Management of Cirrhotic Complications Uncontrolled Ascites. Siwaporn Chainuvati, MD Siriraj Hospital Mahidol University

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1 Management of Cirrhotic Complications Uncontrolled Ascites Siwaporn Chainuvati, MD Siriraj Hospital Mahidol University

2 Topic Definition, pathogenesis Current therapeutic options Experimental treatments Clinical approach

3 Gines P et al. NEJM 2004: Probability of Survival in Patients with Cirrhosis and Refractory Ascites Non-refractory ascites

4 Runyon B et al. Hepatology 2009: , EASL Journal of Hepatology 2010: 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

5 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:

6 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: EASL Journal of Hepatology 2010:

7 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

8 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

9 CIRRHOSIS

10 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

11 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

12 70% occurs after LVP with no expander PICD PRA level> 50% of pretreatment value to > 4 ng/ml*hr at 6 th d 15-50% after LVP with plasma expander PRA Shorter time to ascites recurrence 20% HRS and/or hyponatremia Reduced survival Ruiz-Del-Arbol L et al. Gastroenterology 1997:

13 Development of PCD PICD Depends on the Type of Plasma Volume Expander and the Amount of Ascites Removed % No expander Saline Synthetic expander Albumin Overall <5-6 L >5-6 L Ascites removed Gines et al., Gastroenterology 1988; 94:1493; Gines et al., Gastroenterology 1996; 111:1002; Sola-Vera et al., Hepatology 2003; 37:1147

14 Albumin Infusion in Patients Undergoing Large-Volume Paracentesis: A Meta-Analysis of Randomized Trials Trials ( ) 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) Mortality (11 trials:n= 927) 15% 30% 12% 14.4% Albumin reduces morbidity and mortality among cirrhotic patients, tense ascites, LVP Bernardi M et al. Hepatology 2012:

15 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:S Rosle M et al. Gut 2010: Bhogal H et al. Clin Gastroenterol Hepatol 2011:

16 Contraindications for TIPS Absolute Contraindication Congestive heart failure Age > 70 Severe pulmonary hypertension > 50 mmhg Child-Pugh > 12 HCC Multiple hepatic cysts INR > 5 Uncontrolled encephalopathy Unrelieved biliary obstruction Relative Contraindication Portal vein thrombosis Platelets < 20,000 mm 3

17 Meta-Analyses of TIPS and LVP on Refractory Ascites Lebrec 1996 Rossle 2000 Gines 2002 Sanyal 2003 Salerno 2004 Narahara 2011 n Ascites control Encephalopathy Survival at 1 yr TIPS, % LVP,% P TIPS, % LVP,% P TIPS, % LVP,% < NS NS NS* NS < NS* 19 mo 12 mo NS NS* < < <.005 P Bhogal H et al. Clin Gastroenterol Hepatol 2011:

18 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: Rosle M et al. Gut 2010:

19 Vasoconstrictors, Albumin Terlipressin (2006) Control PCD% Ascites control 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

20 Future options No recommendation to use Vasopressin V2 receptor antagonists Automated Low- Flow Ascites pump system (peritoneovesical) Wong F Journal of Gastroenterol and Hapatol 2012:11-20

21 Automated Low Flow Pump System for the Treatment of Refractory Ascites Bellot P et al. Journal of Hepatology 2013 in press

22 Main outcome Nutritional Support in Patients with Refractory Ascites Parenteralnutritionsupport, 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= LVP per mo 1.1 ( ) 1.3 (1-2.9) 2.1 (1.5-4) A:B= NS A:C=<0.01 B:C= 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

23 Recommendation Cirrhotic with ascites not responsive to diuretics Exclude infection, malignancy, NSAIDS use Refractory ascites (meet criteria) Dietary noncompliance (urine Na 24 hr) Liver Transplant evaluation LVP with albumin (6-8 g/l if >5L of fluid removal) Liver not yet available or frequent paracentesis Consider TIPS No TIPS: Bilirubin > 5 mg/dl, CPT >11, PSE grade >2 Not responsive Responsive

24 Thank You

25 Post-paracentesis Renin Levels Correlate Inversely with Systemic Vascular Resistance Ruiz-Del-Arbol L et al. Gastroenterology 1997:

26 Vasocontrictors + albumin Study Drugs PCD (%) PCD in albumin (%) Moreau 2006 Terlipressin Singh 2006 Terlipressin Appenrodt 2008 Bari 2012 Alessandria 2011 (tense ascites) Midodrine Midodrine+ octreotide+ albumin Albumin 4g/L (half-dose) Ascites recurrence (d) Albumin 10 Vaso ½ Albumin 98 Albumin 112

27 Bernardi M et al. Hepatology 2012 Albumin Control Event Control Event Control PCD in trials comparing albumin vs alternative treatment Odds Ratio (CI)

28 Salerno et al. Gastroenterology 2007 Cumulative probability of transplant free survival according to TIPS and Paracentesis TIPS P= by Log-rank

29 Sheer stress, Vasodilator Cirrhosis: obstruction to flow Portal Hypertension Portosystemic shunting of vasodilators EABV Splanchnic vasodilatation Activation of RAAS &SNS &AVP Systemic arterial vasodilation ASCITES GFR, RBF, Na retention Sensitivity of renal circulation to vasoconstrictor