CHAIR PERSON : PROF.DR.RAVI .K

CO CHAIR PERSON:ASSOC.PROF.DR.KAVYA

PRESENTER:DR.ASHOKVARDHANREDDY.T

PATHOPHYSIOLOGY OF ASCITES

REFRACTORY ASCITES

DEFINITION,

CAUSES

PATHOPHYSIOLOGY

TREATMENT

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.

PORTAL HYPERTENSION

Nitric oxide

SPLANCHNIC VASO

DILATATION

RENAL SODIUM

RETENTION

OVERFILL OF

INTRA VASCULAR

VOLUME

ASCITES

Sympathetic

Activity,

RAAS

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

Clinical examination

Usg abdomen- liver size

portal vein

homogenous – transudate

multiple echogenic shadows –exudate

Fluid collects first in flanks,right upper quadrant ,para colic gutter , and around liver

Multiple echos ,septations ,fibrous strands indicates ascites unrelated to portal hypertension.

Grade 1-Detectable by ULTRASOUND

abdomen.

Grade 2-symmetrical distension of

abdomen.shifting dullness present.

Grade 3 :Marked abdominal distension.

fluid thrill present

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.

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.

Furosemide and spironolactone are the most

commonly used drugs

o 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.

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

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

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 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 .

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 paracentesiswith 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

% .

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

Peritoneo venous shunt.

TIPS(Trans jugular Intrahepatic Portosystemic

Shunt).

Therapeutic paracentesis .

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.

.

Passage of ascitic fluid from abdominal cavity to systemic circulation

Sustained expansion of circulating blood volume

Renin,nor epinephrine,ADH, response to diuretics

Its very good that patient feels better immediately,and it appears rational therapy for refractory ascites …….BUT

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}

Remove the prosthesis and insert new one

1 st described by CELSUS in 20 B.C

Ludvig van beethoven in 1827 received large

volume paracentesis ….2 days after which he

expired.

NECESSITY –

10-20 % of patients are diuretic resistant.

Complications are high with diuretics.

Diuretics take time to reduce ascites.

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 .

1-

Repeated large volume paracentesis.

Ascites can leak in to abdominal

wall/outside.

2-

Total paracentesis

Fluid is removed at once

Less complication rate

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

Few studies –no apparent major changes in

circulatory function

Arterial pressure

PR – No change

Ascites disappears

Creatinine and electrolytes –no change

Intra thoracic pressure

Circulatory function

Stroke volume,cardiac output

cardio pulmonary pressure , Renin

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

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%

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.

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.

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 %

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 given

Diuretics to be continued If BUN and serum creatinine are normal –

200 mg / day spiranolactone or 40 mg /day furosemide + 100 mg /day spironolactone …..

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%

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

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.

After complete drainage of ascitic fluid

{< 100 ml fluid drained /day}.

All patients were prescribed diuretics ,low

sodium diet on followed up.

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.

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

TOTAL BILIRUBIN >5 mg/dl

PT INR>2

CHILD PUGH SCORE>11

MELD SCORE >18

HEPATIC ENCEPHALOPATHY >/= 2

INFECTIONS

RENAL FAILURE

CARDIOPULMONARY DECOMPENSATION

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 %

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

study Type of

ascites

Control of

ascites

Hepatic

encephalop

athy

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

TIPS changes course of cirrhosis from ascites

to hepatic encephalopathy without improving

overall results of paracentesis , in relation to

length of hospitalisation .

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

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

Significant increase in renin ,

creatinine,

serum electrolytes are observed without

albumin infusion.

But no more clinical morbidity and mortality

o hr Terlpressin 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

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;

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

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

.

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.

Severe irritation in bladder

Recurrent urinary tract infections.

Pyelo nephritis

Not approved for practise.

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 dyselectrolytemia/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)

Role of aquaretics

phase III clinical trials –satavaptan +

diuretics showed no further improvement in

control of ascites

Increased morbidity and mortality was also

observed

Recently Tolvaptan is approved for

management of refractory ascites..

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). There was no significant difference

in the frequency of various complications at

the end of follow-up.

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,selected patients

who require LVP atleast 2 times in a

month,or intolrant to LVP,or unwilling to

undergo further LVP were treated with TIPS

12 PATIENTS 11 PATIENTS

Uncovered TIPS PTFE covered TIPS

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

Male : female-5:1 male :female-8:3

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

Clinical success= disappearance of ascites in

1 month

Technical success =post TIPS reduction of

PPG (porto systemic pressure gradient) <12

mm Hg.

Appearance of encephalopathy

TIPS dysfunction= >50 %reduction in flow

velocity ,> 50 % shunt stenosis,or increase in

PPG> 12mm Hg

GROUP 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%

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