REFRACTORY ASCITES

CHAIR PERSON : PROF.DR.RAVI .K

CO CHAIR PERSON:ASSOC.PROF.DR.KAVYA

PRESENTER:DR.ASHOKVARDHANREDDY.T

OBJECTIVES PATHOPHYSIOLOGY OF ASCITES REFRACTORY ASCITES DEFINITION, CAUSES PATHOPHYSIOLOGY TREATMENT

ASCITES Ascites is the most common

complication in patients with cirrhosis.

It develops as a consequence of a severe impairment of liver function and portal hypertension.

PATHOGENESIS OF ASCITES IN CIRRHOSIS

PORTAL HYPERTENSION

Nitric oxide

SPLANCHNIC VASO DILATATION

RENAL SODIUM RETENTION

OVERFILL OF INTRA

VASCULAR VOLUME

ASCITES

Sympathetic Activity,

RAAS

THEORIES OF ASCITES IN PORTAL HYPERTENSION The central event of ascites formation in

cirrhosis is a splanchnic arterial vasodilatation secondary to portal hypertension.

1 Backward theory :pressure due to resistance in liver

2 Forward theory :splanchnic bed vaso dilatation.

3 Overflow theory-Increased plasma volume increases hepatic lymph formation.

4 Underfilling theory – Arterial under filling

DETECTION OF ASCITES Clinical examination Usg abdomen- liver size portal vein homogenous – transudate multiple echogenic shadows – exudateFluid collects first in flanks,right upper quadrant ,para colic gutter , and around liver Multiple echos ,septations ,fibrous strands

indicates ascites unrelated to portal hypertension.

ASCITES GRADING Grade 1-Detectable by ULTRASOUND

abdomen. Grade 2-symmetrical distension of

abdomen.shifting dullness present. Grade 3 :Marked abdominal distension. fluid thrill present

WORLD JOURNAL OF HEPATOLOGY 2009

FACTS ON ASCITES Total ascitic fluid protein is inversely

related to portal hypertension. As the disease severity

increases ,protein levels decrease SBP develops in total ascitic fluid

protein <1 g/dl High concentration of macrophages is

found in ascitic fluid Bloody ascites occurs in 2 % patients

In patients with cirrhosis a complex coagulation process within the ascitic fluid results in intra peritoneal coagulation and primary and secondary fibrinolysis.

The macrophages of ascitic fluid synthesize vasodilatatory substances (e.g., nitric oxide, adreno medullin, vascular endothelial growth factor). The pathophysiologic significance of this finding is unknown.

The concentration of leptin and vascular endothelial growth factor is higher in ascitic fluid than in plasma .

Ascitic fluid has anti bacterial activity, which correlates directly with the total ascitic fluid protein concentration . Substances such as complement, fibronectin, cytokines, and are implicated in this effect.

Infusion of ascitic fluid within the general circulation is associated with important biologic effects, the most important being intravascular coagulation and fever.

REABSORPTION OF ASCITIC FLUID

A single layer of mesothelial cells covers the peritoneal surface of the diaphragm over a connective tissue matrix with a very rich plexus of terminal lymphatic vessels (lymphatic lacunae) .

Lacunae are large enough to allow the passage of erythrocytes, connect the peritoneal cavity with the lumen of the terminal lymphatics.

The submesothelial lymphatic plexus drains into parasternal trunks on the ventral thoracic wall, right lymphatic duct, and right subclavian or internal jugular vein.

During inspiration, lacunae are emptied During expiration, the gaps open and communication is re established.

The estimated mean rate of ascitic fluid reabsorption is 1.4 L/day, ranging from less than 0.5L to more than 4L.

TREATMENT OF ASCITES Furosemide and spironolactone are the

most commonly used drugs

TREATMENT OF ASCITESo Furosemide and spironolactone are

most commonly used drugs

Two different approaches for patients with cirrhosis and ascites-

1 step care approach –sodium restriction

spironolactone 100 mg/day

No response in 4 days 200 mg/day no response in 4 days 400 mg/day

No response at 400 mg spironolactone /day

start furosemide 40 mg /day Can be increased to 160 mg /day Dose escalated by 40 mg every 2 days.

OTHER METHOD Simultaneous administration of Na

restriction , Spironolactone 100 mg/day Furosemide 40 mg/day

4 days

dose increased to 200 spironolactone + 80 mg furosemide

Complications of diuretics

Renal failure Hyponatremia Hepatic encephalopathy Hypo/hyper kalemia Hyper uricemia

PREDICTION OF RESISTANCE TO DIURETICS Furosemide challenge test- 80 mg furosemide iv urine collection for next 8 hrs Urine sodium <50 m Eq for 8 hrs is

indicative of resistance

Random urine Na/k ratio >1 Indicates 24 hr urine Na excretion >78 m

Mol /day.

WORLD JOURNAL OF GASTRO ENTEROLOGY SENOUSY ETAL , 2009 JANUARY

OPD MONITORING OF ASCITES PATIENTS Once in 2 weeks Check body weight BP Look for orthostatic symptoms serum electrolytes Blood urea ,serum creatinine

WORLD JOURNAL OF GASTRO ENTEROLOGY

JANUARY 2009

REFRACTORY ASCITES Refractory ascites applies to the ascites

that cannot be mobilized(minimal /no weight loss)despite adherence to sodium restriction(88 m eq/2000 mg/day) or the early recurrence of which (i.e., after therapeutic paracentesis) cannot be prevented by medical therapy.

International ascites club Arroyo V etal .Hepatology ,1996 .

TYPES 1 DIURETIC RESISTANT ASCITES: Loss of body weight <200 g /day after 4

days of treatment or recurrence cannot be prevented even after

dietary sodium restriction <50 m eq/day {<90 m Eq/day EASL} Furosemide 160 mg/day AND Spironolactone 400 mg/day { SCHIFFS DISEASES OF

LIVER}/ 600 mg /day {HARRISONS TEXT BOOK OF INTERNAL

MEDICINE} for at least 1 week. Recurs rapidly after therapeutic

paracentesis with in 4 weeks {AASLD}

2 DIURETIC INTRACTABLE ASCITES: Ascites cannot be mobilised / recurrence

cannot be prevented due to diuretic induced complications that precludes use of effective diuretic dose.

Eg –Hepatic encephalopathy in absence of any precipitating cause

Increase in creatinine levels >100% to a value >2 mg %

Decrease in serum sodium level by >10 mEq/L to a concentration <125 mEq/L.

Decrease of serum potassiumlevel to <3 mEq/L or an increase to >6 mEq/L despite appropriate measures to normalize potassium concentration.

Most patients with cirrhosis and ascites with serum creatinine >1.2 mg/dl reflects decrease in renal blood flow and GFR by >50 % .

MECHANISMS OF REFRACTORY ASCITES Renal hypo perfusion Impairment of access of diuretics to

effective sites on the tubular cells

excessive reabsorption of Na + in PCT Reduced delivery of sodium to

ascending limb of loop of henle and the distal nephron

TREATMENT Peritoneo venous shunt. TIPS(Trans jugular Intrahepatic

Portosystemic Shunt). Therapeutic paracentesis .

PERITONEO VENOUS SHUNT Remove ascitic fluid before inserting

prosthesis To avoid massive passage of ascitic fluid

in to circulation

Pulmonary edema , Variceal bleed, Intravascular coagulation.

Prophylactic administration of anti staphylococcal antibiotics is recommended atleast for 3 days.

LE VEEN

.

DENVER SHUNT

SHUNTSPassage of ascitic fluid from abdominal cavity to systemic circulation

Sustained expansion of circulating blood volume

Renin,nor epinephrine,ADH, response to diureticsIts very good that patient feels better immediately,and it appears rational therapy for refractory ascites …….BUT

UNFORTUNATELY 40 % obstruction of shunt

with in 1 yr

{Fibrin deposits in valve / catheter,thrombus in venous limb of prosthesis, thrombus in SVC causing obstruction}

10 % small bowel obstruction in long term {intra peritoneal fibrosis}

TREATMENT OF COMPLICATIONS Remove the prosthesis and insert new

one

LARGE VOLUME PARACENTESIS 1 st described by CELSUS in 20 B.C LVP done using bronze tube

Ludvig van beethoven in 1827 received large volume paracentesis ….2 days after which he expired.

TAPPING ASCITIC FLUID(1672)

THERAPEUTIC PARACENTESIS NECESSITY – 10-20 % of patients are diuretic

resistant.

Complications are high with diuretics.

Diuretics take time to reduce ascites.

ADVANTAGES … Therapeutic paracentesis is considered

the best therapy for tense ascites in cirrhosis .

It considerably shortens hospital stay ,the cost of treatment, incidence of complications during hospitalization than among those treated with diuretics .

METHODS 1- Repeated large volume paracentesis. Ascites can leak in to abdominal

wall/outside.

2- Total paracentesis Fluid is removed at once Less complication rate

MODIFIED KUSS NEEDLE

7 cm length 17 G Blunt edged cannula with side holes Left lower quadrant To be connected to suction pump,30 –

60 mins( free flow of ascitic fluid is recommended now)

Precaution – patient should recline on opposite side for 2 hrs to prevent leakage of ascitic fluid

PIG TAIL CATHETER 6 F

PARACENTESIS +/- PLASMA VOLUME EXCHANGE Few studies –no apparent major

changes in circulatory function Arterial pressure PR – No change Ascites disappears Creatinine and electrolytes –no change

CONTRASTINGLY MANY STUDIES SHOW

Intra thoracic pressure

Circulatory function

Stroke volume,cardiac output

cardio pulmonary pressure , Renin

IMPAIRMENT OF CIRCULATORY FUNCTION

plasma renin levels which peaks on 6

th day of paracentesis leads to angiotensin II,nor epinephrine

vaso constriction of intrahepatic vessels-thereby resistance portal pressure

INCIDENCE OF CIRCULATORY DYSFUNCTION Patients admitted for tense ascites and

not on treatment and in 1 week hospital stay-16 %

Paracentesis induced circulatory dysfunction in patients not on plasma volume expansion -75 %

Patients on polygeline {8g/l ascitic fluid}-33-38 %

Patients on albumin {8g/l ascitic fluid}-11-18%

AMOUNT OF ASCITISC FLUID –CIRCULATORY DYSFUNCTION If amount drained is <5 l – incidence is

16% with albumin vs 18 % with synthetic plasma expander .

If 5-9 l- incidence 19% vs 30 %

>9 l 52 % with synthetic plasma expanders.

COMPLICATIONS Risk of peritoneal bleeding 0.5-1 % Leakage of ascitic fluid from tap site…

managed by z technique. PICD (Paracentesis induced circulatory

dysfunction.) Plasma renin increase > 50 % of pre

treatment value to above 4 ng/ml on 6 th day after paracentesis.

CONTRA INDICATIONS Spontaneous bacterial peritonitis

Creatinine >3 mg/dl

Severe hepatic encephalopathy

Hypotension

Disseminated intra vascular coagulation

Caution in patients with abdominal adhesions

Albumin infusion Incidence of Hyponatremia 3.8 % renal impairment -0%

No plasma expander- Hyponatremia – 17 % Renal impairment 11 %

CONCLUSIONS If we drain < 5 l ascitic fluid – less expensive synthetic plasma expanders -

8g/l ascitic fluid can be used

If > 5 l is drained albumin infusion is advised 8 g /l

50% immediately after paracentesis 6 hrs 50 % to be givenDiuretics to be continued If BUN and serum

creatinine are normal –200 mg / day spiranolactone or 40 mg /day

furosemide + 100 mg /day spironolactone …..

LE VEEN SHUNT VS PARACENTESIS

paracentesis Leveen shunt

Ascites episodes 125 38

Lvs obstruction 40 % in 1 yr

Days in hospital 48 +/-6 44+/- 6

Survival 1 yr 57 % 44%

USAGE OF CVP CATHETER FOR LARGE VOLUME PARACENTESIS Innovative idea of usage of cvp catheter

for drainage of ascitic fluid was tried to reduce the hospitalisation rate ,and so morbidity

Shahram agah,sahar tavakoli,Hajar nikbakth,Mehrdokht Najafi,Abdolreza al agha

Colorectal research center ,IRAN UNIVERSITY OF MEDICAL SCIENCES

HOW TO USE Precise percussion and point of highest

fluid accumulation should be marked for puncture site.

Local anesthesia with 5-10 ml of 2 % lignocaine inj.

Punctured using 18 G needle Perpendicular to skin

Guide wire passed through needle. Remove the needle . Pass the catheter through guide wire till

wing meet the skin . catheter outlet attached to urine bag . Drainage started at the rate of 250 -

500 ml/hr. Vital signs checked every 15 mins once

during procedure. 8 g Albumin is infused for 1 l of ascitic

fluid drained.

FOR HOW MANY DAYS After complete drainage of ascitic fluid

{< 100 ml fluid drained /day}. All patients were prescribed diuretics ,low sodium diet on followed up.

USEFUL ? Re admission rate was 1.9 in 1 yr follow

up (2-4 times in routene paracentesis) Serum sodium showed no significant

change , Potassium – no significant change

Creatinine decreased with in 24 hrs.

TIPS

TIPS

TIPS Trans jugular intra hepaic

portosystemicshunt Endogenous vaso constrictor

system Renal function , GFR,response to

diuretics Lymph formation in liver and

other splanchnic organs

marked in renin, aldosterone with in

1 week ADH and Nor epinephrine in

2 weeks

GFR increases , urinary excretion of Na increases in

1-2 weeks Free water clearance

TIPS porto caval gradient In 358 patients with refractory ascites

with TIPS Porto caval gradient decreased from

20.9 10 mm Hg Portal venous pressure 29.4 mm Hg

21.8 mm Hg Ascites resolves in 1-3 months 10 % patients doesn’t respond to TIPS Diuretics are required in >95 % cases

CONTRA INDICATIONS OF TIPS TOTAL BILIRUBIN >5 mg/dl PT INR>2 (relative ) CHILD PUGH SCORE>11 MELD SCORE >18 HEPATIC ENCEPHALOPATHY >/= GRADE 2 INFECTIONS RENAL FAILURE CARDIOPULMONARY DECOMPENSATION

Note:THROMBOCYTOPENIA IS NOT A CONTRA INDICATION AASLD 2013

COMPLICATIONS Most common – hepatic encephalopathy Occurs in > 40 % patients Responds to standard therapy May require to decrease the stent size

Early mortality {with in 30 days} occurs in 12 %

Late mortality in 40 %

OTHER COMPLICATIONS Worsening of Liver function tests due to

liver ischemia due to diversion of portal blood to systemic circulation

Cardiac failure Migration of stent to right heart or lung Endo tipssitis Transient intra vascular hemolysis Reference –API Medicine update ..Aabha nagral

TIPS VS PARACENTESIS FOR REFRACTORY ASCITESstudy Type of

ascitesControl of ascites

Hepatic encephalopathy

survival

LEBREC etal 1994

Refractory ascites

Better with TIPS

NO difference

Worse with TIPS

ROSSLE etal

Refractory & recidivant

Better with TIPS

No difference

Better with TIPS

GINES etal Refractory Better with TIPS

Worse with TIPS

No difference

SANYAL etal

Refractory Better with TIPS

Worse with TIPS

No difference

SALERNO etal2004

Refractory & recidivant

Better with TIPS

Worse with TIPS

Better with TIPS

TAKE HOME MESSAGE TIPS changes course of cirrhosis from

ascites to hepatic encephalopathy without improving overall results of paracentesis , in relation to length of hospitalisation .

AASLD GUIDELINES FEB 2013 Medical therapy – Beta blockers contra indicated

( hypotension) Midodrine 7.5 mg tid can be started

urine output urine sodium mean arterial

pressure Diuretic resistant diuretic

sensitive

Refractoriy ascites discontinue betablockers, add midodrine 7.5 mg

tid If not responding Consider 1 serial therapeutic paracentesis 2 liver transplant 3 TIPS 4 experimental medical treatment

AASLD RECOMMENDATIONS…. Large volume therapeutic paracentesis-

{ atleast 5 L} Total paracentesis is recommended Once in 2 weeks or once in 1 week Colloid replacement- In a randomised

control study 105 patients with tense ascites-

Albumin 1g/L vs without albumin infusion was studied

WITHOUT ALBUMIN VS WITH ALBUMIN Significant increase in renin , creatinine, serum electrolytes are observed

without albumin infusion.

But no more clinical morbidity and mortality

ROLE OF TERLIPRESSIN + MIDODRINE VS ALBUMIN INFUSION

o hr Terlipressin iv 1 mg starting of paracentesis

8 hr iv 1 mg repeat +tab midodrine 5 mg tid

16 hr iv 1 mg repeat EQUIVALENT to albumin in suppressing renin

Chronic therapeutic paracentesis is reserved for only 10 % patients who fail diuretics

As it causes hypo proteinemia, Malnutrition Increased infections

Prognosis of refractory ascites – Bad.,21 % die in 6 months

GUIDELINES ON TIPS TIPS vs Large volume therapeutic paracentesis

Significant survival advantage Better control of ascites More chances of encephalopathy Caution- patients with renal parenchymal

disease on dialysis may not respond well to TIPS

Do not with held diuretics after TIPS New entry- poly tetra fluoro ethylene coated

Stent is better ,patency duration is increased,greater survival;

AASLD ABANDONS PERITONEO VENOUS SHUNTS Why?

Poor long term patency Increased infections No increased survival compared to

medical therapy

Only in patients who are not candidates for TIPS/liver transplant/not fit for serial therapeutic paracentesis

EXPERIMENTS 1 retrospective study on efficacy of

weekly albumin infusion of 50 g in reducing weight in patients with refractory ascites who are not candidates for TIPS ….result awaited

Pilot Randomised control study -0.075 mg oral clonidine bid vs placebo in patients with cirrhosis ,with ascites and plasma nor Epinephrine> 300 pg/ml--- more rapid mobilisation of ascites with fewer complications

3 pilot Randomised control studies Paracentesis + albumin Vs Clondine + spironolactone In patients with refractory ascites and

plasma nor epinephrine >300 pg/ml

Result – fewer hospitalisation in latter group .

EXPERIMENTS

EXPERIMENTS Device that drains ascitic fluid into urinary bladder.ALFA pump system (Automated low flow ascites pump).Flow : catheter in abdominal cavity subcutaneously inserted battery powered pump catheter connected to bladder.

Pump is recharged wirelessly through skin Removes 5 L per charge.

SIDE EFFECTS Severe irritation in bladder

Recurrent urinary tract infections.

Pyelo nephritis

As of now, not approved for practise.

EASL GUIDELINES Median survival period for refractory

ascites is 6 months 1 st best option is liver transplant MELD score >18 Hyponatremia <130 mEq/l LOW Mean arterial pressure Low urine sodium <50 m eq/l High child pughscore >11 All determine duration of survival

LVP is the 1 st line treatment

Diuretics must be discontinued if dys electrolytemia/renal failure/hepatic encephalopathy occurs.

Continue diuretics only when urine sodium >30 mMol/l.

V2 receptor antagonists – satavaptan + fixed dose diuretics is under phase II trials

Improves Na levels,increases weight loss,decreases recurrence of ascites.

TIPS is recommended only if very frequent requirement of LVP/ineffective paracentesis (loculated)

Recently Tolvaptan is approved for management of refractory ascites..

STUDIES IN INDIA Forty cirrhotic patients with refractory or

recurrent ascites were prospectively studied after long term administration of midodrine plus standard medical therapy (n = 20) or standard medical therapy alone (n = 20) in a randomized controlled trial at a tertiary centre.

Virendra singh etal …PGIMER

A significant increase in urinary volume, urinary sodium excretion, mean arterial pressure, and decrease in plasma renin activity (p <0.05) was noted after 1 month of midodrine administration.

There was also a significant decrease in cardiac output and an increase in systemic vascular resistance after midodrine therapy at 3 months (p <0.05)

There was no change in glomerular filtration rate and model for end-stage liver disease (MELD) score.Midodrine addition is superior to standard medical therapy alone in

The control of ascites (p = 0.013) at 3 months.

The mortality rate in the standard medical therapy group was significantly higher than the midodrine group (p <0.046).

TIPS VS COATED TIPS ANNALS OF HEPATOLOGY ..Amarapurkar etal

Back ground- Use of covered TIPS was shown to improve the shunt patency rate over uncovered TIPS.Retrospective analysis was performed to assess efficacy of both methods-over 10 yr period

Who require LVP atleast 2 times in a month,or

Intolerant to LVP,or Unwilling to undergo further LVP were

treated with TIPS

GROUP A GROUP B 12 PATIENTS 11 PATIENTS Uncovered TIPS PTFE

covered Age 56.1+/_4.5 yrs 55.8+/_5.2

yrs Male : female-5:1

male :female-8:3

Followed up with –clinical examination,USG abdomen,doppler examination ,every monthly for 3 months,and every 3 monthly thereafter.

PTFE –POLY TETRA FLURO ETHYLENE

Clinical success= disappearance of ascites in 1 month

Technical success =post TIPS reduction of PPG (porto systemic pressure gradient) to <12 mm Hg.

TIPS dysfunction= >50 %reduction in flow velocity ,> 50 % shunt stenosis,or increase in PPG> 12mm Hg

RESULTSGROUP A GROUP B

CLINICAL SUCCESS 63.3% 81.8%

TECHNICAL SUCCESS

63.3% 81.8%

HEPATIC NCEPHALOPATHY

60% 54.4%

MORTALITY AT 1 YR 70% 63.3%

TIPS DYSFUNCTION REQUIRING RE INTERVENTION 50% 0%

REFERENCES Harrisons text book of internal medicine

18th edition Schiffs diseases of liver 11th edition. Sherlock’s diseases of liver and biliary

tract 12th edition AASLD guide lines 2013 EASL guidelines of liver disease 2012 Indian journal of gastro enterology. .volume

33,isssue4 ,august 2014. Clinical gastroenterology by Rajiv mehta 3rd

edition.

Thanks to

• Dr.RAVI .K professor of medicine• Dr.SUSHRUTH Surgical gastro

enterologist. PMSSY