Tadevosyan 2021
Tadevosyan 2021
Tadevosyan 2021
Intracranial Hypertension
a, b
Aleksey Tadevosyan, MD *, Joshua Kornbluth, MD
KEYWORDS
Cerebral herniation Herniation syndromes Intracranial pressure
Intracranial hypertension Dialysis disequilibrium syndrome
Hepatic encephalopathy
KEY POINTS
Cerebral herniation is a devastating event, with high rates of morbidity and mortality, and
may manifest with symptoms, such as increased nausea, somnolence, and agitation.
Intracranial hypertension and cerebral herniation are not synonymous. Although most
events of herniation do occur in the setting of intracranial hypertension, patients with
spontaneous intracranial hypotension and sinking skin flap syndrome may have cerebral
herniation with low or normal intracranial pressure.
Treatment of intracranial hypertension involves conservative measures, such as head of
bed elevation and midline maintenance of neck position to improve intracranial venous
drainage, augmentation of mean arterial pressure to maintain appropriate cerebral perfu-
sion pressure, and higher-tiered therapies, such as hyperosmolar therapy, sedation and
pentobarbital coma, temporary paralysis, hypothermia, and surgical decompression.
Critically ill patients with sepsis and multiorgan failure (liver failure or acute kidney injury)
and intracranial pathology are at higher risk of developing cerebral edema, intracranial hy-
pertension, and herniation. Care should be taken with seemingly innocuous therapies,
such as dialysis, because volume shifts may cause or exacerbate cerebral edema.
INTRODUCTION
Intracranial pressure (ICP) is defined as the pressure measured within the intracranial
vault. This is a dynamic pressure consisting of a systolic, diastolic, and derived mean
pressure and may fluctuate physiologically. Normal ICP (measured as the mean) typi-
cally is 10 cm H2O to 20 cm H2O, or 7 mm Hg to 14 mm Hg. ICP is governed by the
relationship between volumes of brain tissue, cerebrospinal fluid (CSF), and intracra-
nial blood in the arterial and venous compartments. Expansion of any 1 of these results
a
Department of Neurology, Tufts University School of Medicine, Beth Israel Lahey Hospital and
Medical Center, 41 Mall Road, Burlington, MA 01805, USA; b Department of Neurology, Tufts
University School of Medicine, Tufts Medical Center, 800 Washington Street, Box#314, Boston,
MA 02111, USA
* Corresponding author.
E-mail address: [email protected]
Fig. 2. Cerebral autoregulation. In healthy patients, as CPP is increased, the CBF remains
largely stable within the zone of autoregulation, where arteriolar muscle reactivity leads
to vasoconstriction in the face of increasing pressure. Under low pressures where vascular
tone is low, increase in pressure causes an increase in flow. Above the zone of autoregula-
tion, further increase in pressure leads to passive vessel dilation, hyperemia, and ischemia,
leading to hypertensive encephalopathy. In patients who are chronically hypertensive, the
zone of autoregulation is shifted to the right as a protective measure against systemic hy-
pertension. These patients may be more susceptible to cerebral ischemia with systemic hy-
potension (such as in shock). In patients with severe brain injury, autoregulation may be
lost; thereby, increase in perfusion pressure leads directly to increased CBF, increased intra-
vascular volume, and worsening of an already existing ICP crisis.
For purposes of this review, acute intracranial hypertension and herniation are focused
on. More chronic causes of intracranial hypertension (eg, idiopathic intracranial hyper-
tension) and herniation (eg, slow-growing brain tumors) may cause significant
changes in anatomy and physiology separate from the acute changes discussed in
this article.
Intracranial hypertension may occur relatively uniformly in the cranium due to diffuse
injury, for example, anoxic brain injury or subarachnoid hemorrhage, or may occur in 1
or more brain compartments and cause a differential of pressure across intracranial
structures. This may lead to cerebral herniation, defined as a shift of brain tissue
through a naturally occurring opening in another tissue, which is a life-threatening
296 Tadevosyan & Kornbluth
Subfalcine Herniation
Subfalcine herniation consists of midline shift of the medial structures of the brain, pri-
marily movement of the ipsilateral cingulate gyrus underneath the falx cerebri (also
called cingulate herniation), caused by mass effect in the ipsilateral cerebral hemi-
sphere (Fig. 3A).11 Degree of herniation is quantified by measuring the midline shift
of the septum pellucidum at the level of foramen of Monro.12 Clinically, patients
demonstrate findings consistent with medial frontal lobe dysfunction, including abulia,
emergence of frontal release signs, and loss of initiative.13 In severe cases, subfalcine
herniation can cause unilateral or bilateral compression of the anterior cerebral ar-
teries, pericallosal artery leading to unilateral or rarely bilateral leg weakness, and
acute urinary retention.14–16
Table 1
Review of herniation syndromes11,12
Abbreviations: ACA, anterior cerebral artery; CN3, cranial nerve 3; PICA, posterior inferior cere-
bellar artery.
to the culprit supratentorial mass lesion (known as the false localizing sign) with a
newly upgoing toe an early finding.20
Increased mass effect in the posterior temporal lobe and occipital lobe can cause
herniation of the posterior component of the parahippocampal gyrus, resulting in
the effacement of the lateral quadrigeminal plate cistern as well as displacement
and torsion of the brainstem.11,19 The unique clinical manifestation of this type of her-
niation often is Parinaud syndrome, followed by coma if pressure is not relieved.11,12,21
Central herniation occurs when bihemispheric supratentorial mass effect results in a
downward herniation of the thalamus and midbrain through tentorial incisura and the
medulla through the foramen magnum.11 Radiographic findings occur in the rostral to
caudal direction with the effacement of the perimesencephalic cisterns, inferior
displacement of the quadrigeminal plate, and the basilar artery resulting in Duret hem-
orrhages.22,23 This is followed by acute obstructive hydrocephalus with increased
downward pressure as well as infarction of the vascular territories supplied by the
PCAs, resulting in increased cytotoxic edema and further compression on the brainstem
as herniation continues. Clinically, patients develop agitation, followed by obtundation,
with bilaterally poorly reactive and at times fixed midposition pupils, and then decorti-
cate followed by decerebrate posturing, Cushing triad, and coma, and death.12,24
Tonsillar Herniation
Cerebellar tonsillar herniation can occur in isolation in the setting of increased mass
effect in the posterior fossa or as a result of supratentorial pressure, in which case
298 Tadevosyan & Kornbluth
cerebellum may push the cerebellar vermis and cerebellar hemispheres superiorly
through the tentorial incisura.26 In some instances, rapid decompression of a supra-
tentorial mass or evacuation of hemorrhage may lead to this type of herniation.17
This also can occur in patients with sinking skin flap syndrome who had undergone
surgical decompression for large SDH, severe traumatic brain injury (TBI), or acute
stroke and are postcranioplasty. Cranioplasty, especially with placement of a negative
pressure subgaleal drain, is thought to induce a negative pressure environment supra-
tentorially, thereby pulling the posterior fossa anteriorly and cranially.9,27 As with other
types of herniation with pontomedullary compression, initial clinical symptoms include
obtundation, hemodynamic and respiratory instability, severe bradycardia, life-
threatening arrhythmias, and pinpoint pupils.28,29 There is evolution of pupillary size
from severely miotic to midposition fixed as herniation progresses with upward move-
ment of the midbrain.26 As with DTH, vascular compromise can occur with impinge-
ment of unilateral or bilateral superior cerebellar artery (SCA) or PCA.26,30
Importantly, patients with ATH usually do not have elevated ICP; therefore, clinicians
should not ignore the signs of herniation even with normal ICP if a monitor is present.
Transalar Herniation
Descending herniation occurs from mass effect in the frontal lobe whereby the inferior
frontal gyrus is displaced posteriorly and caudally with respect to the sphenoid wing.11
Ascending herniation occurs with the displacement of the anterior temporal lobe ante-
riorly in the cranial direction over the sphenoid ridge.11 The middle cerebral artery
(MCA) and supraclinoid internal carotid artery are displaced and compressed against
anterior clinoid process, resulting in ipsilateral anterior circulation stroke.11,12,17
Extracranial Herniation
Extracranial herniation describes protrusion of brain matter through a cranial defect
that was caused by trauma or surgery (Fig. 3D). As herniation progresses, brain tissue
may compress against the edges of the skull, causing both venous and arterial infarc-
tion. Clinical findings depend on the area of brain tissue that is herniating.
Although most instances of brain herniation occur in patients with elevated ICP, it also
has been described in patients with intracranial hypotension. Spontaneous intracranial
hypotension (SIH) usually occurs in the setting of a spinal CSF leak.31,32 Targeted or
blind epidural blood patch (EBP) is the mainstay of therapy. The most common clinical
manifestation is acute-onset orthostatic headache.33,34 Brain imaging often shows
smooth diffuse dural enhancement on magnetic resonance imaging (MRI), whereas
in other conditions with dural enhancement, such as carcinomatous, granulomatous,
or bacterial meningitis, dural involvement is nodular, localized, and patchy.35,36 In se-
vere cases, patients rapidly can develop stupor followed by coma.37 On imaging, such
clinical deterioration coincides with caudal displacement of the brainstem, termed,
brain sagging, resulting in downward displacement of the thalamus onto the posterior
fossa, compression of the pons and midbrain against the clivus, impingement of ce-
rebral peduncles, and effacement of the basal cisterns, leading to obstructive hydro-
cephalus.38–40 Subdural hemorrhage (SD) and hygromas can be present and usually
are bilateral; however, unilateral collections occur as well.41–43 A diagnosis of SIH
may be missed or delayed in patients presenting with SD, especially if MRI, demon-
strating the typical features of SIH, is not completed. In lieu of this, it is important to
recognize the possibility of SIH, not hypertension, as the cause of neurologic decline
300 Tadevosyan & Kornbluth
in patients admitted with nontraumatic SD. Some patients with bilateral subdurals and
intracranial hypotension may have bilateral midposition hypoactive and at times
nonreactive pupils with preserved consciousness. Without treating the underlying eti-
ology responsible for SIH, surgical decompression of SD while leading to temporary
improvement in clinical status leads to recurrent subdural collection formation usually
within hours of procedure and worsening caudal herniation because the brain now
exposed is to atmospheric pressure.42,43 On the other hand, when EBP is performed
prior to SDH evacuation and the leak is treated, patients rapidly may develop intracra-
nial hypertension because the mass effect from SDH remains. Henceforth, clinicals
should monitor patients with intracranial mass lesions who undergo EBP carefully.
In this condition, low ICP not always may be present; it is estimated that approxi-
mately 30% to 50% of patients with SIH have normal and sometimes even elevated
ICP.44,45 This makes accurate estimation of ICP in patients with SIH challenging, espe-
cially those with SD with midline shift and herniation from the subdural itself. Trende-
lenburg positioning has been used as a diagnostic and therapeutic tool in patients with
SIH and SD.46 Failure to improve neurologically after Trendelenburg positioning may
imply presence of intracranial hypertension from mass effect and may necessitate
evacuation of subdural fluid collections if the patient is in extremis, followed by treat-
ment of SIH.47
Hyperosmolar Therapy
Hyperosmolar therapy long has been a mainstay in treating acutely elevated ICP, with
the most frequently used formulations being 20% mannitol boluses and hypertonic sa-
line (HTS), 2%, 3% 7.5%, or 23.4%, in the United States. Although recognizing the util-
ity in decreasing ICP, given the paucity of high-quality studies, the most recent
guidelines from the Brain Trauma Foundation do not explicitly recommend the use
of hyperosmolar therapy in patients suffering from intracranial hypertension with
Table 2
Tiers of therapy for intracranial pressure control
Tiers Treatments
Tier 0 HOB >30 , head/neck midline (facilitates venous drainage), euglycemia,
eucapnia, euthermia, SpO2 >94%, avoidance of hyponatremia and
hypotonic fluids, ICP <22 mm Hg, CPP goal >60 mm Hg
Tier 1 Hyperosmolar therapy, EVD placement for CSF diversion
Tier 2 Temporary hyperventilation, increased sedation, neuromuscular blockade
Tier 3 Barbiturates to achieve burst suppression, hypothermia, decompression
Brain Herniation and Intracranial Hypertension 301
Table 3
General overview of conditions causing intracranial hypertension
TBI.48 Many of the studies investigating the use of mannitol and HTS in decreasing ICP
have been small retrospective studies and case series as well as meta-analyses pool-
ing a heterogenous group of patients (TBI, stroke, and intracranial hemorrhage).49–53
In 2008, a small prospective trial by Francony and colleagues54 compared the effects
of single infusion of equiosmolar doses of 20% mannitol and 7.45% of HTS on ICP.
Each arm had 10 patients and of 20 patients 17 were TBI patients and 3 with acute
ischemic stroke. After a prolonged infusion of approximately 20 minutes, both treat-
ment modalities seemed to have an equivalent decrease in ICP (by 37%–41%) with
sustained effect of approximately 120 minutes (with continued decrease in ICP by
23%–32%).54 In a 2015 study by Mangat and colleagues,55 the New York State data-
base of the Brain Trauma Foundation TBI-trac was analyzed retrospectively for pa-
tients admitted with severe TBI with Glasgow Coma Scale score (GCS) less than 8,
who had received either mannitol or HTS. There were 35 patients who received HTS
and 477 who received mannitol, and, after matching of baseline characteristics, 25 pa-
tients from each group were reviewed. There were no statistically significant differ-
ences in mortality at 2 weeks of therapy. In a follow-up study with the same
database, use of HTS was associated with a reduction in total number and percentage
of days with high ICP and low CPP.56
In 4 recent meta-analyses, there were no significant differences in mortality or favor-
able neurologic outcome between HTS and mannitol, although improved control of
intracranial hypertension with HTS.57–60 In the recent Seattle International Severe
Traumatic Brain Injury Consensus Conference (SIBCC) expert panel recommenda-
tions, sodium and osmolarity thresholds of 155 mEq/L and 320 mEq/L, respectively,
are recommended, above which administration of further hyperosmolar therapy likely
is futile.61 In the authors’ institution, alternating boluses of 3% HTS, 250 mL to 500 mL,
and mannitol, 0.5 g/kg to 1 g/kg, are used.
Corticosteroids
Steroids most often are used in patients with vasogenic and not cytotoxic cerebral
edema in an acute setting.62,63 Conditions in which vasogenic edema predominates
include brain tumors; demyelinating conditions, such as multiple sclerosis and acute
disseminated encephalomyelitis; and cerebral abscesses. The utility of corticosteroids
302 Tadevosyan & Kornbluth
therapy, and ventriculostomy. Some patients also had undergone craniectomy. Most
patients in the control arm eventually crossed over and received pentobarbital as
well. Patients who received pentobarbital were observed to have a significant
decrease in ICP, had an improved mortality outcome at 1 month, and neurologic
outcome at 6 months (death and vegetative state).90 In a prospective observational
study from Europe, outcomes of patients with severe TBI who received barbiturates
at 2 doses (high-dose group receiving >2 g/24 h for 3 consecutive days or until death,
n 5 71; and low-dose group, n 5 140) were compared with those who received con-
ventional therapy only (n 5 961).91 After adjusting for age, GCS score, and Injury
Severity Score, no statistically significant differences were observed in mortality at
hospital discharge and at 6 months.91 In a recent Cochrane review, use of barbitu-
rates was associated with decreased ICP, but this did not translate to improvement
in mortality or neurologic morbidity.92 The most recent BTF guidelines recommend
use of high dose barbiturate for suprarefractory intracranial hypertension in hemody-
namically stable patients.48
Hypothermia
Hypothermia after cardiac arrest has been known to improve mortality and neuro-
logic outcomes in patients with cardiac arrest.93,94 It is less clear whether hypother-
mia also improves outcomes in patients who have intracranial injury from other
pathologic processes, with TBI remaining the most feverishly studied pathology. It
has been theorized that hypothermia conveys its beneficial effects via multiple
mechanisms, including reduction of mitochondrial dysfunction and free radical for-
mation, blunting of reperfusion injury, preservation of blood-brain barrier with a
resultant decrease in vasogenic edema, and antithrombotic effects leading to
decreased cerebral vascular microthrombosis.95–97 It is unclear in which patient
population hypothermia should be instituted, including its timing and duration. A
few small, earlier trials have shown that hypothermia may improve mortality and
neurologic outcomes in patients with severe TBI.98–101 In a meta-analysis of 20
RCTs between 1993 and 2011 comparing therapeutic hypothermia (<36 C) versus
normothermia that included 1885 adult patients with severe TBI, hypothermia was
associated with significant reduction in poor neurologic outcome and mortality,
albeit the investigators themselves state of inherent bias and low quality of some
of the included trials.102 In recent years, there have been few large, RCTs that eval-
uated both prophylactic and therapeutic use of hypothermia in patients with severe
TBI. In a multicenter RCT (National Acute Brain Injury Study: Hypothermia II [NABIS:
H II]), patients with severe TBI were randomized to normothermia and hypothermia
groups where cooling was administered to 33 C for 48 hours within 4 hours to 5 hours
of randomization.103 This study did not show a difference in death or severe disability
within 6 months of follow-up. In a subgroup analysis of patients who received surgi-
cal evacuation of hematoma with bone flap off to relieve pressure, however, those
who underwent concurrent hypothermia did statistically better than the control
group.103 Similar conclusions were reached in a previous small RCT, where patients
with severe TBI who had undergone unilateral craniectomy on admission were found
to have favorable neurologic outcome at 12 months after admission after undergoing
moderate hypothermia (33 C–35 C) for approximately 4 days after surgery.104 In the
larger Eurotherm3235 RCT, patients with severe TBI who had undergone hypother-
mia (32 C–35 C) for 48 hours as rescue therapy and replacement for hyperosmolar
therapy (followed by hyperosmolar therapy if needed) did not have improved neuro-
logic outcomes at 6 months and had a statistically significant increase in unfavorable
outcome and all-cause mortality.105 Similarly, in the most recent trial (Prophylactic
304 Tadevosyan & Kornbluth
The decision for any surgical treatment of high ICP and/or cerebral herniation must be
based on the likelihood of benefit to the patient’s outcome. Surgical treatment of intra-
cranial hypertension and herniation usually is targeted at the site of the most mass ef-
fect from the acute injury. Surgical treatment targeted at augmenting CSF drainage
through ventriculostomy catheter placement remains the primary surgical intervention
in diffuse brain injuries. Intracranial hypertension and herniation due to acute hydro-
cephalus is best treated with extraventricular drain (EVD) placement and is preferred
over the use of a lumbar drain due to the risk of transforaminal herniation. EVD place-
ment with continuous CSF drainage currently is supported by the guidelines for
ischemic cerebellar stroke,109 spontaneous ICH,110 and TBI.48
SPECIAL CONSIDERATIONS
Hepatic Encephalopathy and Intracranial Hypertension
Hepatic encephalopathy (HE) refers to a wide spectrum of neuropsychiatric symptoms
in the setting of acute or chronic liver dysfunction and is classified via the following 4
factors: underlying disease, severity of manifestation, time course, and existence of
precipitating factors (Table 4).116,117 Conditions causing HE include drugs, toxins,
Table 4
Characteristics of hepatic encephalopathy116,117
and infections leading to acute liver failure, decompensated chronic cirrhosis, and
certain inborn errors of metabolism.118–121 Cytotoxic and vasogenic edema is a hall-
mark of HE and is in part mediated by hyperammonemia. A detailed discussion of
the complex and incompletely understood pathophysiology of ammonia-induced ce-
rebral edema is outside the scope of this article, but in short it includes a complex
interplay between direct cerebral neurotoxicity of ammonia and other cytokines and
impaired cerebral perfusion as a result of a sepsis-like physiology with high output car-
diac failure, low systemic resistance, and hypotension from seepage of proinflamma-
tory mediators from the splanchnic circulation into the systemic circulation.122–124
Ammonia metabolism primarily occurs in the liver, where it is converted to urea. It
also occurs in the skeletal muscle tissues and the brain, where ammonia is metabo-
lized into glutamine.121 The kidneys play an important role in excretion of ammonia:
in healthy patients, approximately 20% of daily ammonia clearance occurs via renal
excretion.121,125,126 Therefore, critically ill patients with liver dysfunction and acute kid-
ney injury (often caused by the liver dysfunction itself) are at higher risk of developing
hyperammonemia.
Although it is thought that abnormal ammonia levels in the serum do not always
correlate with neurologic symptoms, it has been demonstrated that high levels
(>200 mmol/L) seem to be associated with increased risk of cerebral edema, intracra-
nial hypertension, and herniation.127–129 Treatment of hyperammonemia primarily in-
volves increased gut excretion, with lactulose and rifaximin being mainstays of
therapy, whereas decreasing protein intake. Renal replacement therapy (RRT) is
another important treatment of elevated ICP in patients with hyperammonemia.130,131
Timing and duration of RRT remain understudied, but it is argued that early initiation
may lead to better outcomes.132,133 In a prospective clinical trial, Slack and col-
leagues134 showed an average 22% median decrease in serum ammonia levels within
24 hours of continuous RRT and directly correlated with filtration rate. Methods of RRT
are important to consider as well. Although it would be quicker to perform intermittent
hemodialysis (HD), there is some evidence that continuous RRT might be a safer op-
tion given the graded removal of ammonia and less risk of rebound cerebral
edema.135,136 Current guidelines from the European Association for the Study of the
Liver recommend continuous forms of RRT over intermittent HD in patients with
hyperammonemia.137
As in patients with primary neurologic injury (TBI or acute stroke), there is evidence
that hyperosmolar therapy can decrease ICP in patients with acute liver failure, and
sodium level of at least 145 mmol/L is recommended.120,131,138 In the authors’ institu-
tion, hyperosmolar therapy usually is instituted after serial head CT scans show pro-
gressive edema in conjunction with worsening clinical status and rising ammonia
levels. Many patients with hyperammonemia concurrently are hyponatremic; thus,
care should be taken to not raise the sodium level too rapidly given concerns of os-
motic demyelination syndrome. Therapeutic hypothermia has been used in patients
with acute liver failure with intracranial hypertension with variable success.139,140 In
a prospective study by Jalan and colleagues,141 14 patients with intracranial hyperten-
sion and acute liver failure were cooled to 32 C to 33 C as a bridge to liver transplan-
tation after failing standard medical therapy. Prior to cooling, the mean ICP was
36.5 mm Hg and CPP of 40.1 mm Hg, and at 4 hours the mean ICP decreased to
16.3 mm Hg and CPP increased to 66.4 mm Hg. These changes persisted for at least
the next 24 hours. Of the 14 patients, 1 patient died of brain herniation, and the rest
underwent liver transplantation within a median of 32 hours of cooling with complete
neurologic recovery. In a prospective nonblinded RCT by Bernal and colleagues,142 46
patients with acute liver failure and intracranial hypertension were randomized into a
Brain Herniation and Intracranial Hypertension 307
33 C (moderate hypothermia [MH]) and 36 C (control) groups for 72 hours. No statis-
tically significant differences were noted in hospital mortality (41%–46%) or rate of
complications. In the MH group, however, none of the patients who received trans-
plantation died whereas in the control group 33% of the patients (4/12) undergoing
transplantation passed away. Other treatments of hyperammonemia with variable
success include medications and ammonia scavenging agents, such as high dose
L-carnitine, hydroxocobalamin, biotin, arginine, L-ornithine phenylacetate, and sodium
benzoate.143–146
Box 1
Risk factors associated with development of dialysis disequilibrium syndrome
Primary intracranial processes with elevated ICP (ischemic and hemorrhagic stroke, TBI, SD,
subarachnoid hemorrhage)
Conditions causing cerebral edema (acute demyelinating conditions, encephalitis,
hypertensive emergency, hyperammonemia)
Conditions leading to breakdown of blood-brain barrier (neoplastic, inflammatory and
infectious meningitis, sepsis, Thrombotic thrombocytopenic purpura–hemolytic uremic
syndrome, disseminated intravascular coagulation)
Hyperosmolar state (hyperglycemic nonketotic coma, uremia, hypernatremia)
Severe metabolic acidosis
Missed dialysis days or new to dialysis
Extremes of age
composition is used where sodium concentration usually is 135 mEq/L to 140 mEq/L.
At the authors’ institution, 3% saline infusion frequently is continued simultaneously
with CVVHD to dampen the serum sodium fall. Especially in patients with intracranial
injury undergoing any form of RRT, clinicians should rapidly recognize signs of clinical
decompensation and act to relieve cerebral edema and ICP.
FUTURE DIRECTIONS
DISCLOSURE
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