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Metabolic Brain Disease, Vol. 19, Nos. 3/4, December 2004 (

C 2004)

Management of Patients With Fulminant

Hepatic Failure and Brain Edema

Flemming Tofteng1 and Fin Stolze Larsen1,2

Received January 9, 2004; accepted January 16, 2004

Cerebral edema in acute liver failure is associated with a poor prognosis. Optimization of
cerebral perfusion pressure and blood flow plays a key role in contemporary management of
these patients. However, understanding of the pathophysiology of brain edema is required
for optimal patient management. This review explains the relationships between cerebral
perfusion and edema and summarizes therapies that are currently used in patients with
acute liver failure to prevent and reduce intracranial pressure.
Key words: Acute liver failure; ammonia; brain edema; cerebral blood flow; microdialysis; oximetry; intracranial
pressure; cerebral perfusion pressure.

INTRODUCTION

Fulminant hepatic failure (FHF) is a rare but devastating condition with a poor outcome.
Development of hepatic encephalopathy results in death or the need for emergency liver
transplantation in three out of four patients. More than half of the patients with ALF have
episodes of intracranial hypertension with surges of high ICP exceeding 30 mmHg (Forbes
et al., 1989; Munoz, 1993). Indeed, evidence of brain herniation at autopsy, as well as direct
measurement of ICP has confirmed that brain edema plays a key role in the demise of these
patients.
Considerable efforts have been put in to unravel the pathophysiology of cerebral edema
in FHF. Although it seems well established that cerebral edema is localized to the perivas-
cular space and astrocytes (Laursen, 1982), the pathogenesis appear to be multifaceted,
with alterations in cerebral energetics (Rao and Norenberg, 2001), astrocyte osmoregu-
lation (Cordoba et al., 1996a,b), neurotransmission (Butterworth, 1997), and alterations
in blood-brain barrier (BBB) transport of water and various amino acids (Knudsen et al.,
1993; Larsen and Wendon, 2002; Strauss et al., 2001a,b). Also changes in the regulation
of cerebral blood flow (CBF) of appear to be importance for aggravation of cerebral edema
in FHF (Jalan, 2003; Larsen, 1996).
In patients with FHF there is a considerable intra-individual variation of CBF (Larsen,
1996). The number of proposed treatments to prevent elevated ICP has increased
significantly. Most of these therapies work by reducing the CBF. Although this may be
appropriate in most patients it also raises concern that cerebral oxidative metabolism may

1 Department of Hepatology, A-2121, Rigshospitalet, University of Copenhagen, Denmark.

2 To whom correspondence should be addressed at Department of Hepatology, A-2121, Rigshospitalet, 2100
Copenhagen, Denmark. E-mail: stolze@post3.tele.dk

207
0885-7490/04/1200-0207/0

C 2004 Plenum Publishing Corporation
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208 Tofteng and Larsen

become critically restricted in some patients. Thus, it may be rational to secure brain viabil-
ity not only by monitoring ICP but also by recording changes in cerebral perfusion and/or
oxidative metabolism (Ellis and Wendon, 1996; Tofteng et al., 2002). This paper shortly
reviews treatments that aim to prevent and treat high ICP in FHF with special focus on
why such interventions should be guided by concomitant changes in cerebral perfusion and
oxidative metabolism as determined by brain microdialysis.

BASIC HANDLING AND MONITORING

Management of FHF patients with multiorgan dysfunction requires coordination of a

multidisciplinary team. Critical care management is often considered to have secondary
priority to efforts that seek to recover liver capacity either by liver transplantation or by
liver assisting. Optimal management is, however, most often a prerequisite for successful
liver transplantation or for spontaneous survival by hepatic regeneration.
Volume expansion with saline and colloids (or crystalloids) of the circulating blood
volume should be initiated as soon as possible after admittance of the patient to the
hospital. A central venous line should be inserted regardless of the compromised secondary
hemostasis. It is valuable that volume expansion and access to a central venous system is
secured before transport of the patient to a liver transplantation center, as volume expansion
often increases arterial pressure, systemic oxygenation, and corrects lactate acidosis (Bernal
et al., 2002).
After admission of the patient with FHF to the liver intensive care unit the patient
should be switched to mechanical ventilation if hepatic encephalopathy is overt. Also
invasive monitoring of central hemodynamics should be secured in such cases. If sedation is
indicated for allowing controlled ventilation, short-acting sedatives combined with fentanyl
are preferred, without use of drugs for paralysis as epileptiform activity may be masked.
Broad-spectrum antibiotics should be administered as most patients with FHF suffer from
SIRS or sepsis (Rolando et al., 2000; Vaquero et al., 2003).
Though high ICP often result in death in FHF patients it not clear how to identify the
patients at risk Hanid et al. (1980). High circulating levels of ammonia may be of value
as most patients with an arterial ammonia concentration above 200 µmol/L suffer from
cerebral herniation (Clemmesen et al., 1999; Strauss et al., 2001a,b). In our unit not only
do we insert a Camino catheter if arterial ammonia concentration is above 150 µmol/L, but
also patients fulfilling the liver transplantation criteria or patients suspected to suffer from
high ICP are monitored and are likely to benefit from this close evaluation of changes in
cerebral hemodynamics (Ellis and Wendon, 1996).
It is often assumed that the level of cerebral perfusion pressure (i.e. arterial pressure
minus ICP) reflects if CBF is sufficient or not. This assumption may be inaccurate (Davies
et al., 1994), as it relies on a constant cerebrovascular resistance. The cerebrovascular
resistance tends to decrease during the cause of FHF and may also be influenced by the use of
sedatives and various inotropes (Shawcross et al., 2004). Therefore, ICP monitoring should
be instituted together with either monitoring of cerebral oxidative metabolism, i.e. by a
cerebral microdialysis catheter (Tofteng et al., 2002), or by monitoring of oxygen saturation
in the jugular bulb (Ellis and Wendon, 1996; Larsen et al., 1997; Strauss et al., 2001b).
Bedside analysis of microdialysis samples allows for monitoring the lactate and pyruvate
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Management of Patients With Fulminant Hepatic Failure and Brain Edema 209

concentrations in brain cortex (Tofteng et al., 2002). Alternatively repeated collection

of anaerobe blood samples and analysis of internal jugular vein oxygen saturation gives
important information of global cerebral oxygenation (Strauss et al., 2001a,b). Although
these invasive methods are associated with risk of inducing hemorrhage in patients with
FHF the use of Factor VIIa before the procedure appears to minimize such risks as the
secondary hemostasis is restored (Shami et al., 2003).

PREVENTION OF HIGH ICP

Before reviewing the various treatment modalities that may ameliorate brain edema in
ALF it may be helpful to briefly highlight the pathophysiology of brain swelling, to better
understand the rationale for these interventions (for review see Vaquero et al., 2004, in this
issue).
Arterial ammonia concentration is increased in patients with ALF as amino acid
turnover and nitrogen removal by the failing liver are compromised. Ammonia is extremely
toxic to the brain and may induce seizures and fatal brain damage (Felipo and Butterworth,
2002). Ammonia detoxification in the brain takes place in astrocytes where ammonia
is eliminated via amidation of glutamate to form glutamine, and to a lesser extent by
transamination of pyruvate to alanine (Chatauret et al., 2003). As glutamine and alanine
are organic osmolytes this ammonia detoxification takes place at the expense of astrocyte
swelling, as astrocytes cannot resist the membrane tension generated by disturbances in
the osmotic pressure gradient across the cell membrane. In addition a vasodilating factor is
released due to cell swelling leading to high CBF (Blei and Larsen, 1999). The increasing
CBF is contributing to the surges of high ICP, as blood volume will increase compromising
intracranial compliance.
Considering the genesis of brain edema an obvious way to control water influx to brain
would be to prevent a rise of circulating ammonia levels. Efficient clearance of ammonia
from the circulation either by stimulating the ureagenesis by plasmapheresis (Clemmesen
et al., 2001), muscle uptake of ammonia by ornitin-aspartate (Rose et al., 1999), or by
extracorporeal albumin dialysis techniques (Awad et al., 2001) are under evaluation but
randomized controlled trials to support the use of such treatments remain to be performed
in the clinical setting of ALF.
Restoring the normal osmotic gradient across the BBB and the astrocytes membrane
is another approach to prevent cerebral edema (Larsen and Wendon, 2002). Indeed, an
increase in plasma tonicity by hypertonic saline has recently been demonstrated to reduce
the risk of brain edema and high ICP in a randomized controlled trial (Murphy et al., 2004).
Phenytoin has been reported to prevent development of brain edema in patients with
ALF probably by modulating sodium channel activity (Ellis et al., 2000). However, the use
of this drug is now abandoned in most centers due to its potential “extra-cerebral” serious
side effects.
Induction of mild hypothermia in FHF seems to prevent failure of brain energetics
(Chatauret et al., 2003), the release of the excitatory neurotransmitter glutamate (Chatauret
et al., 2002), and ameliorate brain edema in experimental models (Cordoba et al., 1999;
Master et al., 1999). The value of prophylactive use of hypothermia in patients with ALF
is under evaluation.
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210 Tofteng and Larsen

Increasing the cerebrovascular tone by indomethacin ameliorates brain edema and

prevents high ICP in the experimental setting (Chung et al., 2001). The prophylactive
use of this drug in patients with imminent FHF cannot be recommended as it may result
in renal failure and intestinal ischemia. The use of this potent drug should be limited
to cases with severely elevated ICP not responding to other interventions as described
below.
Although randomized controlled trials have shown that steroids do not improve sur-
vival in patients with FHF the possible value of immunomodulation, such as calcineurin
inhibitors, selective cytochrome inhibitors (P450-2C11), and infliximab, on brain edema is
not settled (Canalese et al., 1982; Dethloff et al., 2004).

MANAGEMENT OF THE PATIENT WITH HIGH ICP

Monitoring of jugular bulb oxygen saturation and brain lactate-pyruvate ratio in

brain cortex, gives valuable bedside information about cerebral perfusion and oxidative
metabolism. It also gives valuable information about the effect of interventions initiated
to reduce ICP. By using such combined monitoring it is clear that high ICP in a patient
with low cerebral perfusion and an increased cerebral tissue lactate-pyruvate ratio, should
be treated differently than the patient with high ICP and cerebral hyperemia and a normal
lactate-pyruvate ratio.

High ICP and Compromised Perfusion

A decrease in jugular bulb saturation below 50% may result in anaerobic cerebral
glycolysis with an increase in the lactate-pyruvate ratio, ischemic brain damage, and aggra-
vation of cerebral edema. An obvious way to decrease ICP, and thereby increase cerebral
perfusion is by reducing intracranial volume by drainage of cerebrospinal fluid as in pa-
tients with brain edema after traumatic brain injury. However, the safety and efficacy of
this method still remains to be determined in patients with FHF.
Mannitol infusion remains the primary treatment of choice to reduce ICP (Ede and
Williams, 1986). Although it has been claimed that the decrease in ICP during mannitol
infusion results from cerebral vasoconstriction, the effect is more likely generated by a
reduction in the interstitial water content, i.e. by cerebral dehydration.
Modulation of water movement across the BBB and astrocytes membrane can also be
secured by infusion of 30% saline (Murphy et al., 2004). It has been shown that hypertonic
saline decreases ICP in patients with ALF, but it remains unknown what happens to CBF and
metabolism using this intervention. It is likely, however, that cerebral perfusion pressure,
and thereby CBF increases (as autoregulation is lost in ALF). If ICP remains unaltered after
mannitol or hypertonic saline infusion the reliability of the ICP signal should be secured,
and subsequently sedation should be increased. It is also possible that such patients may
benefit from induction of mild hypothermia until the liver function is reestablished by liver
transplantation (Jalan et al., 2002).
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Management of Patients With Fulminant Hepatic Failure and Brain Edema 211

High ICP and Cerebral Hyperemia

In some patients CBF increases during the course of FHF due to gradual cerebral arte-
riolar vasodilatation and implies development of cerebral hyperemia and jugular bulb satu-
ration above 75% Larsen et al. (1996), Larsen et al. (2001). The prognosis for patients with
such cerebral “luxury perfusion” and cerebral edema is very poor (Aggarwal et al., 1994).
Besides using sedation, mannitol, and hypertonic saline various specific as well as
unspecific methods to induce cerebral vasoconstriction are currently used in attempts to
decrease CBF and ICP.
Hyperventilation is an indispensable and powerful part of the available treatment
modalities to manage intracranial hypertension in FHF. Hyperventilation induces precap-
illary hypocapnic vasoconstriction and decreases CBF and ICP (Ede et al., 1986; Strauss
et al., 2001a,b). If CBF is decreased substantially by lowering PaCO2 , hypoxia and is-
chemia may occur (Wendon et al., 1994; Durham et al., 1995). However, in a controlled
trial, prophylactic hyperventilation in patients with FHF did not lead to an excess mor-
tality but a prolonged survival (Ede et al., 1986). In most centers patients with FHF are
now being normoventilated, and hyperventilation is only instituted to terminate intracranial
hypertensive episodes. By monitoring ICP and jugular bulb saturation such therapy does
not influence brain metabolism as long as the saturation is maintained above 55% (Larsen
et al., 1997; Strauss et al., 2003).
Maintenance of a cerebral perfusion pressure above 90 mmHg in patients with post-
trauma brain edema has been advocated, based upon the assumption that the lower limit
of autoregulation is right shifted. Theoretically, Strauss et al. (1997) ICP should decrease
during a noradrenaline-induced raise in arterial pressure, because of autoregulatory vaso-
constriction. However, in patients with FHF and loss of autoregulation Strauss et al. (1997),
ICP remains unchanged (Larsen, 1996) or even increases during such therapy (Jalan et al.,
2001) and cannot be recommended.
Hypothermia reduces ICP in patients with severe FHF by decreasing CBF and without
compromising cerebral oxidative metabolism (Jalan, 2003; Jalan et al., 1999). This method
is currently undergoing closer clinical evaluation and seems a powerful tool with only few
potential side effects.
A bolus injection of indomethacin reduces ICP and increases cerebral perfusion pres-
sure in patients with FHF (Clemmesen et al. (1997); Tofteng and Larsen, 2004). This effect
upon ICP and cerebral perfusion pressure does not compromise cerebral oxygenation or
the lactate concentration within the extracellular space of the brain.

CONCLUSION AND PERSPECTIVE

In patients with FHF and brain edema, treatment modalities that aim to prevent or
reduce high ICP most often reduce the precapillary blood volume. Such therapy may
result in brain ischemia if too zealously instituted. Therefore monitoring of ICP should be
supplemented by recording of either cerebral oxygenation by a jugular bulb catheter or by
direct measurement of brain oxidative metabolism by cerebral microdialysis techniques.
Although small experimental and clinical studies indicate that these complications can
be postponed by controlling CBF within normal limits no clinical data exist to demonstrate
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212 Tofteng and Larsen

that any intervention can fully prevent development of brain edema and high ICP. Also a
more recent clinical study shows that restoration of the colloid osmotic pressure gradient
can be achieved by infusion of hypertonic saline and by induction of mild hypothermia.
Confirmatory studies are, however, still awaited.
Future development of treatments that specifically antagonize brain edema will prob-
ably be based on identification of the endogenous factor that dilates the cerebral arterioles
in FHF. In cases with manifest brain edema and high ICP future development of selective
venous vasoconstrictors may turn out to be safer in controlling ICP than treatments that
restrict precapillary blood volume.

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