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Indian J Crit Care Med April-June 2004 Vol 8 Issue 2

IJCCM October-December 2003 Vol 7 Issue 4

Review Article

Intracranial hypertension after traumatic brain injury

Abstract

Ian Seppelt

Traumatic brain injury is a devastating problem with both high mortality and high subsequent morbidity.
Injury to the brain occurs both at the time of the initial trauma (the primary injury) and subsequently due to
ongoing cerebral ischaemia (the secondary injury). Hypotension and hypoxaemia are well recognized causes
of this secondary injury. In the intensive care unit raised intracranial pressure (intracranial hypertension) is
seen frequently after a severe diffuse brain injury and leads to cerebral ischaemia by compromising cerebral perfusion. This paper reviews the pathophysiology of intracranial hypertension and summarises current and experimental approaches to its management in the intensive care unit.
Key Words: Brain injury, cerebral perfusion, decompressive craniectomy, head injury, intracranial pressure.

Introduction

Epidemiology

Traumatic brain injury (TBI) is a common and devastating problem with a high mortality and a high residual
morbidity in survivors. The most cost effective measures
of course are all preventative, including public health
education, the mandatory use of seatbelts in cars and
helmets on motorcycles, appropriate speed limits and
improved road design. When an injury has occurred,
however, it then becomes crucial for the prehospital and
hospital management to be focused on preventing secondary injury and minimizing the chances of a poor outcome. In the neurointensive care unit the issue above all
else is to maintain cerebral perfusion and prevent cerebral ischaemia. Intracranial hypertension leads to cerebral ischaemia and is often the most difficult management problem after a head injury. It is disappointing that
while intracranial hypertension was identified as the
prime pathophysiological entity in TBI in 1951,1 there are
still few therapeutic options available to the clinician and
the overall quality of research is poor.

Traumatic brain injury is the commonest cause of death


in young males in developed countries2 and has been
termed a silent global epidemic.3 Approximately half of
all trauma deaths include a significant TBI which contributes to the death. It is estimated that every year
600,000 people suffer a TBI in the United States of
America (0.3% of the population per year). 42% of these
are hospitalized and the costs, both in hospital and subsequently, can be massive.4

From:
Department of Intensive Care Medicine, The Nepean Hospital, University of
Sydney, Penrith NSW Australia. E-mail: seppeli@wahs.nsw.gov.au
Reproduced with permission from Trauma Care, the official journal of International Trauma Care (ITACCS)

The Australian Traumatic Brain Injury Survey (ATBIS)


prospectively followed all patients who had been admitted to the intensive care unit of 16 tertiary referral trauma
centers over six months in 2000 (Myburgh J, personal
communication). Of 635 patients the hospital mortality
was 20.6%, with 6 month mortality 24% and 12 month
mortality 27%. Survivors were evaluated at 6 and 12
months with the Glasgow Outcome Score (GOS). At 6
and 12 months, 45% and 41% of survivors respectively
had an unfavourable dichotomized GOS (severely disabled or vegetative). Thus a good outcome is achieved in
only about 40% of TBI patients admitted to intensive care.
Unfortunately good India data are not available and
collection of these data should be a priority to inform

Free full text available from www.ijccm.org


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appropriate head injury management in that country.

Pathophysiology
The primary injury is sustained at the time of impact,
with high energy acceleration or deceleration of the brain
within the rigid cranium. The secondary injury is a complex process driven predominantly by cerebral ischaemia and mediated by changes in cerebral blood flow,
local and systemic inflammation, metabolic
derangements, necrosis and apoptotic death of neurons.
While nothing can be done about the primary injury for
an individual, the focus of modern neurointensive care
is to aggressively prevent or minimize any secondary
injury, predominantly by minimising cerebral ischaemia.
Analysis of the US Traumatic Coma Data Bank (TCDB)5
identified hypotension (systolic blood pressure < 90
mmHg), hypoxia (SpO2 < 90% or PaO2 < 50 mmHg),
hypoglycaemia, pyperpyrexia (temp > 39o C) and prolonged hypocapnia (PaCO2 < 30 mmHg) as independent predictors of a poor outcome after head trauma. A
more recent study again found hypoxia, hypotension,
hyperthermia and intracranial hypertension6 the strongest predictors of poor outcome after TBI.
The Monroe - Kelly Doctrine7,8 states that incompressible structures within the cranial vault are in a state of
volume equilibrium, such that any increase of the volumes of one component (i.e. blood, CSF, or brain tissue) must be compensated by a decrease in the volume
of another. If this cannot be achieved then pressure will
rise and once the elastance reserve of the intracranial
space is exhausted then small changes in volume can
lead to precipitous increases in pressure.
More complex is the variation of cerebral blood flow
over time. Three distinct patterns of blood flow have been
recognized after TBI. Sequentially these are the phases
of hypoperfusion, hyperaemia and vasospasm.9 Therapies directed towards hypoperfusion on day one may be
quite inappropriate during the hyperaemic phase on day
four!
During the hypoperfusion phase cerebral blood flow is
reduced with resultant global and regional ischaemia.
Cerebral autoregulation is impaired and cerebral blood
flow depends directly on systemic bloodpressure. Neuronal ischaemia during this phase leads to so called cytotoxic cerebral oedema and intracranial hypertension.

Indian J Crit Care Med April-June 2004 Vol 8 Issue 2

The hyperaemic phase may follow from about day 4,


in about 30% of patients, and may persist for a week or
more. Autoregulation begins to recover and the combination of hyperaemia, inflammation and blood brain barrier injury leads to so called vasogenic cerebral oedema.
Lower cerebral perfusion pressures may be acceptable
as attempts to maintain high cerebral perfusion can actually lead to worsening intracranial hypertension.
A small cohort of patients, particular those with significant traumatic subarachnoid haemorrhage, may subsequently have a period of cerebral vasospasm, which is
often complicated by cerebral hypoperfusion and even
infarction.

Principles of management
Formal evidence based guidelines for the management
of TBI were published by the Brain Trauma Foundation
in 200010 and revised in 2003,11 and complement similar
guidelines elsewhere such as the European Brain Injury
Consortium.12 Whilst these guidelines illustrate how little good quality evidence exists, they provide a framework upon which TBI research can develop, and all modern TBI management should be consistent with the principles in these guidelines. The adoption of standardised
treatment protocols has been clearly shown to improve
outcomes in before and after studies in different ICUs.13

Basic treatment of traumatic brain injury


Initial resuscitation is according to the principles of
Advanced Trauma Life Support (ATLS)14 with due attention to Airway, Breathing, Circultation, Disability and
Exposure - the single most important thing in a head
injury is a clear and unobstructed airway! An early,
unsedated Glasgow Coma Score (GCS) is helpful in
defining severity of TBI and to some extent for prognosis. Comatose patients should be intubated - the basic
principle is that GCS 8 means intubate and this should
be achieved by rapid sequence induction as soon as
there are appropriately skilled personnel available. The
cervical spine must be protected, and is assumed to be
injured until definitively cleared.
Intubated patients should be ventilated to normocarbia,
maintaining PaCO2 between 36 and 40 mmHg. This is
best assessed by end tidal capnography, and generally
corresponds to PETCO2 31 - 35 mmHg. All ventilated head
injury patients should have continuous capnography.
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They must be kept well oxygenated with PaO2 > 90


mmHg and SpO2 > 95%. Hypoxaemia dramatically worsened outcomes in the TCDB dataset. Ventilation can
become difficult if there are other major injuries particularly chest injuries, aspiration of gastric contents, or if
the acute respiratory distress syndrome develops. Appropriate positive end expiratory pressure (PEEP) should
be used. There is no evidence that PEEP impairs cerebral blood flow or elevates ICP15 and indeed ICP may
improve with improved oxygenation.16
An early non contrast CT brain is required to guide
subsequent therapy. All patients should have arterial and
central venous lines, as soon as practical. They should
be fluid resuscitated to euvolaemia and if necessary
vasopressors used to maintain blood pressure - again a
single episode of hypotension dramatically worsened
outcomes in the TCDB.17
ICP monitoring is used in all severe head injuries unless there is a severe coagulopathy. Once an ICP monitor has been placed fluid and vasopressors are used to
maintain a Cerebral Perfusion Pressure (MAP - ICP) of
60 mmHg. Any patient with elevated ICP needs to be
adequately sedated, and many agents are suitable for
this purpose.
o

Patients should be nursed 30 head up unless haemodynamically unstable or needing large doses of noradrenaline, or prevented by unstable spinal or pelvic
injuries. This both maximises venous drainage (preventing a increase in the venous cerebral blood volume) and
minimises ventilator associated pneumonia. Indeed in
one trial the 30o semirecumbent position both significantly
reduced ICP and significantly improved CPP without any
adverse effect on cerebral oxygenation.18
For ongoing fluid management an isotonic crystalloid
is used to maintain serum sodium 140 - 149 mmol/l and
clinical euvolaemia. Patients should be kept normothermic (37o C) with appropriate use of forced air warming
or cooling, and paracetamol. Stress ulcer prophylaxis is
provided with an H2 antagonist. Phenytoin decreases the
risk of early posttraumatic seizures,19 but there is no
benefit continuing the drug past 7 days. Enteral nutrition
is commenced within 24 hours of injury - gastroparesis
is common after TBI and a postpyloric tube may be necessary. Normoglycaemia is maintained with an insulin
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IJCCM October-December 2003 Vol 7 Issue 4

infusion if necessary, as there is an association between


hyperglycaemia on admission and poor neurological
outcomes.20 Sequential calf compressors are used routinely for deep venous thrombosis prophylaxis, and subcutaneous heparin added after 48 hours if there is no
evidence of ongoing bleeding.

Cerebral perfusion pressure


Maintenance of cerebral perfusion is the primary goal
in most guidelines, to minimize any secondary insult
caused by hypoperfusion. The cerebral perfusion pressure (CPP) is defined as the difference between the
mean arterial pressure (MAP) and the intracranial pressure (ICP). An ICP monitor of some kind therefore needs
to be inserted early in all patients with severe traumatic
brain injuries (presenting GCS < 8) and abnormal CT
scan (haematoma, contusions, oedema or basal cistern
compression), as well as those with a normal CT and
any of age > 40 years, motor posturing and systolic blood
pressure < 90 mmHg. Ventriculostomy is preferred, as
this allows the therapeutic option of CSF drainage. A
parenchymal catheter (Camino or Codman) is used if
ventriculostomy is not feasible. Fluid filled subdural catheters were popular in the past but are extremely inaccurate and are no longer recommended.
Arbitrarily a CPP of 60 mmHg is targeted in adults (having been revised from 70 mmHg in the 2003 guidelines).
There is no evidence of benefit in maintaining a higher
CPP and significant adverse systemic effects when high
doses of catecholamines are required to maintain a
higher CPP. A retrospective analysis of the database of
a negative drug trial21 could not detect benefit of a CPP
above 60 mmHg and described a much higher incidence
of the acute respiratory distress syndrome with aggressive attempts to maintain a higher CPP. Some centres
attempt to individually determine the optimal CPP for
each patient, assessing adequacy of cerebral blood flow
with jugular bulb oximetry, transcranial Doppler, near
infrared spectroscopy or more recently brain tissue oximetry, and using Xenon enhanced CT to discriminate
between diffuse and local ischaemia.22
One specific strategy (the Lund therapy) uses measurement of cerebral blood flow to demonstrate adequate
cerebral perfusion, while reducing CPP to > 50 mmHg
using -blockade, clonidine and dihydroergotamine.23
This cerebral blood volume regulation approach requires

IJCCM October-December 2003 Vol 7 Issue 4

further evaluation and validation outside of the University of Lund.

Specific treatment for intracranial hypertension


A spontaneous and persisting ICP above 20 mmHg is
generally accepted as requiring treatment. If the ICP is
elevated despite basic intensive care measures, first
recheck everything! The patient should be optimally positioned with head elevated and without any external
pressure on the neck. Optimal ventilation must be confirmed and further sedation administered to exclude
undersedation. An urgent repeat CT scan is required to
exclude an operable mass lesion.
If a ventriculostomy is in place, CSF can be drained. If
the patient is on a critical point of the intracranial
elastance curve then drainage of 3 - 5 ml CSF can have
a dramatic effect on ICP. Often these patients require
continuous drainage of CSF.

Hyperventilation
Hyperventilation became popular in the 1970s as a
means to reduce ICP in severe TBI. It subsequently became clear however that patients who were
prophylactically hyperventilated had worse outcomes.24
This is because of the cerebral ischaemia caused by
the hyperventilation induced vasoconstriction. Hyperventilation should only ever be used as a desperation measure to buy some time on the way to an operating room.
Fluid management
In the past patients were kept dry but this is inconsistent with the goal of maintaining cerebral perfusion. Cerebral oedema can occur no matter what fluid has been
administered. Euvolaemia should be the primary resuscitative goal for patients with TBI. Choice of fluid is extremely controversial and mainly comes down to the individual biases of clinicians. The Saline versus Albumin
Fluid Evaluation (SAFE) trial25 however showed improved
outcomes in the trauma cohort (17% of 6997 patients) if
0.9% saline rather than 4% albumin was used for fluid
resuscitation. It appears that the survival difference is
seen mainly in the subgroup who sustained a head injury (defined as GCS < 14 with an abnormal CT scan on
presentation). However this study used overall 28 day
mortality as its primary endpoint and this is not a meaningful outcome in TBI. The SAFE investigators are cur-

Indian J Crit Care Med April-June 2004 Vol 8 Issue 2

rently conducting a 2 year followup of all the TBI patients using the extended Glasgow outcome score
(GOSE) for functional evaluation at this time.

Osmotherapy
20% mannitol is the traditional osmotic agent used in
TBI but has significant disadvantages and recently hypertonic saline has been promoted as the agent of choice.
Mannitol decreases interstitial cerebral oedema and thus
intracranial pressure. This mechanism probably only
works in the presence of an intact blood brain barrier,
however, and over a narrow range of plasma osmolality
(290 - 330 mosm/kg). In addition mannitol acts as an
osmotic diuretic and can precipitate hypovolaemia, which
impairs cerebral perfusion and can worsen underlying
cerebral ischaemia. If the blood brain barrier is disrupted
mannitol will enter the brain and actually increase the
cerebral oedema.
Hypertonic saline (HS) has a similar osmotic effect on
the cerebral interstitium but acts as a plasma volume
expander and does not induce an osmolal gap as mannitol does. There is evidence that hypertonic saline also
has neurohumoral and vasoregulatory effects, and may
act as a cerebral vasodilator in the presence of vasospasm. A recent trial directly compared hypertonic saline
and mannitol.26 20 consecutive patients with resistant
intracranial hypertension received boluses of either HS
or mannitol to an endpoint of clinical resolution. There
were significantly fewer episodes of ICH in the HS group
(P < 0.01) with lower rates of clinical failure (P < 0.01).
Patient selection however is important and a recent Australian trial examining the routine prehospital use of HS
in patients with severe TBI showed no difference in outcomes at 6 months.27

Hypothermia
Mild hypothermia has been advocated as a therapy for
TBI but remains controversial. It is clearly beneficial in
animal models but human trials have been complicated
by the effects of hypothermia on coagulation, infection
and myocardial performance. Despite being effective in
decreasing ICP, induced hypothermia was not effective
in a recent large multicentre trial, the National Brain Injury Study: Hypothermia.28 Retrospective analysis suggested that patients who were hypothermic on arrival in
hospital did better if they were not warmed aggressively.
There is probably a place for mild therapeutic hypother123

Indian J Crit Care Med April-June 2004 Vol 8 Issue 2

mia in selected patients but more clinical research is


required to identify the appropriate subgroups.

Neuromuscular blockade
Neuromuscular blockers (NMB) are commonly used
to abolish the ICP surges caused by suctioning or coughing. There is some retrospective evidence however that
raised ICP and worse outcomes are more likely29 if NMBs
are used and it seems reasonable to restrict use to patients with a propensity to ICP surges.
Barbiturates
Barbiturate coma is effective in reducing ICP.30 There
are many complications however, particularly immunosuppression and infectious complications as well as the
predictable hypotension. There is no clinical evidence of
improved patient outcomes after barbiturate coma though
an infusion of thiopentone to achieve EEG burst suppression is still commonly used when trying to control
severe refractory intracranial hypertension.31

Experimental therapies
Corticosteroids
High dose steroids had been used in head injury in the
1970s and then abandoned because of the complications seen. The question has been revisited after the
Cochrane collaboration published a systematic review
suggesting possible improved outcomes. The large Corticosteroid Administration after Severe Head Injury
(CRASH) trial32 in the United Kingdom has recruited over
4000 patients so far and will hopefully provide a definite
answer to this question. A more recent metaanalysis of
19 trials and over 2000 patients33 suggests an insignificant difference in mortality only and steroids currently
cannot be recommended.
Decompressive craniectomy
The concept of surgical decompressive craniectomy
has attracted a lot of interest in the last decade.34 It intuitively makes sense to use a physical therapy to solve a
physical problem but concerns have been raised that
aggressive surgery may lead to survivors in a very poor
functional state. Case series report very positive experience in selected patients. 35 One small prospective
randomised controlled trial in children reported very positive outcomes.36 There is controversy also about how
extensive the craniectomy should be, whether it should
be unilateral or bilateral, and whether or not durotomy
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and duroplasty is performed. The Australian and New


Zealand Intensive Care Society Clinical Trials Group is
currently conducting a large prospective randomised
multicentre study of early decompressive craniectomy
for refractory intracranial hypertension (the DECRA
trial37) which has recruited approximately 40 patients to
date.

Drug Therapy
There have been many unsuccessful pharmacological trials, using specific mediators and antagonists to
minimize the secondary damage after TBI.38 In some
parts of the world the buffer THAM (tromethamine, trishydroxymethyl-aminomethane) is commonly used to
maintain normal pH in intracranial hypertension, though
the results of the only human randomised controlled
trial were equivocal.39 Much research focus has been
on the mitigation of excitotoxicity, where abnormal levels of neurotransmitters lead to massive calcium influx
and subsequent neuronal death. N-methyl-D-aspartic
acid (NMDA) receptor antagonsists looked promising
in theory but ineffective in phase 3 trials.40 Other trials
have examined free radical scavengers. One drug currently undergoing trials is amantadine, which acts presynaptically to enhance dopamine release and inhibit
dopamine reuptake, in patients with a diffuse axonal injury. A small phase 2 trial of 35 patients41 suggested improved functional outcomes after 6 weeks of amantadine and this needs to further investigated in a large
phase 3 study. Old drugs too are being reevaluated. Indomethacin,42 for example, has been postulated as a
treatment for the hyperaemia subsequently seen in refractory ICH.

Summary
Intracranial hypertension after traumatic brain injury is
a complex problem with potentially catastrophic consequences if mismanaged. Early after the injury attention
must be focused on good basic intensive care with emphasis on preventing any secondary brain injury. Subsequently treatment becomes more difficult if hyperaemia develops. There are few brain specific therapies available and most human clinical trials in TBI have been
disappointing. Bifrontal decompressive craniectomy is
undergoing major human trials at present but needs to
be properly evaluated before being generally adopted
as there is the potential to save life but at the expense of
numbers of severely disabled and vegetative patients.

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