hepatic insufficiency - intracranial hypertension - brain edema
insuficiência hepatica - hipertenção intracraniana - edema encefálico
Acute liver failure, also known as fulminant hepatic failure (FHF), embraces a spectrum
of clinical entities characterized by acute liver injury, severe hepatocellular dysfunction,
and hepatic encephalopathy. This is an uncommon, but not rare, condition with approximately
2,000 cases annually in the United States and a mortality rate ranging from 50% to
90%, despite intensive care therapy[1],[2]. Cerebral edema leading to intracranial hypertension complicates approximately 50%
to 80% of patients with severe FHF (grade III or IV coma), in whom it is the leading
cause of death[2],[3],[4].
Brain edema in FHF patients is a relatively recent concept. In a 1944 report of 125
autopsies of military patients who had died from a condition he called fatal hepatitis
(previously referred to as idiopathic acute yellow atrophy of the liver), Lucké[5] noted little alteration in the brain except for edema, but did not describe cerebral
herniation. The first reports of brain edema and cerebral herniation as complications
of FHF only emerged in the 1980s[6],[7]. It is also noteworthy that brain edema and intracranial hypertension are not recognized
common features of chronic liver failure, despite some case reports and small series[8],[9]. The recent recognition of brain edema in FHF patients could be due to the advances
in FHF patient care. Previously, FHF patients were dying from early hepatocellular
insufficiency complications, mainly hemorrhage or sepsis[5].
Changes in cerebral hemodynamics and metabolism have been widely reported in patients
with FHF[10]. Findings suggest that hemodynamic and metabolic changes occur in progressive phases
which, if not reversed, can result in brain death. In the earliest phase, cerebral
blood flow is low and coupled with low metabolic demands of the brain[11]. As the disease progresses, cerebral blood flow becomes excessive (uncoupled) in
relation to metabolic demand[12], systemic cerebrovascular autoregulation is impaired[13], intracranial blood pressure (ICP) decreases[12], and cerebral swelling develops[14].
There is a clear need to characterize these physiologic changes and their progression
in order to facilitate clinical management of FHF patients. A delay or reduction in
cerebral swelling could potentially provide time for medical treatment to restore
liver function or allow for the diseased liver to be replaced.
The aim of this paper was to review the pathophysiology of cerebral hemodynamic and
metabolic changes in FHF in order to improve understanding and monitoring of intracranial
dynamic complications in FHF.
PATHOPHYSIOLOGY OF INTRACRANIAL HYPERTENSION IN FHF PATIENTS
PATHOPHYSIOLOGY OF INTRACRANIAL HYPERTENSION IN FHF PATIENTS
Cerebral edema and intracranial hypertension complicates approximately 75% to 80 %
of patients with FHF and grade III or IV encephalopathy, in whom it remains a leading
cause of death. Currently, the mechanism underlying cerebral edema and intracranial
hypertension in the presence of FHF is multi-factorial in etiology and only partially
understood[15]. Putative contributing mechanisms include cytotoxicity as a result of osmotic effects
of ammonia, glutamine, other amino acids, and proinflammatory cytokines. Cerebral
hyperemia and vasogenic edema occur due to disruption of the blood-brain barrier with
rapid accumulation of low molecular substances. Dysfunction of sodium-potassium adenosine
triphosphatase (ATPase) pump with loss of autoregulation of cerebral blood flow has
been implicated as a cause of hyperemia[10],[11].
Normal intracranial pressure (ICP) is 5 to 10 mmHg and intracranial hypertension becomes
clinically relevant at ICPs exceeding 20 mmHg. Severe intracranial hypertension compromises
cerebral perfusion pressure. By definition, cerebral perfusion pressure is the difference
between mean arterial pressure and cerebral venous pressure. As cerebral venous pressure
can be approximated by ICP, cerebral perfusion pressure is equal to mean arterial
pressure minus ICP[14]. An increase in ICP reduces cerebral perfusion pressure, and thus decreases cerebral
blood flow. This reduction in the cerebral blood flow may cause cerebral ischemia
or infarction, resulting in neurological deficits in FHF survivors. A rise in ICP
is the mechanical consequence of an increase in the intracranial volume. The central
nervous system (CNS) is protected by the skull, which is rigid and incompressible.
Within the skull itself, three different compartments can be defined: the brain, cerebrospinal
fluid and blood. If the volume of a given compartment decreases, this results in some
intracranial compensation capacity or compliance. When the volume of another compartment
decreases, resulting in some intracranial compensation capacity or compliance, and
increase exceeds this compliance, any further addition of volume leads to a rise in
ICP (Monro-Kellie Theory)[10],[11].
PATHOPHYSIOLOGY OF BRAIN EDEMA IN FHF
PATHOPHYSIOLOGY OF BRAIN EDEMA IN FHF
Role of ammonia-glutamine
The main determinant molecule involved in astrocyte swelling, at least triggering
this pathological condition, is ammonia. Astrocyte glutamine synthetase plays an ammonia-detoxifying
role by amidation of glutamate to glutamine[16],[17]. In hyperammonemic conditions, glutamine is increased in astrocytes and astrocyte
swelling occurs. In rats with induced hyperammonemia, astrocyte swelling reduced when
an inhibitor of glutamine synthetase, methionine sulphoximine, was administered[18]. This could explain why the edema is focused primarily on the astrocyte, because
the neurons, capillaries and other general membranes of the CNS have unusually low
water permeability[19]. Glutamine could have a relevant role in oxidative/nitrosative stress as a critical
factor in ammonia-induced cell injury[20]. The increase in brain glutamine appears to be an early event, as evidenced by the
two-fold increase seen only 24 hours after performance of portocaval anastomosis in
rats[21]. Inhibition of glutamine formation results in amelioration of ammonia-induced swelling
in rat brain in vivo and in isolated astrocytes in vitro
[22]. Accumulation of glutamine alone, however, does not provide a complete explanation
for the development of brain edema. Other elements must be involved to account for
the development of brain swelling[23]. One possibility is the involvement of other organic osmoles, such as alanine. Alanine,
which can be generated from transamination of glutamine, is also increased in rat
brain of FHF models. Notably, whereas glutamine increases rapidly in the early stages
of hepatic encephalopathy and remains elevated to the same extent during coma stages,
alanine continues to progressively rise concomitant with worsening hepatic encephalopathy[23],[24]. Other organic osmoles, such as myo-inositol or taurine, appear to be unchanged
or only slightly decreased in experimental models with FHF[25].
Role of the blood-brain barrier
Astrocytes are important components of the blood-brain barrier. Any change in astrocytes
also implies a potential change in integrity of the blood-brain barrier. In addition,
three major causes of astrocyte swelling are considered: 1) cellular edema; 2) vasogenic
edema; and 3) aquaporins. Of these three, the latest to be reported are aquaporins,
described in 1992 as water channels. Subsequently, many isoforms have been identified[26]. Aquaporin 4 is the most important of the aquaporins in the development of cerebral
edema observed in FHF. It is highly expressed in the plasma membrane of astrocytes
and abundant in astrocyte cells bordering the subarachnoid space, ventricle and blood
vessels[26].
High levels of aquaporin 4 were noted in areas where astrocytes come into direct contact
with capillaries, ependymal layer and pia. In addition, the basolateral membrane of
the ependymal cells lining the subfornical organ is positive for aquaporin 4. The
sites of aquaporin expression in the brain suggest a role in the transport of water
across the blood-brain barrier and thus in cerebrospinal dynamics and the formation
of brain edema[7]. Therefore, aquaporins are also associated with apoptosis in the CNS[26].
With regard to vasogenic edema, the ion channels, exchangers and transporters are
important factors in cell volume regulation[26],[7]. Changes in these systems may result in the loss of ion homeostasis and the subsequent
accumulation of intracellular water[27]. These ion transporters and exchangers include Na-K-Cl cotransporter-1, which plays
an important role in cell swelling/brain edema. The activation of Na-K-Cl cotransporter-1
is important in astrocyte swelling by ammonia where this activation is mediated by
Na-K-Cl cotransporter-1 as well as its oxidation/nitration and phosphorylation[28]. Alterations in blood-brain barrier permeability, if present, appear to play a more
secondary and/or facilitating role as opposed to being the central determinant of
brain water accumulation in FHF[29].
HEMODYNAMIC CHANGES
Understanding the regulation of cerebral blood flow and the coupling of cerebral blood
flow to metabolism are essential to following the changes that take place in critical
injury of the CNS, as occurs in patients with FHF[29].
Regulation of cerebral blood flow
The brain has a unique capacity to adjust blood flow to changes in functional and
metabolic activity (flow-metabolism coupling or metabolic regulation), changes in
perfusion pressure (pressure autoregulation), or alterations in arterial content of
oxygen or carbon dioxide (oxygen or carbon dioxide vasoreactivity)[30]. In addition, cerebral blood flow can be altered through the direct influence of
connections between specific centers in the brain and blood vessels (neurogenic regulation)[31].
In patients with FHF, a wide spectrum of values of cerebral blood flow has been reported,
ranging from abnormally low to abnormally high levels[31]. This broad spectrum of cerebral blood flow in FHF most likely reflects a real situation
where cerebral blood flow is subjected to the influence of multiple factors[32], such as disease severity, systemic hemodynamic or extrahepatic complications. Despite
these variations, it is now generally accepted that cerebral oxidative metabolism
is preserved in FHF, with cerebral blood flow usually remaining higher than the metabolic
needs of the brain (so-called luxury perfusion)[31],[32].
Coupling of cerebral blood flow to metabolism
Under normal circumstances, cerebral blood flow is tightly matched to the level of
the brain’s requirement for oxygen and glucose; this match is referred to as flow-metabolism
coupling or metabolic regulation. During seizure activity, both glucose utilization
and blood flow can increase by 200% to 300%. Conversely, when the level of cerebral
metabolism is reduced, such as during barbiturate anesthesia or coma, a commensurate
reduction in blood can be seen[33]. Temperature also has an important influence, as glucose utilization in most regions
of the CNS changes by approximately 5% to 10% for each degree Celsius change in body
temperature[34]. Although many proposed mediators have been shown to induce vessel dilatation and
increase local flow, the exact mechanism involved is currently unknown[33],[34],[35].
Extracellular pH change may be the mechanism by which metabolism influences blood
flow as both hydrogen ions and lactate accumulate in areas of increased metabolism[33]. The resulting decrease in pH causes local vasodilation, possibly by altering membrane
permeability or receptor function[34]. Changes in extracellular potassium (K+) occur with neuroactivation, which leads some investigators to speculate that this
ion is the mediator of flow-metabolism coupling. Topical application of K+ causes cerebral pial arterioles to dilate in a concentration-dependent fashion[35],[36]. In addition, during initial seizure activity, pH remains unchanged, while increases
in the extracellular concentration of potassium cations are evident (K+). These observations support the role of extracellular K+ concentration as a regulator of the blood flow response to changes in metabolism[36].
Adenosine has received much attention as a putative mediator between neuronal activity
and the supply of substrates. This purine derivative is rapidly produced by the degradation
of adenosine triphosphate via 5’-nucleotidase reaction and is a potent dilator of
cerebral vessels[36],[37]. Numerous findings point to adenosine as an attractive candidate for the coupling
of blood flow to oxidative metabolism. Initial rapid and significant elevations in
extracellular adenosine occur during increased cerebral metabolic activity, hypotension,
hypoxia, and seizure[36],[38]. Adenosine levels double after only five seconds of ischemia and increase six-fold
after the onset of hypoxia during which time cerebral blood flow begins to rise significantly[38].
Prostaglandins and other eicosanoids (products of arachidonic acid metabolism) can
be rapidly synthesized and released by cerebral microvessels and have been postulated
as putative mediators coupling metabolism and blood flow[38],[39],[40],[41],[42]. With the exception of the vasodilator prostacyclin, arachidonic acid derivatives
are potent vasoconstrictors at low concentrations. Nitric oxide (NO) may be an important
mediator in the control of cerebral circulation[43],[44],[45]. Nitric oxide causes vasorelaxation, and intravenous administration of NO synthetase
inhibitor results in a dose-dependent reduction in cerebral blood flow[46],[47].
Increase in cerebral blood flow and intracranial blood volume in FHF
There is a growing body of evidence that increased cerebral blood flow is of critical
importance for the development of brain edema and the high ICP that occurs in FHF
patients[48],[49]. Some reports describe decreased cerebral blood flow in patients suffering from
acute liver failure[29], but most investigations have found high cerebral blood flow associated with intracranial
hypertension in FHF[50]. Studies suggests that impaired vascular autoregulation in the brain could be responsible
for this increase in cerebral blood flow and blood volume[32],[50]. Patients with signs of cerebral edema and intracranial hypertension have been shown
to have higher cerebral blood flow compared to patients without edema[48],[50],[51]. Although there is wide inter-individual variation in cerebral blood flow among
FHF patients, higher cerebral blood flow has been associated with poorer prognosis[27],[31]. Failure of cerebral blood flow autoregulation with consequent development of cerebral
hyperemia, edema, and intracranial hypertension is typically seen late during the
course of encephalopathy[29],[32]. The cerebral vasodilatation in patients with FHF may result from substances produced
within the bran itself, i.e., locally-induced cerebral hyperemia. The exact cause
of this increased cerebral blood flow in FHF is unknown. Nitric oxide has been implicated
but the increased NO in the brains of FHF patients may be secondary to an increase
in cerebral blood flow, rather than a primary event. Inflammation markers (IL-1 ß,
TNF alpha, IL-6) and systemic inflammatory response have been associated with increased
cerebral blood flow and ICP in FHF, and with poor outcome[27]. Increased activation of N-methyl-D-aspartate receptors as a consequence of ammonia
toxicity increases neuronal NO synthetase and NO production[22]. The association of systemic inflammation with impaired regulation of cerebral blood
flow might be related to the role of necrotic liver in intracranial hypertension in
FHF[13]. The observation that brain edema and intracranial hypertension are complications
of FHF and not of chronic liver disease, lead to the hypothesis that these phenomena
may, in part, result from products of acutely necrotic liver[14]. Although these findings are suggestive, the role of products from necrotic liver
in cerebral edema and intracranial hypertension remains unclear[14],[15].
The respective role of all these phenomena in the development of intracranial hypertension
in FHF has yet to be determined. It can be hypothesized however, that brain edema
(increase in brain volume) secondary to the osmotic effect of glutamine in astrocytes,
and cerebral hyperemia (in blood volume) secondary to vasodilation (cytokines, products
of necrotic liver, glutamine, etc.) may contribute to intracranial hypertension, resulting
in brain stem herniation and brain stem death in FHF[13],[14],[51]. During all these FHF phenomena, the brain may respond by altering the expression
of genes coding for various proteins whose role may be critical to some CNS functions,
including the maintenance of cell volume neurotransmission[27],[29].
Cerebral blood flow autoregulation
Cerebral autoregulation denotes the maintenance of a relatively constant cerebral
blood flow despite variations in cerebral perfusion pressure. This physiological response
acts to protect the brain from the harmful effects (i.e., ischemia or hyperemia) of
large swings in perfusion pressure. Lassen coined the term “autoregulation” to explain
the relatively constant blood flow values he found during induced hypotension[39]. However, since then, autoregulation has become confused with other dynamic regulating
processes. In the strictest sense, autoregulation refers only to the cerebrovascular
response to changes in cerebral perfusion pressure and is sometimes specifically referred
to as pressure autoregulation. Cerebral vessels also dilate or constrict as a physiological
response to cellular metabolic activity, but this is not properly termed autoregulation.
The influence of neuronal metabolism on blood flow should be termed metabolic regulation
or flow-metabolism coupling[40],[45],[46].
Three different mechanisms have been proposed to account for the cerebrovascular responses
to changes in perfusion pressure. The myogenic theory states that changes in intravascular
pressure alter stretch forces on vascular smooth muscle cells, and these muscle cells
intrinsically contract or expand in response to varying degrees of stretch. The neurogenic
theory proposes that specific brain centers have direct and indirect arterial connections
and the vascular responses are mediated through these connections[41]. Finally, the metabolic theory for control of the pressure autoregulation is based
on the finding that the primary determinant of regional flow is local cerebral metabolic
activity (flow-metabolism coupling). Certain neuropeptides, adenosine, potassium,
and hydrogen ion concentrations have all been shown to influence cerebral blood flow
and have, therefore, been proposed as metabolic coupling agents. However, these unique
theories may not be mutually exclusive. Since pressure autoregulation is a dynamic
process, it may involve a combination of mechanisms[41],[43],[52].
Measuring cerebral pressure autoregulation may provide clinically useful information
and is probably best understood, not as a single physical quantity with a simple metric,
but rather as a distributed phenomenon, perhaps reflecting large vascular beds. There
are two methods for assessing the status of cerebral autoregulation: static and dynamic[53]. Regarding static autoregulation, most investigators of cerebral autoregulation
have looked at the steady-state relationship between cerebral blood flow and cerebral
perfusion pressure or mean arterial pressure without considering the time course of
changes in flow following changes in pressure. This approach is the static type used
to derive the classic autoregulation curve cerebral autoregulation paper[45]. This curve shows a plateau region that is almost flat, corresponding to a constant
cerebral blood flow for changes in mean arterial pressure over a physiological range
(60-160 mmHg). In this method, cerebral autoregulation is evaluated daily at a mean
arterial pressure of 20 to 30 mmHg by intravenous infusion of norepinephrine, and
simultaneously measuring mean velocity, mean arterial pressure and cerebral perfusion
pressure[53]. The most frequently-used methods for estimating changes in cerebral perfusion are
transcranial Doppler ultrasonography, xenon-133 clearance, and stable CT-demonstrated
cerebral blood flow[44]. Other techniques reported to reflect tissue perfusion include arterio-jugular venous
oxygen difference to estimate cerebral blood flow changes, electromagnetic flow meters,
near-infrared spectroscopy, laser Doppler flowmetry, and jugular venous occlusion
plethysmography[44]. In dynamic autoregulation methods, an important variable influencing autoregulatory
response is time, and this dynamic autoregulation is probably more clinically important
than static measures[52],[54],[55]. This method is used to describe transient changes in cerebral blood flow after
rapid changes in mean arterial pressure. According to this procedure, there is a starting
delay of 2 seconds, taking up to 10-15 seconds for the baroreflex mechanism to restore
pressure to its previous level. In the normal brain, cerebral blood flow volume returns
to its baseline level much sooner than does mean arterial pressure, and the speed
of recovery is affected by PaCO2 levels. With the dynamic method, it is possible to characterize the interaction between
pressure autoregulation and other variables such as PCO2 and pharmacological agents. The most frequently-used method for estimating changes
in cerebral perfusion is transcranial Doppler ultrasonography[55],[56].
CEREBRAL AUTOREGULATION IN FHF
CEREBRAL AUTOREGULATION IN FHF
Under normal conditions, the metabolic requirements of the brain, increase or decrease
in parallel with brain activity. This autoregulation occurs, independently of changes
in mean arterial pressure or cardiac output, whenever blood pressure varies within
the limits of 60 to 160 mmHg. Landmark studies by Larsen et al.[57] have clearly shown that cerebral blood flow autoregulation is lost in patients with
FHF. This loss of autoregulation can be explained by the presence of vasodilatation
of cerebral arterioles[31],[32]. Although the pathophysiological mechanism of impaired cerebral blood flow autoregulation
in FHF remains unknown, it is believed to be caused by toxic substances released from
the failing liver. If loss of cerebral blood flow autoregulation in patients with
FHF is of pathophysiological importance in the development of hepatic encephalopathy
and cerebral edema, it must be assumed that cerebral blood flow autoregulation is
reestablished shortly after hepatic recovery of liver function[57],[58]. Strauss et al.[58] showed that cerebral perfusion, as determined by mean velocity in the middle cerebral
artery, increased in response to an elevation of mean arterial pressure in patients
with FHF. The effect of elevated mean arterial pressure on mean velocity allowed evaluation
of the cerebral blood flow autoregulation curve. Defective autoregulation was observed
in the patients regardless of etiology of FHF or treatment with N-acetylcysteine[58]. This finding is in accordance with the results of previous studies of FHF patients[29],[57],[58] and of studies on rats with thioacetamide-induced liver failure[57],[58]. More importantly, cerebral blood flow autoregulation was restored shortly after
improvement of hepatic function, whether spontaneous or following liver transplantation.
In fact, cerebral autoregulation was re-established even before hepatic encephalopathy
was completely alleviated. In the study by Strauss et al.[58], involving a small number of patients, the re-establishment of cerebral blood flow
autoregulation was observed within one to two days after liver transplantation and
three to four days after spontaneous hepatic recovery[57],[58].
Loss of cerebrovascular autoregulation has been documented in several types of brain
insult or ischemia. It has been further shown experimentally that in these injured
brains, increased perfusion pressure without compensatory control of ICP results in
deterioration of neurological function[57]. Pathological vasodilatation, evidenced by a marked fall in resistance in the cerebrovascular
bed in response to rising pressure, is an inappropriate response for the damaged brain.
This suggests that pathological cerebral vasodilation may be an important and largely-overlooked
cause of increased ICP in the brain suffering an acute generalized insult such as
hepatic encephalopathy in FHF[49].
FINAL REMARKS
Fulminant hepatic failure is a multisystem disorder with a high mortality rate requiring
a multidisciplinary team approach for its management. Intracranial hypertension is
an important cause of death in patients with FHF and, therefore, an aggressive approach
to monitoring and therapy is essential if outcome is to be improved. Hepatic encephalopathy
and brain edema appear to share common pathogenic roots, with a key role of ammonia
and critical involvement of astrocytes in both complications. The study of one helps
to understand the other: whereas FHF facilitates the study of causal relationships
in a more robust manner, chronic liver failure provides the opportunity to study brain
compensatory mechanisms. This integrated view also provides a better perspective to
judge the pathophysiological relevance of other factors in the manifestation of the
disease.
Cerebral blood flow autoregulation in previous studies has demonstrated restoration
of cerebral autoregulation after improvement in liver function, indicating a connection
between liver function and regulation of CBF.
Given the relatively small number of patients with FHF, it is imperative that future
trials address the role of various therapeutic modalities during different stages
of the disease in multicenter randomized clinical trials.
