Management of Cirrhotic

Complications

“Uncontrolled Ascites”

Siwaporn Chainuvati, MD

Siriraj Hospital

Mahidol University

Topic

Definition, pathogenesis

Current therapeutic options

Experimental treatments

Clinical approach

Probability of Survival in

Patients with Cirrhosis and

Refractory Ascites

Gines P et al. NEJM 2004:1646-54

Non-refractory

ascites

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

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

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

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

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

CIRRHOSIS

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

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

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

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

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

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

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

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

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

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

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

Automated Low Flow Pump

System for the Treatment of

Refractory Ascites

Bellot P et al. Journal of Hepatology 2013 in press

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

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

Thank You

Post-paracentesis Renin Levels Correlate Inversely with Systemic

Vascular Resistance

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

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

Odds Ratio (CI)

Albumin Control

Event Control Event Control

PCD in trials comparing albumin

vs alternative treatment

Bernardi M et al. Hepatology 2012

Cumulative probability of transplant

free survival according to TIPS and

Paracentesis

P= 0.035 by

Log-rank

TIPS

Salerno et al. Gastroenterology 2007

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