.01
B:C= 0.046
LVP per mo 1.1 (0.8-2.5) 1.3 (1-2.9) 2.1 (1.5-4) A:B= NS
A:C=<0.01
B:C= 0.034
Encephalopathy 18 (45%) 15 (37.5%) 31 (77.5%) A:B= NS
A:C=<0.01
B:C= <0.01
GI bleeding 10 (25%) 13 (32.5%) 21 (52%) A:B= NS
A:C=<0.01
B:C= <0.01
HRS 6 (15%) 9 (22.5%) 15 (37.5%) A:B= NS
A:C=<0.01
B:C= <0.01
SBP 7 (17.5%) 9 (22.5%) 15 (37.5%) A:B= NS
A:C=<0.01
B:C= <0.01
Liver
transplantation
3 (7.5%) 4 (10%) 3 (7.5%) NS
Sorrentino P et al. Journal of Gastroenterol and Hapatol 2012
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Recommendation
Cirrhotic with ascites not responsive to diuretics
Exclude infection,
malignancy, NSAIDS use
Refractory ascites (meet
criteria)
Dietary noncompliance (urine Na 24 hr)
LVP with albumin (6-8 g/L if >5L of
fluid removal)
Liver Transplant evaluation
Liver not yet available or
frequent paracentesis
Consider TIPS
Not responsive Responsive No TIPS: Bilirubin > 5 mg/dl,
CPT >11, PSE grade >2
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Thank You
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Post-paracentesis Renin Levels Correlate Inversely with Systemic
Vascular Resistance
Ruiz-Del-Arbol L et al. Gastroenterology 1997:579-586
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Study Drugs PCD (%) PCD in
albumin
(%)
Ascites
recurrence (d)
Moreau 2006 Terlipressin 27 23
Singh 2006 Terlipressin 23 10
Appenrodt
2008
Midodrine 61 31
Bari 2012 Midodrine+
octreotide+
albumin
18 25 Albumin 10
Vaso 8
Alessandria
2011
(tense
ascites)
Albumin 4g/L
(half-dose)
14 20 ½ Albumin 98
Albumin 112
Vasocontrictors + albumin
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Odds Ratio (CI)
Albumin Control
Event Control Event Control
PCD in trials comparing albumin
vs alternative treatment
Bernardi M et al. Hepatology 2012
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Cumulative probability of transplant
free survival according to TIPS and
Paracentesis
P= 0.035 by
Log-rank
TIPS
Salerno et al. Gastroenterology 2007
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Cirrhosis:
obstruction to flow Portal
Hypertension
Sheer
stress,
Vasodilator
Splanchnic
vasodilatation
Portosystemic
shunting of
vasodilators
Systemic
arterial
vasodilation
EABV
Activation of
RAAS &SNS
&AVP
Sensitivity of
renal
circulation to
vasoconstrictor GFR, RBF,
Na retention ASCITES