Download Intensive Management of Hepatic Failure

Intensive Management of Hepatic Failure
Mary E. Rinella, M.D.1 and Arun Sanyal, M.D.2
ABSTRACT
A substantial number of patients with liver failure are admitted to the intensive
care unit; thus a thorough understanding of the prevention and treatment of complications
in such patients is imperative. The management of liver failure is demanding and often
involves the combined efforts of many specialists. Critically ill patients with hepatic failure
encompass a broad spectrum of disease, ranging from acute liver failure in a patient with no
prior history of liver disease, to acute on chronic liver failure. The initial assessment and
management of acute liver failure are reviewed with an emphasis on the prevention and
treatment of brain edema in the pretransplant setting. The current treatment of complications resulting from decompensated chronic liver disease such as portal hypertensive
bleeding; infection, renal failure, and hepatic encephalopathy are then discussed.
KEYWORDS: Liver failure, cerebral edema, portal hypertension, management
T
he management of liver failure is demanding
and often involves the combined efforts of many specialists. Critically ill patients with hepatic failure encompass
a broad spectrum of disease, ranging from acute liver
failure in a patient with no prior history of liver disease,
to end-stage decompensated cirrhosis. Both sides of this
spectrum present clinical challenges that involve many
organ systems. Although both sides in acute and chronic
liver failure can have a poor prognosis, careful and
comprehensive intensive care can improve outcome and
bridge eligible patients to liver transplantation. Because
acute and chronic liver failure are very distinct clinical
entities, they will be discussed separately.
ACUTE LIVER FAILURE
Acute liver failure (ALF) is a rapidly progressive, often
fatal syndrome characterized by jaundice, encephalopathy, and coagulopathy leading to multiorgan failure in a
patient with no prior history of liver disease.1,2 In recent
years, advancements in supportive care have improved
survival and provided a more effective bridge to trans1
Division of Hepatology, Northwestern University, Chicago, Illinois;
Division of Gastroenterology, Department of Internal Medicine,
Virginia Commonwealth University, Richmond, Virginia.
Address for correspondence and reprint requests: Arun Sanyal,
M.D., Division of Gastroenterology, Department of Internal Medicine, Virginia Commonwealth University, MCV Box 980341,
Richmond, VA 23298-0341. E-mail: [email protected].
2
plantation. Although ALF remains one of the most acute
serious illnesses, thoughtful intensive management can
optimize the patient’s chances for spontaneous hepatic
regeneration or a successful liver transplant.3 When
possible, etiology-targeted therapy should be initiated
(Table 1). The goal of management should be focused
on the prevention of systemic infection, multiorgan failure, hepatic encephalopathy (HE), and ultimately the
development of brain edema.4–6 At this time liver transplantation is the only definitive therapy for those who
fulfill criteria for poor prognosis7–9 (Table 2). The
challenge to the clinician is selection of patients for
transplant that have low likelihood of spontaneous survival but are not too ill to benefit from transplantation.
The principles of management of ALF are reviewed here:
INITIAL EVALUATION AND MANAGEMENT
Early diagnosis and identification of the subject that is
unlikely to improve spontaneously constitute a critical
first step in the management of ALF. The initial triage
Non-pulmonary Critical Care: Managing Multisystem Critical Illness; Guest Editor, Curtis N. Sessler, M.D.
Semin Respir Crit Care Med 2006;27:241–261. Copyright # 2006
by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York,
NY 10001, USA. Tel: +1(212) 584-4662.
DOI 10.1055/s-2006-945528. ISSN 1069-3424.
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Table 1
Etiology-Targeted Therapy
Etiology
Potential Therapies
TOXIC
Acetaminophen
N-acetyl cysteine
Amanita poisoning
Penicillin and silibinin
VIRAL
Herpes simplex virus
Acyclovir
Acute heptatitis B
Antivirals?
2006
and an accurate history cannot be overemphasized because both treatment and prognosis are significantly
affected by the underlying etiology. A detailed account
of the psychiatric history, including suicidal ideation
and family support, is essential to assess suitability
for transplantation. The timing of the psychiatric evaluation is of particular importance, given the rapid deterioration in mental status that occurs in such patients.
METABOLIC
Wilson’s disease
Transplant
Autoimmune hepatitis
Corticosteroids
VASCULAR
Acute Budd-Chiari syndrome
Directed thrombolysis,
transjugular intrahepatic
portosystemic shunt
PREGNANCY
Acute fatty liver of
Urgent delivery
DISEASE-TARGETED THERAPY
A thorough discussion of the differential diagnosis of
ALF is beyond the scope of this review; however,
Table 1 provides a summary of common etiologies of
ALF for which potential therapies exist. Only acetaminophen will be discussed in more detail because it is the
most common etiology of liver failure in the United
States and has an effective antidote.
pregnancy/HELLP
HELLP, hemolysis elevated liver enzymes low platelets.
of a patient with acute liver injury to an intensive care
unit (ICU) is based on the presence of altered mental
status and the degree of coagulopathy. It is imperative
to admit most subjects with acute liver injury with an
international normalized ratio (INR) > 1.5 and all
subjects with mental status changes. Rapid deterioration can occur and is often irreversible in the patient
with ALF. It is therefore imperative that decisions
regarding prognosis and appropriateness for liver transplant be made early, and potentially suitable patients
should be referred to a liver transplant center early in
the evaluation process.
The management of patients in liver failure
requires a multidisciplinary approach involving hepatologists, transplant surgeons, intensivists, and other subspecialists. The importance of a thorough physical exam
Table 2
King’s College Criteria for Acute Liver Failure
Acetaminophen induced
Arterial blood pH < 7.3 (regardless of degree of
encephalopathy)
If no acidosis then all three of the below criteria:
Prothrombin time > 100 seconds
Serum Creatinine > 2.5 mg/dL
Grade 3 or 4 encephalopathy
Nonacetaminophen induced
Prothrombin time > 100 seconds
If prothrombin time < 100 seconds, then any of the below
criteria (regardless of degree of encephalopathy):
Drug-induced, non-A, non-B, halothane hepatitis
Time from jaundice to encephalopathy > 7 days
Age < 10 or > 40 years
Prothrombin > 50 seconds
Bilirubin > 17.5 mg/dL
Acetaminophen
Idiopathic and drug-related liver injuries are the most
common causes of ALF in the United States.10 Of the
drug-related causes, acetaminophen overdose is the most
common cause of ALF in the United Kingdom and
United States. Overdose can be either intentional or
unintentional.11–13 The patient, family, and close contacts
must be questioned about regular alcohol use, dieting, diet
pills, medications, or recent illness that may have resulted
in poor nutrition. These factors greatly affect toxicity
either through upregulating cytochrome p450 (alcohol
and other drugs) promoting the formation of toxic intermediates, or through glutathione depletion. Such details
are important because as little as 2.6 to 4.0 g of acetaminophen can lead to liver failure in this setting.14–17
It is worth noting that, at the time of presentation, a patient with acetaminophen-induced liver failure
may have undetectable blood levels of acetaminophen.
This is particularly true when the toxicity manifests itself
several days after ingestion of acetaminophen for therapeutic purposes in a susceptible subject. However, in
the majority of cases, detectable acetaminophen levels
are present at the time of presentation. When acetaminophen overdose is confirmed, N-acetylcysteine (NAC)
must be initiated in a timely manner, ideally within
16 hours of ingestion, to have a significant impact on
survival. NAC decreases injury through enhancement of
glutathione synthesis resulting in less formation of
acetaminophen’s hepatotoxic intermediate.18,19 Even if
the patient is delayed in reaching the hospital or the
diagnosis is not forthcoming, there is evidence that late
administration of NAC can be beneficial.20 NAC may
also improve outcome through its effects on microcirculatory function. A large multicenter study (the
ALF study group) is currently addressing the utility of
NAC in nonacetaminophen-induced ALF.
INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL
Table 3
Acute Liver Failure: General Management Guidelines
On Admission
Monitoring
Daily
IV access, CVP and arterial
Tid
Hourly
If Indicated
Blood sugar
Mental status
Mechanical intubation,
line, Foley catheter
Thorough history
and physical
Interview family members
Laboratories
Liver panel, renal panel,
ICP monitoring
Basic laboratories, AFP,
CBC, PT, Hep A,B,C
arterial ammonia
serologies, HSV, CMV,
(or more if mental
EBV, ceruloplasmin, ANA,
status deteriorating
anti-sm Ab, SPEP,
phosphate,
HIV, acetaminophen
level, toxicology screen,
factor V level
Blood gas
Changes in
ICP monitor
cosyntropin stimulation
test, TSH, blood type,
blood cultures
Imaging
US with Doppler
Head CT for neurological
changes or suspected
edema
Directed therapy where indicated
Drugs, cooling for
cerebral edema
AFP, alpha feta protein; ANA, antinuclear antibody; anti-sm Ab, antismooth muscle antibody; CBC, complete blood count; CMV, cytomegalovirus; CT, computed tomography; CVP, central venous pressure; EBV, Epstein-Barr virus; HSV, herpes simplex virus; HIV, human immunodeficiency virus; ICP, intracranial pressure; IV, intravenous; PT, prothrombin time; SPEP, serum protein electrophoresis; TSH, thyroid stimulating
hormone; US, ultrasound.
MONITORING AND GENERAL GUIDELINES
Acute hepatic dysfunction has profound effects on many
organs. Therefore, one must remain cognizant of the
ramifications of specific therapies on other systems. The
mental status must be documented several times daily, in
addition to frequent assessment of hepatic synthetic
function and blood glucose (Table 3). Although a liver
biopsy may be helpful if the diagnosis is in question, it can
be unreliable in predicting outcome and is risky given the
presence of underlying coagulopathy.21 Low serum phosphate and elevated a fetoprotein can be encouraging signs
of hepatic regeneration.22,23 In a retrospective analysis of
ALF patients, 74% of patients with phosphate levels
< 2.5 were alive at 1 week, in contrast to none in those
with a serum phosphate > 5.24
Coagulopathy in ALF does not usually require
correction unless an invasive procedure is planned or
overt bleeding is present because the use of fresh frozen
plasma (FFP) can mask deterioration of liver function. A
common indication for the correction of coagulopathy
is placement of a central line. Traditionally, FFP and
cryoprecipitates have been used for the correction of
coagulopathy in subjects with ALF. This is only partially
effective in correcting coagulopathy and its effects are
short-lived. It is also associated with a risk of transmitting
cytomegalovirus infection and may contribute to volume
overload and pulmonary edema, especially when renal
function begins to deteriorate. Alternate approaches include the use of plasmapheresis where a volume of plasma
equal to the amount infused is removed to prevent
volume overload. Recently, recombinant factor VII
(40 mg/kg) has been used in conjunction with FFP to
rapidly correct coagulopathy prior to either intracranial
pressure monitor or central line placement in patients
with ALF.25
MECHANICAL VENTILATION
Mechanical ventilation should be initiated once encephalopathy deteriorates to grade 3 (West Haven criteria) to protect the airway.26,27 In addition to preventing
aspiration in the patient with compromised mental status,
intubation and sedatives help control agitation, which can
lead to surges in intracranial pressure. Patients with
encephalopathy beyond grade 3 are very difficult to
manage without intubation and sedation.28
Sedation is best achieved with a short-acting
sedative alone or in combination with a short-acting
narcotic. Recent evidence supports the use of propofol
for this purpose. In a small study, propofol was given to
seven patients with ALF and profound encephalopathy.
Intracranial pressure (ICP) remained normal in six of
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seven patients with ALF given propofol at 50 mg/kg/
min, suggesting propofol may have independent beneficial effects on ICP.29 Paralytics are usually avoided
because they can mask seizure activity. However, they
may be used in specific cases to facilitate management
when the subject does not respond appropriately to
sedation. In such cases, it is imperative to consider the
possibility of seizure activity if the clinical picture
continues to deteriorate. H2 antagonists or proton
pump inhibitors may decrease the incidence of ulcer
disease in mechanically ventilated patients30; however,
the theoretical risk of increasing the incidence of
pneumonia has not been studied in this population.
PREVENTION AND MANAGEMENT
OF COMPLICATIONS
Circulatory Dysfunction
Derangements in circulatory function manifest early in
ALF and are often progressive. They are characterized by
generalized vasodilation, increased cardiac output, decreased systemic vascular resistance, and a low mean
arterial pressure (MAP).31–33 It is challenging to distinguish this clinical picture from the hemodynamics of
sepsis, particularly given that infection is common and
often a fatal complication.34 Factors such as adrenal
insufficiency also complicate management by making
the vasculature less responsive to vasopressive agents.35,36
In general terms, fluids and vasopressors should
be used to maintain adequate cerebral perfusion pressure
(CPP) (50 mm Hg to 65 mm Hg) while avoiding
cerebral hyperemia from hyperperfusion.37,38 Because
the circulatory disturbance in ALF is characterized by
vasodilation and increased cardiac output, norepinephrine is frequently the vasopressor of choice.
Infection
Patients with ALF are particularly susceptible to severe
infection due to many immunological defects such as
defective phagocytic function and decreased complement levels.39–42 Bacterial or fungal sepsis is a frequent
cause of death in this population. Much like other
immunocompromised hosts, their response to infection
is atypical in that signs such as fever or leukocytosis are
absent in 30% of cases.43 Thus sepsis is both frequent
and difficult to diagnose in subjects with ALF. In a
prospective study of 887 patients with ALF, one or more
bacterial infections occurred in 37.8%; however, an
incidence of up to 80% has been reported.44 Of these,
gram-positive cocci were the most common organisms
isolated, although Escherichia coli and Klebsiella were also
frequent pathogens.45 Overall, pneumonias make up
50% of bacterial infections in ALF with bacteremia
and urinary tract infections occurring in 20 and 25%,
Figure 1 The effect of antibiotic prophylaxis on the prevalence
of documented infection patients with acute liver failure.
(Adapted from Salmeron et al.47)
respectively. These infections presented at a median of
5, 3, and 2 days after the onset of ALF.44
Given the frequency of both gram-negative and
gram-positive infections in this population, broad spectrum antibiotic coverage should be administered avoiding aminoglycosides due to their nephrotoxicity.34
Although no randomized controlled trials have demonstrated improved survival with prophylactic antibiotics,
parenteral antibiotics are associated with a lower incidence of infection46 (Fig. 1).47 Given these data, prophylactic broad-spectrum antibiotics seem justifiable
given that uncontrolled infection in such patients is
often catastrophic.48,49
Systemic Inflammatory Response Syndrome
Even in the absence of documented infection, systemic
inflammatory response syndrome (SIRS) is common in
those with ALF and is likely due to a surge of cytokine
release.50 In a study from King’s College, 57% of 887
patients with ALF developed SIRS. The presence of
SIRS on admission was independently associated with
more severe illness, worsening of encephalopathy, and
subsequent death. In those patients that were infected
(54%), mortality increased with each additional component of SIRS. At this point it remains unclear how
additional infection contributes or which component of
the observed inflammatory response originates from
humoral factors released by the necrotic liver.34,46,51
Adrenocortical Insufficiency
Adrenocortical insufficiency can worsen hyperdynamic
cardiovascular collapse typical of ALF or septic shock.52
This should be considered when the patient fails
INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL
Figure 2 Factors leading to the development of brain edema and potential therapeutic interventions.
to respond to volume resuscitation.35 In sepsis, supraphysiological doses of steroids in patients with adrenal
insufficiency have been shown to reduce vasopressor
requirements and improve outcome.36,53 Adrenal
dysfunction appears to also be prevalent in patients
with ALF; 62% of patients with ALF were found to
have an abnormal response to high-dose corticotrophin
stimulation. The patients with pronounced hemodynamic instability had more marked evidence of adrenal
insufficiency, suggesting that it may contribute to the
pattern of cardiovascular collapse seen in liver failure.54
The benefit of stress-dose steroids in this population
needs to be tested in a randomized-controlled trial;
however, given these data, it is reasonable to look for
and consider treating adrenal insufficiency in patients
with ALF.
Renal Failure
Renal failure is common in those with advanced liver
failure and is multifactorial in etiology. Common causes
of renal failure in this population include prerenal
azotemia, renal ischemia, acute tubular necrosis, and
hepatorenal syndrome. A majority of patients with
ALF complicated by profound hypotension and cerebral
edema will require renal replacement therapy.31 Due to
the marked vasodilation that characterizes such patients,
continuous venovenous hemofiltration (CVVH) tends to
be better tolerated and may have more beneficial effects
on ICP.55,56 Moreover, intermittent hemodialysis has
been associated with increases in ICP and decreases in
CPP, whereas the opposite has been shown in patients
receiving CVVH.55,57
Hepatic Encephalopathy and the Development
of Intracranial Hypertension
The development of HE and subsequent cerebral edema
and intracranial hypertension (ICH) define prognosis in
patients with ALF.2,7,58 Treatment options for such
patients are limited. As a result, 30% of patients
with ALF and cerebral edema succumb to cerebral
herniation while awaiting an organ.7,31 Without urgent
transplantation, mortality can exceed 90% in those who
have uncontrolled ICH.
The pathogenesis of cerebral edema is complex
(Fig. 2). ALF leads to many hemodynamic changes,
including impairment of cerebrovascular autoregulation
and blood flow. This impairment makes the standard
assumption that CPP ¼ MAP ICP less reliable.38
Other factors such as high arterial ammonia levels
contribute to brain edema through the accumulation
of glutamine and alanine in astrocytes. In response to
swelling, a vasodilating factor is released that leads to
increased CBF and thus increased ICP.59
Arterial ammonia levels > 200 mmol/L in the
setting of ALF have been shown to herald impending
cerebral herniation and poor outcome.60,61 Other
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Figure 3 Proposed algorithm for the use of an intracranial pressure monitor.
markers of brain cell dysfunction and damage such as
s100-b and neuron-specific enolase (NSE) have also
been evaluated as potential predictors of impending
herniation in the setting of ALF and acute on chronic
liver failure with negative results.62 Currently, no serum
markers of brain cell dysfunction reliably demonstrate
neurological injury and poor outcome.
Unfortunately, it can be difficult to predict which
patients are likely to develop elevated ICP. Clinical signs
such as arterial hypertension, fever, and agitation can
precede episodes of severe ICH; however, these are not
reliable predictors because elevated ICP is often clinically silent.63 Although a computed tomographic (CT)
scan is usually used to look for cerebral edema, a normal
scan does not exclude the presence of edema because its
appearance on imaging may be delayed.
INTRACRANIAL PRESSURE MONITORING
A significant clinical challenge in the management of
ALF is the decision to place an ICP monitor. There are
no strict guidelines related to the use of these monitors
and experience across institutions is highly variable.
Noninvasive techniques have not proven to be beneficial and direct ICP monitoring is the only reliable
modality for the measurement of ICP. The benefit
that can be derived from ICP monitoring is twofold.
First, it allows for the early detection and treatment of
ICH because it can be clinically silent.63 Second, it can
provide invaluable information about the likelihood of
neurological recovery when deciding whether to proceed with liver transplantation, such as when CPP is
persistently low. Sustained CPP < 40 mm Hg predicts
a high likelihood of ischemic brain injury that typically
results in a poor neurological outcome after transplantation.64,65 Figure 3 proposes an algorithm for the use
of ICP monitors in ALF.
Although treatments aimed at reducing ICP can
be used without an ICP monitor, an accurate ICP
reading permits targeted therapy to optimize CPP and
detect abrupt surges in pressure that necessitate additional therapy. Concomitant measurement of jugular
bulb oxygen saturation,32,66 which allows measurement
of brain oxygen utilization, can also be useful in the
management of these patients.32 Jugular bulb oxygen
saturation > 80% or < 60% predicts elevation in ICP
with good sensitivity and specificity.31 Jugulovenous O2
saturations < 50% may herald an increase in anaerobic
cerebral glycolysis, increased lactate:pyruvate ratio, and
worsening cerebral edema.67
When and in Whom to Insert an Intracranial
Pressure Monitor
To justify the risks of ICP monitor placement, the
monitor needs to be placed under controlled circumstances, when increased ICP is likely to rise but before
uncontrolled ICH and herniation occur. ICP monitoring should be considered for mechanically ventilated
patients with grade 3 or 4 encephalopathy with poor
prognosis (Table 2) but who are otherwise good candidates for liver transplant (Fig. 3). Other predictors of
increased ICP such as arterial ammonia > 150 mmol/L
could be used to time monitor placement. In those with
poor prognosis without orthopedic liver transplant
(OLT), ICP monitoring can guide therapy and prevent
surges in ICH before and during OLT.
Risks of Intracranial Pressure Monitoring
As with all interventions, the risks of ICP monitor
placement need to be balanced against the accuracy and
usefulness of the information to be gained. No randomized, controlled trial is available to compare different
INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL
catheters in the setting of ALF. Types of catheters include
epidural, subdural, parenchymal, and intraventricular
catheters. Blei et al performed a survey of transplant
centers across the United States. They estimated that
20% of ICP monitoring resulted in intracranial bleeding.
Epidural catheters had the lowest rate of bleeding complications (3.8%) and subdural and parenchymal catheters
the highest; 20% and 22%, respectively.68 A recent multicenter study from the ALF study group showed that ICP
monitors were only used in 92/332 patients (28%) with
ALF and severe encephalopathy; however, the frequency
of monitoring differed between centers. Ten percent had
intracranial bleeding as a result of the ICP monitor. In
two of these patients, ICP monitoring was directly
associated with the patient’s death.69 Although the risk
of complications is greater,70 subdural catheters give a
more reliable estimate of ICP than epidural catheters.68
Bleeding complications can be decreased significantly with the use of recombinant factor rVIIa given
immediately before the procedure.25 The frequency of
factor VII dosing was variable in this study; however, as a
group all patients that received factor VII normalized
their prothrombin time (PT) and were able to have ICP
monitors placed (compared with 38% in the FFP alone
group). The ideal initial dose and subsequent doses of
factor VII necessitates further study.71 The data show
that ICP monitoring can be an effective tool for managing elevated intracranial pressure; however, ICP monitors have not been shown to improve survival. Currently
there is no consensus about the use of ICP monitoring or
whether the more accurate but higher-risk subdural
catheters or the less accurate but safer epidural catheter
should be used. Individual centers will continue to use
what they are comfortable with; however, their decision
may be influenced by the decreased availability of epidural catheters.
induction and maintenance of hypernatremia (145 to
155 mmol/L) in patients with grade 3 or 4 encephalopathy resulted in a decreased incidence and severity of
ICH.72 Other techniques to reduce brain water accumulation through the reduction of arterial ammonia
remain under investigation.73–75
Prevention and Treatment of Increased
Intracranial Pressure
Routine measures such as elevation of the head of the
bed to 30 degrees,55 sedation, minimal stimulation, and
mechanical ventilation to minimize cerebral stimulation
should be adhered to whenever possible. The management should be focused on maintaining an adequate
CPP (> 50 mm Hg) while minimizing elevations in ICP
(< 20 mm Hg). Blood pressure should be maintained to
achieve a CPP between 50 and 65 mm Hg. Prolonged
CPP below 50 mm Hg in the setting of ICH or an ICP
greater than 40 mm Hg is associated with poor outcome.65
THIOPENTAL SODIUM
HYPERTONIC SALINE
The use of hypertonic saline is thought to help restore
the osmotic gradient across the astrocyte membrane. A
randomized, controlled trial recently demonstrated that
MANNITOL
Mannitol administration leads to increased plasma osmolality in brain capillaries, resulting in movement of
water out of the brain according to Starling’s law. It has
been shown to decrease episodes of cerebral edema and
result in improved survival in a cohort of patients with
ALF (47.1 and 5.9%, respectively, p ¼ .008).76 Its use,
however, is limited in renal failure and can lead to a
paradoxical increase in brain swelling if osmolality is not
controlled. If more than two doses are to be used, plasma
osmolality must be checked to assure that it remains
< 320 Osm/L.
HYPERVENTILATION
Hyperventilation is an effective technique to decrease
cerebral blood flow (CBF) and ICP. It does so through
precapillary hypocapnic vasoconstriction and helps restore CBF autoregulation.61,77–79 Although prophylactic
hyperventilation appears to be ineffective in preventing
the development of ICH,77 it can be useful in controlling
acute surges in ICP.
INDOMETHACIN
Indomethacin leads to cerebral vasoconstriction effects
via altering cerebral temperature and extracellular pH
and inhibition of the endothelial cyclooxygenase pathway.80 Its effectiveness has been proven in an animal
model81 and in a small cohort of patients with ALF.82
However, due to its multiple systemic side effects in
patients with ALF, its routine use cannot be supported.
In a small, uncontrolled study, thiopental sodium was
effective in reducing ICP.83 Unfortunately, its use is
associated with significant hemodynamic derangements
that may necessitate escalation of vasopressor or inotropic
support. Thus thiopental use should be reserved for
surges of ICH unresponsive to standard medical therapy.
HYPOTHERMIA
Moderate hypothermia (32 to 33 C) in animal models of
ALF has been effective in improving encephalopathy
and reducing brain water.84,85 Clinical studies of hypothermia have also shown significant reduction in ICP.
Jalan et al were able to demonstrate that cooling patients
with refractory ICH to 32 C decreased ICP to < 20 mm
Hg. Subsequently they demonstrated a reciprocal increase in ICP with rewarming.86 Since this study, the
same and other groups have also shown that moderate
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hypothermia is effective in the prevention of ICH in
ALF, as a bridge to transplant,87 and during liver transplantation88 to prevent surges in ICP. The mechanism
of action is presumed to be multifactorial but includes
reduction of CBF, cerebrospinal fluid (CSF) ammonia,
and extracellular glutamate concentrations. Although
hypothermia may be beneficial to the brain in decreasing
ICP, it also impacts coagulation and may promote
infection and cardiac rhythm disturbances. It is difficult
to know, however, if hypothermia exacerbates such
factors because these are well-known complications of
liver failure per se. Some have raised concern that
hypothermia may impair hepatic regeneration and ‘‘commit’’ patients to transplant.89,90 The degree to which
hypothermia influences such factors needs to be addressed in a well-designed randomized, controlled trial
before its use in routine practice can be justified.
LIVER ASSIST DEVICES
Liver assist devices are of two general types: biological
devices and artificial devices. Biological devices use living
hepatocytes to replace liver function, whereas artificial
devices such as the molecular absorbent recirculating
system (MARS) aim to remove injurious substances
from the circulation. Most of the trials in ALF have
used either porcine hepatocytes [bioartificial liver (BAL)
device]91 or human HepG2 cells (ELAD [extracorporeal
liver assist device]).92 A large multicenter study of BAL
in ALF resulted in no survival advantage.93 In a small
randomized controlled trial, ELAD resulted in less
severity of encephalopathy without improvement in
survival.94 Overall, the data on bioartificial liver devices
are disappointing in that they are quite costly and have
not resulted in improved synthetic function or survival.95
MARS removes free and albumin-bound toxins
via a polysulfone membrane.96,97 In contrast to bioartificial devices, MARS has mainly been tested in acute on
chronic liver failure (AoCLF). Two small randomized
clinical trials have shown improvement in encephalopathy and increased survival.98,99 MARS also appears to be
effective in ameliorating renal function in hepatorenal
syndrome and hemodynamics through increasing systemic vascular resistance (SVR).100 Although not a
primary end point, survival was improved in a prospective, randomized, controlled trial of MARS in liver failure.99 The study was terminated prematurely due to
perceived ethical considerations. Unfortunately, had as
little as one or two deaths occurred in the MARS group
the difference in survival would have no longer been
statistically significant. The results of this trial would
have had a more profound impact if the study had
achieved its targeted enrollment. A recent meta-analysis
found that MARS offered no significant survival benefit
over standard medical therapy.101 MARS appears to be
well tolerated; however, a fair number of patients devel-
2006
oped thrombocytopenia; thus its use should be restricted
in patients with DIC.102
LIVER TRANSPLANTATION FOR ACUTE
LIVER FAILURE
Because the mortality of patients with ALF is almost
universal once they meet criteria for poor prognosis
(Table 2), they receive the utmost priority. The Status
1 classification has remained from the former process of
organ allocation. To receive this listing, the patient must
have no prior history of liver disease and fulfill criteria for
ALF with poor prognosis.
Intensive medical supportive care is geared toward
the avoidance of complications that could preclude
transplant. The decision to proceed with transplantation
is a difficult one not only from a medical management
perspective but also due to the limited time available to
assess the patient’s social support network, mental stability, compliance, and wishes. Psychiatric stability and
strong social support are essential to a successful transplant. It is imperative to accurately document active
drug or alcohol abuse, suicidal ideation, or history of a
previous suicide attempt because these are examples of
potential contraindications to transplant.
ACUTE OR CHRONIC LIVER
FAILURE—GENERAL CONSIDERATIONS
Critically ill patients with cirrhosis admitted to the ICU
have poor survival even if they survive the initial ICU
stay. Mortality can reach 100% in cases complicated by
septic shock.103–106 Acute hepatic decompensation in a
patient with chronic liver disease (AoCLF) is most
commonly precipitated by gastrointestinal bleeding or
infection. As a result of this, major functions of the liver
such as the synthesis of key proteins, detoxification, and
metabolic regulation are impaired to various degrees.
The imbalance created by the physiological needs of the
critically ill patient and the liver’s limited ability to
perform key functions leads to life-threatening complications such as renal failure, infection, HE, cholestasis,
ascites, and bleeding.
An important step in the initial management of
patients with AoCLF is the identification and treatment
of the precipitating factor that led to acute decompensation. Patients admitted to the ICU with AoCLF
should be managed with a simultaneous multifaceted
approach that will bridge eligible patients to transplantation and improve short-term survival in nontransplant
candidates.
PORTAL HYPERTENSIVE BLEEDING
Portal hypertensive hemorrhage is a serious and frequent
complication of advanced cirrhosis.107–109 Bleeding can
INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL
Table 4
Child-Pugh Score
Score
Bilirubin/mmol/L
Albumin/g/L
INR
Ascites
Encephalopathy
1
<2
> 3.5
< 1.3
Absent
0
2
2.1–3
2.8–3.5
1.3–1.5
Mild
I/II
3
>3
< 2.7
> 1.5
> Moderate
III/IV
The Child-Pugh score is derived from the sum of the assigned points in each category. Child-Pugh A,
B, and C are defined as < 6, 7–9, and > 10, respectively. INR, international normalized ratio.
originate from gastroesophageal varices, portal hypertensive gastropathy, or less commonly from portal colopathy, duodenal or rectal varices. A successful outcome
depends on accurate diagnosis, prompt resuscitation,
hemodynamic support, management of complications,
and control of active bleeding. Clinical factors associated
with bleeding include deterioration of liver function,
portal vein thrombosis, hepatocellular carcinoma, and
ongoing alcohol use.110
In cirrhosis, portal hypertension is the result of
the combined effects of increased portal venous inflow
and an increased resistance to that flow.111 The corrected
sinusoidal pressure gradient is inversely associated with
risk of bleeding as well as outcome after bleeding.112–114
A hepatic venous pressure gradient (HVPG) of 12 mm
Hg is a threshold value, with variceal hemorrhage
occurring above this level112 and therapeutic intervention aiming at a reduction below this value.115,116 However, many studies have shown that if portal pressure is
reduced in a sustained manner by 20%, the risk of
bleeding is low (10% at 2 years), even if the HVPG
remains above 12 mm Hg.109,117
Acute variceal hemorrhage (AVH) occurs in 30 to
35% of patients with cirrhosis and is associated with
significant mortality. A recent retrospective analysis reported in-hospital, 6-week, and overall mortality rates of
14.2%, 17.5%, and 33.5%, respectively, suggesting improved therapy of AVH has impacted survival.118 Oneyear survival following a variceal bleed greatly depends on
the severity of liver disease assessed by the Child-Pugh
classification (Table 4). Mortality after a variceal hemorrhage is 5% and 50% in Child-Pugh A and C cirrhotic
patients, respectively,119 and 70% of those that survive
will rebleed.110,120 A hepatic venous pressure gradient
> 20 mm Hg after an acute bleed is an independent
predictor of poor outcome. Such measurements may be
useful to assess prognosis and tailor therapy.114
The management of patients with gastroesophageal varices involves (1) prevention of the initial bleed
(primary prophylaxis is beyond the scope of this review),
(2) management of the acute bleed, and (3) prevention of
rebleeding (secondary prophylaxis).
Variceal Hemorrhage—General Considerations
Acute hemorrhage typically presents with hematemesis
with or without melena or hematochezia. Hemody-
namic instability is often present and needs to be
addressed with continuous cardiac monitoring and
good intravenous access. Knowledge of the central
venous pressure is helpful to gauge the adequacy of
volume administration without overresuscitating the
patient because this can provoke more bleeding from
previously decompressed varices or lead to other complications such as acute pulmonary edema.121,122 Prophylactic endotracheal intubation should be considered
in the setting of significant upper gastrointestinal
hemorrhage prior to endoscopic intervention for airway
protection. Figure 4 proposes an algorithm for the
management of AVH.
Esophageal Variceal Hemorrhage
Mortality associated with AVH has improved in the
past decade.123 Based on data comparing patients
presenting with AVH from 1981–82 to 1988–91, the
late cohort experienced a significant decline in mortality at 30 days (20.8% vs 29.6%, p ¼ .0001) and at 6 years
(69.7% vs 74.5%, p ¼ .0001). For patients who survived
the first 30 days, survival was slightly better in the late
cohort on multivariate analysis (p ¼ .01).124 Spontaneous cessation of bleeding occurs in 50% of patients;
however, 60% of these patients will rebleed if there is no
intervention.120 Therapeutic options for the management of variceal hemorrhage include pharmacological
therapy (somatostatin, octreotide, vasopressin, or terlipressin), endoscopic therapy (endoscopic band ligation
or sclerotherapy), balloon tamponade, transjugular intrahepatic portosystemic shunt (TIPS) or surgical
shunts (Fig. 4). Pharmacological treatment is effective
and should be initiated on admission to the ICU.
Although studies have shown some drugs to be as
effective as endoscopic therapy,125,126 this is controversial; thus we recommend endoscopic intervention in
addition to pharmacotherapy for the control of variceal
hemorrhage.
Gastric Variceal Hemorrhage
Gastric varices represent a less frequent, but important
source of bleeding in patients with portal hypertension.
They are present in up to 57% of patients with esophageal varices secondary to portal hypertension.127 Less
commonly, they are found in the absence of esophageal
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2006
Figure 4 Proposed algorithm for the management of acute variceal bleeding.
varices.128 If isolated gastric varices are noted imaging
must be performed to exclude splenic vein thrombosis
because this is managed with splenectomy. In 117
patients with fundal varices, the size of the vessels, the
presence of red spots, and the degree of liver decompensation were predictors of bleeding.129 Although
bleeding from gastric varices is less common than bleeding from esophageal varices, bleeding episodes are often
more severe and carry a higher mortality.128,130–132
The management of bleeding from gastric varices differs from that of esophageal varices. Although
gastric varices in continuity with esophageal varices can
be managed by endoscopic band ligation, isolated
varices in the fundus of the stomach are not amenable
to either sclerotherapy or band ligation.133 However,
numerous reports have documented the efficacy of
cyanoacrylate injections (tissue glue) in achieving hemostasis in bleeding fundic varices.134,135 Cyanoacrylate glue leads to more rapid variceal obliteration and
more effective hemostasis than alcohol injection.134
Severe complications associated with intravariceal cyanoacrylate glue injection include mediastinitis, CVA,
and cardiac and pulmonary vascular glue emboli.136–138
Recently, pilot studies have found thrombin injections
to be another promising approach.139 Yet another way
to control bleeding gastric varices is with special detachable endoscopically placed snares.140,141 Although
there is limited experience with the technique in the
United States, the Japanese report success with balloonoccluded retrograde transvenous obliteration (B-RTO)
of isolated gastric varices.142,143 Unfortunately, most of
these modalities are not routinely available in the
United States.
The first-line approach to the control of actively
bleeding fundic varices is balloon tamponade. The airway must be protected when this approach is taken. This
is, however, a temporizing measure and such varices have
a great propensity to rebleed over time. It is therefore
reasonable to decompress the portal vein with a TIPS as
the definitive procedure of choice in most patients before
discharge from the hospital.144,145 It is often necessary to
embolize prominent portosystemic collaterals at the time
of TIPS to reduce the risk of bleeding. When this is not
done, nonselective b-blockers may be used to reduce the
INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL
risks of rebleeding, although the data to support such an
approach are weak at best. In those with well-preserved
liver function, a surgical shunt can also provide longterm relief from bleeding.146
Portal Hypertensive Gastropathy
Portal hypertensive gastropathy (PHG) is a manifestation of portal hypertension. Endoscopically it is
characterized by a mosaic mucosal pattern with varying
degrees of submucosal hemorrhage. It is often asymptomatic but may lead to chronic transfusion–requiring
blood loss or acute bleeding (rarely). Although portal
gastropathy is more often seen in the setting of gastroesophageal varices, its severity does not correlate with
portal pressure. Nevertheless, bleeding is often ameliorated by reduction of portal pressure. Both octreotide
and nonselective b-blockade can be helpful in decreasing acute bleeding and the degree of rebleeding from
PHG via reduction of portal blood flow.147–149 In
refractory cases, TIPS can be effective at reducing
transfusion requirements.150
THERAPIES TO ACHIEVE HEMOSTASIS
Drug Therapy
Drug therapy is an integral component of the management of acute portal hypertensive hemorrhage and
should be started on presentation. To optimize the
effectiveness of drug or endoscopic therapy, clotting
abnormalities must be corrected. Target INR and
platelet count should be 1.5 and 75, respectively. In
the setting of renal failure platelets may be dysfunctional and DDAVP (Desamino-D-Arginine Vasopressin) should be considered. FFP alone or in combination
with rFVIIa can be given to rapidly correct coagulopathy. A recent randomized, clinical trial showed that
when given in addition to standard therapy, 100 mg/kg
of rFVIIa may improve control of bleeding in patients
with advanced cirrhosis.151
Somatostatin or octreotide, its synthetic analogue,
stops acute bleeding from varices in 80% of cases.152 It
does so through a reduction of portal pressure via effects
on vasoactive peptides or through the prevention of
postprandial hyperemia (blood meal). Octreotide has
an excellent safety profile and can be given initially as a
subcutaneous bolus of 50 to 100 mg followed by a
continuous infusion of 50 mg/h for 3 to 5 days. Although
it does decrease portal pressure acutely, these effects
appear to be short lived due to rapid tachyphylaxis.153
Nevertheless, studies have shown a significant decrease
in rebleeding after endoscopic therapy in those receiving
octreotide infusion.154,155
Vasopressin reduces splanchnic blood flow in
addition to portal pressure. It is effective in controlling
variceal hemorrhage; however, its use is limited due to
systemic effects such as coronary and mesenteric ischemia.156 If vasopressin is used in conjunction with nitroglycerin, these effects can be minimized.157,158
Terlipressin is a synthetic analogue of vasopressin
with a longer half-life and fewer side effects. It is
effective in the treatment of acute variceal bleeding
with or without endoscopic therapy and has been shown
to reduce mortality.125,159 It appears to be as effective as
vasopressin or endoscopic treatment126,160 in controlling
acute variceal hemorrhage, but is not yet available in the
United States.
Endoscopic Therapy
Endoscopic variceal band ligation (EBL) is currently the
preferred endoscopic technique for the management of
esophageal varices. It is at least as effective as endoscopic
sclerotherapy (EST) but has a superior safety profile and
lower complication rate.133,161,162 EBL also decreases
the incidence of bleeding, when given as primary prophylaxis,163,164 and death165 from variceal bleeding.
Band ligation leads to strangulation and subsequent
obliteration of the banded varix.
EST involves the injection of a sclerosant (sodium
morrhuate, ethanolamine, or polidocanol) into or around
a varix. This leads to coagulative necrosis and obliteration of varices in the vicinity of the injection. Complications related to EST tend to occur more frequently and
be more severe than with EBL and include esophageal
ulceration, stricturing, esophageal perforation, pleural
effusion, and sepsis. Despite a higher complication
rate, a role still exists for EST. It can be a useful adjunct
to EBL in the setting of massive hemorrhage with poor
visibility because the location of injection need not be as
precise to achieve hemostasis.
Regardless of the choice of endoscopic management for acute bleeding, follow-up endoscopy within
1 to 2 weeks for further banding is essential to decrease
the risk of rebleeding. EBL should then be continued in
the future until variceal obliteration is achieved.
Balloon Occlusion
Balloon tamponade is effective in the 5 to 10% of
patients in which hemostasis cannot be achieved acutely
with medical or endoscopic therapy. It successfully stops
bleeding from esophagogastric varices through external
compression of varices, but rebleeding occurs in 50%.166
Many types of tubes exist (Sengsten-Blake Tube, Warne
Surgical Products, Ltd., Armagh, Ireland, UK; and
Linton Tube, Bard Manufacturing, Covington, Georgia, USA) with mild variations; however, in most cases;
inflation of the gastric balloon is adequate to stop
variceal hemorrhage. It is quite effective as a bridge to
more definitive therapy (TIPS or surgery) and cannot be
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in place for more than 24 hours given the significant risk
of esophageal necrosis and rupture.167
Transjugular Intrahepatic Portosystemic
Shunt (TIPS)
TIPS involves placing a stent within the liver that
bridges a branch of the intrahepatic hepatic vein with
an intrahepatic branch of the portal vein, allowing
diversion of blood flow away from the cirrhotic liver,
decompressing portal pressures, and reducing the impetus to bleed. In experienced hands TIPS is a very
effective method for stopping acute hemorrhage from
esophageal varices but can be less effective in gastric
variceal bleeding.168 In the setting of variceal bleeding,
TIPS should be reserved for cases that are refractory to
endoscopic therapy,169 or in the case of gastric varices,
used in conjunction with embolization. If recurrent
bleeding occurs in a patient with a TIPS in place, the
most important intervention is interrogation of the
TIPS to document and treat thrombosis or stenosis.
Until recently, TIPS was complicated by frequent stenosis and thrombosis.168 Polytetrafluoroethylene (PTFE)-coated stents have significantly improved
stent patency and the need for reintervention.170–172
Although they have not been directly compared with
surgical shunts, these data suggest they offer comparable
results.
Surgery
TIPS has significantly reduced the need for shunt
surgery; however, surgery remains a good option in
selected cases when TIPS is not technically feasible or
fails or in patients with significant portal hypertension in
the face of preserved hepatic synthetic function. The
long-term patency rate of shunt surgery is thought to be
superior to that of TIPS; however, newer coated stents
may challenge this assumption.170–172 Surgical alternatives for acute portal hypertensive hemorrhage include
total or selective shunt surgery, devascularization proceTable 5
Precipitants of Hepatic Encephalopathy
Infection
Gastrointestinal bleeding
Medical noncompliance
Medication—sedatives, narcotics, other
Electrolyte disturbances
Portosystemic shunting
Transjugular intrahepatic portosystemic shunt
Spontaneous
Dehydration
Excessive protein load
Constipation
Worsening liver function
2006
dures (Suguira or modification) or liver transplantation.
If surgery is necessary, it is best done at a center with
extensive experience.
COMPLICATIONS ASSOCIATED WITH
VARICEAL BLEEDING
Hepatic Encephalopathy
The initial approach to the patient with HE should focus
on the identification and correction of any precipitant in
addition to treatment of the encephalopathy. Common
precipitants include gastrointestinal (GI) bleeding,
medications, infection, dehydration, electrolyte disturbances, constipation, excessive protein load, portosystemic shunting (TIPS or spontaneous), and worsening
liver function (Table 5). Potential precipitants such as
these must be individually considered and subsequently
excluded. In the case of infection, spontaneous bacterial
peritonitis (SBP) is the most common infection in this
population and must be ruled out with a diagnostic
paracentesis as already discussed. Often, HE is the
only manifestation of SBP.
TREATMENT OF HEPATIC ENCEPHALOPATHY
Nonabsorbable disaccharides and antibiotics have been
shown to modify gut flora and decrease blood ammonia
levels, but these are not necessarily related (indicating
nonbacterial sources of ammonia, which may also be
decreased by these compounds). Lactulose is the firstline therapy for HE. It is most effective if given orally
and titrated to a dose that achieves three to four soft
bowel movements a day. A common mistake in the ICU
is continued lactulose despite diarrhea in the encephalopathic patient. Not only will this not improve encephalopathy, it may worsen it through free water
depletion. If the patient is having adequate bowel movements on lactulose, but continues to be confused, several
agents can be added. Nonabsorbable antibiotics such as
neomycin or rifaxamin are effective for the treatment of
HE either alone or in conjunction with lactulose. Metronidazole is also efficacious; however, side effects limit
prolonged use. Zinc is a cofactor for the urea cycle and
can increase the clearance of ammonia. Zinc levels are
decreased in patients with cirrhosis and HE. Supplementation with zinc sulfate 600 mg/d normalizes zinc
levels, decreases ammonia, and improves HE.173
Branched-chain amino acids have not convincingly
shown improvement in HE; however, they may be
considered in patients that are not receiving protein in
any form.174,175
When HE is refractory to medical treatment
other possibilities must be entertained. In those with a
TIPS, occlusion or narrowing of the stent lumen can
improve mental status.176,177 If no TIPS or surgical
shunt is present, abdominal imaging should be obtained
INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL
Table 6 Diagnostic Criteria for Hepatorenal Syndrome
(International Ascites Club)
MAJOR
Chronic or acute liver disease with advanced hepatic failure
and portal hypetension
Creatinine > 1.5 mg/dL or24-hour creatinineclearance < 40mL/min
location from the gut is thought to be the most common
mode of ascitic fluid inoculation.189,190 Predisposing
factors for the development of SBP include advanced
liver disease, gastrointestinal bleeding, ascitic total protein fluid content 1 g/dL and a previous history of
SBP.181,191–193
Absence of shock, ongoing infection, use of nephrotoxic
drugs, gastrointestinal or renal fluid losses > 500 g/d or
> 1000 g/d in the setting of edema
Urine protein < 500 mg/dL
No ultrasonographic evidence of primary renal disease
No sustained improvement in renal function after hydration
MINOR
Urine sodium < 10 mEq/L
Urine osmolality > plasma osmolality
Urine red blood cells < 50 per high power field
Urine output < 500 mL/d
Serum sodium < 130 mEq/L
For the diagnosis of hepatorenal syndrome, all major criteria must be
met. Minor criteria are supportive but not necessary for the diagnosis.
to look for a prominent portosystemic collateral that
could be radiographically embolized.178
Infection
Bacterial infections complicate 35 to 66% of cases of
gastrointestinal bleeding in patients with AoCLF.179–184
Not only is infection common after bleeding, it may also
provoke rebleeding.179 Furthermore, bacterial infection
and the use of prophylactic antibiotics are independently
associated with failure to control variceal hemorrhage in
the first 5 days of admission.180 Many randomized,
controlled trials have shown that antibiotic prophylaxis
targeted at enteric organisms (such as quinolones or
third-generation cephalosporin) is effective in the prevention of postbleeding infection in cirrhotic patients. In
addition, a meta-analysis of randomized, controlled
trials concluded that antibiotic prophylaxis resulted in
less infections and improved short-term survival in
bleeding patients with cirrhosis.185 Given these data,
prophylactic systemic antibiotics should be given to
cirrhotic patients with gastrointestinal hemorrhage.
Spontaneous Bacterial Peritonitis
SBP is a frequent and severe complication in those with
cirrhosis and ascites.186 It is associated with significant
morbidity and mortality by precipitating renal failure in
30%,187 worsening HE, and causing hemodynamic collapse in an already critically ill patient. The deterioration
of renal function is the most sensitive predictor of inhospital mortality.187,188 Renal failure often results from
a reduction in effective circulating blood volume, cytokine surges, and activation of the renin-angiotensin
system precipitated by infection.187,188 Bacterial trans-
INTERPRETATION OF A DIAGNOSTIC PERITONEAL TAP
It is crucial to have a very low threshold to perform a
diagnostic paracentesis in the patient with suspected
SBP. Ideally, this should be done prior to the initiation of antibiotics. Peritoneal fluid should be sent
for cell count, culture, albumin, total protein, LDH
(lactate dehydrogenase) and glucose. Blood culture
bottles should be inoculated at the bedside to improve
yield.
SBP is defined as an ascitic fluid polymorphonuclear (PMN) 250 cells/mm3, in the setting of a
positive monomicrobial ascitic fluid culture.194,195 Culture positivity can fluctuate from one tap to the next;
thus culture-negative neutrocytic ascites should be
treated with antibiotics as previously outlined.196
Monomicrobial non-neutrocytic bacterascites is
another common variant of SBP. It is defined as a fluid
cell count < 250 cells/ mm3 with a positive culture.197
Runyon and Hoefs and Chu et al found that 62 to 86%
of cases of monomicrobial bacterial ascites resolve spontaneously, and those that did not resolve were symptomatic on presentation.197,198 Thus, in a clinically stable
asymptomatic patient, one could observe or consider
repeat diagnostic paracentesis. However, in a critically
ill patient with AoCLF in the ICU, antibiotic therapy
may be the best course of action.
TREATMENT OF SPONTANEOUS BACTERIAL PERITONITIS
Patients should be given a non-nephrotoxic antibiotic
with good enteric coverage such as a third-generation
cephalosporin. Cefotaxime 2 g (q8h) is the beststudied antibiotic for the treatment of SBP.199,200
Other antibiotics of comparable spectrum can be
used and can be tailored if the organism is identified.
Once the patient has been on antibiotics for 48 hours,
a diagnostic tap must be repeated to assess response to
treatment. If there is not a significant decrement in the
white blood cell (WBC) count, antibiotic coverage
should be broadened. Once treatment efficacy is established, antibiotics should be given for 5 days.201 Intravenous albumin is integral to the treatment of SBP
and should be used in conjunction with antibiotics. It
has been shown in a randomized, controlled trial to
decrease the incidence of renal failure and subsequent
mortality when compared with antibiotics alone.202
Based on these data, albumin should be given at a
dose of 1.5 mg/kg on day 1 and 1 mg/kg on day 3. A
recent study compared albumin to plasma expansion
with hydroxyethyl starch. Fernandez and colleagues
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2006
found that only albumin improved hemodynamics in
patients with SBP, suggesting that it may also have
direct effects on the vascular endothelium.203 Lifelong
secondary antibiotic prophylaxis is mandatory in the
patient with a history of SBP. Oral quinolones are
most commonly used (norfloxacin); however, many
antibiotics are effective for secondary prophylaxis of
SBP.
Table 6 illustrates the International Ascites Club classification of HRS.
The pathophysiology of HRS is complex.
Splanchnic arteriolar vasodilation leads to central vasodilation and compensatory activation of systemic and
renal vasoconstrictor systems.107,211 The resultant renal
vasoconstriction leads to reduced glomerular filtration
rate and increased water and sodium retention.
ASCITES
Ascites is the result of avid water and sodium retention
characteristic of the altered hemodynamics of cirrhosis
and portal hypertension. It is associated with a 50%
2-year survival. Uncomplicated ascites is managed
with sodium restriction (< 88 mmol/d) and diuretics;
potassium sparing (i.e., spironolactone) alone, or in
combination with a loop diuretic (i.e., furosemide).
Diuretics are advanced until therapeutic efficacy is
achieved or limited by worsening renal function or
hyponatremia. In diuretic-refractory or resistant cases
repeat large-volume paracentesis (LVP) with albumin
infusion, TIPS, or peritonovenous shunts can be
effective in improving the ascites but does not improve
survival.204,205
Ascites can be a difficult problem to manage
in the ICU. Copious colloid and crystalloid infusion
inevitably worsens ascites and diuretic use is often
limited by hyponatremia, hypotension, or renal failure.
Massive ascites can also alter respiratory mechanics and
make breathing more labored or mechanical ventilation
more challenging. Occasionally, massive ascites can
worsen renal failure through compression of the renal
arteries. LVP should be reserved for patient discomfort
and improvement of respiratory mechanics when possible to avoid large-volume shifting and activation of
vasoactive neurohumoral systems after paracentesis that
can worsen renal perfusion. Such changes can be minimized with the use of albumin (6 to 8 g/L removed).
Albumin administration helps maintain intravascular
volume and minimize postparacentesis circulatory dysfunction.205,206
Treatment of Hepatorenal Syndrome
Liver transplantation is the ultimate treatment for
HRS. After transplantation renal function returns to
baseline in most cases.212,213 Combination drug therapy that counteracts renal and systemic vasoconstriction
leading to arterial hypotension and central hypovolemia
with vasoconstrictors and plasma expanders, respectively, is the most effective strategy. Terlipressin, a
long-acting vasopressin analogue that stimulates
splanchnic V1a vasopressin receptors increases blood
pressure, GFR (glomerular filtration rate), and urine
volume in patients with HRS.214,215 Unfortunately,
terlipressin is not yet available in the United States.
In a small study of patients with HRS I, the combination of the a-agonist midodrine (7.5 mg tid), octreotide
(100 g SQ tid), and albumin (25 g/day) was effective in
improving renal function.216 In a more recent study,
these findings were confirmed and insertion of a TIPS
in a subset of patients led to further improvement in
renal function.217
RENAL FAILURE
Twenty percent of cirrhotic patients with tense ascites
develop renal failure characterized by the hepatorenal
syndrome (HRS).207,208 HRS is defined as functional
renal impairment in a patient with advanced liver disease
in the setting of normal tubular function and renal
histology209 (Table 6). Two types of HRS have been
described; HRS I and HRS II, based upon the rapidity
and extent of renal failure.210 HRS I is characterized by a
rapid and severe deterioration of renal function with
survival measured in days to weeks, and HRS II represents a more indolent and stable renal dysfunction.
LIVER TRANSPLANTATION—CHRONIC
LIVER DISEASE
Allocation of organs in chronic liver disease changed on
February 27, 2002. The model of end-stage liver disease
(MELD) system was adopted to objectify the way in
which livers were allocated in the United States. It is a
survival model based on a composite of three laboratory
values: serum bilirubin, serum creatinine, and INR.
The model was originally used to assess short-term
mortality in cirrhotic patients undergoing elective
TIPS placement.218 This model was subsequently validated as an independent predictor of survival in
patients with cirrhosis.219,220 Thus priority on the liver
transplant waiting list is based on the patient’s blood
group and the MELD score without emphasis on
waiting time.
SUMMARY
Management of the patient with acute or chronic
hepatic failure remains a challenging problem, despite
advances in intensive care. Liver failure typically has
profound effects on other organ systems and the effects
of therapeutic interventions on other organs must be
INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL
considered. A multidisciplinary approach is most effective and urgent transfer to a transplant center is mandatory in potential transplant candidates. Ideally, good,
comprehensive intensive care can support the patient
into spontaneous hepatic recovery; however, often
the goal of therapy is to bridge patients to definitive
therapy—liver transplantation.
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