PSSLD workshop

Bhawalpur

Prof Ghias Un Nabi Tayyab

MBBS (Pb), MRCP (UK), FCPS (Pak), AGAF (USA)

Refractory Ascites & HRS

 Ascites
Ascites is defined as the pathologic accumulation of fluid in the
peritoneal cavity

Both the 2 older theories of ascites formation,

Underfill theory
Overflow theory
are relevant at different stages of the natural history
of cirrhosis

The most recent theory:

The arterial vasodilation hypothesis with net capillary
permeability and the hydraulic & oncotic pressure gradients,
matches best with the actual hemodynamic data
 Ascites in Cirrhosis
Ascites is the most common complication of decompensated
cirrhosis

Develops in 5–10% of patients with compensated

cirrhosis per year
Within 10 years after the diagnosis of compensated cirrhosis,
approximately 58% of patients will have developed ascites

The development of ascites is the final consequence of a series of

anatomic, pathophysiologic and biochemical abnormalities occurring in
patients with cirrhosis
 Pathogenesis 4

The development of Portal Hypertension (PHT) is the first step toward fluid retention in
cirrhosis, as the consequence of avid renal retention of sodium and water

Patients with cirrhosis but without PHT do not develop

ascites
Patients with cirrhosis whose urinary excretion of sodium is
significantly < dietary intake will accumulate sodium and
water, leading to ascites

A portal pressure >12 mmHg is required for fluid retention:

Ascites will usually disappear if portal pressure is reduced below 12
mmHg, e.g., after a surgical or radiologic porto-systemic shunt
 Portal Hypertension (PHT)

 Nitric oxide

Vasodilatation

Renal Sodium retention

Overfill of intravascular volume

Ascites formation

 Sympathetic nervous activity, renin, aldosterone

 Definitions

 Uncomplicated Ascites
 Ascites when not infected, refractory or
associated with impairment of renal function
 Grade 1(mild) – ascites in only detectable by
ultrasound examination
 Grade 2 (moderate) – Ascites causing moderate
symmetrical distention of the abdomen
 Grade 3 (large) – Ascites causing marked
abdominal distension
 Definitions

• Refractory Ascites
• Ascites that cannot be mobilized or early
recurrence of which cannot be prevented
by medical therapy.
– Diuretic resistant ascites – refractory to
dietary sodium restriction and intensive
diuretic treatment
– Diuretic intractable ascites – refractory to
therapy due to development of diuretic
induced complications that preclude the use
of effective diuretic dosage.
Diagnostic Criteria of Refractory
Ascites
Clinical Implications of Refractory Ascites
Hepatorenal syndrome
Functional Renal failure occurring in
patients with advanced Liver disease
because of significant drop in renal
perfusion
How common is this problem?

Compensated Cirrhotics

Decompensated Cirrhotics

Risk Factors?
Incidence
7-10% in hospitalized cirrhotics with ascites
20% at 1 year, 40% at 5 years

Risk Factors
Epidemiology
Advanced ascites (diuretic resistant)
Large volume paracentesis w/o albumin (15%)
SBP (20%)
Intake of NSAID’s

Prognosis
Worst prognosis of all complications of cirrhosis
Type 1 median survival: <2 weeks
Type 2 median survival: ~6 months
Majority of the patients
with refractory ascites
have HRS 2
 Diagnosis
Initial investigations

Underlying cause of ascites is frequently obvious from the

history and physical examination

• Essential investigations on admission: Diagnostic Paracentesis with

measurement of ascitic fluid albumin or protein, neutrophil count and
culture and ascitic amylase.
• Ascitic fluid cytology should be requested when there is a clinical
suspicion of underlying malignancy.
• Abdominal ultrasound scan to evaluate the appearance of the liver,
pancreas, and lymph nodes as well as the presence of
splenomegaly, which may signify portal hypertension.
• Blood tests should for measurement of urea and electrolytes, liver
function tests, prothrombin time, and full blood count.
 Diagnosis
Abdominal Paracentesis

A. Commonest site for an ascitic tap is approximately

15 cm lateral to the umbilicus, and is usually done in
the left or the right lower abdominal quadrant.
B. For diagnostic purposes, 10–20 ml of ascitic fluid
should be withdrawn (ideally using a syringe with a
blue or green needle) for inoculation of ascites into two
blood culture bottles and an EDTA tube.
C. Paracentesis is not contraindicated in patients with
an abnormal coagulation profile
 Diagnosis
Ascitic fluid investigation

Ascitic fluid neutrophil count and culture:

Ascitic fluid neutrophil count of >250 cells/mm3
(0.25x109/L) is diagnostic for SBP.
RBC in cirrhotic ascites: <1000cells/mm3
Blood ascitic fluid: >50,000cells/mm3
• inoculation of ascitic fluid into blood culture bottles will
identify an organism in approximately 72–90% of cases
 Diagnosis
Ascitic fluid investigation

Ascitic fluid protein and ascitic fluid

amylase:
a.Exudate (protein conc>25g/L): caused by malignancy
b.Transudate (protein conc<25g/L): caused by cirrhosis
Serum ascites-albumin gradient (SA-AG) has 97%
accuracy in categorizing ascites.
SA-AG = serum albumin conc – ascitic fluid albumin conc.
As a high ascitic amylase is diagnostic of pancreatic ascites, ascitic
fluid amylase should be determined inpatients where there is clinical
suspicion of pancreatic disease.
 Diagnosis
Ascitic fluid investigation

Ascitic fluid cytology:

Only 7% of ascitic fluid
cytologies are positive yet
cytological examination is 60–
90% accurate in the diagnosis
of malignant ascites.
Treatment
 Management of refractory ascites

Management of RA should follow a step-wise approach of

Dietary sodium restriction along medical therapy

large volume paracentesis (LVP) or

Insertion of a transjugular intrahepatic portosystemic

shunt (TIPS) in appropriate patients, and

consideration for liver transplant (LT)

Singhal S, Baikati KK, Jabbour II, et al. Management

of refractory ascites. Am J Ther. 2012;19:121–32. 23
 Alcohol
abstinence,
treat auto
immune, HBV
& HCV
Dietary
Liver
Sodium
Transplant
restriction

Treatment
Modalities
TIPS & Fluids intake
Shunting restriction

Large Volume
Paracentesis
Diuretics
 Treatment
Therapeutic Paracentesis

Patients with large or refractory ascites are usually initially

managed by repeated large volume paracentesis. Several
controlled clinical studies have demonstrated that large volume
paracentesis with colloid replacement is rapid, safe, and
effective.
Total paracentesis is generally safer than repeated
paracentesis, if volume expansion is administered post-
paracentesis.
Failure to give volume expansion can lead to post-paracentesis
circulatory dysfunction with impairment of renal function and
electrolyte disturbances
Dietary Sodium Restriction

The cornerstone of ascites management is

limiting daily sodium intake to 88 mmol or 2 gm
per day and increasing urinary sodium
excretion by using diuretics, thereby inducing a
negative sodium balance and therefore weight
loss.

26
Compliance with dietary Na restriction

Dietary sodium restriction is confirmed

by a 24-hour urine collection containing
less than 78 meq of sodium or
urine sodium less than the urine
potassium on a random sample)

27
Progression to diuretic-resistance is
generally an irreversible process unless
there is a reversible component to the liver
disease (eg, alcoholic hepatitis) or the
patient undergoes a successful liver
transplant.

28
 RA and B-blockers
The first step in treatment of patients with refractory ascites:
While on beta blockers (especially if azotemia is present) is to stop
the beta blockers.
This step can improve blood pressure, renal function, and
diuretic-responsiveness.

For similar reasons, angiotensin receptor blockers or enzyme

inhibitors should also be stopped.

Patients should be questioned about the use of NSAIDs, which

should be discontinued.

29
RA and B-blockers
Safety of nonselective B-blockers in patients with refractory
ascites has been questioned recently.

A prospective observational study found that patients with

refractory ascites who received nonselective beta blockers had
worse survival compared with those who did not.
A related concern is the potential to reduce renal perfusion in
patients whose renal perfusion pressure and ability to maintain
natriuresis are already compromised.

Need further studies……………

Sersté T et al. Deleterious effects of beta-blockers on

survival in patients with cirrhosis and refractory ascites.
Hepatology 2010; 52:1017.
Wong F, Salerno F. Beta-blockers in cirrhosis: friend and
foe? Hepatology 2010;52:811.
30
 RA and Midodrine
Midodrine an a1-adrenergic agonist increases the
effective arterial blood volume by causing splanchnic
vasoconstriction, and it improves renal perfusion and
glomerular filtration and is useful in refractory ascites

Singh V, Dhungana SP, Singh B, et al. Midodrine in patients with cirrhosis and
refractory or recurrent ascites: a randomized pilot study. J Hepatol 2012; 56:348.

31
RA and Midodrine
Midodrine at a dose of 7.5 mg to 10 mg orally three times
daily (with titration of the dose to achieve the desired
increase in blood pressure) can improve renal perfusion,
increase renal sodium excretion, and reduce ascites
espacially in patients with RA and relatively lower blood
presssure.
AASLD recommends Midodrine for the
management of RA
Need further studies……………

Singh V, Dhungana SP, Singh B, et al. Midodrine in patients with cirrhosis and
refractory or recurrent ascites: a randomized pilot study. J Hepatol 2012; 56:348.

32
Large Volume Paracentesis.
LVP, usually performed as an outpatient procedure,

• Effective and safer in managing large volume ascites

compared to diuretic therapy
• Lower incidence of renal dysfunction, electrolyte
abnormalities and much less disturbances to the
systemic and hemodynamic status
• Survival rates were no different.

Usually patients will have 4–6 L of ascitic fluid removed in a

single session of paracentesis.

Gin´es P, et al. Comparison of paracentesis and diuretics in the t

reatment of cirrhotics with tense ascites. Results of
a randomized study. Gastroenterology. 1987;93:234–41. 33
Large Volume Paracentesis.
Intravenous human albumin (HAS) infusions is
recommended after LVP to prevent:

The development of paracentesis induced circulatory dysfunction (PICD)

• PICD is associated with rapid re-accumulation of ascites, and a 20%

risk of developing renal dysfunction.
• PICD is objectively defined as increase in plasma renin activity (PRA)
to >50% of the levels pre-paracentesis to a final value >4 ng/mL/h.

This generally occurs with LVP of >5 L of ascites; there is minimal risk of
PICD with smaller volume paracentesis.

34
 Large Volume Paracentesis.

The American Association for the Study of Liver Disease

recommends infusion of 6–8 g of albumin/L of ascites
removed with a paracentesis of >5 L,
a practice associated with an apparent survival
advantage.
There have been conflicting reports of using
midodrine, an oral a1-adrenergic agonist with vasopressor
effect, as an alternative for the prevention of PICD following
LVP

Runyon BA. AASLD Practice Guidelines Committee. Management of

adult patients with ascites due to cirrhosis: an update. Hepatology. 2009;
49:2087–107.
35
TIPS for RA
(transjugular intrahepatic portosystemic shunt)

TIPS is a prosthesis placed in a radiologically created

channel within the liver parenchyma that connects a
branch of the portal vein with a branch of the hepatic
vein. It functions like a side-to-side portocaval shunt
and is very effective in lowering portal pressure.

Rossle M. TIPS: 25 years later. J Hepatol. 2013;59:1081–93.

36
TIPS
Decrease in portal pressure following
successful TIPS insertion leads to
improvement in systemic hemodynamics and
increased EABV, therefore reducing
neurohormonal activation.

This improves renal perfusion, favoring salt

and water excretion as early as 4 weeks post
TIPS insertion

37
TIPS

The currently preferred covered stent is

coated with polytetrafluoroethylene (PTFE) to prevent neointimal
proliferation and hence TIPS stenosis in the post insertion
period 38
TIPS
A metaanalysis of individual patient data from four randomized
controlled trials comparing LVP to TIPS in cirrhotic patients with
RA* found TIPS to be more efficacious in the control of ascites
(89.4% versus 42%).
Another meta-analysis demonstrated that the risk of ascites
recurrence decreased with TIPS when compared to LVP.

Bai M et al. TIPS improves liver transplantation-free

survival in cirrhotic patients with refractory ascites: an updated
metaanalysis. World J Gastroenterol. 2014;20:2704–14.

39
ALFA pump

The ALFA pump is a new technology that was

introduced for patients with refractory ascites in
recent years.
This device is subcutaneously implanted and
battery-powered, and moves ascites from the
peritoneal cavity to the urinary bladder to facilitate
removal of fluid by urination.

40
The programmable and rechargeable pump transports small amount of
ascites continuously from the peritoneal cavity into the bladder
to be eliminated by micturition

41
ALFA pump

Alfa pump has internal sensors that monitor the

pressure of the bladder and peritoneal cavity. When
there is no ascites in the peritoneal cavity or the bladder
is full, the ALFA pump will stop working.
Compared with repeated LVP, the ALFA pump is more
acceptable for patients with refractory ascites and
improves the quality of life.

42
ALFA pump

Initial problems included high pump infection rate, as

well as high rates of pump malfunction and catheter
dislodgement.
These were overcome by mandating prophylactic
antibiotic and by improving pump and catheter design
and implantation techniques.

43
Liver transplantation
• Liver transplantation can radically reverse Portal Hypertension.

• All patients with ascites should be considered as potential candidates for

liver transplantation.

• Patients with refractory ascites, spontaneous bacterial peritonitis, or

hepatorenal syndrome should be prioritized based on their Model for
End-Stage Liver Disease score.

• There is a remarkable improvement in the survival rate after liver

transplantation.

44
An algorithm for the management of ascites and refractory ascites

Gastroenterology Report, Volume 5, Issue 2, May 2017, Pages 104–112, https://doi.org/10.1093/gastro/gox010

The content of this slide may be subject to copyright: please see the slide notes for details.
THANK YOU
SHAHID/UMDC 49
 The prognosis of refractory ascites is very grim and thus

Prognosis of RA
expedited referral to a liver-transplantation center is
critical for appropriate transplant candidates.

SHAHID/UMDC 50
 Treatment
Bed rest

patients with cirrhosis and ascites, assumption of upright posture is associated

with activation of the renin-angiotensin-aldosterone and sympathetic nervous
system, a reduction in glomerular filtration rate and sodium excretion, as well
as a decreased response to diuretics.
These data strongly suggest that patients should be
treated with diuretics while on bed rest.
 Treatment
Dietary salt Restriction

Sodium restriction has been associated with lower

diuretic requirement, faster resolution of
ascites, and shorter hospitalization.
Dietary salt should be restricted to 90 mmol/day
(5.2 g) salt by adopting a no-added salt diet and
avoidance of pre prepared foodstuffs
Treatment
Management of hyponatremia in patients on diuretic therapy
 Treatment
Diuretics

Diuretics have been the mainstay of treatment of ascites since the 1940s when
they first became available.
• Spironolactone is the drug of choice in the initial treatment of ascites due to
cirrhosis. The initial daily dose of 100 mg may have to be progressively
increased up to 400 mg to achieve adequate natriuresis.
• It achieves a better natriuresis and diuresis than a ‘‘loop diuretic’’ such as
frusemide.
• Most frequent side effects of spironolactone in cirrhotics are those related to
its antiandrogenic activity, such as decreased libido, impotence, and
gynaecomastia in men and menstrual irregularity in women
• Hyperkalaemia is a significant complication that frequently limits the use of
spironolactone in the treatment of ascites.
 Treatment
Diuretics

• Furosemide is a loop diuretic which causes marked natriuresis and

diuresis in normal subjects.
• It is generally used as an adjunct to spironolactone treatment because
of its low efficacy when used alone in cirrhosis.
• The initial dose of furosemide is 40 mg/day and it is generally
increased every 2– 3 days up to a dose not exceeding 160 mg/day.
High doses of furosemide are associated with severe electrolyte
disturbance and metabolic alkalosis, and should be used cautiously.
• Simultaneous administration of furosemide and spironolactone
increases the natriuretic effect.
Treatment
Diuretics
Treatment
Therapeutic Paracentesis

Following paracentesis, ascites recurs in the

majority (93%) if diuretic therapy is not
reinstituted, but recurs in only 18% of
patients treated with spironolactone.
Reintroduction of diuretics after paracentesis
(usually within 1–2 days) does not appear to
increase the risk of postparacentesis
circulatory dysfunction.
Treatment
Prognosis

The development of ascites is associated with a

mortality of 50% within two years of diagnosis.
Once ascites becomes refractory to medical therapy,
50% die within six months.
Despite improving fluid management and patient quality
of life while awaiting liver transplantation, treatments
such as therapeutic paracentesis and TIPS do not
improve long term survival without transplantation for
most patients.
Therefore, when any patient with cirrhosis develops
ascites, suitability for liver transplantation should be
considered.
 An algorithm for the management of hyponatremia

Gastroenterology Report, Volume 5, Issue 2, May 2017, Pages 104–112, https://doi.org/10.1093/gastro/gox010

The content of this slide may be subject to copyright: please see the slide notes for details.
 Case
A 50-year-old lady is hospitalized for restlessness and
confusion. She has HCV related Liver cirrhosis for the
past 7 years, and now complicated by ascites for the
past 6 months. She takes lactulose with four to five
loose stools per day. She has been taking furosemide
and spironolactone with good response to diuretics
but lately she used to have a rise of Creatinine forcing
the treating physician to reduce the dose of diuretics.
3 Days ago she underwent a 5 Lt paracentesis for
abdominal distention. She was also given a tablet of
nimesulide by the USG specialist doing paracentesis
 Case
On physical examination, temperature is 36.4 °C
(97.5 °F), blood pressure is 102/74 mm Hg, pulse
rate is 78/min, and respiration rate is 16/min; BMI is
24.
She is disoriented to time and date. The mucous
membranes are dry.
She has mild tenderness all over the abdomen and
has a palpable left lobe of liver with 7 cm enlarged
spleen.
Shifting dullness is positive.
Questions
What is your Diagnosis or Differential Diagnosis?

What type of ascites is this lady suffering from?

What tests will you like to run?

Possible Answers
C related Cirrhosis
PSE
Ascites
Diuretic Intractable ascites ( Not
resistant)
? SBP
? HCC
?HRS type 1/2/3
Case: Lab Data
Laboratory studies
Hb 9.0,MCV 105, Plt 45,000, WBC 7,500, Neutrophils 75%
INR: 1.3 (normal range, 0.8-1.2)
Albumin: 2.6 g/dL (26 g/L)
Total bilirubin: 2.1 mg/dL
Blood urea nitrogen: 38 mg/dL (13.6 mmol/L)
Creatinine: 2.5 mg/dL (221 µmol/L)
Urinalysis: Normal, No proteinuria
AFP: 50 ng/ml
Ascitic fluid: Low SAAG ascites with WBC 2500/cmm and Polys 85 %
USG abdomen: Cirrhotic liver with 15 CM sized spleen, debrinous ascites,
echogenic kidneys, and varices at splenic hilum. No focal defect in liver
Her baseline creatinine is 0.7. Blood culture results are pending. Her
diuretics and lactulose are discontinued.
What is the Final Diagnosis
 C related Cirrhosis
PSE
Ascites
Diuretic Intractable ascites ( Not resistant)
SBP
? HCC
?HRS type 1
What is the expected Mortality?
How common is this problem?

Compensated Cirrhotics

Decompensated Cirrhotics

Risk Factors?
Incidence
7-10% in hospitalized cirrhotics with ascites
20% at 1 year, 40% at 5 years

Risk Factors
Epidemiology
Advanced ascites (diuretic resistant)
Large volume paracentesis w/o albumin (15%)
SBP (20%)
Intake of NSAID’s

Prognosis
Worst prognosis of all complications of cirrhosis
Type 1 median survival: <2 weeks
Type 2 median survival: ~6 months
What is the possible Pathophysiology in
the development of HRS
Two theories

Systemic Vasodilation theory

Hepatorenal reflex theory

Pathogenesis
Pathophysiology
Splanchnic arteriolar vasodilatation
– Decreased effective arterial volume
(EAV)
– Decreased systemic vascular
resistance
– Hypotension
– Activation of vasoconstrictor systems

Renin-Angiotensin Angiotensin-
Aldosterone-System
Sympathetic Nervous System
Anti-Diuretic Hormone
Pathophysiology
Hyperdynamic circulation
Hypotension from reduced effective art vol
Low systemic vascular resistance (SVR)
Baroreceptor activation
SNS activation leading to increased
contractility
Increased cardiac output
What could be the etiology in this patient?

DCLD

Diuretics

SBP

Recent Hx of LVP

Intake of NSAID
 Precipitating Factors

In type 1 HRS, a precipitating event is identified in 70 to 100% of patients with HRS,

and more than one event can occur in a single patient.

Identifiable precipitating factors

include:
Large-volume paracentesis without albumin infusion
Gastrointestinal bleeding
Acute alcoholic hepatitis
Bacterial infections
NSAID’s

•large-volume paracentesis without albumin expansion precipitates type 1 HRS in 15%

•25% of patients who present with acute alcoholic hepatitis eventually develop HRS

•Intravascular volume depletion by overdose diuretic use or lactulose induced

diarrhea have been considered triggering factors for HRS
What is the initial step before labelling HRS?

1.5 -2 liters of isotonic saline to see any

improvement in hemodynamics and urine
output
Extreme care after initial 750 ml in people
above 50 with co morbids
Case
Which of the following is the most appropriate initial treatment for acute
kidney injury in this patient?

1) Terlipressin
2) Octreotide
3) Midodrine
4) Midodrine and octreotide
5) Norepinephrine
6) 25% albumin
7) Terlipressin and Albumin
8) Octreotide and Albumin
What are Other Possible therapies?

Merits and Demirts of each possible

therapy
 Management of Hepatorenal
syndrome

Pharmacological TIPS

liver
transplantation

RRT
Artificial liver support
 General
 Stop diuretics, and nephrotoxic agents. potassium-sparing diuretics (such as
measures
spironolactone) are contraindicated because of the risk of hyperkalemia,
and loop diuretics (such as furosemide) may be ineffective.
Therefore, large-volume ascites should be treated with repeated large-
volume paracenteses and the intravenous administration of albumin (8
g of albumin per liter of ascites removed)
 CVP measurement "preclude volume related ARF"
 Fluid challenge : Expansion of intravascular volume with
Albumin: 1gm/kg up to 100 gm IV repeated after 12 hours provided that CVP is
<10mmhg during the first day then 20-40gm in the second day with follow up of S .
Creat.
Saline or volume expanders
 Search for sepsis: tapping of ascites for WBC, GM stain & culture. Culture of
blood , urine, cannula tips. Start Broad spectrum antibiotic promptly.
Specific treatment
lines
1.

Pharmacologic treatment (Bridging therapy)
Vasoconstrictors
 Albumin
1. Liver transplantation (the only definitive therapy)
2. TIPS (HRS 2)
3. Renal replacement therapy
 Arterio-venous Hemofiltration
 Veno-venous Hemofiltration
1. MARS (HRS 1)
 Vasoconstrictors plus albumin:
- Include IV terlipressin, IV norepinephrine, SC octeriotide +
oral Midodrine.
Pharmacologic ttt:
- TTT should be continued until creatinin normalization.
Median Duration of treatment is 7 days.
- Induce reversal (decreased s. creat to <1.5mg/dl) in 40-60% of
patients.
- Terlipressin + albumin (best evidence) prolong short term survival as recently
confirmed by meta-analysis.
Dose and duration . It should be started at a dose 0.5 – 1 mg i.v. (slow
push) every 4 – 6 h. If there is no early response (>25 % decrease in
creatinine levels a% er 2 days), the dose can be doubled every 2 days up
to a maximum of 12 mg / day (i.e., 2 mg i.v. every 4 h). Treatment can be
stopped if serum creatinine does not decrease by at least 50 % after 7
days at the highest dose. In patients with early response, treatment
should be extended until reversal of HRS (decrease in creatinine below 1.5
mg / dl) or for a maximum of 14 days .
A more rational method for adjusting the dose of vasoconstrictors is by
monitoring mean arterial blood pressure (an indirect indicator of
vasodilatation). This method has been used for adjusting the dose of
midodrine plus octreotide. Doses of octreotide and midodrine are titrated
to obtain an increase in the mean arterial pressure of at least 15 mm Hg.
- One small randomized trial showed that noradrenalin infusion may be equivalent
to terlipressin.
Attempts to use dopamine in combination with vasoconstrictors
conferred a better success rate, but this could be attributed to
vasoconstrictor therapy.

Similarly, the oral prostaglandin-E1 analog misoprostol or intravenous

prostaglandin infusion did not induce significant changes in GFR or
sodium excretion. Improvement in renal function occurred in one report
but could be explained by volume expansion.

The endothelin-A antagonist BQ-123 demonstrated a dose-dependent

renal improvement in three treated patients, but there still is
controversy over the role of endothelin blockers in HRS because
subsequent studies showed a paradoxic vasodilating effect of
endothelin in patients with cirrhosis
Terlipressin in HRS

Meta-analysis: terlipressin therapy for the hepatorenal syndrome

F. Fabrizi, V. Dixit & P. Martin APT 2006 24:935-44
 Terlipressin in HRS
The pooled rate of patients who reversed hepatorenal
syndrome after terlipressin therapy was

0.52 (95% CI, 0.42; 0.61), P =0.0001; I2= 24.6%.

The pooled frequency of responder patients who showed

hepatorenal syndrome recurrence after terlipressin
withdrawal was

0.55 (95% CI, 0.40; 0.69), P =0.00001; I2= 44.3%.

Meta-analysis: terlipressin therapy for the hepatorenal syndrome

F. Fabrizi, V. Dixit & P. Martin APT 2006 24:935-44
• Six randomised trials were eligible for inclusion

• 3 trials (total 51 patients) assessed terlipressin 1 mg bd for 2 to 15 days

• Co-interventions included albumin, fresh frozen plasma, and cimetidine

• Terlipressin reduced mortality rates by 34%

• The control group mortality rate was 65%

• Terlipressin improved renal function assessed by creatinine clearance,

serum creatinine and urine output
Terlipressin - Cardiac: angina MI & arrhythmia
- GI: cramps, vomiting, diarrhea,
intestinal ischemia.
- Periph: finger ischemia, skin and
scrotal necrosis.
- Others: HTN, bronchospasm, dyspnea

Noradrenaline Chest pain and ventilatory

hypokinesia
Octeriotide (glucagon release Diarrhea , tingling
inhibitor)
Midodrine (alfa adrenergic agonist) HTN
 The only (definitive) treatment associated with improved
survival for both HRS1 & 2.
 Pretreatment is important and improves LTX outcome
Liver transplantation:
(morbidity & mortality).
 After LTX calcinurine inhibitors (cyclosporine & tacrolimus)
should be avoided, azathioprine , steroids and IL2 receptor
blockers should be used instead until diuresis is started.
 The main problem of LTX in HRS1 is its applicability owing to
their extremely short survival. HRS should be allocated to the
first places of the waiting list.
TIPS, is an alternative treatment of type 1 HRS in patients without response to
terlipressin plus albumin.

o TIPS is effective in reversing type 2 HRS, The introduction of covered stents in

management of refractory ascites and type 2 HRS, mainly in those patients with

TIPS:
relatively good liver function.

o 2 pilot studies have recently evaluated transjugular intrahepatic portacaval shunt

(TIPS) in type 2 HRS: one showed marked reduction of s. creatinin in 8 out of 9
patients with long-term survival in 2 pts. The second showed significant
improvement in all patients as regard s. creatinin and ascites with 70% 1 year
survival probability. (Guevara & Arroyo, 2011).

o TIPS may improve renal perfusion and decrease RAAS activity.

o It can be considered also if HRS recurs after successful vasoconstrictor ttt

specially if liver transplantation is not likely in the near future.
Renal replacement
therapy :
Renal-replacement therapy in the form of hemodialysis or continuous
venovenous hemofiltration has been used in the management of the
hepatorenal syndrome, particularly in patients awaiting transplantation or in
those with acute, potentially reversible conditions (e.g., alcoholic hepatitis).

Complications during hemodialysis, particularly hypotension, bleeding, and

infections, are common. Unfortunately, the optimal renal-replacement method
for patients with the hepatorenal syndrome is not clear, nor is it clear whether
renal replacement therapy will improve the prognosis for patients who are not
candidates for a liver transplant.

Moreover, there are no data from studies comparing renal-replacement therapy

with vasoconstrictor administration. Until such data are available, it seems
reasonable to start therapy with vasoconstrictors and albumin alone unless there
is an urgent need for hemodialysis (i.e., because of severe hyperkalemia,
metabolic acidosis, or volume overload), and to reserve hemodialysis for
patients who do not have a response to vasoconstrictor therapy.
In a small, randomized study, the molecular adsorbent
recirculating system (MARS), a modi$ed dialysis method using
an albumin-containing dialysate, was shown to improve the 30-
Extracorporial albumin
day survival in 8 patients with HRS-1 compared with 5 patients
treated with intermittent venovenous hemo$ ltration alone .

dialysis:
However, clear beneficial effects on systemic hemodynamics and
on HE were observed. MARS is still considered to be an
experimental therapy and its use in patients with type-1 HRS
cannot be recommended outside prospective pathophysiological
or therapeutic investigations.
Conclusions
Hepatorenal syndrome is a diagnosis of exclusion
HRS has high rates of mortality
Must give a fluid challenge prior to making the diagnosis
Initial treatment involves albumin, ?octreotide, and terlipressin therapy
Long term treatment involves consideration of liver disease stage,
precipitating factors, co morbids and patient preferences
What is the final
treatment in this
lady?
Liver transplantation
She underwent Liver
transplantation 16/52
ago and just finished her
therapy for HCV and in
between stented for
anastomotic stricture