Balancing volume resuscitation and ascites management

in cirrhosis
Federico Pollia and Luciano Gattinonia,b
a
Dipartimento di Anestesiologia, Terapia Intensiva e
Scienze Dermatologiche, Università degli Studi di
Milano and bDipartimento di Anestesia, Rianimazione e
Terapia del Dolore, Fondazione IRCCS Ca’ Granda -
Ospedale Maggiore Policlinico, Milan, Italy
Correspondence to Luciano Gattinoni, MD, FRCP,
Dipartimento di Anestesia, Rianimazione e Terapia del
Dolore, Fondazione IRCCS Ca’ Granda - Ospedale
Maggiore Policlinico, Via F. Sforza 35; I-20100 Milan;
Italy
Tel: +39 02 5503 3232; fax: +39 02 5503 3230;
e-mail: gattinon@policlinico.mi.it
Current Opinion in Anaesthesiology 2010,
23:151–158
Purpose of review
Patients with cirrhosis have total extracellular fluid overload but central effective
circulating hypovolaemia. The resulting neurohumoral compensatory response favours
the accumulation of fluids into the peritoneal cavity (ascites) and may hinder renal
perfusion (hepatorenal syndrome). Their deranged systemic haemodynamics
(hyperdynamic circulatory syndrome) is characterized by elevated cardiac output with
decreased systemic vascular resistance and low blood pressure.
Recent findings
Molecular and biological mechanisms determining cirrhosis-induced haemodynamic
alterations are progressively being elucidated. The need for a goal-directed assessment
of volume resuscitation (especially with volumetric techniques) in patients with cirrhosis
is becoming more and more evident. The role of fluid expansion with albumin and the use
of splanchnic vasopressors in a variety of cirrhosis-related conditions has recently been
investigated.
Summary
The response to fluid loading in patients with advanced cirrhosis is abnormal, primarily
resulting in expansion of their noncentral blood volume compartment. Colloid solutions,
in particular albumin, are best used in these patients. Albumin may be effective in
preventing the haemodynamic derangements associated with large-volume
paracentesis (paracentesis-induced circulatory dysfunction), in preventing renal failure
during spontaneous bacterial peritonitis and, in association with splanchnic
vasopressors, in caring for patients with the hepatorenal syndrome.

Keywords
ascites, fluid therapy, haemodynamics, liver cirrhosis, serum albumin

Curr Opin Anaesthesiol 23:151–158

ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
0952-7907

the various body compartments. Ascites is the accumu-

Introduction
Liver disease is not an infrequent condition for patients
admitted to ICUs. Cirrhosis represents the final evolution
of advanced liver disease. Outcomes for critically ill
patients with cirrhosis remain poor, with mortality rates
exceeding 40% [1]. When organ system complications of
cirrhosis develop (most notably, acute renal failure [2]),
mortality rates can reach 80% [3].
In this review, we will examine the haemodynamic
derangements peculiar to patients with cirrhosis and
ascites. We will outline the response of their cardiovas-
cular systems to volume expansion and – eventually –
discuss the specific role of albumin in this regard.
Haemodynamic derangements associated
with cirrhosis
Liver cirrhosis is associated with altered regulation
of total body water volume and distribution within
0952-7907 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
lation of fluids in the peritoneal cavity and represents
the most common complication of advanced liver
disease [4]. The current view of ascites regards its pro-
cess of accumulation as an aspect of the more general
disturbed haemodynamic framework of patients with
cirrhosis.
Ascites was originally thought to result from liver
disease-associated hypoalbuminaemia, causing unba-
lanced Starling forces within the splanchnic circula-
tion. Subsequently, it became clear that renal sodium
retention played a central role. Two opposing theories
were, therefore, developed. According to the ‘overflow’
theory [5], renal sodium retention is the primary abnorm-
ality. The associated total body water expansion
would cause excess water to be lost across the splanchnic
capillaries into the peritoneal space. In contrast, accord-
ing to the ‘underfilling’ theory [6], the primum movens
is the portal hypertension-associated release of medi-
ators causing arteriolar vasodilation, primarily in the
DOI:10.1097/ACO.0b013e32833724da

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 152 Intensive care and resuscitation

Figure 1 Pathophysiological alterations in cirrhosis

Cirrhosis
(portal hypertension)

Endothelial dysfunction
(release of nitric oxide...)

Haemodynamic derangement
Splanchnic arteriolar vasodilation
Hyperdynamic circulation

Effective circulating volume

Hepatorenal
depletion
syndrome

Activation of:
Increased -Renin–angiotensin–aldosterone system Renal vasoconstrction:
cardiac output -Antidiuretic hormone reduced glomerular filtration rate
- Sympathetic nervous system

Sodium retention Water retention

Extracellular fluid compartment

overload

-Ascites accumulation
-Hyponatraemia
- ...

Unifying view of the pathophysiological modifications occurring in cirrhosis, involving multiple neurohumoral systems and linking haemodynamic
derangements with ascites accumulation and with renal dysfunction in a coherent framework.

splanchnic region. This reduces the central effective therefore activating a neurohumoral response which
circulating volume [7] (i.e. that part of the intravas- induces the kidney to avidly retain sodium and water
cular volume capable of interacting with arterial baror- (Fig. 1). Today, most evidence supports this latter
eceptors) and causes relative arterial hypotension, theory.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Pathophysiology of ascites and neurohumoral profile in
patients with cirrhosis
Cirrhosis involves anatomic [8,9] and functional [10–12]
alterations whose final result is portal hypertension. This,
primarily via the release of soluble mediators from the
dysfunctional endothelium [13–17], induces vasodilation
of the splanchnic arteriolar bed [18].
Arteriolar vasodilation with pooling of blood into the
splanchnic district causes ‘underfilling’ of the arterial
system [19] and is associated with a drop in arterial
pressure. This causes the activation of the renin–angio-
tensin–aldosterone system, the sympathetic nervous
system and induces nonosmotic release of arginine vaso-
pressin [20]. A compensatory vasoconstrictor and anti-
natriuretic response aiming at maintaining arterial pres-
sure is thus initiated. Because of severe vasoconstriction,
glomerular filtration rate is reduced and the kidney
excretes water and solutes less efficiently [21]. Moreover,
it also actively and avidly retains sodium and water due to
the activation of the renin–angiotensin–aldosterone sys-
tem. Eventually, extracellular fluid overload is observed,
which tends to accumulate within the peritoneal cavity in
the form of ascites as a consequence of the altered
intestinal capillary pressure, and possibly permeability,
associated with the state of portal hypertension and
splanchnic vasodilation. Moreover, it contributes to the
typical hyperdynamic circulatory syndrome.
The cardiovascular system in cirrhosis and the
hyperdynamic circulatory syndrome
The hyperdynamic circulatory syndrome, frequently
encountered in patients with cirrhosis, is characterized
by increased cardiac output (CO), low arterial blood
pressure (BP) and reduced peripheral vascular resistance
[22]. Increased CO seems to have multiple determinants,
including greater preload secondary to the rise in extra-
cellular fluid volume, reduced afterload secondary to the
fall in systemic vascular resistance and increased heart
rate [23]. In patients with the hyperdynamic circulatory
syndrome, splanchnic blood flow is increased and this,
possibly, contributes to perpetuating portal hypertension
in a vicious circle [24].
Patients with cirrhosis tend to be resistant to the vaso-
pressor effects of norepinephrine, angiotensin II [25] and
vasopressin [26], possibly because of reduced sensitivity
of adrenergic receptors to their ligands [27,28] or the
presence of endogenous vasodilators (nitric oxide, calci-
tonin gene-related peptide, . . .) and autonomic nervous
system dysfunction [29–31].
Finally, despite increased CO, cirrhosis per se may be
associated with impaired heart function (cirrhotic cardio-
myopathy [32]), which usually remains an elusive con-
dition, as these patients’ hearts typically work against
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Volume resuscitation in cirrhosis Polli and Gattinoni 153
reduced afterloads. Cardiovascular stress may, however,
reveal systolic dysfunction, with ejection fraction being
unable to increase appropriately [33]. Diastolic dysfunc-
tion is also present due to the structural heart modifi-
cations occurring in cirrhosis [34]. Therefore, acute
changes in filling pressures, such as after acute fluid
expansion, may put patients with cirrhosis at increased
risk of developing congestive heart failure. Finally,
electrophysiological abnormalities (e.g. QT interval pro-
longation [35,36]) may also render them prone to major
dysrhythmic events.
Body fluids distribution in cirrhosis
Animal and human studies have shown an abnormal
distribution of body fluids within the various body com-
partments [37] in patients with cirrhosis. Splanchnic
blood volume is increased and accounts for more than
22% of all circulating volume. In contrast, the ‘central’
effective circulating volume (i.e. that part of intravascular
volume contained in the heart, lungs and central arterial
tree that is ‘sensed’ by arterial baroreceptors) has been
shown, with dilutional techniques, to be significantly
reduced, especially in patients with advanced disease
[7]. Indeed, many lines of evidence support the fact that
cirrhosis is characterized by relative effective hypovolae-
mia, despite total extracellular fluid overload. The activa-
tion of salt and water-retaining hormonal mechanisms –
as pointed out previously – is the strongest evidence for
this, being a marker of the activation of arterial baror-
eceptors secondary to the hypotensive state associated
with arterial ‘underfilling’. In this sense, it is interesting
to note that cirrhotic patients with hypertension have
only blunted hyperdynamic states [38].
Effects of fluid expansion in patients with
cirrhosis
Fluid loading may be necessary to ensure haemodynamic
stability in cirrhotic patients, characterized by relative
hypovolaemia and, possibly, to prevent complications
such as the hepatorenal syndrome. However, fluids
may simply expand the extravascular compartment,
thereby worsening organ function and contributing to
the maintenance of ascites.
Accurate haemodynamic management is, therefore,
important. In fact, although in this group of patients
volume expansion may fail to normalize BP, it may
nonetheless be associated with an improvement in car-
diac function and peripheral vascular resistance, large
enough to ameliorate end-organ perfusion. Indeed, it
has been shown that, in severely ill patients with cirrhosis
(Child–Pugh classes B and C), volume expansion reduces
plasma levels of renin, suggesting that some degree of
subclinical increase in the effective circulating volume
does indeed occur [39]. The reduction in endogenous
 154 Intensive care and resuscitation
vasoconstrictors per se may help preserve renal function
despite persistently altered systemic haemodynamics.
Optimization of the haemodynamic state has also been
advocated in the management of patients with cirrhosis
undergoing liver transplantation. Outcomes have been
shown to be improved in patients in whom stable
haemodynamics – as reflected by greater values of the
ratio of CO to blood volume and reduced mean circulation
time – could be maintained after living donor liver
transplantation, even within the context of a persistent
hyperdynamic circulatory syndrome [40,41]. This
possibly resulted from improved portal blood flow favour-
ing liver regeneration.
Cirrhosis is characterized by impairment in free water
[42] and sodium excretion, secondary to nonosmotic
release of arginin vasopressin, activation of the renin–
angiotensin–aldosterone system and enhanced sym-
pathetic nervous system activity. Recently, reduced
expression of aquaporin-2 channels has also been impli-
cated [43]. Therefore, in cirrhosis, fluid expansion with
crystalloids simply tends to induce volume overload
while only transiently improving cardiac performance.
Artificial and natural colloids are known to have longer
intravascular half-lives than crystalloids [44], and, there-
fore, appear to be better choices. Because of their oncotic
power, they are capable of driving water intravascularly.
This effect is also transient, with subsequent redistribu-
tion of a fraction of the administered albumin out of blood
capillaries, partly into the peritoneal cavity.
Data on the specific haemodynamic responses to fluid
expansion in cirrhosis are sparse. Patients with mild
disease tend to show normal responses to fluid loading,
with their central blood volumes increasing appropriately
after intravenous infusions. In contrast, in advanced dis-
ease, plasma volume expansion and correction of the
central circulatory deficit with its associated hypotensive
state does not occur. Noncentral blood volume overload
and worsening vasodilation only seems to take place [45].
Abnormal responses to fluid infusion may partly be
related to the increased vascular (arterial) compliance
observed in patients with cirrhosis [46–49], which may
be related to structural abnormalities of the vascular wall
or to the effect of mediators such as nitric oxide, calci-
tonin gene-related peptide [50] or downregulated C-type
natriuretic peptide [51].
Recently, a haemodynamic goal-based approach for guid-
ing fluid management has been investigated in a group of
patients with advanced cirrhosis and functional renal
failure [52]. Fluid expansion with 400 ml of 20% albumin
brought about a significant increase in central blood
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
volume, as reflected by the global end-diastolic volume
index, a surrogate measure reflecting it, and an improve-
ment in cardiac index. Central venous pressure, on the
contrary, was not modified by the intervention. A similar
goal-directed approach to albumin infusion also improved
renal function in patients with renal failure undergoing
paracentesis [53]. Not only are static central pressure
determinations poor guides for fluid resuscitation, as
largely documented [54], but, in this specific subgroup
of patients, dynamic central pressure monitoring also
seems to add no value. This had also previously been
documented in patients with cirrhosis undergoing liver
transplantation [55]. The usefulness of central pressure
monitoring is particularly reduced in patients with cir-
rhosis, especially because the measurement is itself
difficult to interpret due to the increased intraabdominal
pressure. Therefore, volumetric measurements seem to
be of greater value in assessing the haemodynamic status
of patients with cirrhosis.
The role of albumin
Albumin has had alternating fortunes in the critical care
community. Previous meta-analyses have variously con-
cluded that albumin was harmful for critically ill patients
[56], that it was safe but not superior to other volume
expanders [57] and, finally, that it could be administered
if judged clinically appropriate [58]. Meta-analyses were
biased by the different sample sizes, protocols, albumin
formulations and control treatments tested in the various
studies that were examined and no definitive conclusion
could, therefore, be reached [59].
A pivotal large randomized clinical study [60] [the Saline
versus Albumin Fluid Evaluation (SAFE) study], in
almost 7000 patients admitted to an ICU, has recently
found that fluid resuscitation with 4% albumin was not
superior to physiological saline as far as mortality and
several secondary outcomes were concerned. On the
basis of this result, current guidelines maintain the
similarity of fluid resuscitation with natural and artificial
colloids or crystalloids [61]. The SAFE study, however,
has been criticized, as the population investigated
included only mildly to moderately ill patients (up to
55% had no organ failures) and was unselected, deliber-
ately not including those patients who could possibly
benefit the most from albumin administration, such as
patients with liver disease.
The role of albumin in the specific population of patients
with cirrhosis has been better established, appearing to
have a role in at least three areas of interest: prevention of
paracentesis-induced circulatory dysfunction, prevention
of renal failure during spontaneous bacterial peritonitis
and treatment of the hepatorenal syndrome in addition
to vasoconstrictors.

Prevention of paracentesis-induced circulatory
dysfunction
Control of ascites is difficult to obtain with diuretics (and
a sodium-restrictive diet) alone because the ascitic fluid
contains albumin [62] and oncotic forces tend to sustain
the condition by continuously driving fluids into the
peritoneal cavity. Evacuation of fluids, together with
protein and sodium, from the abdomen with paracentesis
is superior to diuretics alone in controlling ascites and is
associated with fewer complications [63,64]. Current
guidelines, indeed, suggest that large-volume paracent-
esis should be used in patients with tense or refractory
diuretic-resistant ascites [65].
The most frequent adverse event associated with paracent-
esis is paracentesis-induced circulatory dysfunction. This is
a condition of haemodynamic derangement mimicking
the hyperdynamic circulatory syndrome of cirrhosis [66],
described in up to 75% of patients after large-volume
paracentesis. Traditional theories maintain that the rapid
decrease in intraabdominal pressure obtained with para-
centesis would putatively promote reaccumulation of
fluids in the peritoneal cavity, with ensuing acute central
effective hypovolaemia. Alternatively, it is possible that the
relief in abdominal tension reduces intrathoracic pressure,
which improves CO. A compensatory decrease in systemic
vascular resistance occurs with secondary effective circu-
lating hypovolaemia [67,68]. The renin–angiotensin–
aldosterone system is thus activated and plasma norepi-
nephrine levels increase, worsening renal function and
favouring dilutional hyponatraemia [66,69]. Paracentesis-
induced circulatory dysfunction is not spontaneously
reversible and has been associated with poorer outcomes
[70], which makes its prevention important.
Paracentesis-induced circulatory dysfunction can be pre-
vented with volume expansion. Initial studies from the
1980s, based on the experience accumulated in clinical
hepatology [71], favoured the use of albumin, which has
been shown to be highly effective [63,69,72–74]. Several
concerns, however, exist over albumin infusions. First,
albumin is a human plasma derivative product and poten-
tial transmission of pathogens (mainly prions) remains a
problem. As a protein, it can also induce allergic reactions
[75]. Second, infusion of albumin has been shown to exert a
negative impact on its own biological cycle, potentially
promoting its own degradation [76] or downregulating its
synthesis [77]. Third, and more important, despite the
improvement in clinical and biochemical markers associ-
ated with paracentesis-induced circulatory dysfunction, no
data support any significant benefit on the ultimate out-
come of survival [70,72]. Finally, the cost of the albumin
solution is high.
Therefore, studies have focused on possible alternative
volume expanders. However, neither artificial colloids
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Volume resuscitation in cirrhosis Polli and Gattinoni 155
nor crystalloids have convincingly been proven to be
equivalent to albumin in preventing paracentesis-
induced circulatory dysfunction [70,78–82], especially
when large volumes of ascites are evacuated. Data indi-
cating differences in survival associated with albumin or
artificial colloids are not available [83]. Liver dysfunction,
however, can be worsened with some colloids such as
hydroxyethyl starch [84].
Recently, vasopressors have been proposed to contain
the haemodynamic disturbances associated with large-
volume paracentesis. Terlipressin has been found to be
as effective as albumin [85–87]. Midodrine and norepi-
nephrine are also being studied with differing [88]
but promising results [89,90]. However, the associated
cardiovascular adverse events reduce their potential
usefulness, especially in those patients most likely
to have paracentesis-induced haemodynamic derange-
ments [91].
At present, balancing all available data, current guide-
lines suggest that after paracentesis fluid infusion may be
necessary only after evacuation of at least 4–5 l of ascites.
In that case, 6–8 g of albumin per litre of removed fluid
should be given [65]. The removal of smaller volumes
does not activate the release of humoral mediators [92].
Some authorities, therefore, advocate that only small-
volume paracentesis (together with adequate diuretic
and dietary therapy) should be performed [93]. This
should not induce significant haemodynamic derange-
ments and does not require postprocedural albumin
infusions.
Prevention of renal failure during spontaneous bacterial
peritonitis
Spontaneous bacterial peritonitis is the infection of
the ascitic fluid, possibly originating from the trans-
location of intestinal bacteria [94]. Renal failure occurs
in about one-third of patients with this condition [95],
significantly worsening their prognosis. Circulating cyto-
kines and vasodilators seem to account for this form of
renal failure, possibly with a pathogenesis involving
effective circulating volume hypovolaemia. In rando-
mized controlled clinical trials, the infusion of albumin
has been found to reduce the incidence of renal failure
and improve survival [96,97]. Therefore, the most shared
view is that, apart from antibiotic therapy, infusion of
1.5 g/kg albumin on the day of diagnosis and 1 g/kg of
albumin on the third subsequent day is beneficial for
patients with spontaneous bacterial peritonitis who
are developing or have developed renal failure. How-
ever, it has recently been proposed that only patients
meeting strict biochemical criteria (serum creatinine
>1 mg/dl, blood urea nitrogen >30 mg/dl or total bili-
rubin >4 mg/dL) might benefit from the infusion of
albumin [65,98].
 156 Intensive care and resuscitation
Treatment of the hepatorenal syndrome
The hepatorenal syndrome is a functional form of acute
renal failure that can develop in advanced cirrhosis or
fulminant hepatic failure [99]. It is thought to originate
from severe vasoconstriction [100] of renal arterioles in
response to neurohumoral mediators activated by central
effective circulating volume hypovolaemia coupled with
the systemic circulatory dysfunction of cirrhosis [101].
The final consequence is reduced renal perfusion and
glomerular filtration rate [102]. It is interesting to note
that no anatomic abnormality is detected, and that kid-
neys of affected patients transplanted into noncirrhotic
individuals usually resume normal function [103], as do
those of affected patients after receiving liver trans-
plantation [104]. Prognosis in patients developing the
hepatorenal syndrome is particularly poor [2]. The
important diagnostic issues have been recently reviewed
elsewhere [105].
Definitive treatment for the rapidly aggressive forms of
the hepatorenal syndrome includes transjugular intra-
hepatic portosystemic shunt [106,107] and liver transplan-
tation. However, volume expansion and vasoconstrictors
play an important supportive role, their rationale being
to increase the effective circulating volume. Studies
have shown that the use of octreotide with midodrine or
norepinephrine [108] together with albumin [109,110]
improves renal function and mortality. Terlipressin has
also proved to be effective [111,112], but survival could not
be found to be different from placebo [113]. Albumin,
indeed, seems to add to the vasopressor alone [114], both
because of its role as a volume expander and because of
putative potentiating effects at the receptor level.
Conclusion
Patients with cirrhosis and ascites have the hyperdynamic
circulatory syndrome, characterized by central effective
circulating hypovolaemia – secondary to decreased
systemic vascular resistance – and increased CO. This
is associated with activation of neurohumoral mediators
with water and salt-retaining properties (which deter-
mine expansion of the extracellular fluid compartment)
and vasoconstrictor effects (which may lead to functional
renal failure, the hepatorenal syndrome). Volume expan-
sion may be appropriate to blunt this compensatory
response and to protect end-organ perfusion. However,
these patients tend to respond abnormally to fluid chal-
lenges, which may be scarcely effective. In fact, they
mainly increase their noncentral blood volume, especially
in advanced disease. Goal-directed therapy with volu-
metric indicators may be particularly useful. Colloid
solutions, owing to their increased intravascular half-
lives, may be the best choice for these patients. In this
sense, albumin plays a major role, in particular, as these
patients are frequently hypoalbuminaemic because of
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
their liver disease. Albumin infusions, in particular, have
a definite role in preventing haemodynamic derange-
ments associated with large-volume paracenteses (para-
centesis-induced circulatory dysfunction) in preventing
renal failure during spontaneous bacterial peritonitis and,
together with splanchnic vasopressors, in caring for
patients with the hepatorenal syndrome.
Acknowledgements
L.G. is currently the principal investigator of a study (ALBIOS study)
aimed at determining the role of fluid therapy with albumin in septic
patients.
There are no conflicts of interest.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
 of special interest
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