Refractory ascites s a common problem to treat in any physician care ......approach has been given importance.

1. CHAIR PERSON : PROF.DR.RAVI .K
CO CHAIR PERSON:ASSOC.PROF.DR.KAVYA
PRESENTER:DR.ASHOKVARDHANREDDY.T

2.  PATHOPHYSIOLOGY OF ASCITES
 REFRACTORY ASCITES
 DEFINITION,
 CAUSES
 PATHOPHYSIOLOGY
 TREATMENT

3.  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.

4. PORTAL HYPERTENSION
Nitric oxide
SPLANCHNIC VASO
DILATATION

5. RENAL SODIUM
RETENTION
OVERFILL OF
INTRA VASCULAR
VOLUME
ASCITES
Sympathetic
Activity,
RAAS

6.  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

7.  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.

8.  Grade 1-Detectable by ULTRASOUND
abdomen.
 Grade 2-symmetrical distension of
abdomen.shifting dullness present.
 Grade 3 :Marked abdominal distension.
fluid thrill present

9.  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

10.  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 .

11. 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.

12.  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.

13.  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.

14.  Furosemide and spironolactone are the most
commonly used drugs

15. o Furosemide and spironolactone are most
commonly used drugs

16.  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

17.  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.

18.  Simultaneous administration of Na
restriction ,
 Spironolactone 100 mg/day
 Furosemide 40 mg/day
 4 days
dose increased to 200 spironolactone
+
80 mg furosemide

19.  Complications of diuretics
 Renal failure
 Hyponatremia
 Hepatic encephalopathy
 Hypo/hyper kalemia
 Hyper uricemia

20.  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

21.  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

23.  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 .

24.  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}

25.  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

26.  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.

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

28.  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

29.  Peritoneo venous shunt.
 TIPS(Trans jugular Intrahepatic Portosystemic
Shunt).
 Therapeutic paracentesis .

30.  Remove ascitic fluid before inserting
prosthesis
 To avoid massive passage of ascitic fluid in to
circulation
 Pulmonary edema ,
 Variceal bleed,
 Intravascular coagulation.

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

32. .

34. 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

35.  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}

36.  Remove the prosthesis and insert new one

37.  1 st described by CELSUS in 20 B.C
 Ludvig van beethoven in 1827 received large
volume paracentesis ….2 days after which he
expired.

39.  NECESSITY –
 10-20 % of patients are diuretic resistant.
 Complications are high with diuretics.
 Diuretics take time to reduce ascites.

40.  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 .

41.  1-
 Repeated large volume paracentesis.
 Ascites can leak in to abdominal
wall/outside.
 2-
 Total paracentesis
 Fluid is removed at once
 Less complication rate

43.  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

45.  Few studies –no apparent major changes in
circulatory function
 Arterial pressure
 PR – No change
 Ascites disappears
 Creatinine and electrolytes –no change

46.  Intra thoracic pressure
Circulatory function
 Stroke volume,cardiac output
 cardio pulmonary pressure , Renin

47.  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


48.  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%

49.  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.

50.  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.

51.  Spontaneous bacterial peritonitis
 Creatinine >3 mg/dl
 Severe hepatic encephalopathy
 Hypotension
 Disseminated intra vascular coagulation
 Caution in patients with abdominal adhesions

52.  Albumin infusion
 Incidence of Hyponatremia 3.8 %
 renal impairment -0%
 No plasma expander-
 Hyponatremia – 17 %
 Renal impairment 11 %

53.  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 …..

54. 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%

55.  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

56.  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

57.  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.

58.  After complete drainage of ascitic fluid
 {< 100 ml fluid drained /day}.

All patients were prescribed diuretics ,low
sodium diet on followed up.

59.  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.

62.  Trans jugular intra hepaic portosystemicshunt

 Endogenous vaso constrictor
system
 Renal function , GFR,response to
diuretics
 Lymph formation in liver and other
splanchnic organs

63.  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

64.  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

65.  TOTAL BILIRUBIN >5 mg/dl
 PT INR>2
 CHILD PUGH SCORE>11
 MELD SCORE >18
 HEPATIC ENCEPHALOPATHY >/= 2
 INFECTIONS
 RENAL FAILURE
 CARDIOPULMONARY DECOMPENSATION

66.  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 %

67.  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

68. 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

69.  TIPS changes course of cirrhosis from ascites
to hepatic encephalopathy without improving
overall results of paracentesis , in relation to
length of hospitalisation .

70.  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

71.  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

72.  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

73.  Significant increase in renin ,
 creatinine,
 serum electrolytes are observed without
albumin infusion.
 But no more clinical morbidity and mortality

74. 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

75.  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

76.  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;

77.  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

78.  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

79.  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
.

81. 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.

82.  Severe irritation in bladder
Recurrent urinary tract infections.
Pyelo nephritis
Not approved for practise.

83.  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

84.  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)

85.  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..

86.  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

87.  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)

88. 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.

89.  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

90.  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,USG
abdomen,doppler examination ,every
monthly for 3 months,and every 3 monthly
thereafter.

91.  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

92. 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%

93.  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.

94. Thanks to
• Dr.RAVI .K professor of medicine
• Dr.SUSHRUTH Surgical gastro
enterologist. PMSSY