THE USE
OF HUMAN
albumin SOLUTIONSIN ITALYTABLE OF CONTENTS

Introduction
5

Chapter 1
The structure, metabolism and functions of albumin

11

Chapter 2
Fluid therapy: use of crystalloids and colloids

17

Chapter 3
Therapeutic use of albumin in liver cirrhosis

29

Chapter 4
Therapeutic use of albumin in critical patients and in otherpathological conditions

The use of human albumin solutions in Italy

INTRODUCTION
Pharmaceutical research is making great progress:
currently there are no fewer than 7,000 innovative
products at an advanced state of clinical development.
This positive “tsunami” will make new and often
revolutionary therapies available to patients.
It is a development that goes hand-in-hand with thosebenefits in terms of health and better living obtained
from products offered by current therapeutic options,such as medicines derived from human blood.
Albumin is one such product and since the 40s it has
been a fundamental instrument in fluid therapy, and still
today is unique for its properties and tolerability.
In terms of therapeutic efficacy but also efficiency
measured in cost/benefit terms, albumin is essential not
only for the treatment of various stages of cirrhosis but
also for other pathologies.
Considerable clinical evidence has led healthcare
authorities and scientific societies to lay down precise
rules to ensure an ever-more appropriate use.
This publication, by bringing together the latest
information on the functions, structure, properties andtherapeutic indications of albumin solutions, sets out topromote prescriptive appropriateness and contributetowards optimising albumin use to the advantageof patients, even where its use has not yet beenstandardised.
Massimo Scaccabarozzi, President of Farmindustria

3Chapter 1
THE STRUCTURE,
METABOLISM AND
FUNCTIONSOF ALBUMIN

The use of human albumin solutions in Italy

The structure, metabolism
and functions of albumin
Structure
Albumin is the most abundant protein circulating in the human body (3.5-5 g/dl),making up about 50% of plasma’s overall protein content.
It is a small globular protein (molecular weight: 66.5 kDa) made up of a single 585
amino acid sequence structured into three repeating homologous domains (I, II
and III), each of which divided into two specific sub-domains (A and B). Of the 35
cysteine residues in the albumin molecule, 34 are involved in internal disulfide
bonds that stabilise the molecule’s spatial configuration, while the cysteine inposition 34 (Cys-34) remains free, constituting the molecule’s principle active site.
[1-3]

Metabolism
In physiological conditions, the liver synthesises about 10-15 gm of albumin a day,which are released into the bloodstream with limited or no intracellular storage.
Hormonal factors such as insulin, cortisol and growth hormones (GH) stimulate theproduction of albumin while pro-inflammatory mediators, including cytokines such as
interleukin 6 (IL-6) and the tumour necrosis factor α (TNF-α), have an inhibitory effect.
About 30-40% of the albumin produced remains within the vascular compartment,
while the remaining part is distributed in the interstices and tissues. Protein leaves
the vascular compartment by transcapillary migration and returns through thelymphatic system with a circulatory half-life equivalent to about 16-18 hours, which ismuch less than its total half life of between 12 and 19 days in a healthy young adult.
Its catabolism is a widespread process that involves many tissues but its principal
sites are muscles, liver and kidneys, while a small amount is lost in the gastrointestinal
tract. [1-3]Functions
The scientific findings of recent years have clearly shown that albumin has a long
list of clinically important functions. Besides its well-known oncotic power, albumin
performs many activities grouped under the definition of non-oncotic properties(Figure 1).
Figure 1
Oncotic (A) and non-oncotic(B) properties of the albumin
molecule.

A

Bond with H+

Antioxidant
Free radical neutralisation andion metal bondingHighmolecular
weightActionAnti-inflammatory
immunomodulation

High plasma
concentration

6

B

pH regulation
Net negative
chargeBond with LPS,
TNF-a inhibition,bond with PG,
Redox status regulation

Solubilisationand transport

Bonds with endogenous andexogenous substances including drugs

Antithrombotic
effects
NO - bonding

Regulation of fluid distribution

Endothelium stabilisation
Immunomodulation and anti-inflammatory action

ONCOTIC FUNCTIONNON-ONCOTIC FUNCTION

The structure, metabolism and functions of albumin

ONCOTIC POWER
Albumin is the principal fluid distribution modulator
in the various compartment of the human bodyaccounting for 70-80% of plasma’s oncotic pressure.
Two-thirds of its oncotic power derives from the direct
osmotic effect of its molecular mass, while one-thirdis due to the Gibbs-Donnan effect, which, due to the
net negative charge of the pH physiological molecule,allows protein to attract and retain positively charged
molecules (especially sodium) and thus water in theintravascular compartment.
These features, together with its long circulatory halflife and total half-life (see above) make albumin an
excellent plasma expander and at present constitutethe main reason for its use in clinical practice. [3]NON-ONCOTIC PROPERTIESAlbumin is endowed with a series of biologicalproperties that are independent of its oncotic
power and closely related to the molecule’s dynamic
and flexible structure. [1-3] The main non-oncotic
properties are briefly set out below.
Binding, transport and detoxification
The albumin molecule contains a large number ofbinding and transport sites. The main domains are able

to fold into hydrophobic pockets that open and closeand host large insoluble anions, while cationic groups
situated on the molecule’s surface allow the formationof ionic bindings with many substances.
Consequently, albumin binds and transports alarge variety of hydrophobic molecules, including
endogenous substances (such as cholesterol, fatty
acids, bilirubin and thyroxine) or exogenous (such as
medicinal products and toxic molecules, for example
a-toxin G), metallic transition ions and gases (such as
nitric oxide) with clear implications in terms of theirsolubilisation, transport and metabolism.

Given the close correlation between structureand function, the limited total concentration of
circulatory albumin and molecular variations
that occur in many acute and chronic pathologies
have an important and negative impact uponthese functions, for example, by altering thepharmacokinetics and pharmacodynamics of anumber of medicines, including antibiotics, withobvious consequences upon their efficacy andsafety. [3]7The use of human albumin solutions in Italy

RECENT SCIENTIFIC EVIDENCE
CLEARLY DEMONSTRATES THAT
albumin PERFORMS A
LONG SERIES OF CLINICALLYIMPORTANT FUNCTIONS:BESIDES ITS WELL-KNOWN
ONCOTIC POWER, IT PERFORMSMANY OTHER ACTIVITIES THATCOME WITHIN THE DEFINITIONOF NON-ONCOTIC PROPERTIES.

Antioxidant action
The albumin molecule is the main extracellular sourceof reduced sulfhydryl groups (-SH), which play astrong scavenger role of the reactive oxygen andnitric oxide species, respectively ROS and RNS (freeradicals), making protein the body’s main circulatory
antioxidant.
Cysteine residue in position 34 (Cys-34) is the largest
extracellular reservoir of reduced sulfhydryl groups,
thereby constituting the main circulatory antioxidant
system.
Under physiological conditions, and according to the
reduced status of the sulfhydryl group in position Cys34, three albumin isoforms can be identified:• 70-80% circulates as mercaptalbumin (HMA),
characterised by a reduced Cys-34 with apreserved functional activity;• 20-30% circulates as non-mercaptalbumin-1(HNA1), with the reversibly oxidised Cys-34 residue
and linked to small thiol molecules, with impaired
functionality;• 5% circulates as non-mercaptalbumin-2 (HNA2),
with a not reversibly oxidised Cys-34 residue, witha consequent and definitive loss of functionality.
In chronic and acute pathological states characterised
by pro-oxidant and pro-inflammatory circulatory
micro environment the share of oxidised albumin issignificantly higher and represents an independent
predictor of mortality. [4]Albumin’s antioxidant function also depends on thecapacity of the N-terminal part of the molecule tobind various metallic ions, including copper, cobalt,
nickel, zinc and iron, thus preventing from catalysing
chemical reactions that generate them free radicals.
In this manner, not only does albumin neutralise free
radicals, but also reduces their formation.
The modulation of the inflammatory
and immunological response
Albumin can modulate the secretion and activation ofvarious mediators of inflammatory and immunologicalresponse, including pro-inflammatory cytokines (TNFalfa) and factors of complement (C5a). Alongsidedirect mechanisms, this action of albumin seems to be
mediated by the capacity to antagonize the effects ofoxidative stress.

8

The structure, metabolism and functions of albumin

Moreover, albumin is capable of binding theprostaglandin E2 (PGE2), that have an immunosuppressive effect by reducing its bioavailability.
It has recently been demonstrated thatin patients with hepatic insufficiency, theadministration of exogenous albumin cancontribute towards the re-establishment of acondition of immuno-competence throught a
reduction in PGE2, in such patients that are also
at great risk of developing bacterial infections
and sepsis. [5]Antithrombotic action
Albumin is able to bind nitric oxide mainly at the levelof the Cys-34 site with the consequent formation of
nitroso-albumin. This compound appears to preventthe rapid inactivation of nitric oxide and prolong its
anti-aggregating effect on platelets. In addition to theforegoing activity, albumin also seems to perform aheparin-like anticoagulant function.
Capillary permeability and endothelial
stabilisation
Albumin contributes to the vascular integrity bybinding to interstitial matrix (glycocalyx) in the subendothelial space, thereby contributing towards themaintenance of normal capillary permeability.
This function may derive not only from the highnegative charge with its consequent electrostatic
repulsion of negatively charged molecules but
also from a mechanical action explained by thephenomenon of spatial occupation.
Moreover, albumin plays an active role in stabilising
endothelial functionality during bacterial infection by
reducing the activation of endotethial cells, preserving
capillary permeability and preventing neutrophil
adhesion to the endothelium.
Regulation of acid-base equilibrium
Albumin’s molecular structure comprises 16 imidazole
residues of histidine that provide the molecule with its
intra and extra-buffer functionality, which can provide
positive charges in the case of alkalosis and negative
charges in the case of acidosis.

concentration has emerged. This derives from thesum of a quantitative factor corresponding to thecirculatory albumin concentration and a qualitative
factor corresponding to the amount of albumin witha normal molecular structure. In brief, the molecule’s
global functions deriving from its oncotic and nononcotic properties depend not only on the circulatory
quantity of albumin but also upon its structural
integrity.
Patients with acute and chronic illnesses often exhibit
hypoalbuminaemia which represents one of themain prognostic factors for predicting morbidity andmortality. Alongside a reduction in the quantity ofcirculatory albumin, such pathological conditions leadto structural alterations that can negatively impact
numerous molecular functions
This means that in these patients the efficacious
albumin concentration is certainly below thecirculatory serum albumin concentration routinely
measured with standard laboratory methods.
Consequently, the exogenous administration ofalbumin should serve the twin purpose of increasing
both the total quantity of circulatory albumin and the
proportion of functionally integrated albumin. [3,6]Bibliography[1] Quinlan GJ, Martin GS, Evans TW. Albumin: biochemical properties
and therapeutic potential. Hepatology 2005; 41:1211–1219[2] Fanali G, Di Masi A, Trezza V, et al. Human serum albumin: frombench to bedside. Mol Aspects Med 2012; 33: 209-90[3] Garcia-Martinez R, Caraceni P, Bernardi M, Gines P, Arroyo V, Jalan
R. Albumin: pathophysiologic basis of its role in the treatment of
cirrhosis and its complications. Hepatology 2013; 58:1836-46[4] Oettl K, Stauber RE. Physiological and pathological changes in theredox state of human serum albumin critically influence its binding
properties. Br J Pharmacol 2007, 151: 580-590[5] O’Brien AJ, Fullerton JN, Massey KA, et al. Immunosuppression inacutely decompensated cirrhosis is mediated by prostaglandin E2
Nat Med 2014, 20:518-23[6] Domenicali M, Baldassarre M, Giannone FA, et al. Post-transcriptional changes of serum albumin: clinical and prognostic significance inhospitalized patients with cirrhosis. Hepatology 2014; 60: 1851-60

Concept of an efficacious albumin concentration
In recent years the concept of an efficacious albumin

9Chapter 2
FLUID THERAPY:USE OF CRYSTALLOIDS
AND COLLOIDS

The use of human albumin solutions in Italy

Fluid therapy:
the use of crystalloids and colloids
Fluid therapy is usually used to replenish good volume losses and restore aneffective circulation as well as correcting electrolytic disorders and reinstating an
acid-base equilibrium.
Fluid replacement is carried out by the use of different solutions belonging to
two large and distinct categories of substances: crystalloids and colloids. This
classification, despite dating back to the second half of the nineteenth century, is
still in force. It was invented by Thomas Graham, a Scottish chemist, who divided
substances on the basis of their capacity to pass through a parchment membrane.
Crystalloids refer to substances that can pass through such a membrane while
colloids refer to those that cannot.

Crystalloids
Crystalloids are electrolytic solutions made up of small molecules that can passthrough most semi-permeable biological membranes and very easily spread
into extracellular space. Among the most commonly used crystalloids there are
5% glucose solutions, 0.9% saline solutions, Ringer’s lactate or acetate solution,
electrolytic solutions and, in general, all solutions obtained by mixing various lowmolecule weight molecules with water.
Crystalloids are sometimes used as solutions for restoring or maintaining
normovolaemia and as a vehicle for administering medicinal products. The choiceof the individual crystalloid will be based upon the pathology to be dealt with. The“ideal” solution would be one that reflects the composition and concentration of theliquid lost by the body. [1,2]

Fluid therapy

IS USUALLY USED TO REPLENISH
GOOD VOLUMETRIC LOSSES
AND restore AN EFFECTIVE
CIRCULATION AS WELL AS
FOR correcting ELECTROLYTICDISORDERS AND REINSTATINGAN ACID-BASE EQUILIBRIUM.

Fluid therapy: use of crystalloids and colloids

Colloids
Colloids are intermediate solutions halfway between
solution and diffusion in which larger and heavier
molecules being unable to pass through most semipermeable biological membranes remain in a finely
dispersed or “micro-heterogeneous” state. These
preparations are able to produce an increase inoncotic pressure and increase plasma volume byattracting water from extra-cellular space. [1,2]The colloids available for clinical use are of two types:• artificial or synthetic colloids (non-protein
colloids)• natural colloids (plasma and human albumin)
ARTIFICIAL OR SYNTHETIC COLLOIDS
Synthetic, colloid solutions are all mixtures containing
dextrans, gelatins and starches. Individual colloids
differ from one another by their capacity to expand
plasma volume according to each fluid’s colloidosmotic pressure (COP). The use of synthetic
colloids varies considerably on account of the large
variety of evaluations as to the clinical indications
and contraindications due to adverse reactions andtaking into account the regulatory and prescriptive
indications in force in various nations. [3]Dextrans
Dextrans are polysaccharides with a high molecularweight composed by glucose residues able to exercise
a COP of 40 mmHg. Dextrans can cause infrequent
but potentially very serious adverse reactions:anaphylactic/ anaphylactoid shock, fluid overloadwith pulmonary edema, a platelet dysfunction leading
to spontaneous bleeding and acute kidney failure.
Therefore, they are contraindicated for patients withdiabetes or renal impairment. In practice, dextrans are
rarely used in Italy.
Gelatins
Gelatins, purified polypeptide solutions obtained
from the hydrolysis of animal collagen (usually
bovine), produce a limited plasma expansion of shortduration on account of the rapid renal eliminationand deterioration by the reticuloendothelial system’s

VOLUMIC REPLACEMENT IS
CONDUCTED BY THE USE OF
DIFFERENT SOLUTIONSBELONGING TO TWO LARGEAND DISTINCT CATEGORIESOF SUBSTANCES:
crystalloids e colloids.
protease. They entail the risk of triggering allergic
reactions and inducing bleeding and kidney failure.
Starches
Starches are complex polysaccharides of which
various types exist. They can be distinguished bytheir origin (whether from corn or potatoes) andstructure (molecular weight, C2/C6 ratio or thenumber of replacements). Although representing atheoretical alternative to crystalloids for the expansion
or maintenance of blood volume, they are substances
extraneous to the body, and if administeredintravenously they are not metabolised and they
accumulate in cells. It can be reasonably supposedthat this characteristic provides the theoretical basefor the long known and severe adverse reactions
associated with the use of such compounds (kidney
failure, bleeding, hepatic damage, allergic reactions
and pruritus).
A number of products with modified formulations
have been developed in recent years to reduce therisk of adverse reactions (molecular size, number of
replacements or C2/C6 ratio). Among such products,hydroxyethyl starch (HES) is the most investigatedand used synthetic colloid. It is a branched chain
polysaccharide similar to glycogen and mainlycomprising amidopectins (98%) and exercises anoncotic pressure (COP) of about 30 mmHg (6%solution).
These products, announced as “innovative andpossessing a high safety profile”, may, however, cause
serious adverse reactions, thus retaining important
contraindications in some clinical conditions. In
addition big concernes arised about the validity of thecritical studies done by dr. Boldt, the so mentioned“Boldt case”.

13The use of human albumin solutions in Italy

The “Boldt case” and the recent recommendations ofregulatory agencies on the clinical use of starch
The new synthetic starches witnessed a first phaseof distribution spurred on by numerous studies
published by Joachim Boldt, a former professor andHead of the Department of Anaesthesiology andIntensive Care at Giessen University, Germany, andauthor of a large number of publications on starches
and their therapeutic benefits.
However, the findings of these publications became
the subject of serious questioning after the discovery
of widespread and repeated infringements of theprinciple of Good Clinical Practice (GCP) and theabsence of any approval by the Ethical Committee
for most of the trials conducted by Boldt. Moreover,the editors of 18 scientific reviews in the fieldof anaesthesiology and other fields, jointly andpublicly confuted the reliability of the findings ofthese studies. Furthermore, besides infringing GCP
principles, it was also discovered that many data
had been blatantly modified and falsified. Joachim
Boldt was, therefore, suspended from his clinicalpositions and teaching post. [4] The case, having
received widespread attention in the scientificworld and the media, led the regulatory authorities,
especially the European Medicines Agency (EMA)
and the US Food and Drug Administration (FDA), toreview the indications and modify specific marketing
authorisations (MA) of synthetic starches containing
HES, and especially in view of the latest recent
randomised clinical trials.
Three important randomised clinical trials (VISEP, 6S
and CHEST) [5,6,7] on the treatment of hypovolaemia
and hypovolemic shock in critical patients in intensive
care, with severe sepsis or burns, have not only
shown the non-therapeutic superiority of HES withrespect to crystalloids (saline), but that there is also
a greater overall risk of hepatic and renal toxicity(up until the need for dialysis) and mortality in thiscategory of patients.
Following a systematic revision of the available
studies, conducted at the European level in therecommendations of the Pharmacovigilance Risk
Assessment Committee (PRAC), EMA, therefore,
issued strongly restrictive indications in 2013 on
the use of synthetic starches in specific populations
and imposed modifications to the data sheet ofthe products involved. [8,9] As regards Italy, AIFA
(Italian Medicines Agency) took steps to adopt
EMA’s indications. Moreover, the Coordination
Group for Mutual Recognition and Devolved

14

Procedures for human use (DMDh) approved PRAC’s
recommendations. [10]The summary of AIFA’s recommendations is as follows:• Products containing HES must only be used forthe treatment of hypovolaemia caused by acutehaemorrhage whenever crystalloids are deemed
insufficient.
• Products containing HES must be used at
the lowest effective dose for the shortest
duration. Treatment must be guided by continual
haemodynamic monitoring so that as soon as
appropriate haemodynamic values are reached
the infusion can be interrupted.
• Products containing HES are now
contraindicated in the following conditions:• sepsis• burns• renal failure or renal replacement therapy• intracranial or cerebral haemorrhage• critical patients (typically undergoing
intensive care)• hyperhydrated patients including patientswith pulmonary edema• dehydrated patients• hyperkalaemia (only applicable toproducts containing potassium)• severe hyponatraemia or severe
hyperchloraemia• severe coagulopathy• severely compromised hepatic function• congestive heart failure• patients with organ transplants

NATURAL COLLOIDS
Human albumin is the principal natural colloid.
Human albumin solutions are available both at low
concentrations (5%) that can produce a COP of 20mmHg and at high concentrations (20-25%), with a
COP of 70 mmHg. It should be noted that the latter isthe highest COP obtainable from colloidal solutions.
As concerns its clinical use, we can anticipate thatthe therapeutic indications of albumin constitutea subject that, on the one hand, encounters areasof considerable agreement and, on the other,widespread national and international questioning.
In the discussion of the clinical indications for theuse of albumin, both the consensual and the critical
positions will be the subject of the next chapter.

Fluid therapy: use of crystalloids and colloids

Bibliography[1] Varrier M, Ostermann M. Fluid composition and clinical effects. Crit
Care Clin 2015; 31:823-37[2] Rewa O, Bagshaw SM. Principles of fluid management. Crit Care
Clin 2015; 31:785-801[3] Lira A, Pinsky MR. Choices in fluid type and volume duringresuscitation: impact on patient outcomes. Ann Intensive Care
2014; 4:38
[4] Editors-in-Chief statement regarding published clinical trials conducted without IRB approval by Joachim Boldt. Minerva Anestesiol
2011; 77:562-3[5] Brunkhorst FM, Engel C, Bloos F, et al; German Competence
Network Sepsis (SepNet). Intensive insulin therapy and pentastarch
resuscitation in severe sepsis. N Engl J Med 2008; 358:125-39[6] Perner A, Haase N, Guttormsen AB, et al; 6S Trial Group;
Scandinavian Critical Care Trials Group. Hydroxyethyl starch
130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med
2012; 367:124-34[7] Myburgh JA, Finfer S, Bellomo R, et al; CHEST Investigators;
Australian and New Zealand Intensive Care Society Clinical Trials
Group Hydroxyethyl starch or saline for fluid resuscitation in
intensive care. N Engl J Med 2012; 367:1901-11[8] http://www.ema.europa.eu/docs/it_IT/document_library/Referrals_
document/Hydroxyethyl_starch-containing_medicines_107/
Position_provided_by_CMDh/WC500162500.pdf[9] http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/
human/referrals/Hydroxyethyl_starch-containing_medicines/
human_referral_prac_00[10] http://www.agenziafarmaco.gov.it/sites/default/files/IT_DHPC_HES_common.pdf

HUMAN albumin
IS THE PRINCIPAL
NATURAL COLLOID

Chapter 3
THERAPEUTIC USE
OF ALBUMININ LIVER CIRRHOSISThe use of human albumin solutions in Italy

Therapeutic use of albumin inliver cirrhosis
Physiopathological backgroundHypoalbuminaemia is a typical characteristic of cirrhosis. It is the result of areduction in hepatic synthesis, the dilution of protein content in extracellular fluid
following an expansion of the total plasma volume, an increase in catabolism of themolecule and a higher rate of transcapillary passage towards extra-vascular space,at least in patients with refractory ascites. [1,2]Besides quantitative change, albumin undergoes structural and functional changes
that are probably facilitated by the pro-inflammatory and pro-oxidant state of theadvanced cirrhosis. [1,2]A cirrhotic patient’s albumin is characterised by extensive post-transcriptional
modifications that involve a number of sites on the molecule, thus compromisingnormal physiological functions. [3]In physiological terms decompensated cirrhosis is characterised by two major
systemic events: circulatory dysfunction and chronic inflammation.
These alterations are closely correlated to one another and contribute towards multiorgan dysfunction and failure. [4]Predominant haemodynamic alteration is a progressive reduction in effective
volaemia as a result of the decline in peripheral vascular resistance, mainly at thesplanchnic level due to the production of vasoactive substances (e.g. nitrogenoxide, carbon monoxide, endocannabinoids) that induces vasodilation and limits
vasoconstrictor response. The activation of neurohumoral compensation systems,
including the renin-angiotensin-aldosterone system (RAA), the sympathetic nervous

Patients WITH

DECOMPENSATEDCIRRHOSIS AREHYPOVOLEMIC
AND EXHIBITCARDIOVASCULAR.

p18

Therapeutic use of albumin in liver cirrhosis

system (SNS) and vasopressin (ADH), in its turn,produces vasoconstriction and the retention of sodium
and water in the kidney. Thus, in functional terms,
patients with decompensated cirrhosis are hypovolemicand exhibit cardiovascular hypoactivity, although theircardiac flow may be normal or high. Nevertheless, afall in cardiac output, with the consequent worseningof effective hypovolaemia is found in more advanced
stages of the illness due to the development of aclinically observed cardiac dysfunction, the so-called“cirrhotic cardiomyopathy”. At the terminal stage,
the extreme decline in effective volaemia directly
produces a further decline in perfusion in the kidneys
and other organs, thus generating ischemic tissue injury
leading to the development of multi-organ failure. In
this physiopathological scenario, the conservationof effective blood volume is the primary objective intreating these patients. [4]Patients with decompensated cirrhosis also exhibit
a chronic condition of systemic inflammation, due
to the stimulation of immune system cells by thetranslocation of bacteria and their fragments from theintestinal lumen to the blood stream as a result of thequantitative and qualitative changes taking place in
the intestine. The cytotoxic agents released during the
inflammatory process contribute towards the creationof a vicious circle by producing splanchnic vasodilationand suppressing cardiac contractility, thus aggravating
circulatory dysfunction. They can also contributedirectly to organ dysfunction by inducing microvascular
coagulation and cell damage. [4]The level of inflammation and oxidative stress increases
rapidly in patients with acute-on-chronic liver failure; aclinical syndrome characterised by the development of
hepatic and extrahepatic organ failure (kidneys, brain,lungs, coagulation and circulation) and by a high riskof immediate mortality and often precipitated by an
identifiable clinical event such as bacterial infection or
acute alcoholic hepatitis. [5]On the basis of the foregoing physiopathologicalevidence, albumin administration can exercise - throughthe molecule’s oncotic and non-oncotic properties - a
beneficial effect in various phases of the foregoingvicious cycle that combines circulatory dysfunction,
inflammatory response and oxidative stress in patientswith decompensated cirrhosis. (Figure 1).

PORTAL HYPERTENSIONALBUMINAUMANA

BACTERIAL TRANSLOCATIONHUMAN
ALBUMIN

PAMPSREACTIVE OXYGEN AND NITROGEN SPECIESPROINFLAMMATORY MOLECULESINFLAMMATIONSSPLANCHNICVASODILATIONCARDIACDYSFUNCTION

EFFECTIVEHYPOVOLAEMIAHEPATICFAILURERENAL
DYSFUNCTIONDAMAGE/DYSFUNCTIONIMMUNE
CELL/ORGAN
DYSFUNCTIONADRENERGICFAILUREHEPATICSUSCEPTIBILITY
ENCEPHALOPATHY
TO SHOCKMULTI-ORGANFAILUREHYPONATREMIA ASCITES HEPATORENALSYNDROME

Figure 1. Principal physiopathological and clinical events indecompensated cirrhosis. The arrows indicate the possible
sites of albumin’s beneficial action through its oncotic andnon-oncotic properties. PAMP: pathogen associated molecularpattern.

Current use of albumin in hepatology
The therapeutic use of human albumin in
hepatology is a common practice, sustainedby numerous scientific findings and by theguidelines of leading national and international
scientific associations. [6.7]

The principal indications on the use of albumin are
currently represented by some clinical complications
associated with the most advanced stages of cirrhosis,
all characterised by a marked condition of effective
hypovolaemia: the prevention of post-paracentesis
circulatory dysfunction (PPCD), kidney failure induced

19

The use of human albumin solutions in Italy

by spontaneous bacterial peritonitis (SBP) and the
diagnosis and treatment of the hepatorenal syndrome(HRS) in association with vasoconstrictors.
The recent publication of the findings of the trial‘ANSWER’ has revealed significant benefits from thelong-term albumin treatment on patients with cirrhosis
and uncomplicated ascites who do not respond todiuretic treatment. [8]However, other pathological conditions related tohepatic cirrhosis such as severe hyponatraemia andseptic shock, can also benefit from the administrationof albumin, but currently they lack the backing ofequally solid scientific evidence.
In this context, it is important to underline thestrange situation as regards obtaining marketing
authorisations in Italy. The reimbursement andprescription of albumin through the National HealthService (NHS) are governed by Note 15, issued in 2005
by the Italian Medicines Agency (AIFA), which limits its
use to:• after large-volume evacuative paracentesis in
cirrhosis of the liver;• serious hydrosaline retention in ascitic cirrhosis,
in the nephrotic syndrome or in malabsorption
syndromes (e.g. due to post-surgery shortintestine or protein dispersion) that does not
respond to appropriate diuretic treatment, often
when associated with hypoalbuminaemia andparticularly with clinical signs of hypovolaemia.

While Note 15 does not, on the one hand, include
all the indications found in the technical sheets
approved in non-EC countries, on the other it does
allow the chronic use of albumin in ascites therapy.
The existence of different guidelines, often not
updated, due to differences in procedures as alsoin prescriptive practice, not only nationally but also
within the same region, means that universality
and equity in healthcare treatment - virtues of the
Italian health system - cannot be guaranteed.

AISF-SIMTI recommendations for theappropriate use of albumin in cirrhosis of theliver
For the foregoing reasons the Associazione Italiana
per lo Studio del Fegato (AISF) (the Italian Association

20

for the Liver Research) and the Società Italiana di
Medicina Trasfusionale e Immunoematologica (SIMTI)(the Italian Society of Transfusion Medicine and
Immunohaematology) appointed a joint committee ofexperts to review the literature available and set out
practical clinical recommendations for the use of humanalbumin on patients with cirrhosis of the liver in orderto furnish a shared instrument for prescribing this blood
product in an appropriate manner so as to prevent
its use in ways not based on scientific evidence andharmonise its prescription at a national level(Tables 1 and 2). [9]Table 1. Grading efficacy tests and recommendations(adopted from the GRADE system)QUALITY OF EFFICACY TESTS
A - HIGH
It is very unlikely that further research can change our ideason the reliability of the estimate of effects.
• Various high quality studies with constant results• In special cases: a large, high quality, multi-centre study
B - MODERATE
It is likely that additional research will make an important impact
on our view about the reliability of the estimate of effect andmodify it.
• A high quality study• Various studies with some limitations
C - LOW
It is very likely that additional research will make an important
impact on our view about the reliability of the estimate of effectand will probably modify it.
• One or more studies with serious limitations
D - VERY LOW
Any estimate of effect remains very uncertain.
• Expert opinion• No direct proof of experimental efficacy• One or more studies with very serious limitations
STRENGHT OF THE RECOMMENDATIONS
1 - Strong
Factors that influence the strength of the recommendations
include the quality of the efficacy tests, presumably importantresults for both patient and cost.
2 - Weak
Variability in the choices and values or greater uncertainty: it ismore likely that a weak recommendation is justified.
The recommendation is given with less certainty: high cost or
excess consumption of resources.
Source: http://www.simti.it/pdf/volume_albumina.pdf

Therapeutic use of albumin in liver cirrhosis

Table 2. Summary of the recommendations for the use of albumin in patients with cirrhosis of the liver
CLINICAL CONDITIONDOSE AND TIMESOF ADMINISTRATION

DCPP
prevention

6-8 g per litre of ascitic Mandatory
liquid removed
in all patients

Paracentesis> 5 litres
Paracentesis< 5 litres

Prevention ofrenal failure
after PBS

High-risk
patients

1,5 g/kg at diagnosis+
1 g/kg on the third day

Low-risk*patients

INDICATIONS FORALBUMIN USEQUALITY OF THE
EFFICACY TESTS AND
RECOMMENDATION’SSTRENGTH
A1

Preferred in the eventthat there arecontraindications for theuse of synthetic colloids
or crystalloids

B1

Mandatory
in all patients

A1

To be considered
for single patients

B1

SER diagnosis

1 g/kg/die for 2
consecutive days

To be used on a regular
basis

D1

Treatment of type 1
SER (in association withvasoconstrictor)

1 g/kg at diagnosis+ 20-40 g/die until
the suspension of
the vasoconstrictors

Mandatory
in all patients

A1

Long-term treatmentof ascites

To be defined

To be considered for
ascites that are difficult
to treat

C1

Treatment of serious
hyponatraemia

To be defined

To be considered if
standard therapy is
without response

D1

Currently not indicated

B1

Prevention of renal failure after –bacterial infection other than
PBS
Treatment for septic shock

To be defined

To be considered
for all patients

C1

Treatment of hepatic
encephalopathy–

Currently notindicated

B1*Low-risk patients: serum bilirubin <4 mg/dl and serum creatinine <1 mg/dl.
PPCD: post-paracentesis circulatory dysfunction; HPS: hepatorenal syndrome; SBP: spontaneous bacterial
peritonitis.

Source: http://www.simti.it/pdf/volume_albumina.pdf

21

The use of human albumin solutions in Italy

The AISF-SIMTI recommendations were officiallypresented during a conference organised by theCentro Nazionale Sangue (CNS) (National BloodCentre) in March 2016 at the Istituto Superiore di
Sanità (National Institute of Health) in Rome.
PREVENTION OF POST-PARACENTESIS CIRCULATORYDYSFUNCTION (PPCD)
Evacuative paracentesis is the primary treatment forpatients with tense or refractory ascites. Removal ofa large volume of ascites (> 5 litres) may cause theso-called post-paracentesis circulatory dysfunction
characterised by a brusque and lasting deterioration of
the condition of effective hypovolaemia in association
with a significant increase in patient mortality. [10]This complication is overcome by the use of plasma
expanders during and/or at the conclusion ofparacentesis. Albumin was found to be superior
to crystalloids and synthetic colloids in cases ofparacentesis of over 5 litres of ascites, while nosignificant differences were found with the removal ofsmaller volumes. [11, 12]
AISF-SIMTI RECOMMENDATIONS• Albumin must be administered after
paracentesis higher than 5 L at a dose of
6-8 g/L of ascites removed as it lowers theincidence of PPCD and improves the clinicaloutcome of the patient (A1).
•When the quantity of ascites removed
exceeds 5 L, the use of plasma expanders is
not recommended as they are less effective
in PPCD prevention (A1). Moreover, thecombination of albumin and other plasma
expanders is not recommended in order toreduce the albumin dose (D1).
•When the quantity of ascites removed isless than 5 L, albumin can be used in thecase of possible risks associated with theadministration of crystalloids and synthetic
colloids (volume overload, renal failure,coagulopathy) (B1).
• The use of vasoconstrictors in place of albuminor the use of low doses of albumin should be
limited to controlled clinical trials (C1).

The recommended dose (6-8 g per litre of ascites
removed) should not be reduced arbitrarily.

22

PREVENTION OF RENAL FAILURE
AFTER SPONTANEOUS BACTERIAL PERITONITIS
Spontaneous bacterial peritonitis (SBP) represents themost frequent bacterial infection found with cirrhosisof the liver and is an important cause of in-hospitalmortality (about 20% of all cases). The developmentof renal failure, independently of the resolution of theinfection, is an independent predictor of mortality, [13]The administration of albumin, together with antibiotic
therapy, significantly reduces the incidence of renal
failure after SBP and also improves in-hospital and3-month survival. This positive result is clearly exhibitedin patients in more advanced stages of illness definedby serum bilirubin >4 mg/dL and serum creatinine >1
mg/dL, while it appears even more controversial with
low-risk patients (with serum bilirubin <4 mg/dL andserum creatinine <1 mg/dL). [14]AISF-SIMTI RECOMMENDATIONS• Albumin (1.5 g/kg body weight at diagnosis
and 1 g/kg body weight at day 3) must be
administered in association with antibiotic
therapy in cirrhotic patients with SBP given that
this approach reduces the incidence of renal
failure and improves survival (A1).
• Patients with serum bilirubin <4 mg/dL andserum creatinine <1 mg/dL are at low risk ofdeveloping renal failure after SBP. In this groupof patients, the benefit of albumin is not clear
and the decision to administer it should betailored to the individual (B1).
• The use of crystalloids and colloids insteadof albumin or in association with it is notrecommended (D1).
• The use of low doses of albumin should be
limited to controlled clinical trials (level C1).

DIAGNOSIS AND TREATMENT OF THE
HEPATORENAL SYNDROME
The hepatorenal syndrome (HRS) is a form of“functional” renal failure which in the absence oftherapy has an ominous short-term prognosis.
A HRS diagnosis, besides excluding organic causesof nephropathy, is based upon failure to respond toplasma expansion, to be performed according tothe opinion of the experts of the International Clubof Ascites (ICA) with an albumin dose of 1 g/kg body

Therapeutic use of albumin in liver cirrhosis

THE hepatorenal syndrome
IS A FORM OF RENAL FAILURE.
WHICH IN THE ABSENCE OF
THERAPY IS “FUNCTIONAL”
FOR AN OMINOUS SHORT-TERM
PROGNOSIS.
LONG-TERM TREATMENT OF ASCITES
weight for two consecutive days, even if no specificstudies on the question exist. [15]As concerns treatment, the combined administrationof albumin and vasoconstrictors (the most used
is terlipressin, but also noradrenaline and theassociation of octreotide and midodrine) was foundto be significantly better than a placebo or albuminalone, for curing renal failure and improving 3-monthsurvival. [16]AISF-SIMTI RECOMMENDATIONS• Albumin administered (1 g/kg body weight
for two consecutive days) should be used to
expand plasma volume for differential HRS
diagnosis (D1).
• Albumin must be administered with terlipressin
to patients with type I HRS at a dose of 1 g/
kg body weight on day 1 followed by 20-40
g die until the suspension of terlipressin (A1).
When possible, the albumin dose should becalibrated according to the level of central
venous pressure. Alternatively, albumin should
be reduced or interrupted in the presenceof clinical signs of volume overload and/or
pulmonary edema (A1).
• Albumin should be administered alongwith other vasoconstrictors (noradrenalineor midodrine plus octreotide) in patientswith type 1 HRS in the same doses used for
terlipressin (A1).
• If patients with type 2 HRS are treated withvasoconstrictors, albumin should be added in
the dosages used for type 1 HRS (B1).

The long-term administration of albumin for
the treatment of ascites, although based ontheoretical physiopathological premises (effective
hypovolaemia is the root cause of the renal
retention of sodium and water) still remains amatter of controversy in the field of hepatology, on
account of the lack of definitive scientific evidence
to substantiate its clinical benefit.
However, this use is permitted by the Italian
National Health Service but the reimbursement for
non-hospital prescriptions is limited to patients withascites non-responsive to standard diuretic therapy(Note 15 of the Italian Medicines Agency).
Only two randomised clinical trials, whose
experimental design cannot, in one case, be easilytransferred to current clinical practice and whose
results, in the other, are limited by the low numberof patients involved, have shown a benefit fromthe chronic administration of albumin in ascitic
decompensation management. [17,18]
The lack of successive confirmatory trials, together
with the high cost of this therapeutic strategy,
explains why the long-term infusion of albumin
is not included among the recommendations ofinternational guidelines.

23

The use of human albumin solutions in Italy

TREATMENT OF SERIOUS HYPONATRAEMIA
A reply to this controversial clinical problem wasprovided by the findings of the Italian, non-profit,
multi-centre randomised trial promoted by the
Italian Medicines Agency (ANSWER study, Clinical
Trials.gov: NCT 01288794) which evaluated longterm albumin treatment in patients with hepatic
cirrhosis and ascites non responsive to diuretic
treatment. [8]This study compared two groups of
cirrhotic patients with non-complicatedascites. One was treated with conventional(antimineralocorticoids + furosemide) and theother with conventional therapy + albumin(40 grams two times a week for two weeks
and successively 40 grams once a week, withpatients monitored for 18 months). The end
points of the trial were survival (primary end
point), the need to recur to paracentesis,
the appearance of cirrhosis complications,the quality of life, and admission to hospital(secondary end points). The trial findings
were very positive. There was a significant
increase in the survival rate and statisticallysignificant benefits for the following parameters:
paracentesis, refractory ascites, spontaneousbacterial peritonitis, episodes of renal failure,
type 1 hepatorenal syndrome and grade III-IV
hepatic encephalopathy. A reduction in hospital
admission and an improvement in life quality
were also observed. [8]**The description of the findings of the Answer trial
does not form part of the AISF – SIMTI document.

AISF-SIMTI RECOMMENDATIONS• Long-term albumin administration can beconsidered efficacious in the treatment of
ascites in association with diuretics (C1).
• The efficacy, dosage and timing of albumin
administration must be defined by controlled,
randomized trials with an adequate sample
size.**This recommendation precedes the publication of
the findings of the Answer trial.

24

The serum concentration of sodium is an important
negative prognostic factor in cirrhosis: hyponatraemia,
especially when serious (<125 mmol/L), can by itself
induce neurological complications or degenerate
into hepatic encephalopathy and can promote
the emergence of pontine myelinolysis after livertransplant. [19]Basing themselves upon strong physiopathologicalreasoning - in other words the reduction of the
non-osmotic hypersecretion of ADH through an
improvement of effective hypovolaemia - many
hepatologists consider albumin infusion an effective
treatment for hyponatraemia although no clinicalstudies exist on the question.
AISF-SIMTI RECOMMENDATIONS• On the basis of physiopathological premises,
albumin could be efficacious for correcting
serious hyponatraemia (<125 mmol/L), nonresponsive to standard therapy, especiallyas regards patients with hyponatraemia
correlated symptoms or awaiting livertransplants (D1).

TREATMENT OF SEPTIC SHOCK
Patients with septic shock exhibit an improvement insurvival when a therapeutic response is immediate
and based upon a combination of broad-spectrum
empirical antibiotic therapy, vasoconstrictors andvolume replacement.
Although a only few patients with cirrhosis wereenrolled in the available trials, (two in particular: SAFE
and ALBIOS) and the findings cannot, therefore, be
automatically applied to the condition of cirrhosis withseptic shock, some considerations do favour the use ofalbumin. [20,21]
In the first place, expansion with saline solution or
Ringer solution requires the infusion of large volumesof liquids which may worsen the patient’s existing
ascites and edema. Moreover, the use of HES solutions,as mentioned, raises fears on account of the increased
risk of renal and hepatic damage and coagulopathy. In
conclusion, one specific benefit of albumin could also
derive from the molecule’s non-oncotic properties as
they could antagonise some of the physiopathologicalmechanisms linked to septic shock.

Therapeutic use of albumin in liver cirrhosis

AISF-SIMTI RECOMMENDATIONS• Albumin could be efficacious and safe incirrhotic patients affected by septic shock (C1).

PREVENTION OF RENAL FAILURE DURING BACTERIAL
INFECTIONS OTHER THAN SBP
Bacterial infections are a frequent complication inpatients with hepatic cirrhosis and an important direct
and indirect cause of death. As in the case of SBP,
other bacterial infections can lead to complications
with the emergence of renal failure, which will
determine a significant decline in the survival rate.
The efficacy of albumin administration for bacterial
infections other than SBP is still being studied. Two
randomised clinical trials failed to find significant
benefits from albumin administration either in terms of
the incidence of renal failure or survival. [22,23]
However, post-hoc analyses have suggested a possible
positive effect for clinically more serious patients andwith more advanced hepatic illnesses.
In order to reply to this question, a large, European
multi-centre trial is currently in course (INFE- CIR2, ClinicalTrials.gov: NCT 02034279), promoted by
the Chronic Liver Failure Consortium (CLIF), whose
purpose is to evaluate the effect of the albumin
administration in high-risk patients, as defined by thepresence of hepatic and renal insufficiency as also by
the positive parameters of the systemic inflammatory
response syndrome (SIRS) and the kind of infection.

AISF-SIMTI RECOMMENDATIONS• The administration of human albumin in
association with antibiotics is currently notindicated in cirrhotic patients with bacterial
infections other than SBP (B1).

In patients WITH ADVANCEDHEPATIC CIRRHOSIS,
albumin ADMINISTRATIONIS INDICATED FOR CLINICALCONDITIONS IN WHICH
TREATMENT OR PREVENTION
IS ABSOLUTELYINDEPENDENT OF THE
PATIENT’S plasma albumin
CONCENTRATION.

TREATMENT OF HEPATIC ENCEPHALOPATHY
Hepatic encephalopathy (EE), an alteration in mental
state often induced by a precipitating event (bacterial
infection, gastrointestinal bleeding, renal failurep25

The use of human albumin solutions in Italy

or hyponatraemia) is one of the most importantcomplications of cirrhosis, and associated with a highmortality rate, poor quality of life and high risk of
relapse. [24]A small randomised clinical trial has found albumin
administration, which in theory could reduce thedamage occasioned by the oxidative stress associatedwith the development of EE, to be inefficacious inresolving acute episodes of the illness. [25]

AISF-SIMTI RECOMMENDATIONS• Albumin administration is currently notindicated for the treatment of hepatic
encephalopathy (B1).

to threshold of albuminaemia values above which
its use is advised against. In order to underline theconcept that the prescription of albumin must not
be correlated with laboratory findings on its plasma
concentration, the committee of experts made thefollowing recommendations.

AISF-SIMTI RECOMMENDATIONS• In the specific context of patients withadvanced cirrhosis, the presence of
hypalbuminaemia must not be a necessary
requisite for prescribing albumin.
• As in other clinical contexts, in patients withadvanced cirrhosis, hypalbuminaemia is not, byitself, an indication for prescribing albumin (B1).

HYPOALBUMINAEMIACOMPARISON BETWEEN INTERNATIONAL GUIDELINES
In patients with advanced hepatic cirrhosis, theadministration of albumin is indicated for clinicalconditions in which treatment or prevention isabsolutely independent of the concentration of plasma
albumin in the patient. It is no coincidence that noneof the foregoing recommendations makes reference

As already stated, the guidelines of the American
Association for the Study of Liver Diseases (AASLD)
and the European Association for the Study of theLiver (EASL) [6] makes provision for the use of albumin
for the prevention of PPCD and renal failure induced

THE PRESCRIPTION OF albumin FOR
THE LONG-TERM TREATMENT
OF ASCITES IS POSSIBLE IN ITALY
THANKS TO NOTE 15 OF THE ITALIANMEDICINES AGENCY (AIFA).
26

Therapeutic use of albumin in liver cirrhosis

by SBP and for the diagnosis and treatment of HRS in
association with vasoconstrictors.
As regards these three indications, the Italian AISFSIMTI recommendations are substantially in agreementwith AASLD and EASL guidelines, although moredetailed in describing the scope of albumin use andthe absence of indications on the use of other plasma
expanders.
However, AASLD and EASL guidelines do not deal withother clinical indications such as chronic albumin use,
non-SBP bacterial infections, septic shock and hepatic
encephalopathy, which, instead, are the subject of
AISF-SIMTI recommendations. The sole exception
is represented by serious hyponatraemia for whichalbumin can be administered as, for that matter, in
AISF-SIMTI recommendations.
This difference can, first and foremost, be explained bybearing in mind that EASL guidelines were publishedin 2010 and ASSLD’s in 2013, and thus the findingsof randomised clinical trials on non-SBP bacterial
infections and hepatic encephalopathy, which albeit
negative, were not available. Secondly, as alreadystated, albumin prescription for the long-term
treatment of ascites is possible in Italy thanks to Note
15 of the Italian Medicines Agency (AIFA).
Bibliography[1] Garcia-Martinez R, Caraceni P, Bernardi M, et al. Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its
complications. Hepatology 2013; 58:1836-46[2] Arroyo V, García-Martinez R, Salvatella X. Human serum albumin,
systemic inflammation, and cirrhosis. J Hepatol 2014; 61:396-407[3] Domenicali M, Baldassarre M, Giannone FA, Naldi M, Mastroroberto M, Biselli M, Laggetta M, Patrono D, Bertucci C, Bernardi M,
Caraceni P. Post-transcriptional changes of serum albumin: clinicaland prognostic significance in hospitalized patients with cirrhosis.
Hepatology 2014; 60:1851-60[4] Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanismsof decompensation and organ failure in cirrhosis: from peripheralarterial vasodilation to systemic inflammation hypothesis. J Hepatol 2015; 63:1272-84[5] Moreau R, Jalan R, Gines P, et al; CANONIC Study Investigatorsof the EASL–CLIF Consortium. Acute-on-chronic liver failure is adistinct syndrome that develops in patients with acutedecompensation of cirrhosis. Gastroenterology 2013; 144: 1426-37[6] European Association for the Study of the Liver. EASL clinicalpractice guidelines on the management of ascites, spontaneousbacterial peritonitis, and hepatorenal syndrome in cirrhosis. J
Hepatol 2010; 53:397-417[7] Runyon BA. Introduction to the revised American Association for
the Study of Liver Diseases. Practice Guideline management of
adult patients with ascites due to cirrhosis 2012. Hepatology 2013;
57:1651-3[8] Caraceni P et al. Long term albumin administration improves

survival in patients with decompensated cirrhosis. Final results of
the “ANSWER Study” ILC2017-LB-4191 International Liver Congres
2017 Amsterdam, The Netherlands, 19-23 April 2017[9] Caraceni P, Angeli P, Prati D, Bernardi M; Italian Association for the
Study of the Liver (AISF), Liumbruno GM, Bennardello F, Piccoli P,
Velati C; Italian Society of Transfusion Medicine and Immunohaematology (SIMTI). AISF-SIMTI position paper: the appropriate use ofalbumin in patients with liver cirrhosis. Blood Transfus 2016; 14:8-22[10] Ruiz-del-Arbol L, Monescillo A, et al. Paracentesis-induced circultory dysfunction: mechanism and effect on hepatic hemodynamics
in cirrhosis. Gastroenterology 1997; 113:579-86[11] Ginès A, Fernandez-Esparrach G, Monescillo A, et al. Randomized
controlled trial comparing albumin, dextran-70 and polygelin in
cirrhotic patients with ascites treated by paracentesis. Gastroentrology 1996; 111: 1002-10[12] Bernardi M, Caraceni P, Navickis RJ, Wilkes MM. Albumin infusion inpatients undergoing large-volume paracentesis: a meta-analysis ofrandomized trials. Hepatology 2012; 55: 1172-81[13] Tandon P and Garcia-Tsao G. Renal dysfunction is the most impotant independent predictor of mortality in cirrhotic patients withspontaneous bacterial peritonitis. Clin Gastroenterol Hepatol 2011;
9: 260-5[14] Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on
renal impairment and mortality in patients with cirrhosis and spotaneous bacterial peritonitis. N Engl J Med 1999; 341: 403-9[15] Angeli P, Gines P, Wong F, et al; International Club of Ascites.
Diagnosis and management of acute kidney injury in patients withcirrhosis: revised consensus recommendations of the International
Club of Ascites. Gut 2015; 64:531-7[16] Gluud LL, Christensen K, Christensen E, Krag A. Terlipressin forhepatorenal syndrome. Cochrane Database Syst Rev 2012; 9:CD005162[17] Gentilini P, Casini-Raggi V, Di Fiore G, et al. Albumin improves the
response to diuretics in patients with cirrhosis and ascites: resultsof a randomized, controlled trial. J Hepatol 1999; 30:639-45[18] Romanelli RG, La Villa G, Barletta G, et al. Long-term albumin
infusion improves survival in patients with cirrhosis and ascites: an
unblinded randomized trial. World J Gastroenterol 2006; 12:1403-7[19] Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and mortlity among patients on the liver transplant waiting list. N Engl J Med
2008; 359:1018-26[20] Finfer S, McEvoy S, Bellomo R, et al; SAFE Study Investigators. Impact of albumin compared to saline on organ function and mortalty
of patients with severe sepsis. Intensive Care Med 2011; 37:86-96[21] Caironi P, Tognoni G, Masson S, et al; ALBIOS Study Investigators.
Albumin replacement in patients with severe sepsis or septic shock.
N Engl J Med 2014; 370:1412-21[22] Guevara M, Terra C, Nazar A, Solà E, et al. Albumin for bacterial
infections other than spontaneous bacterial peritonitis in cirrhosis.
A randomized, controlled study. J Hepatol 2013; 57:759-65[23] Thévenot T, Bureau C, Oberti F, et al. Effect of albumin in cirrhotic
patients with infection other than spontaneous bacterial peritonitis.
A randomized trial. J Hepatol 2015; 62:822-30[24] Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Assocition for the Study of Liver Diseases and the European Association
for the Study of the Liver. Hepatology 2014; 60:715-35[25] Simón-Talero M, García-Martínez R, Torrens M, et al. Effects of
intravenous albumin in patients with cirrhosis and episodic hepatic
encephalopathy: a randomized double-blind study. J Hepatol 2013;59:1184-92

27

Chapter 4
THERAPEUTICUSE OF ALBUMIN
IN CRITICAL PATIENTSAND OTHER PATHOLOGICALCONDITIONSThe use of human albumin solutions in Italy

Therapeutic useof albumin in critical patientsand other pathologicalconditions
In addition to cirrhosis, albumin is administered for a wide range of pathologicalconditions and illnesses. Certainly, “critical patients in intensive care” represents
a wide and heterogeneous area of use in which major randomised multi-centric
trials, conducted over the past two decades, have progressively permitted betterprescription appropriateness as concerns some indications that still remain
controversial, while the superiority of albumin with respect to crystalloids has still
not been clearly demonstrated.

Albumin in critical patients
The use of fluids for vital support and re-animation is a widely used practice in theintensive care of critical patients. Albumin has been used for decades in a wide
variety of pathological situations including shock, sepsis, multiple-injuries, burns,
acute respiratory distress syndrome (ARDS), cerebral haemorrhage and manyothers. [1]The physiopathological rationale at the basis of albumin use is well founded
and fully discussed: it is based on the combination of the molecules’ oncotic
properties (plasma expansion), and multiple non-oncotic properties (transport andneutralisation of endogenous and exogenous toxic substances, antioxidant andanti-inflammatory properties, the buffer function for alterations of the base-acidequilibrium and the maintenance of capillary integrity).
Non-protein crystalloids and colloids have also been proposed and used for theforegoing pathologies, but the debate on the advantages of each type of solution
is still on going.
In 1998, a Cochrane meta-analysis conducted on 30 randomised clinical trials
highlighted a higher mortality risk, amounting to 6%, in patients to whom albumin
had been administered for treating traumatic hypovolaemia, major surgery, burns
or hypoproteinaemia. [2]However, successive meta-analysis including a larger number of randomised
clinical trials failed to confirm this negative effect on mortality in these categories
of patients. [3,4]Therefore, to clarify the use and safety of albumin in patients undergoing intensive
care, an extensive, double-blind, randomised clinical trial (Saline versus Albumin
Fluid Evaluation study, SAFE study) recruited 6997 patients requiring volume
support and administered them either crystalloids (saline solution) or albumin. [5]The SAFE trial did not find significant differences in mortality at 28 days, andabove all confirmed that albumin can be safety used in critical patients.
One of the reasons for the diversity in the findings in the different trials is due to thefact that the term “critical patient in intensive care” includes very diverse kinds ofpatients in both clinical and physiopathological terms. Consequently, the effect ofalbumin may differ according to the type of patient in question.

30

Therapeutic use of albumin in critical patients and in other pathological conditions

THE DENOMINATION“critical patients in
intensive care” INCLUDESPATIENTS WHO DIFFERCONSIDERABLY IN CLINICALAND PHYSIOPATHOLOGICALTERMS.

If albumin has, on the one hand, shown to negatively
impact the survival of patients with cerebral trauma,
on the other hand it does appear to be beneficial inother conditions (e.g. extensive burns, ARDS) andespecially cases of severe sepsis and septic shock,as these are situations in which the effects of themolecule’s non-oncotic properties are found to be very
useful.
SEVERE SEPSIS AND SEPTIC SHOCK
The first important evidence of albumin’s favourable
effect in patients with severe sepsis emerged from theSAFE study where multivariate analysis highlighted asurvival advantage for this subgroup. This finding waslater confirmed by the results of a meta-analysis on
trials conducted on patients with severe sepsis andseptic shock. [6]
In 2014 the findings of an open-label, randomized
multicentre trial (Albumin Italian Outcome Sepsis;
ALBIOS trial), designed to evaluate the survival benefitof volume support where albumin was compared to
crystalloids in patients with serious sepsis admitted
to intensive care. [7] The ALBIOS trial failed todemonstrate albumin’s superiority in terms of survival,
although confirming the safety of its use and its
efficacy in terms of improving some haemodynamic
parameters. However, a post-hoc analysis revealeda slight but statistically significant reduction in themortality of the septic shock patient sub-group.
Successive meta-analysis, albeit based on a low
number of randomised studies, seems to confirm

the advantage in this patient sub-group, thus
indicating the need for further randomised clinical
trials. [8]The current recommendations of the “surviving sepsis
campaign” group (2016) indicate crystalloids as thefirst line treatment for volumic support in patientswith severe sepsis or septic shock. The use of albumin
is recommended in crystalloid solutions in the eventthat a considerable volume is required by the patient,but too high to be infused with crystalloids alone.
Synthetic colloids, on the basis of substantial evidence,are strongly contraindicated in the treatment ofpatients with serious sepsis/ septic shock. [9]The foregoing recommendations for the infusion ofliquids in severe sepsis are as follows:• the use of crystalloids is recommended as
first-line treatment in intensive care for severe
sepsis and septic shock.
• the use of albumin is recommended in infusion
therapy for severe sepsis and septic shock
when patients need large quantities of liquids.

BURNS
The first clinical use of albumin was in the treatmentof American soldiers who sustained burns during theattack on Pearl Harbour in 1941. Since then albumin

31

The use of human albumin solutions in Italy

has been used to treat burn patients, even if recently
its use was not recommended in the first phases ofintensive care of burn patients and in accordance tothe advice of some experts the treatment had to be
exclusively limited to crystalloids.
Although burn therapy has had very satisfactory
outcomes with respect to the past results, a recently
observed liquid overload, the so-called “creep
syndrome”, today represents a serious complicationin burn resuscitation. [10]Excessive crystalloid administration and thewithdrawal of colloids in certain phases of the burnpatient’s resuscitation are, today, deemed the mostimportant factors for the appearance of “fluid creep”.
[11]

HEART SURGERYAlbumin is preferred to synthetic colloids
in paediatric heart surgery and in adults inextracorporeal circulation, and not only forhaemodilution in priming heart-lung machine circuits
but also for perioperative volume expansion. [16]Finding hypalbuminaemia at the pre-operatingphase is widely recognised as a reliable negative
prognostic factor of post-operating mortality andmorbidity. [17]A recent randomised clinical trial has documented
that in patients with low levels of albumin prior toan aortocoronary bypass operation, the exogenous
supplement of albumin in quantities proportional tothe degree of hypoalbuminaemia reduces the risk ofacute post-operational renal damage with respect tountreated patients. [18]Some studies highlight the importance of the useof colloids and, especially, albumin including early
treatment, particularly where large quantity of liquids
are required. [12,13]

MAJOR LIVER SURGERY (EXTENDED LIVER RESECTION,LIVER TRANSPLANT)

Early albumin treatment in resuscitating the burnpatient would have the effect of reducing the total
quantity of liquids to be administered in order tomaintain effective volaemia through its effect on
Startling forces and/or for its regenerating/protective
action on endothelial glycocalyx. [14]Given that the majority of patients undergoing these
operations exhibit an underlying condition of hepatic
cirrhosis, the use of albumin should be referenced tothe conditions described above. In specific cases,
albumin may be preferentially used to correct
hypovolaemia and in cases of significant losses ofascitic liquid due to post-operating surgical drainage.
[19]

The results of a recently published clinical trial
conducted on paediatric burn patients highlighted
that early albumin administration in children withburns > 15-45% of total body surface reduces thequantity of crystalloids with a statistically significant
reduction in cases of “fluid creep” and hospitalisation.
[15]

Other pathological conditions
The clinical use of albumin has been proposedin many pathological conditions. In some cases
this was based on sound physiological principles
but occasionally proposed without the support ofevidence obtained from solid clinical trials.
Some clinical situations are listed below which makeprovision for the use of albumin whenever special
conditions exist.

PROTEIN LOSING ENTEROPATHY AND/ OR STATESOF MALNUTRITION
For nutritional purposes, albumin must be
replaced by enteral nutrition or by total
parenteral nutrition. Albumin administration
can be evaluated in these cases only when thefollowing conditions apply contemporaneously:
1. serious diarrhoea with severe liquid loss,
unresponsive to dietetic therapy;
2. severe hypoalbuminaemia (<2 g/dL);
3. clinical manifestation of hypovolaemia(hypotension, tachycardia, oliguria) and/or ananasarcous state.
NEPHROTIC SYNDROME
Albumin use, whose infusion into patients withnephrotic syndrome usually causes an increase inalbuminuria which defeats every expected effect upon32

Therapeutic use of albumin in critical patients and in other pathological conditions

volaemia and albuminaemia, could, however, have alimited use in two conditions:
1. in patients with albuminaemia <2 g/dL andsevere clinical manifestations of hypovolaemia
and pulmonary edema;
2. in an acute nephrotic syndrome at thecommencement of steroidal therapy.

EXTRACORPOREAL PURIFICATION SYSTEMS
Among the extracorporeal purification systems, the“Molecular Adsorbent Recirculating System” (MARS),
based on the use of exogenous albumin on accountof its binding and detoxification properties, finds
specialist clinical application in the treatment of somecases of hepatic failure and irrepressible cholestatic
pruritus. [22]PLASMAPHERESISSERIOUS NEONATAL JAUNDICE

Blood circuit

diaMARS® AC250

diaMARS® IE250

MARS® FLUX

In the specific case of serious neonatal jaundice withthe risk of severe neurological impairment or death,albumin can be used in order to bind circulating(indirect) bilirubin. [21]THE EARLY ADMINISTRATIONOF albumin IN PAEDIATRICPATIENTS WITH TOTALSURFACE BODY BURNS > 15-45%
REDUCES THE QUANTITY
OF CRYSTALLOID INFUSION.

Albumin circuit

diaFLUXThe use of albumin is appropriate in the case ofplasma volume replacement higher than 20 mL/Kg ina single or repeated sessions within the space of one
week.
Crystalloids or of albumin-crystalloid solutions canbe considered in small plasma volume replacements.
[20]

Dialysate circuit

Figure 1. Molecular Adsorbent Recirculating System (MARS).

33

The use of human albumin solutions in Italy

Albumin IS RECOMMENDED
IN INFUSION THERAPYOF SEVERE SEPSISAND SEPTIC SHOCK WHEN
PATIENTS REQUIRE considerable
quantities of liquids.

OVARIAN HYPERSTIMULATION SYNDROME
A recent revision of the literature has demonstrated
possible benefits from albumin administration in theprevention of the ovarian hyperstimulation syndromein high-risk subjects. [23]In conclusion, it should be noted that at times albumin
administration is based more upon direct clinicalexperience than upon scientific findings, thus leading
to a situation of enormous variance in the prescriptionof this precious resource, in Italy as in the rest of theworld.
Most inappropriate prescriptions refer to albumin
use for nutritional measures or for the correctionof hypoalbuminaemia per se (not associated withhypovolaemia) which still today is found in many
medical fields (e.g. general surgery, internal medicine,
geriatrics, and oncology).
A series of conditions are listed below in which the useof albumin is not corroborated by scientific evidence:• chronic hypoalbuminaemia• malnutrition(or otherwise for nutritional purposes)• general surgical operations (post-operational)• cicatrisation of wounds• nephrotic syndrome (chronic)• protein losing enteropathy and malabsorption(uncomplicated)• acute or chronic pancreatitis• cerebral ischaemia.

34

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administration in critically ill patients: systematic review of
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administration. A meta-analysis of randomized, controlled trials.
Ann Intern Med 2001 Aug; 135:149-64[4] Alderson P, Bunn F, Lefebvre C et al. Human albumin solution
for resuscitation and volume expansion in critically ill patients.
Cochrane Database Syst Rev 2004 Oct[5] Finfer S, Bellomo R, Boyce N et al. A comparison of albumin andsaline for fluid resuscitation in the intensive care unit. N Engl J Med
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resuscitation fluid for patients with sepsis: a systematic review andmeta-analysis. Crit Care Med 2011 Feb; 39:386-91[7] Caironi P, Tognoni G, Masson S et al. Albumin replacement inpatients with severe sepsis or septic shock. N Engl J Med 2014 Apr;
370:1412-21[8] Xu JY, Chen QH, Xie JF et al. Comparison of the effects of albumin
and crystalloid on mortality in adult patients with severe sepsis
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Therapeutic use of albumin in critical patients and in other pathological conditions

THE THERAPEUTIC USE
OF HUMAN albumin IN
HEPATOLOGY IS CORROBORATEDBY NUMEROUS scientificfindings AND BY THE GUIDELINES
OF THE PRINCIPAL NATIONALAND INTERNATIONALSCIENTIFIC ASSOCIATIONS.
doi: 10.1097/BCR.0b013e3181cb8c72[14] Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MGA,

The endothelial glycocalyx: composition, functions and visualization.
Pflugers Arch. 2007 Jun;454(3):345-59. Epub 2007 Jan 26[15] Müller Dittrich MH, Brunow de Carvalho W, Lopes Lavado E,
Evaluation of the “Early” Use of Albumin in Children with Extensive
Burns: A Randomized Controlled Trial. Pediatr Crit Care Med. 2016
Jun;17(6):e280-6[16] Russell JA, Navickis RJ, Wilkes MM. Albumin versus crystalloid forpump priming in cardiac surgery: meta-analysis of controlled trials.
J Cardiothorac Vasc Anesth 2004 Aug; 18:429-37[17] Karas PL, Goh SL, Dhital K. Is low serum albumin associatedwith post-operative complications in patients undergoingcardiac surgery?, Interact Cardiovasc Thorac Surg. 2015
Dec;21(6):777-86[18] Lee EH, Kim WJ, Kim JY, et al. Effect of exogenous albumin in
the incidence of post-operative acute kidney injury in patients
undergoing off-pump coronary artery by-pass surgery with apreoperative albumin level of less than 4.0 gdl. Anesthesiology
2016; 123: 1001-11[19] Haynes GR, Navickis RJ, Wilkes MM. Albumin administration:
what is the evidence of clinical benefit? A systematic review
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Review and Network Meta-Analysis. Sci Rep 2016 Jan; 6:19093

The use of human albumin solutions in Italy

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June 2017