Is there still a need for

HSA ABDURACHMAN
Sub-Div. Gastro-Entero-Hepatology
Department of Internal Medicine
Padjadjaran University Faculty of Medicine
Dr Hasan Sadikin Hospital
BANDUNGc

LIVER CIRRHOSIS

Chronic, diffuse process

Conversion of normal liver architecture

Structurally abnormal nodules

Multiple causes

Initially develop without symptoms & signs

Progress: - Portal Hypertension

- Liver Failure

COMPLICATIONS OF LIVER CIRRHOSIS

Ascites and Edema

- Hepato-Renal Syndrome (HRS)
- Spontaneous Bacterial Peritonitis (SBP)

Portal hypertensive bleeding

Hepatic Encephalopathy
10 yrs: Decompensated in 60%
Survival rate 50%

FACTORS INVOLVED in the PATHOGENESIS of

RENAL DYSFUNCTION and ASCITES FORMATION in
CIRRHOSIS

Renin-Angiotensin-Aldosterone System
Sympathetic Nervous System
Atrial Natriuretic Peptide
Arachidonic Acid Metabolites
Nitric Oxide
Endothelin
Carbon Monoxide

MARKED CIRCULATORY DYSFUNCTION in

CIRRHOSIS and ASCITES
Low systemic vascular resistance
Low arterial pressure
Abnormal blood volume distribution
Reduced central blood volume
Marked stimulation of vasoconstrictors and antinatriuretic
system (RAA and SNS)
Intense circulatory dysfunction
is greatly reduced: HRS

renal perfusion / function

ALBUMIN INFUSIONS in CIRRHOSIS and ASCITES:

attempt to reduce the formation of ascites and / or
improve circulatory and renal function

ASCITES AS COMPLICATIONS OF LIVER

CIRRHOSIS
Grade 1
- Clinically silent
- Detectable only by USG

Grade 2: abdominal distension

Grade 3: tense, marked abdominal

distension

ALBUMIN USE? (1)

In Acute & Chronic illness:
Serum albumin inversely related to risk of death
For each 2.5 g/L decrement:
24% - 56% increased risk of death
Underlying condition is of greater prognostic significance
compared to absolute albumin level

ALBUMIN USE? (2)

Meta analysis on 30 RCT incl. 1419 critically ill pts:
higher risk of death in albumin treated group1
Meta analysis on 55 RCT incl. 3504 critically ill pts:
no conclusions whether Albumin improves or
worsens survival2
Australia & New Zealand: RCT 17 ICU incl. 7000 pts3
Use in Chronic Liver Diseases: Liver Cirrhosis?

1.Cochrane Injuries Group. BMJ 1998; 317:235-240

2. Wilkes,Navickis. Ann Intern Med 2001: 135:149-164
3.Finfer,Bellomo,Myburgh.BMJ 2003: 326:559-560

Albumin Use? (3)

Guidelines for the use of Albumin are to
aid practitioners:
supply,safety,cost concern,
appropriate indications and efficient use
Should be evidence-based
Developed using a consensus approach of
medical experts
Cook. Current Topics. Jan 2001 [Medline]

Albumin Use? (4)

If based on clinical experience and have not
been proved in prospective investigations:
Use of Albumin infusions is controversial
Debate fostered by the high cost and
limited availability

Inappropriate indications in Liver Cirrhosis:

nutritional supplementation
just hypoalbuminemia
increasing drug efficacy
low volume paracentesis

Cook. Current Topics. Jan 2001 [Medline]

USED of ALBUMIN in
CIRRHOSIS IS CONTROVERSIAL

Some of albumin indications:

supported by results of RCTs
based only on clinical experience and have not been proved
in prospective investigations

High cost and limited availability of albumin

Meta analysis on albumin infusions in critically ill patients:
may increase mortality

ARTERIAL VASODILATATION HYPHOTESIS

Compensated Cirrhosis

Decompensated

Hepatorenal Syndrome

Moderate Peripheral
Vasodilation (e.g splanchnic)

Severe Paripheral
Vasodilation

Extreme Peripheral
vasodilation

Moderate Decrease Effective

Arterial Blood Volume (EABV)

Severe Decrease
EABV

Extreme Decrease
In EABV with Hypotension

Moderate increase Plasma

Renin, Aldosterone,
Norepinephrine and
Vasopressin Concentrations

Severe Rise in Plasma

Renin, Aldosterone,
Norepinephrine and
Vasopressin Concentrations

Moderate Renal Vasoconstriction

With Renal Sodium
And Water Retention

Severe Renal Vasoconstriction

With Renal Sodium
And Water Retention

Extreme Renal Vasoconstriction

With Renal Sodium And
RENAL
Water Retention
FAILLURE

Plasma Volume Expansion

may be modifled by hypoalbuminemia

Plasma Volume Expansion

may be modifled by hypoalbuminemia

Plasma Volume Expansion

Return of plasma Renin
Aldosterone, Norepinephrine
and Vasopressin Concentrations
To Normal Value
Gines, Arroyo, Rodes, Schrier:
Ascites and renal dysfunction in

Inadequate to Normallze
Renal Hemodynamics
Plasma Renin, Aldosterone
Norepinephrine and
Vassopresin Concentrations

Ascites Formation

Extreme Elevation of Plasma

Renin, Aldosterone,
Norepinephrine and
Vasopressin Concentrations

Plasma Renin, Aldosterone

Norepinephrine and Vasopressin
Concentrations Remain high levels

Further Ascites Formation

Cirrhosis with Ascites

MARKED CIRCULATORY DYSFUNCTION:
Low systemic vascular resistance, arterial
hypotension,
and high cardiac output
Low systemic vascular
resistance: due to marked
splanchnic
vasodilatation as consequences of increased
activity of:
NO, PGs and vasodilator peptides

Abnormal distribution of blood volume & EABV

Marked stimulation of vasoconstrictor and

antinatriuretic systems (RAAS, SNS)
Dilutional hyponatremia and renal dysfunction:
unfavourable prognosis

Abelman WH, Hepatology 1994;20: 1356-1358

Ascites should be treated

Survival 50% at 2 yrs
Diuretic-resistant develop in 10%
Survival in diuretic-resistant:
50% at 6 mos, 25% at 1 yr
Complications of Ascites:
-

SPONTANEOUS BACTERIAL PERITONITIS

HEPATORENAL SYNDROME
Hernias (rupture / incarceration)
Respiratory complications
Dietary complications
Limited physical activity

Refractory Ascites
DIURETIC-RESISTANT ASCITES:
Ascites that cannot be mobilized or
Early recurrence of which cannot be prevented
due to lack of response to
sodium restriction and diuretic therapy

DIURETIC-INTRACTABLE ASCITES:
Ascites that cannot be mobilized or
Early recurrence of which cannot be prevented
due to development of diuretic-induced complications
that preclude use of effective dosage
International Ascites Club,1996

Diuretic-resistant Liver
Cirrhosis
Inability to mobilize ascites despite Na restriction
and maximum oral diuretics (160 mg furosemide
plus 400 mg spironolactone)
Development of azotemia, hepatic encephalopathy,
progressive electrolyte imbalance
Large Volume Paracentesis
remove 4 6 L ascites/d in conjunction with iv
albumin 6-8 g/L ascites removed
Arroyo ea. Hepatology 1996:23:164-176
Runyon.Semin Liver Dis.1997;17:163-175

Effect of Albumin in Cirrhosis with

Ascites

1. In the management of circulatory

and
renal dysfunction

During 40s 60s:

Albumin to reduce ascites formation
Ascites did not decrease despite increased serum albumin
and normal oncotic pressure !

Albumin to improve circulatory and renal function:

Increased total blood volume, reduction of vasoconstrictors
and RAAS: Only in LC with slightly impaired renal function
In severe renal dysfunction: albumin plus vasoconstrictors

Gines & Arroyo.Gut 2000;46:588-590

Effect of Albumin in Cirrhosis with Ascites

2. In the prevention of renal

dysfunction1
Deterioration of impaired circulatory dysfunction
due to:
Large Volume Paracentesis (LVP)
Sponteous Bacterialis Peritonitis (SBP)

Gines & Arroyo.Gut 2000;46:588-590

Effect of Albumin in Cirrhosis with Ascites:

LVP

2. In the prevention of renal

dysfunction2

Early favourable hemodynamic effect due to:

Suppression of vasoconstrictor and natriuretic factors
Increased plasma natriuretic peptide

Post Paracentesis circulatory dysfunction:

Impairment of EABV: Marked activation of vasoconstrictor and
while plasma volume unchanged
Not spontaneously reversible
Impairment of renal function and dilutional hyponatremia
Decreased survival

natriuretic factors

Prevented successfully by
Albumin 8g/l ascites removed
Albumin plus vasoconstrictor

Gines ea.Gastroent. 1988;84:1493-1502

Gines & Arroyo.Gut 2000;46:588-590

Paracentesis-Induced Circulatory
Dysfunction
Effects on Plasma Volume and RAAS
Plasma volume (ml)

Plasma renin activity (ng/ml/h)

40

4000

30

3000
2000

20

1000

10

Before

After

Before

After
Salo et al, J Hepatol 1997

Paracentesis Induced Circulatory Dysfunction

Albumin vs no Albumin
Renal failure/Hyponatremia

Plasma Renin Activity (ng/ml.h)

p<0.01

p=NS

p<0.01

12

20

A
15
8
10

5
0

Albumin

No Alb

Albumin

No Alb

Gines et al, Gastroenterology 1988

Effect of Albumin in Cirrhosis with Ascites:

2. In the prevention of renal

dysfunction3

SBP:
Spontaneous infection of ascites due to passage of
intestinal bacteria
Changes in circulatory function

renal failure in

1/3 pts

Due to high level of cytokines and vasodilator factors in

plasma
and ascitic fluid
Impaired prognosis
Effective prevented by antibiotic treatment combined
with
Albumin: 1.5 g/kgBW at day 1
1 g/kgBW days 2 and 3

Sort ea.N Engl J Med.1999;341:403-510

Role of Albumin in Cirrhosis with Ascites:

In the treatment of Hepato-Renal

Syndrome1
HRS:
Extreme expression of circulatory dysfunction in
cirrhosis with ascites
Very low arterial pressure and total systemic
vascular resistance
Marked overactivity of RAAS, SNS, ADH and
endothelin
Marked arterial vasoconstriction in kidney, muscle,
skin, and brain

Gines & Arroyo.Gut 2000;46:588-590

Role of Albumin in Cirrhosis with Ascites:

In the treatment of Hepato-Renal

Syndrome2
HRS:
Plasma volume expansion with
Albumin or
Peritoneovenous shunting or
vasoconstrictors: little success
Marked improvement after combination treatment of
vasoconstrictor (ornipressin, midodrine,
octeotride)
and Albumin for several days/weeks
Interim treatment of HRS prepared for liver transplantation

Guevara ea.Hepatology;1998;27:35-41
Angeli ea.Hepatology.1999;29:1690-1697

Concl. Use of Albumin in LC

Beneficial effect of Albumin:
modest and limited only to LC with slightly impaired renal function
who respond to conventional treatment: clinically not relevance to
justify such therapy in most of LC with ascites

Albumin in LC with diuretic-resistant acsites:

could prevent renal impairment by maintaining EABV

Albumin in LC with diuretic-resistant ascites:

very effective in preventing renal function deterioration due to LVP
and SBP; improve survival in SBP

In improving renal function in HRS with

established circulatory dysfunction:
Albumin alone is not effective
Albumin plus splanchnic vasoconstrictors

KONSENSUS
PENGGUNAAN ALBUMIN PADA
SIROSIS HATI
PPHI-PGI-PEGI
26 27 April 2003
Nikko Hotel, Denpasar, Bali

INDIKASI PEMBERIAN ALBUMIN

SBP BERAT
HRS TYPE 1
Sebagai pengembang plasma sesudah
paracentesis volume besar ( > 5 liter)

Kadar albumin < 2,5 g/dl pada sirosis hati

dengan komplikasi sistemik yang berat

CARA PEMBERIAN LAR. ALBUMIN

Kecepatan infus:

- Albumin 20%: 1 ml/menit

- Albumin 5%: 2-4 ml/menit

Parasentesis volume besar > 5 L:

Dosis: 6 8 g/1 L cairan asites yang dikeluarkan

Cara: 50% dalam 1 jam pertama sisanya diberikan dalam 6 jam

HRS tipe 1:

Albumin diberikan bersama-sama dengan obat-obat vasoaktif

(noradrenalin , oktreotid, terlipresin, ornipresin,)
Hari I: 1 g/ kg BB, hari II dst: 20- 40 g/ hari, kemudian dihentikan
bila CVP 18 cm H2O

SBP:

Dosis: 1,5 g/kg BB hari 1; dengan antibiotika

Cara: Saat diagnosis, diberikan dalam 6 jam kemudian 1 g/kg BB
hari ke-2 dan 3

Sirosis Hati

dengan komplikasi:

- Dosis = selisih kadar albumin x kgBB

PEMANTAUAN
Status hemodinamik
Tanda vital (tekanan darah, nadi, respirasi, CVP)
Irama jantung
Foto toraks

Status koagulasi
Status ginjal

Produksi urin, ureum - kreatinin

Elektrolit

Kadar albumin serum diperiksa 24 48 jam

Pemantauan disesuaikan dengan kondisi rumah sakit
setempat

EFEK SAMPING
Dekompensasi jantung
Edema paru
Risiko perdarahan - perdarahan varises
Penumpukan nitrogen bodies
Akumulasi obat, metal, hormon di ruang interstisial
Bersifat antikoagulan, menghambat agregasi trombosit
dan antitrombin III

Hipokalsemia
Reaksi transfusi? Tercemar virus heat resistant?

Serum Albumin:

Predominant serum-binding protein

Comprises:
75% 80% of normal plasma colloid
oncotic
pressure and
60% of protein content

Serum values 3.5 4.5 g/l

Total body content 300 500 g

Synthesis in hepatic cells only : 9 - 12 g / d

Half-life 20 days, degradation rate 4% / d

Hypoalbuminemia maybe due to

Decreased albumin production

Defective synthesis due to hepatocyte damage
Deficient intake of amino acids
Increased losses of albumin via disease
Stress-induced catabolism of body protein
Hemodilution

Liver Cirrhosis:

20%: normal nutritional state

40%: protein malnutrition
10%: energy (calorie) malnutrition
30%: protein-energy malnutrition (PCM)
Due to :
reduced dietary intake (anorexia, dietary
restriction?)
impaired digestion & absorption of
nutrients
reduced protein synthesis
Moriwaki et al, 2001

Dietary Management Problem

in Liver Cirrhosis:

Catabolism during progression of the disease

Impaired protein metabolism
AAA
BCAA
Hyperinsulinism and Insulin resistance
10% 30% DM in Liver Cirrhosis
Protein (and calorie) deficiency
Intolerance to oral protein intake: induce
Hepatic Encephalopathy

PORTAL
UNDERFILLING THEORY HYPERTENSION
SPLANCHNIC ARTERIAL
VASODILATATION
ARTERIAL HYPOTENSION

HIGH PRESSURE BARORECEPTOR

MEDIATED ACTIVATION OF THE
RAAS. SNS

VASOCONSTRICTION IN RENAL
CIRCULATION IN OTHER NON SPLANCHNIC
CIRCULATION

IMPAIRED FREE WATER EXCRETION

SODIUM AND WATER RETENTION

Schrier ea.Hepatology 1988;8:1151-1157

FORWARD THEORY

PORTAL
HYPERTENSION
SPLANCHNIC ARTERIAL
VASODILATATION

FORWARD INCREASE OF
SPLANCHNIC CAPILARY
PRESSURE AND PERMEABILITY

LYMPH FORMATION
LYMPH RETURN

AFTERIAL VASCULAR
UNDERFILLING AND ACTIVATION
SODIUM RETAINING MECHANISM

SODIUM AND WATER

RETENTION

ASCITES
Podolsky, Isselbacher.Harrisons Principal of Internal Medicine,14 th ed.
1994, 1492