Traumatic brain injury: physiology, mechanisms, and outcome

Jurgens Nortje and David K. Menon

Purpose of review
This review on traumatic brain injury consolidates the substantial
current literature available on the pathophysiology, mechanisms,
developments, and their subsequent effects on outcome. In
particular, it tries to conceptualize why our greatly improved
understanding of pathophysiology and neurobiology in traumatic
brain injury has not translated into clear outcome improvements.
Recent findings
Early cerebral ischaemia has been characterized further, with
ischaemic brain volume correlating with 6-month outcome. The
Brain Trauma Foundation has revised perfusion pressure
targets, and there are additional data on the outcome impact of
brain tissue oxygen response and asymmetric patterns of
cerebral autoregulation. Mechanistic studies have highlighted
the role of inflammation and introduced concepts such as
therapeutic vaccination and immune modulation. Experimental
neurogenesis and repair strategies show promise. Despite
continuing gains in knowledge, the experimental successes
have not yet translated to the clinic. Indeed, several major
articles have attempted to understand the clinical failure of
highly promising strategies such as hypothermia, and set out the
framework for further studies (e.g. addressing decompressive
craniectomy). High-dose mannitol has shown promise in poor
grade patients, while hypertonic saline has shown better
intracranial pressure control. Negative results may be the
consequence of ineffective therapies. However, there is a
gathering body of work that highlights the outcome impact of
subtle neurocognitive changes, which may not be quantified
adequately by outcome measures used in previous trials. Such
knowledge has also informed improved definition of mild
traumatic brain injury, and allowed validation of management
guidelines.
Summary
The evidence base for current therapies in this heterogeneous
patient group is being refined, with greater emphasis on longterm functional outcomes. Improved monitoring techniques
emphasize the need for individualization of therapeutic
interventions.
Keywords
traumatic brain injury, neuroprotection, outcomes, ischaemia
Curr Opin Neurol 17:711718.

2004 Lippincott Williams & Wilkins.

Department of Anaesthesia, University of Cambridge, Cambridge, UK

Correspondence to David K, Menon, Professor of Anaesthesia, University of
Cambridge, Box 93, Addenbrookes Hospital, Cambridge CB2 2QQ, UK
Tel: +44 1223 217 889; fax: +44 1223 217 887; e-mail: dkm13@wbic.cam.ac.uk
Current Opinion in Neurology 2004, 17:711718

Abbreviations
CMRglc
CPP
FDG
GCS
ICP
PET
PtiO2
SjO2
TBI

cerebral metabolic rate for glucose

cerebral perfusion pressure
2-deoxy-2-[18F]fluoro-D-glucose
Glasgow Coma Score
intracranial pressure
positron emission tomography
brain tissue oxygen tension
jugular bulb oximetry
traumatic brain injury

2004 Lippincott Williams & Wilkins

1350-7540

Introduction
There continues to be a better understanding of the
pathophysiology of head injury, deriving from mechanistic studies in experimental models and clinical head
injury. Clinical data have resulted in some renement of
therapeutic targets. However, there are still problems in
translating successful experimental therapies into the
clinical context. A related problem is the failure of highly
promising strategies (such as hypothermia) in traumatic
brain injury (TBI), despite their success in other clinical
settings (such as cardiac arrest). Some of these failures
may be partly due to crude outcome measures in trials.
Indeed, there is increasing interest in later and more
detailed assessment of neurocognitive decits, which
may have signicant impact on patient outcomes.

Cerebral ischaemia, dysautoregulation, and

energy failure
The prevention and treatment of cerebral ischaemia are
major clinical targets in TBI. Coles et al. [1 . .], using
positron emission tomography (PET), characterized the
incidence and possible mechanisms of cerebral ischaemia within 24 h of severe TBI. They estimated the
ischaemic brain volume and showed its correlation with a
poor Glasgow Outcome Score at 6 months post-injury.
Worryingly, jugular bulb oximetry (SjO2) did not predict
this ischaemia, because approximately 13% of the brain
needed to be critically ischaemic before SjO2 dropped
below 50%. Conversely, the basis of current thresholds
[2,3] for dening ischaemia using SjO2 were also
questioned by Chieregato et al. [4 .], who studied 12
patients with Cushings syndrome during angiographic
sampling of venous efux. With careful bilateral angiographic positioning, they showed normal SjO2 values that
were signicantly different from previous data (with a
lower limit of 44.7%). If applicable to the setting of TBI,
these ndings have prognostic and therapeutic implications. However, there is clear evidence of perfusion
utilization mismatching in TBI [1 . .], and a higher critical
711

712 Trauma and rehabilitation

SjO2 threshold may need to be set to account for the

elevation of SjO2 by venous efux from hyperaemic
regions. Steiner et al. [5 .] used PET to demonstrate
pericontusional hypoperfusion, and showed that a
20 mmHg elevation in cerebral perfusion pressure
(CPP) resulted in only a modest increase in cerebral
blood ow in these areas. These data imply only limited
clinical efcacy of this manoeuvre, a nding that is
consistent with the ndings by Robertson et al. [6],
which lead to a revision of the recommended CPP
targets from the Brain Trauma Foundation (website:
http://www2.braintrauma.org/guidelines).
Further studies on assessment of cerebral autoregulation
(i.e. the brains ability to keep cerebral blood ow
relatively constant despite changes in CPP) have
contributed to current knowledge. Lang et al. [7 .], in a
prospective study of 40 patients, validated the use of PRx,
the moving correlation index between mean arterial
pressure and intracranial pressure (ICP), as a measure of
autoregulatory efciency. A PRx value greater than 0.3
implies impaired cerebral vasomotor reactivity (i.e. the
ICP follows the mean arterial pressure in a parallel
fashion), while PRx less than 0.3 indicates preserved
cerebrovascular reactivity. Steiner et al. [8,9] supported
the usefulness of PRx in TBI and demonstrated a close
relationship between dysautoregulation and abnormal
cerebral metabolism. Schmidt et al. [10 .] showed a
signicant association between interhemispheric asymmetry in autoregulatory efciency and increased mortality, with worse autoregulation on the side of the lesion.
Other publications have addressed the possibility that
different drugs used to augment CPP may have specic
effects. Both experimental [11] and clinical [12] data
have been published. Kroppenstedt et al. [11] studied
the effects of early (4 h) and late (24 h) intravenous
norepinephrine infusion in an experimental randomized
study of cortical brain-injured rats. This well-conducted
study showed that norepinephrine signicantly increased
pericontusional cortical perfusion (laser Doppler owmetry) with no effect on oedema formation. Johnston et
al. [12] compared the effects of dopamine or norepinephrine when used to elevate CPP from 65 mmHg to
85 mmHg. They found large inter-individual differences
in drug doses required to achieve CPP targets, but no
signicant differences in ICP, or in regional or global
cerebral oxygenation.
There are attempts to demonstrate the benet of
interventions in the most vulnerable areas of the brain
following TBI, an area characterized by Menon [13] as
the traumatic penumbra. Nordstrom et al. [14], using the
Lund protocol, monitored metabolism in pericontusional
and normal tissue using intracerebral microdialysis, and
showed differential sensitivities to CPP reductions in the

two regions. This paper is one of a clutch of publications

addressing the use of multi-parameter local intracerebral
monitoring with microdialysis catheters and brain tissue
oxygen tension (PtiO2) sensors. Meixensberger et al. [15 .]
studied the effects of using PtiO2 over 1.33 kPa
(10 mmHg) as a secondary therapeutic target in ICP/
CPP guided management algorithms in 93 patients.
While PtiO2 was successfully maintained at higher levels
in the test group, there was no difference in clinical
outcome. Van Santbrink et al. [16 .] introduced the
concept of brain tissue oxygen response (i.e. changes in
PtiO2 in response to changes in PaO2), and showed that
greater responsiveness in the rst 24 h was associated
with an unfavourable outcome. Soehle et al. [17]
introduced the concept of PtiO2-autoregulation
dened as the ability of the brain to maintain PtiO2
despite changes in the CPP and suggested that this
approach provided a guide to appropriate CPP targets.
Sarrafzadeh et al. [18] correlated intracerebral microdialysis and PtiO2 during episodes of cerebral hypoxia (often
precipitated by hyperventilation), and proposed that the
presence of anaerobic metabolism probably depended
on the duration and severity of the hypoxic episode.
Not all episodes of cerebral energy crisis are the
consequence of classical ischaemia [19 .,20 .]. Vespa et
al. [19 .] describe a metabolic crisis (characterized by
low glucose levels despite the absence of lactate
elevation) in the absence of classical ischaemia in a
poor-outcome patient group. Wu et al. [21], using 2deoxy-2-[18F]uoro-D-glucose (FDG)-PET, demonstrated a signicant decrease in cerebral metabolic rate
for glucose (CMRglc) in grey matter (P50.001), but not
in white matter (P40.1) after TBI, attributed to
decreased hexokinase activity. Patients with higher
CMRglc grey matter to white matter had a better
recovery at 12 months. Hattori et al. [22] continued this
theme by showing that CMRglc in the thalamus, brain
stem and cerebellum signicantly correlated with level
of consciousness at the time of the FDG-PET.
Interest has also focused on microcirculatory abnormalities following TBI. The mismatching of perfusion to
oxygen utilization demonstrated in PET studies [1 . .]
may be the manifestation of dysautoregulation that has
been documented by many previous authors (see above).
However, studies that have combined PtiO2 monitoring
and PET have shown that there may be major
microcirculatory abnormalities following TBI [23 .],
with signicant gradients for oxygen diffusion in injured tissue. The structural basis of these physiological changes was documented in exquisite detail by
Rodriguez-Baeza et al. [24 .].
For the practising clinician, perhaps one of the most
important developments in the last year has been

Traumatic brain injury Nortje and Menon 713

the downward revision of the Brain Trauma Foundations guidelines on CPP targets (website: http://www2.
braintrauma.org/guidelines). These changes are based on
data that have accumulated following a key paper by
Robertson et al. [6], and suggest a CPP target of 60,
rather than 70 mmHg.

Pathophysiology and repair

DeWitt and Prough [25 .] provide a useful review of the
impact of TBI on the cerebral vasculature, tying together
both experimental and human data on the mechanisms
of inammation.

Inflammation
Extensive work continues into the investigation of
inammation after TBI, in an attempt to identify and
manipulate pathophysiological processes. Numerous
animal and human studies (Table 1) [2630,31 .,32
35,36 .,37 .,3840,41 .,4244,45 . .,46,47] have continued
the search for potential molecular therapeutic targets.
There is increasing interest in the role of immunity in
both disease mechanisms and potential therapies, with
Boddie et al. [48] reviewing immune suppression in
isolated head injury, and Kipnis et al. [36 .] proposing
therapeutic vaccination, whereby the bodys immune
repair mechanisms are boosted.
Neurogenesis and repair

Strategies to regenerate and repair central nervous

system damage in experimental models continue to be
explored [49 . .,50 . .]. Neurogenesis and glial proliferation

occur in the subventricular zone in rats after TBI [51].

Although this phenomenon may contribute little to
lesion repair, studying gene expression in this setting
may provide important clues [52]. Evolving concepts in
this context include the potential of endogenous
precursors as a potential source of neuronal replacement
[53 . .] and the role of reactive astrocytes and proteoglycans in the glial scar as a barrier to neural regeneration.
This barrier may be overcome by chondroitinase and
brain-derived neurotrophic factor [54 . .]. Intravenous
marrow stromal cells [55], transplanted human progenitor
cells [56 .], and pre-differentiated neural precursors [57]
have shown promise in rat studies. These may act as
direct precursors for neural and glial repopulation [57],
provide neurotrophic support for native cells [55], or
work by both mechanisms [56 .].

Clinical interventions: hypothermia, osmotic

therapy and surgical decompression
Therapeutic hypothermia has been revisited in a
number of reviews [58 .,59,60 .,61 . .,62 . .,63 .], with continuing debate as to the mechanism of action. Although
of proven value in management of cardiac arrest, and in
control of raised intracranial pressure, some caution is
advocated in its use due to serious side-effects
[60 .,61 . .,62 . .], including suppression of innate immunity [64]. Despite showing benets in neurological
outcome, possibly related to a target temperature of
32338C, duration of 2448 h and a rate of rewarming
within 24 h, McIntyre et al. [60 .] conclude that there is
not sufcient evidence for its use outside of a research

Table 1. Recent publications on pathophysiology in neurotrauma

Study
Lymphocytes regulate neuropeptide gene expression (VIP and PACAP) after neuronal injury in mice
Nociceptin/orphanin FQ receptor antagonists prevent prostaglandin induced vasodilatation after TBI
Voluntary exercise can endogenously upregulate BDNF and enhance recovery (rats)
NEP1-40 (Nogo receptor antagonist) promotes functional recovery and axonal regeneration in spinal cord injury (review)
IL-6 (paradoxically) may have a neuroprotective role following TBI in mice
T cell-mediated protective autoimmunity is mediated by early microglial activation and can be boosted
Capsaicin pre-treatment depletes neuropeptides causing inhibition of neurogenic inflammation
Complement receptor related protein y (Crry) inhibits both complement pathways and mediates neuroprotection
Post-TBI angiogenesis is associated with upregulation of angiopoietin-1 (Ang-1) and downregulation of Ang-2
[1H] PK11195 maps glial activation after TBI, but this is not consistently attenuated by successful neuroprotection
Vaccination with Cop-1, a synthetic co-polymer used in MS, attenuates neuronal loss due to axonal injury
Atorvastatin reduces deficits and increases hippocampal and lesional neuronal survival, synaptogenesis and angiogenesis
Cytoplasmic localization of pericontusional PARP expression early after TBI suggests that apoptosis is an early event
CSF F2-isoprostane levels are higher in males post-TBI, and may be better attenuated by hypothermia
Oxidative load increases with age and male gender, and is reduced by hypothermia, but less so than excitotoxicity
APOE e4 allele associated with increased CSF aspartate and L/P ratio
Changes in CSF lipid profiles post-TBI are associated with selective depletion of ApoE containing lipoproteins
CSF levels of free fatty acids are increased after TBI, and levels are a marker of outcome
New ELISA assay for S100B documents temporal patterns in CSF and plasma concordant with previous techniques
Significant correlation between peak IL-6 levels and GOS
Initial serum IL-1b correlates with poor outcome
HPA-axis dysfunction, adrenal insufficiency common in TBI, correlate with higher IL-6 (but not TNFa) levels

Type

Reference

Animal
Animal
Animal
Animal
Animal
Animal
Animal
Animal
Animal
Animal
Animal
Animal
Human
Human
Human
Human
Human
Human
Human
Human
Human
Human

[26]
[27]
[28]
[29]
[30]
[31 .]
[32]
[33]
[34]
[35]
[36 .]
[37 .]
[38]
[39]
[40]
[41 .]
[42]
[43]
[44]
[45 . .]
[46]
[47]

VIP, vasoactive intestinal peptide; PACAP, pituitary adenylyl cyclase-activating peptide; TBI, traumatic brain injury; BDNF, brain-derived neurotrophic
factor; NEP1-40, NogoA antagonist; PK11195, antagonist for peripheral type benzodiazepine receptors; MS, multiple sclerosis; NMDA, N-methyl-Daspartate; PARP, poly(adenosine diphosphate-ribose) polymerase; CSF, cerebrospinal fluid; HPA-axis, hypothalamic-pituitary-adrenal axis; APO,
apolipoprotein; L/P, lactate/pyruvate; ELISA, enzyme-linked immunosorbent assay; GOS, Glasgow Outcome Score; TNF, tumour necrosis factor.

714 Trauma and rehabilitation

setting. However, Kochanek and Safar [65] suggest that

hypothermia may require titration to effect, rather than a
blanket protocol for all patients. The time of onset of
hypothermia after injury is also deemed to be important
and a possible cause of negative results [66]. What is
certain is that hyperthermia should denitely be avoided
[67]. Also of interest, Shiozaki et al. [68 .] showed that
moderate hypothermia (318C) conferred no additional
clinical benet in TBI patients with intracranial hypertension refractory to mild hypothermia (348C), and
animal work by Suzuki et al. [69] hints at a possible
sex difference in the benecial effects of posttraumatic
hypothermia.
Work with osmotic therapy has addressed both mannitol,
and newer interventions. In a further study with high
dose mannitol, Cruz et al. [70 .] showed that poor grade
severe TBI patients [Glasgow Coma Score (GCS) of 3
and bilateral abnormal pupillary widening], randomized
to receive high-dose mannitol (approximately 1.4 g/kg),
showed improved recovery of pupillary responses and a
higher proportion of favourable 6-month outcomes
(43.5% versus 9.5%; P50.02) when compared with a
control group receiving half that dose (approximately
0.7 g/kg). Vialet et al. [71] found that patients randomized to receive 2 ml/kg of 7.5% saline (approximately
350 mOsmoles/dose) had better ICP control than those
receiving 2 ml/kg of 20% mannitol (approximately 175
mOsmoles/dose), but mortality and neurological outcome did not differ. Cooper et al. [72 .] compared the
pre-hospital use of hypertonic saline resuscitation of
hypotensive patients with the use of conventional uid
in severe TBI in one of the rst prospective randomized
trials addressing the issue. ICP control was better in the
hypertonic saline group, but not signicantly so, and
there were no differences in outcome.
One of the options for treating severe refractory
intracranial hypertension is decompressive craniectomy,
an operation during which a large area of skull is
removed to increase the volume of the cranial cavity and
thus decrease the pressure. Hutchinson and Kirkpatrick
[73 .] review the current evidence available, the surgical
techniques as well as the divided neurosurgical opinion
on its risks and benets. They conclude that there is a
clear need for a randomized controlled trial to resolve
these issues, a suggestion that is addressed by the
recently initiated multicentre RESCUE-ICP study
(Randomized Evaluation of Surgery with Craniectomy
for Uncontrollable Elevation of Intra-Cranial Pressure;
website: http://rescueicp.com/).

Outcome in traumatic brain injury

While some of the clinical studies quoted above have
shown benet in small numbers of patients, there
continues to be concern regarding the clinical failure of

otherwise promising therapies such as hypothermia, and

our inability to translate experimental success into
clinical efcacy. One possible cause for these disappointments may be due to inadequacies in our assessment of
outcome. Indeed, there is increasing interest in delineating later outcomes in more detail.
A regional US population-based retrospective cohort
study [74] revealed a 30-day fatality rate of 29% for
moderate to severe TBI and 0.2% for the mild (reecting
a small, but statistically signicant reduction in long-term
survival). Interestingly, while the mortality for moderate
to severe TBI is high, those patients surviving 6 months
had a similar subsequent mortality to persons with mild
TBI. Lee et al. [75 .] showed that inuences on outcome
begin before admission, with the level of pre-hospital
care associated with the risk of mortality.
Others have documented the effect of sex and co-morbid
injury on outcome. Slewa-Younan et al. [76] retrospectively examined a matched sample of males and
females with TBI, and found that men had greater injury
severity than women (reected by lower GCS and longer
post-traumatic amnesia duration), but there was no
signicant gender difference on outcome when corrected
for severity at admission. Macciocchi et al. [77] showed
that while the presence of TBI as a comorbidity limited
functional recovery in spinal cord injury, it did not
lengthen hospital stay or the completion of rehabilitation.
Although severe TBI is associated with a high mortality
in the acute period, the long-term morbidity and
mortality of this complex condition is less well
appreciated. Research into TBI outcome has seen a
change in emphasis from mortality in the rst instance,
to a more functional outcome prediction. Various injury
severity scores are predictive of outcome. These include
GCS in the rst 24 h (disputed by Balestreri et al. [78]),
length of loss of consciousness, length of posttraumatic
amnesia, and length of stay in acute or rehabilitation
centres. Toschlog et al. [79] demonstrated a weak
correlation of Injury Severity Score and GCS with
rehabilitative potential in TBI. Cifu et al. [80 .] looked
at the potential benets of individual rehabilitative
therapy and its effect on rehabilitative outcome. Using
the Functional Independence Measure, they found that
therapy intensity was predictive of motor functioning at
discharge (P50.001), but was not predictive of cognitive
gain. Bush et al. [81] validated a model examining the
contribution of premorbid variables, injury severity, and
functional and cognitive status after injury, to 1-year
outcome after TBI. They concluded that both cognitive
and functional status have a signicant effect on 1-year
outcome, and they called for further research into this
area.

Traumatic brain injury Nortje and Menon 715

There is an increasing emphasis on studying outcomes

beyond a year after TBI. While most patients show little
functional improvement, some show dramatic improvements in the 15-year interval, and a small minority
decline [82 . .]. Variables such as race, Functional Independence Measure assessment, and selected neuropsychological tests may be predictive of subsequent
change at 1 year. Surprisingly, higher eye opening scores
on the admission GCS were associated with a tendency
to worsen between 1 and 5 years after injury. Dawson et
al. [83] found that recovery of attention and continuous
memory in the acute period after trauma was signicantly correlated with outcomes at 4 years, but not 1 year
after injury. Dikmen et al. [84 . .] documented the
neuropsychological, emotional, and functional decits
35 years after moderate to severe TBI, and showed
variable impact in different spheres. Personal care,
ambulation and standard of living were least affected;
while leisure and recreation, major role activity, social
integration, cognitive competency, and nancial independence were most severely affected. Interestingly, the
length of impaired consciousness appeared to have a
greater effect on outcome than did anatomical lesions.
Despite these problems, it is surprising that Dawson et
al. [83] found that, in moderate/severe TBI, there was
remarkably good recovery of abilities to return to work or
school, despite substantial ongoing psychological distress.

Children have a good prognosis with rapid symptom

resolution and minimal residual decits. Adults, on the
other hand, seem to display an acute stage (312
months) during which cognitive symptoms are common,
but most of these recover. When litigation or compensation is involved, symptoms are more likely to persist
longer than 12 months, often accompanied by depression, stress and chronic pain.
The relative cost benet advantages of early computed
tomography and hospital observation in the setting of
mild TBI have been the subject of investigation. Af
Geijerstam et al. [88] showed, in a Swedish model, that
when comparing the cost of in-hospital observation with
acute computed tomography and home care, the latter
costs about a third less. In a prospective study, Falimirski
et al. [89 .] found that loss of consciousness alone was not
predictive of signicant head injury, and recommended
the use of objective criteria such as constitutional signs
and symptoms before employing costly interventions
such as head computed tomography (even in alcohol
intoxicated patients). Fabbri et al. [90 . .] prospectively
applied the proposed guidelines (Table 2) of the
Neurotraumatology Committee of the World Federation
of Neurosurgical Societies on mild head injury to 5578

Table 2. Neurotraumatology Committee of the World Federation of

Neurosurgical Societies model for mild head injury

Mild head injury

The importance of mild neurocognitive decits is also
an evolving theme in the context of mild TBI. Hospitaltreated mild TBI is common (100300/100 000 population per year) and presents a signicant public health
burden, addressed by the WHO Collaborating Centre for
Neurotrauma Task Force in 1997. Carroll et al.
[85 . .,86,87] reviewed the epidemiology, diagnosis, prognosis, treatment and costs of mild TBI and made a
number of recommendations. One welcome outcome was
a specic denition of mild TBI: (1) The patient should
have acute brain injury resulting from mechanical energy
to the head from external physical forces. (2) Operational
criteria for clinical identication include a GCS of 1315
30 min after injury (or later upon presentation for
healthcare) with one or more of the following: (a) confusion or disorientation, (b) loss of consciousness for
30 min or less, (c) posttraumatic amnesia for less than
24 h and/or (d) other transient neurological abnormalities
such as focal signs, seizure, and intracranial lesion not
requiring surgery. (3) These manifestations must not be
due to drugs, alcohol, medications, caused by other
injuries or treatment for other injuries (e.g. systemic
injuries, facial injuries or intubation), caused by other
problems (e.g. psychological trauma, language barrier or
coexisting medical conditions) or caused by penetrating
craniocerebral injury [85 . .].

GCS

Low risk Medium risk

High risk

15

14 or 15 with
neurodeficits or
skull fracture or
risk factors with/
without clinical
findings
(1) Amnesia
(2) Diffuse
headache
(3) Vomiting
(4) Loss of
consciousness
Yes
Yes
(1) Coagulopathy
(2) Age 460
years
(3) Previous
neurosurgery
(4) Pre-trauma
epilepsy
(5) Alcohol and/or
drug misuse
CT scan

Clinical findings No

Neurodeficits
Skull fracture
Risk factors

No
No
No

Imaging

No

Disposition

Home

15 with clinical
findings

(1) Amnesia
(2) Diffuse
headache
(3) Vomiting
(4) Loss of
consciousness
No
No
No

CT scan or skull
X-ray
In hospital (36 h
In hospital
after CT or 24 h
(2448 h),
after skull X-ray)
followed by home
followed by home
observation
observation

The model is based on five variables: Glasgow Coma Score (GCS),

clinical findings, neurological deficits, skull fracture and risk factors
[90 . .]. CT, computed tomography.

716 Trauma and rehabilitation

patients. A model taking into account local resources and

budget constraints was found to be highly predictive of
clinical outcome.

Conclusion
There are several reasons why otherwise promising
interventions may fail in clinical trials [91]. There is
increasing recognition that real world outcomes after
TBI require assessments beyond those provided by the
classical Glasgow Outcome Score. An assessment of
neurocognitive, social and emotional decits can provide
a better characterization of the burden of residual
morbidity, while providing important therapeutic targets.
Quantication of these problems will also provide
important tools for the measurement of success of new
interventions, some of which may arise from novel
understanding of disease biology. However, other
advances will depend on rening the application of
existing therapies, and providing robust proof for their
efcacy in high quality randomized controlled trials. It is
important to recognize, however, that any paradigms of
patient management that evolve from such research
must recognize and make allowance for individual
differences in patients and their varying therapeutic
needs.

Acknowledgements
Dr Nortje is funded by a British Journal of Anaesthesia/Royal College of
Anaesthetists Fellowship. The authors are also supported by the
Medical Research Council (Grant No. G9439390 ID 65883).

References and recommended reading

Papers of particular interest, published within the annual period of review, have
been highlighted as:
.
of special interest
..
of outstanding interest

Coles JP, Fryer TD, Smielewski P, et al. Incidence and mechanisms of

..
cerebral ischemia in early clinical head injury. J Cereb Blood Flow Metab
2004; 24:202211.
This prospective study demonstrates the presence of early cerebral ischaemia in
TBI, despite the lack of bedside monitoring indicators.
1

Gibbs EL, Lennox WG, Nims LF, et al. Arterial and cerebral venous blood.
Arterial-venous differences in man. J Biol Chem 1942; 144:325332.

Datsur DK, Lane MH, Hansen DB, et al. Effects of aging on cerebral
circulation and metabolism in man. In: Birren JE, Butler RN, Greenhouse SW,
et al., editors. Human aging. A biological and behavioral study. Washington,
DC: US Government Printing Office; 1963. pp. 5976.

Chieregato A, Calzolari F, Trasforini G, et al. Normal jugular bulb oxygen

saturation. J Neurol Neurosurg Psychiatry 2003; 74:784786.
This paper shows interesting results after considering the normal SjO2 values in
use, and attempting to replicate them with modern techniques.
4

Steiner LA, Coles JP, Johnston AJ, et al. Responses of posttraumatic

pericontusional cerebral blood flow and blood volume to an increase in
cerebral perfusion pressure. J Cereb Blood Flow Metab 2003; 23:1371
1377.
This technical paper provides further insight into the behaviour of pericontusional
brain tissue and its blood flow with changes in pressure.

5
.

Lang EW, Lagopoulos J, Griffith J, et al. Cerebral vasomotor reactivity testing

in head injury: the link between pressure and flow. J Neurol Neurosurg
Psychiatry 2003; 74:10531059.
This important validation paper used PRx to monitor and quantify cerebral
vasomotor reactivity in TBI and showed the close link between cerebral blood flow
and ICP.
7

Steiner LA, Coles JP, Johnston AJ, et al. Assessment of cerebrovascular

autoregulation in head-injured patients: a validation study. Stroke 2003;
34:24042409.

Steiner LA, Coles JP, Czosnyka M, et al. Cerebrovascular pressure reactivity

is related to global cerebral oxygen metabolism after head injury. J Neurol
Neurosurg Psychiatry 2003; 74:765770.

10 Schmidt EA, Czosnyka M, Steiner LA, et al. Asymmetry of pressure

autoregulation after traumatic brain injury. J Neurosurg 2003; 99:9918.
This prospective study used a correlation coefficient between the CPP and flow
velocity on transcranial Doppler to measure autoregulation, with noteworthy
results.

11 Kroppenstedt SN, Thomale UW, Griebenow M, et al. Effects of early and late
intravenous norepinephrine infusion on cerebral perfusion, microcirculation,
brain-tissue oxygenation, and edema formation in brain-injured rats. Crit Care
Med 2003; 31:22112221.
12 Johnston AJ, Steiner LA, Chatfield DA, et al. Effect of cerebral perfusion
pressure augmentation with dopamine and norepinephrine on global and
focal brain oxygenation after traumatic brain injury. Intensive Care Med 2004;
30:791797.
13 Menon DK. Procrustes, the traumatic penumbra, and perfusion pressure
targets in closed head injury. Anesthesiology 2003; 98:805807.
14 Nordstrom CH, Reinstrup P, Xu W, et al. Assessment of the lower limit for
cerebral perfusion pressure in severe head injuries by bedside monitoring of
regional energy metabolism. Anesthesiology 2003; 98:809814.
15 Meixensberger J, Jaeger M, Vath A, et al. Brain tissue oxygen guided
treatment supplementing ICP/CPP therapy after traumatic brain injury. J
Neurol Neurosurg Psychiatry 2003; 74:760764.
This paper is important in its illustration of the use of PtiO2 to supplement the
traditional ICP/CPP approach to the management of patients with severe TBI.

16 van Santbrink H, vd Brink WA, Steyerberg EW, et al. Brain tissue oxygen
response in severe traumatic brain injury. Acta Neurochir (Wien) 2003;
145:429438.
This prospective cohort study identified the clinical relevance and prognostic value
of the concept of brain tissue oxygen response.

17 Soehle M, Jaeger M, Meixensberger J. Online assessment of brain tissue

oxygen autoregulation in traumatic brain injury and subarachnoid hemorrhage.
Neurol Res 2003; 25:411417.
18 Sarrafzadeh AS, Kiening KL, Callsen TA, Unterberg AW. Metabolic changes
during impending and manifest cerebral hypoxia in traumatic brain injury. Br J
Neurosurg 2003; 17:340346.
19 Vespa PM, McArthur D, OPhelan K, et al. Persistently low extracellular
glucose correlates with poor outcome 6 months after human traumatic brain
injury despite a lack of increased lactate: a microdialysis study. J Cereb
Blood Flow Metab 2003; 23:865877.
Introducing the concept of a metabolic crisis in the absence of ischaemia after TBI,
this study contributed to our understanding of the complex metabolic changes in
these patients.

20 Glenn TC, Kelly DF, Boscardin WJ, et al. Energy dysfunction as a predictor
of outcome after moderate or severe head injury: indices of oxygen, glucose,
and lactate metabolism. J Cereb Blood Flow Metab 2003; 23:12391250.
This prospective study looked at the effect of cerebral metabolic indices on
outcome and focused attention on the use of non-glycolytic fuel utilization by the
brain.

21 Wu HM, Huang SC, Hattori N, et al. Selective metabolic reduction in gray

matter acutely following human traumatic brain injury. J Neurotrauma 2004;
21:149161.
22 Hattori N, Huang SC, Wu HM, et al. Correlation of regional metabolic rates
of glucose with Glasgow coma scale after traumatic brain injury. J Nucl Med
2003; 44:17091716.
23 Menon DK, Coles JP, Gupta AK, et al. Diffusion limited oxygen delivery
following head injury. Crit Care Med. 2004; 32:13841390.
This prospective study in TBI introduced the concept of diffusion barriers to
cellular oxygen delivery.

24 Rodriguez-Baeza A, Reina-de la Torre F, Poca A, et al. Morphological

features in human cortical brain microvessels after head injury: a threedimensional and immunocytochemical study. Anat Rec 2003; 273A:583593.
This post-mortem study provided exceptional images and insight into the
pathophysiological and structural changes occurring after TBI.

Robertson CS, Valadka AB, Hannay HJ, et al. Prevention of secondary

ischemic insults after severe head injury. Crit Care Med 1999; 27:2086
2095.

Traumatic brain injury Nortje and Menon 717

25 DeWitt DS, Prough DS. Traumatic cerebral vascular injury: the effects of
concussive brain injury on the cerebral vasculature. J Neurotrauma 2003;
20:795825.
This excellent detailed review ties together the current knowledge on the changes
in the cerebral vasculature after TBI.

26 Armstrong BD, Hu Z, Abad C, et al. Lymphocyte regulation of neuropeptide

gene expression after neuronal injury. J Neurosci Res 2003; 74:240247.
27 Ford J, Armstead WM. Nociceptin/orphanin FQ alters prostaglandin
cerebrovascular action following brain injury. J Neurotrauma 2004; 21:187
193.
28 Griesbach GS, Hovda DA, Molteni R, et al. Voluntary exercise following
traumatic brain injury: brain-derived neurotrophic factor upregulation and
recovery of function. Neuroscience 2004; 125:129139.
29 Lee DH, Strittmatter SM, Sah DW. Targeting the Nogo receptor to treat
central nervous system injuries. Nat Rev Drug Discov 2003; 2:872878.
30 Penkowa M, Giralt M, Lago N, et al. Astrocyte-targeted expression of IL-6
protects the CNS against a focal brain injury. Exp Neurol 2003; 181:130
148.
31 Shaked I, Porat Z, Gersner R, et al. Early activation of microglia as antigen.
presenting cells correlates with T cell-mediated protection and repair of the
injured central nervous system. J Neuroimmunol 2004; 146:8493.
This experimental paper suggests that manipulating adaptive immunity can
influence the survival of cells after a central nervous system insult.
32 Nimmo AJ, Cernak I, Heath DL, et al. Neurogenic inflammation is associated
with development of edema and functional deficits following traumatic brain
injury in rats. Neuropeptides 2004; 38:4047.
33 Rancan M, Morganti-Kossmann MC, Barnum SR, et al. Central nervous
system-targeted complement inhibition mediates neuroprotection after closed
head injury in transgenic mice. J Cereb Blood Flow Metab 2003; 23:1070
1074.
34 Nourhaghighi N, Teichert-Kuliszewska K, Davis J, et al. Altered expression of
angiopoietins during blood-brain barrier breakdown and angiogenesis. Lab
Invest 2003; 83:12111222.
35 Grossman R, Shohami E, Alexandrovich A, et al. Increase in peripheral
benzodiazepine receptors and loss of glutamate NMDA receptors in a mouse
model of closed head injury: a quantitative autoradiographic study. Neuroimage 2003; 20:19711981.
36 Kipnis J, Nevo U, Panikashvili D, et al. Therapeutic vaccination for closed
head injury. J Neurotrauma 2003; 20:559569.
This paper raises an innovative approach to the management of TBI.

37 Lu D, Goussev A, Chen J, et al. Atorvastatin reduces neurological deficit and

increases synaptogenesis, angiogenesis, and neuronal survival in rats
subjected to traumatic brain injury. J Neurotrauma 2004; 21:2132.
This paper provides important laboratory evidence in the pharmacological
modulation of TBI.

38 Ang BT, Yap E, Lim J, et al. Poly(adenosine diphosphate-ribose) polymerase

expression in human traumatic brain injury. J Neurosurg 2003; 99:125130.
39 Bayir H, Marion DW, Puccio AM, et al. Marked gender effect on lipid
peroxidation after severe traumatic brain injury in adult patients. J
Neurotrauma 2004; 21:18.
40 Wagner AK, Bayir H, Ren D, et al. Relationships between cerebrospinal fluid
markers of excitotoxicity, ischemia, and oxidative damage after severe TBI:
the impact of gender, age, and hypothermia. J Neurotrauma 2004; 21:125
136.

46 Tasci A, Okay O, Gezici AR, et al. Prognostic value of interleukin-1 beta

levels after acute brain injury. Neurol Res 2003; 25:871874.
47 Dimopoulou I, Tsagarakis S, Kouyialis AT, et al. Hypothalamic-pituitaryadrenal axis dysfunction in critically ill patients with traumatic brain injury:
incidence, pathophysiology, and relationship to vasopressor dependence and
peripheral interleukin-6 levels. Crit Care Med 2004; 32:404408.
48 Boddie DE, Currie DG, Eremin O, Heys SD. Immune suppression and
isolated severe head injury: a significant clinical problem. Br J Neurosurg
2003; 17:405417.
49 Hallbergson AF, Gnatenco C, Peterson DA. Neurogenesis and brain injury:
managing a renewable resource for repair. J Clin Invest 2003; 112:1128
1133.
This is an elegant review highlighting the theories and strategies involved in
neurogenesis and neuronal repair.

..

50 Royo NC, Schouten JW, Fulp CT, et al. From cell death
regeneration: building a new brain after traumatic brain injury. J
Exp Neurol 2003; 62:801811.
This extensive review looks at the potential delayed interventions
specific focus on potentiation of neuronal precursors and cell
therapies.

..

in TBI with
replacement

51 Chen XH, Iwata A, Nonaka M, et al. Neurogenesis and glial proliferation

persist for at least one year in the subventricular zone following brain trauma
in rats. J Neurotrauma 2003; 20:623631.
52 Yoshiya K, Tanaka H, Kasai K, et al. Profile of gene expression in the
subventricular zone after traumatic brain injury. J Neurotrauma 2003;
20:11471162.
53 Parent JM. Injury-induced neurogenesis in the adult mammalian brain.
Neuroscientist 2003; 9:261272.
This very well-illustrated review examines the potential of manipulating endogenous
precursors to achieve neurogenesis after TBI.

..

54 Silver J, Miller JH. Regeneration beyond the glial scar. Nat Rev Neurosci
2004; 5:146156.
This well-written review focuses on the concept of a glial scar, why neuronal
regeneration fails in its presence, and puts forward potential therapies to overcome
these problems.

..

55 Mahmood A, Lu D, Chopp M. Intravenous administration of marrow stromal

cells (MSCs) increases the expression of growth factors in rat brain after
traumatic brain injury. J Neurotrauma 2004; 21:3339.
56 Hagan M, Wennersten A, Meijer X, et al. Neuroprotection by human neural
progenitor cells after experimental contusion in rats. Neurosci Lett 2003;
351:149152.
This rat study provided important information, not only about neuronal replacement, but also about the introduction of neurotrophic factors, which may improve
the survival of damaged host cells.

57 Hoane MR, Becerra GD, Shank JE, et al. Transplantation of neuronal and
glial precursors dramatically improves sensorimotor function but not cognitive
function in the traumatically injured brain. J Neurotrauma 2004; 21:163174.
58 Henderson WR, Dhingra VK, Chittock DR, et al. Hypothermia in the
management of traumatic brain injury. A systematic review and meta-analysis.
Intensive Care Med 2003; 29:16371644.
This systematic review and meta-analysis looks at the available evidence
supporting the use of hypothermia in the management of TBI.

59 Kabon B, Bacher A, Spiss CK. Therapeutic hypothermia. Best Pract Res Clin
Anaesthesiol 2003; 17:551568.
60 McIntyre LA, Fergusson DA, Hebert PC, et al. Prolonged therapeutic
hypothermia after traumatic brain injury in adults: a systematic review. JAMA
2003; 289:29922999.
This is another review addressing the usefulness of therapeutic hypothermia in
TBI.

41 Kerr ME, Ilyas Kamboh M, Yookyung K, et al. Relationship between apoE4

allele and excitatory amino acid levels after traumatic brain injury. Crit Care
Med 2003; 31:23712379.
This paper provides further evidence of the theory of a genetic influence in the
response to TBI.

42 Kay AD, Day SP, Kerr M, et al. Remodeling of cerebrospinal fluid lipoprotein
particles after human traumatic brain injury. J Neurotrauma 2003; 20:717
723.

..

to neuronal
Neuropathol

43 Pilitsis JG, Coplin WM, ORegan MH, et al. Free fatty acids in cerebrospinal
fluids from patients with traumatic brain injury. Neurosci Lett 2003; 349:136
138.

61 Polderman KH. Application of therapeutic hypothermia in the ICU:

opportunities and pitfalls of a promising treatment modality. Part 1:
Indications and evidence. Intensive Care Med 2004; 30:556575.
This extensive two-part review looks at the evidence for the use of hypothermia in
TBI. Taking into account mechanisms, therapeutic uses, and side effects, it makes
recommendations and provides an excellent overview of the up-to-date thinking
regarding this therapeutic modality.

44 Petzold A, Keir G, Lim D, et al. Cerebrospinal fluid (CSF) and serum S100B:
release and wash-out pattern. Brain Res Bull 2003; 61:281285.

..

45 Winter CD, Pringle AK, Clough GF, Church MK. Raised parenchymal
interleukin-6 levels correlate with improved outcome after traumatic brain
injury. Brain 2004; 127:315320.
This important paper not only postulates the role of interleukin-6 as a possible
endogenous neuroprotective cytokine, but also introduces the technique of using
intracerebral microdialysis to measure inflammatory protein levels locally in the
brain.

..

62 Polderman KH. Application of therapeutic hypothermia in the intensive care

unit: opportunities and pitfalls of a promising treatment modality. Part 2:
Practical aspects and side effects. Intensive Care Med 2004; 30:757769.
This is the second part of this excellent review.
63 Zygun DA, Doig CJ, Auer RN, et al. Progress in clinical neurosciences:
therapeutic hypothermia in severe traumatic brain injury. Can J Neurol Sci
2003; 30:30713.
This review article summarizes the data supporting the use of therapeutic
hypothermia and looks at issues such as rewarming and optimal temperature.

718 Trauma and rehabilitation

64 Hashiguchi N, Shiozaki T, Ogura H, et al. Mild hypothermia reduces

expression of heat shock protein 60 in leukocytes from severely head-injured
patients. J Trauma 2003; 55:10541060.

79 Toschlog EA, MacElligot J, Sagraves SG, et al. The relationship of Injury

Severity Score and Glasgow Coma Score to rehabilitative potential in
patients suffering traumatic brain injury. Am Surg 2003; 69:491497.

65 Kochanek PM, Safar PJ. Therapeutic hypothermia for severe traumatic brain
injury. Jama 2003; 289:30073009.

66 Shann F. Hypothermia for traumatic brain injury: how soon, how cold, and
how long? Lancet 2003; 362:19501951.
67 Marion DW. Controlled normothermia in neurologic intensive care. Crit Care
Med 2004; 32:S43S45.
68 Shiozaki T, Nakajima Y, Taneda M, et al. Efficacy of moderate hypothermia in
.
patients with severe head injury and intracranial hypertension refractory to
mild hypothermia. J Neurosurg 2003; 99:4751.
This study provided useful clinical information in the quest to optimize targets in
therapeutic hypothermia.
69 Suzuki T, Bramlett HM, Dietrich WD. The importance of gender on the
beneficial effects of posttraumatic hypothermia. Exp Neurol 2003; 184:1017
1026.
70 Cruz J, Minoja G, Okuchi K, Facco E. Successful use of the new high-dose
mannitol treatment in patients with Glasgow Coma Scale scores of 3 and
bilateral abnormal pupillary widening: a randomized trial. J Neurosurg 2004;
100:376383.
This study focused attention on the potential benefits of high-dose mannitol in a
seemingly unsalvageable patient group and warrants further study.

71 Vialet R, Albanese J, Thomachot L, et al. Isovolume hypertonic solutes

(sodium chloride or mannitol) in the treatment of refractory posttraumatic
intracranial hypertension: 2 ml/kg 7.5% saline is more effective than 2 ml/kg
20% mannitol. Crit Care Med 2003; 31:16831687.
72 Cooper DJ, Myles PS, McDermott FT, et al. Prehospital hypertonic saline
resuscitation of patients with hypotension and severe traumatic brain injury: a
randomized controlled trial. JAMA 2004; 291:13501357.
This was the first prospective randomized controlled trial in the pre-hospital setting
with long-term outcome as the main primary outcome measure.

73 Hutchinson PJ, Kirkpatrick PJ. Decompressive craniectomy in head injury.

.
Curr Opin Crit Care 2004; 10:101104.
This brief review lays out the topic of decompressive craniectomy in TBI from a
surgical perspective.
74 Brown AW, Leibson CL, Malec JF, et al. Long-term survival after traumatic
brain injury: a population-based analysis. NeuroRehabilitation 2004; 19:37
43.
75 Lee A, Garner A, Fearnside M, Harrison K. Level of prehospital care and risk
of mortality in patients with and without severe blunt head injury. Injury 2003;
34:815819.
This interesting retrospective review highlights the association between prehospital care and outcome.

76 Slewa-Younan S, Green AM, Baguley IJ, et al. Sex differences in injury

severity and outcome measures after traumatic brain injury. Arch Phys Med
Rehabil 2004; 85:376379.
77 Macciocchi SN, Bowman B, Coker J, et al. Effect of co-morbid traumatic
brain injury on functional outcome of persons with spinal cord injuries. Am J
Phys Med Rehabil 2004; 83:2226.
78 Balestreri M, Czosnyka M, Chatfield DA, et al. Predictive value of Glasgow
Coma Scale after brain trauma: change in trend over the past ten years. J
Neurol Neurosurg Psychiatry 2004; 75:161162.

80 Cifu DX, Kreutzer JS, Kolakowsky-Hayner SA, et al. The relationship between
therapy intensity and rehabilitative outcomes after traumatic brain injury: a
multicenter analysis. Arch Phys Med Rehabil 2003; 84:14411448.
This multicentre prospective study assessed the impact of individual therapy on
functional outcome after TBI and provides valuable insights into an oft-neglected
area.
81 Bush BA, Novack TA, Malec JF, et al. Validation of a model for evaluating
outcome after traumatic brain injury. Arch Phys Med Rehabil 2003; 84:1803
1807.

82 Hammond FM, Grattan KD, Sasser H, et al. Five years after traumatic brain
injury: a study of individual outcomes and predictors of change in function.
NeuroRehabilitation 2004; 19:2535.
This insightful study went a long way to dispelling the myths that there is no change
in function a year after TBI. It is an essential read for professionals caring for TBI
patients.

..

83 Dawson DR, Levine B, Schwartz ML, Stuss DT. Acute predictors of realworld outcomes following traumatic brain injury: a prospective study. Brain Inj
2004; 18:221238.
84 Dikmen SS, Machamer JE, Powell JM, Temkin NR. Outcome 3 to 5 years
after moderate to severe traumatic brain injury. Arch Phys Med Rehabil 2003;
84:14491457.
This important observational cohort study emphasised the long-term morbidity
after TBI and its consequences on the whole of society.

..

85 Carroll LJ, Cassidy JD, Holm L, et al. Methodological issues and research
recommendations for mild traumatic brain injury: the WHO Collaborating
Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med 2004:113
125.
This paper extensively reviews and formalizes many of the issues encountered in
mild TBI.

..

86 Carroll LJ, Cassidy JD, Peloso PM, et al. Prognosis for mild traumatic brain
injury: results of the WHO Collaborating Centre Task Force on Mild
Traumatic Brain Injury. J Rehabil Med 2004:84105.
87 Carroll LJ, Cassidy JD, Peloso PM, et al. Systematic search and review
procedures: results of the WHO Collaborating Centre Task Force on Mild
Traumatic Brain Injury. J Rehabil Med 2004; (43 Suppl):1114.
88 Af Geijerstam JL, Britton M, Marke LA. Mild head injury: observation or
computed tomography? Economic aspects by literature review and decision
analysis. Emerg Med J 2004; 21:5458.
89 Falimirski ME, Gonzalez R, Rodriguez A, Wilberger J. The need for head
computed tomography in patients sustaining loss of consciousness after mild
head injury. J Trauma 2003; 55:16.
This study provides important evidence for whether computed tomography aids
the management of this common problem.

90 Fabbri A, Servadei F, Marchesini G, et al. Prospective validation of a

proposal for diagnosis and management of patients attending the emergency
department for mild head injury. J Neurol Neurosurg Psychiatry 2004;
75:410416.
This important paper validates the Neurotraumatology Committee of the World
Federation of Neurosurgical Societies (NCWFNS) proposal for the management
of mild TBI.

..

91 Doppenberg EM, Choi SC, Bullock R. Clinical trials in traumatic brain injury:
lessons for the future. J Neurosurg Anesthesiol 2004; 16:8794.