REVIEW ARTICLE
CNS Drugs 2012; 26 (7): 613-636
1172-7047/12/0007-0613/$49.95/0
Adis ª 2012 Springer International Publishing AG. All rights reserved.
A Review of Neuroprotection
Pharmacology and Therapies in Patients
with Acute Traumatic Brain Injury
Kevin W. McConeghy,1,2 Jimmi Hatton,2 Lindsey Hughes3 and Aaron M. Cook1,2
1 UK Healthcare Pharmacy Services, Lexington, KY, USA
2 Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington,
KY, USA
3 Department of Neurosurgery, University of Kentucky, Lexington, KY, USA
Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Overview of Traumatic Brain Injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Causes of Secondary Neurological Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1
Extracellular Contributors to Secondary Neurological Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2
Intracellular Contributors to Secondary Neurological Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Translating Neuroprotective Agents from the Bench to the Bedside . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Pharmacotherapeutic Agents Used for Traumatic Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1
Calcium-Channel Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2
Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3
Ciclosporin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4
Deltibant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5
Modulation of Excitotoxicity and Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6
Progesterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.7
Statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.8
Pegorgotein (PEG-SOD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.9
Tirilizad . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.10 Zinc Supplementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. The Future of Treatment for Patients with Traumatic Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
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Traumatic brain injury (TBI) affects 1.6 million Americans annually. The
injury severity impacts the overall outcome and likelihood for survival.
Current treatment of acute TBI includes surgical intervention and supportive
care therapies. Treatment of elevated intracranial pressure and optimizing
cerebral perfusion are cornerstones of current therapy. These approaches do
not directly address the secondary neurological sequelae that lead to continued brain injury after TBI. Depending on injury severity, a complex cascade
of processes are activated and generate continued endogenous changes affecting cellular systems and overall outcome from the initial insult to the
brain. Homeostatic cellular processes governing calcium influx, mitochondrial
function, membrane stability, redox balance, blood flow and cytoskeletal
McConeghy et al.
614
structure often become dysfunctional after TBI. Interruption of this cascade
has been the target of numerous pharmacotherapeutic agents investigated
over the last two decades. Many agents such as selfotel, pegorgotein (PEGSOD), magnesium, deltibant and dexanabinol were ineffective in clinical
trials. While progesterone and ciclosporin have shown promise in phase II
studies, success in larger phase III, randomized, multicentre, clinical trials is
pending. Consequently, no neuroprotective treatment options currently exist
that improve neurological outcome after TBI. Investigations to date have
extended understanding of the injury mechanisms and sites for intervention.
Examination of novel strategies addressing both pathological and pharmacological factors affecting outcome, employing novel trial design methods
and utilizing biomarkers validated to be reflective of the prognosis for TBI
will facilitate progress in overcoming the obstacles identified from previous
clinical trials.
1. Overview of Traumatic Brain Injury
Traumatic brain injury (TBI) continues to be an
important cause of morbidity and mortality worldwide. In the US alone, approximately 1.7 million
Americans sustain a TBI each year, of which over
50 000 succumb to the injury and at least 35% of
the 230 000 hospitalized survivors will be faced
with long-term disability.[1-3] This injury also places
a significant emotional and economic burden on
both the patient and their families as the population most commonly affected is young men whose
economic future is generally compromised. Research efforts have dramatically improved our
understanding of TBI pathology over the last few
decades. Although some progress has been made
with prevention measures and clinical care efforts
in early resuscitation, the overall neurological
recovery and long-term morbidity continues to
be a significant healthcare challenge.[4]
Classifications of TBI are used clinically to
describe the severity of injury using physical assessment and radiographic measures. Common
clinical examples include the Glasgow Coma
Scale (GCS) and the Marshall CT score, which is
based on the nature of the intracranial injury.
Prognostic models have been validated to predict
early outcome after severe TBI with some accuracy.[5] The post-resuscitation GCS is often used
to classify injury severity and predict outcome.
Patients with a GCS of 8 or less are categorized as
severe TBI. Mortality approaches 40% in many
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studies of severe TBI patients and up to 60% of
survivors are left with significant disability.[6-8]
Moderate TBI is defined as a GCS of 9–13.
Mortality rates are much lower in these patients
when compared with severe TBI (approximately
10%).[9] However, depression, inattention, learning deficits and loss of executive function are
common after moderate TBI, leaving many of
these patients with insidious disabilities that impact their ability to resume working or even
executing activities of daily living. Mild TBI is
defined by a GCS of 14–15.[10] These patients
often have complete resolution of symptoms over
time, although as many as 90% of patients report
dizziness or headache up to 1 month after their
injury.[11,12] This presentation is clinically described
as post-concussion syndrome and may also include
fatigue, irritability, depression, difficulty concentrating, insomnia or emotional lability.[11,13] The
precise incidence of these symptoms and their
typical time to resolution is ill-defined.
The Marshall CT Score classifies the radiographic findings and provides specific information about the injury type as opposed to the
clinical presentation assessed by the GCS (table I).
Focal injuries are generally caused by a direct
and linear force to the cranium, leading to direct
compression of neural tissue and local, more superficial, damage. Haemorrhagic contusions and
intraparenchymal haematomas are more common in the frontal and temporal lobes, where the
brain comes into contact with a rougher surface
CNS Drugs 2012; 26 (7)
Neuroprotection in TBI
615
Table I. Marshall CT classification of traumatic brain injury
Class
Description
I. Diffuse injury I
No visible pathology on CT scan
II. Diffuse injury II
Cisterns are present with minimal midline shift and/or: lesion densities present, no high- or mixed
density lesion >25 mL, may include bone fragments and foreign bodies
III. Diffuse injury III (swelling)
Cisterns are compressed or absent with minimal midline shift, no high- or mixed density lesion >25 mL
IV. Diffuse injury IV (shift)
Midline shift >5 mm, no high- or mixed density lesion >25 mL
V. Evacuated mass lesion
Any surgically evacuated lesion
VI. Non-evacuated mass lesion
High- or mixed density lesion >25 mL and not surgically evacuated
of bone. This results in destruction of focal neural
tissue and expected vasogenic oedema, but not
widespread deterioration of neurons or axons.
Epidural and subdural haematomas are further
examples of injuries that compress the underlying/adjacent brain tissue with subsequent focal
neurological dysfunction. If there is protracted
compression, however, diffuse oedema and elevated intracranial pressure (ICP) can evolve,
and the patient will present with a much poorer
neurological examination. Diffuse injuries also
present with a poor neurological examination
despite the potentially benign appearance of initial neuroimaging. These include diffuse axonal
injury (DAI), global ischaemia and diffuse oedema. DAI is due to the widespread shearing of
axons, usually due to acceleration/deceleration or
rotational forces, and involves deep white matter
structures, including the brainstem. Clinically, it
is common to see patients with a combination of
TBI classifications (e.g. subdural haematoma
with contusion), rather than one isolated subtype
of injury. Penetrating injury or blast injury may
also be classified as TBI, but for the purposes of
this review we will focus primarily on closed head
injury. Readers are referred to other reviews for
details on different mechanisms of TBI.[14,15]
TBI results in both primary and secondary
injuries. Primary injuries, such as contusions and
epidural haematomas (described above), are those
immediately resultant from the initial impact or
insult. This physical damage is immediate, while
secondary injury is a delayed response occurring
from a complex group of cellular and molecular
responses to the primary injury. DAI can cause
both primary injury to neurons as well as secondary injuries.[16] This secondary injury is furAdis ª 2012 Springer International Publishing AG. All rights reserved.
ther exacerbated by ongoing ischaemia, elevated
ICP and disrupted cerebral blood flow leading to
further cell death. Both primary and secondary
injury can ultimately result in cell death and irreversible damage. However, the delayed onset of
secondary injury can provide the opportunity for
possible prevention or attenuation.[17]
Currently, the mainstay of therapy for TBI is
removal of haematomas and revision of significant skull fractures along with supportive therapies
aimed at maintaining perfusion and oxygenation
to tissues. For patients without an operable lesion
(or after surgical intervention), control of ICP
(goal <20 mmHg), cerebral perfusion pressure
(CPP, goal >60 mmHg) and systemic, and perhaps
local, oxygenation are cornerstones of intensive
care unit management.[18] Other necessary medical interventions are commonly employed such as
early enteral nutrition, maintenance of fluid volume,
and prevention and treatment of complications
such as hyperthermia, hyponatraemia, seizures,
pneumonia, venous thromboembolism and stressrelated mucosal bleeding.[18-20] Many of these
therapies can have an impact on the outcome of a
TBI patient. However, aside from avoiding events
such as hypoxia and hypotension, there is little
evidence that these supportive care therapies
inherently have a direct effect on brain tissue
preservation. Since the primary injury cannot be
reversed, the major opportunity for interventions
that could prevent further neurological decline is
in reversing or preventing the secondary injury.
Currently, there is no neuroprotective agent demonstrated in a large, phase III clinical trial to
improve neurological outcome. The purpose of
this article is to review the pathophysiology of
TBI, discuss trials investigating neuroprotective
CNS Drugs 2012; 26 (7)
McConeghy et al.
616
therapies in TBI that have been completed or are
underway and to posit some future directions for
optimizing clinical trial design in TBI patients.
The methods for this review included a systematic search of PubMed, clinicaltrials.gov and the
Cochrane Library database (the Cochrane central
register of controlled trials) for studies reporting TBI outcomes related to neuroprotection,
both clinical and experimental published from
1966 through January 2012. To identify additional articles, reference sections were reviewed
from the related citations in PubMed. Articles included were randomized controlled trials, experimental animal and systematic and meta-analysis
reviews reported in English. Search terms, MeSH
subject headings and limits were (‘traumatic
brain injury’ OR ‘concussion’ OR ‘penetrating
injury’) AND ‘neuroprotection’ AND (‘progesterone’ OR ‘glutamate antagonists’) OR ‘excitotoxicity’ AND (‘animal’ OR ‘human’ OR ‘placebo
controlled’ OR ‘randomized controlled trial’).
Clinical trials and controlled cortical impact
animal models were given preference over in vitro
and mechanistic studies, one animal study demonstrating a positive outcome was considered appropriate for inclusion.
2. Causes of Secondary Neurological
Injury
The secondary injury process in TBI is typified
by a complex cascade of processes that are simultaneously reacting to the primary injury to
the brain and attempting to mitigate the ensuing
damage to the brain cells (figure 1).[16,21-23] Many
of these processes occur along the spectrum of
severity of TBI (mild through severe), although
severe TBI models have most often been used to
elucidate the various pathological issues in secondary neurological injury. Excitatory neurotransmitters are released in high quantities after
injury, promoting elevations in cellular metabolism and cation influx. Cellular membranes are
damaged due to oxidation and ion flux. Immune
activation occurs in response to injury, sometimes with deleterious consequences to the injured cells. Intracellular homeostasis is disrupted
by membrane potential gradient perturbations
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Glutamate/
NMDA
Cerebral
perfusion
Mitochondrial
failure
Vasogenic
oedema
Ischaemia
TBI
Bloodbrain barrier
disruption
Free
radicals
Calpain
activation
Caspase
activation
Immune
dysfunction
Fig. 1. Processes and mediators associated with secondary
neurological injury after traumatic brain injury (TBI).
and the need for energy-expensive repair mechanisms to restore cell structure and function.
What follows is a delicate balance of cellular fitness, affected by cellular metabolic competence,
oxidative stress and numerous systemic factors.
This balance dictates the recovery of the cell or
cell death, either by necrosis or apoptosis.
2.1 Extracellular Contributors to Secondary
Neurological Injury
Blood flow alterations are common after TBI,
often due to impaired cerebral autoregulation
and substances produced in response to injury.[22]
Disruption of cerebral autoregulation leads cerebral blood flow to be reliant upon the CPP for
adequate perfusion.[24] Hypotension in these
patients can be devastating, as evidenced by the
increased risk of mortality (at least 2-fold).[18,25]
Maintenance of cerebral blood flow is a cornerstone of early TBI treatment. Systemic hypotension is avoided by administering isotonic or
hypertonic intravenous fluids and vasopressors
(when necessary).[18,20] The global cerebral blood
flow pattern in TBI can be variable, but generally
seems to be bimodal, falling to near-ischaemia
levels (20 mL/min/g), then rising to near normal
CNS Drugs 2012; 26 (7)
Neuroprotection in TBI
levels (approximately 50 mL/min/g).[26,27] Blood
flow is reduced immediately after TBI, mediated
by vasoconstricting prostaglandins and other
local factors, most likely as a result of reduced
oxygen demand in the brain in response to injury.
Cerebral blood flow increases thereafter due to
vasodilation from cellular acidosis, increases in
bradykinin and inducible nitric oxide synthetase
(iNOS) activity, and increases in excitatory neurotransmitters. This hyperaemia can exacerbate early
cerebral oedema and intracranial hypertension.[28]
Ischaemia/reperfusion injury and other blood
flow abnormalities are also evident early in TBI.[29,30]
Cellular hypoxia has only recently been easily
measurable at the bedside, with devices such as
the intraparenchymal brain tissue oxygen monitor. Mismatches between cerebral blood flow and
cerebral metabolic rate of oxygen often lead to
ischaemia.[31,32] Mass-occupying lesions such as a
subdural haematoma also may compress local
vasculature and cause ischaemia in the region of
the haematoma. Decompression of these areas by
surgical evacuation of the haematoma leads to
ischaemia/reperfusion injury, often resulting in
oxidative damage to vulnerable tissue. One cohort study demonstrated that nearly 50% of TBI
patients (ranging from mild to severe injury) had
cerebral vasospasm during the first 2 weeks after
injury.[33] Increasing injury severity seemed to be
associated with increased risk of vasospasm
(mean GCS on admission of 7 in patients with
vasospasm, 10 in patients without vasospasm,
p = 0.001). Clinically, it is rarely screened for,
despite the fact that some small clinical trials
suggest a neuroprotective benefit in preventing
vasospasm.[34,35]
2.2 Intracellular Contributors to Secondary
Neurological Injury
Oxidative stress is high after TBI and causes direct
damage to brain tissues.[36,37] Oxidation of haemoglobin, arachidonic acid metabolic by-products,
and disruption in the integrity of mitochondrial
membranes leads to elevated concentrations of
reactive species such as superoxide (O2-) and
peroxynitrite (OONO-). These reactive species
may overwhelm endogenous antioxidant stores,
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617
such as superoxide dismutase (SOD), causing
DNA damage and lipid peroxidation, which can
propagate well beyond the site of origin.[38,39]
The inflammatory response to TBI, like in many
other types of critical illness, can either be harmful or helpful, depending on the maintenance of
homeostasis and ‘normal’ function.[23,40,41] Nuclear factor kappa B (NF-kB) seems to play a role
in perpetuating the immune response to TBI. NFkB is known to increase genetic transcription of
pro-inflammatory mediators such as tumour necrosis factor-a (TNFa) and interleukin (IL)-6.[42]
The role of IL-1 and IL-6 are poorly understood,
but these inflammatory cytokines are present in
high concentrations in the injured brain.[23,43]
Generally, these cytokines promote oedema formation and immune activation, which may implicate
these pro-inflammatory mediators in the early
TBI swelling response.[43,44]
Complement activation after TBI results in a
multifactorial process including increased neutrophil chemotaxis, increased cerebral oedema,
cell lysis, cerebral ischaemia and blood-brain
barrier breakdown.[45] The blood-brain barrier
appears to open periodically within the first
24 hours of TBI, thereby permitting the passage
of proteins and other substances that otherwise
would be excluded from the brain.[46] This may
result in alterations of brain osmolarity and oedema formation. The dynamic actions of the
blood-brain barrier after TBI have been difficult
to illustrate, although it is clear that increased
permeability of this restrictive surface represents
a window of opportunity for neuroprotective
agents to be administered and have enhanced
penetration and concentration in the brain.
The balance of the inflammatory and immune
response is that these processes, under sufficient
homeostatic control, promote healing and repair.
Macrophage infiltration and microglia activation occur after TBI, primarily to consume and
clear remnants of damaged or dead tissue. Bloodbrain barrier disruption allows systemic immune
cells to enter the CNS compartment, supporting
the local inflammatory response. Other evidence
suggests that immune activation is associated
with anti-apoptotic activity and improved neurological recovery. Taken together, the varied
CNS Drugs 2012; 26 (7)
618
actions of the inflammatory cells support the
concept that the immune response is a doubleedged sword.[41,42]
Cerebral oedema often leads to elevations in
ICP. Different types of oedema have been described in TBI, although clinically vasogenic and
cytotoxic oedema are most pertinent. Vasogenic
oedema is seen in numerous types of neurological
problems such as meningitis and brain tumour
and is typified by protein extravasation (so-called
‘third-spacing’).[47] This oedema is usually related
to acute inflammation and bradykinin release.
Vasogenic oedema may represent some of the
reason for blood-brain barrier disruption after
TBI. Over-expression of aquaporin (AQP) channels, which permit the movement of water into
the lateral ventricles, may exacerbate cerebral
oedema as well.[48] Conversely, cytotoxic oedema
is related to cellular swelling and is typical of the
neurotoxic process that often follows severe TBI.
Direct disruption of cellular membranes may
cause cellular fluid disturbances and perturb
normal cell function. Dysregulation of ion flux
is also implicated in cytotoxic oedema. For instance, sodium and calcium are seen in high intracellular concentrations after TBI, whereas
potassium is more common in the extracellular
space (likely due to malfunction of Na+/H+ exchange pumps and other similar acid/base or
electrical gradient transporters).[47]
Calcium is a significant factor in the progression
of secondary injury and swelling after TBI. For
neurons, calcium is a common element of various
apoptosis pathways. In TBI, several reasons for
increased intracellular calcium concentrations are
present. The principle examples of such factors are
excitatory neurotransmitters such as glutamate,
which are in high concentration in the brain after
TBI.[23] Glutamate acts on the NMDA, kainite and
2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptors, which cause calcium
and sodium influx into the cell. Excessive NMDA
agonism results in tremendously elevated intracellular calcium concentrations. High intracellular
concentrations initiates various apoptotic pathways
related to the cytochrome C/mitochondrial permeability transition pore and proteases such as calpains and caspases.[23,49,50]
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McConeghy et al.
Excessive calcium influx is initially buffered
by the sarcoplasmic reticulum. As intracellular
calcium homeostasis is lost, regulation by the
sarcoplasmic reticulum is saturated. The excess
calcium is taken up by the mitochondria, which
acts as a ‘calcium sink’ under situations of
stress.[51] Several stimuli, such as cellular redox
status, pH and calcium concentration, may cause
the mitochondrial permeability transition pore
(MPTP) to form. This leads to a depolarization
of the mitochondria and disrupts the mitochondrial electrical membrane potential.[52] The mitochondria swell with calcium uptake, leak due to
intra-organelle oedema, and adenosine triphosphate (ATP) production becomes deficient. Ultimately, the minimal supply of ATP in a highly
metabolically active cell leads to cellular energy
failure. Furthermore, cytochrome C is released,
which also promotes apoptosis.[52]
Elevated intracellular calcium also results in
the activation of proteases such as calpains and
caspases, which begin disassembling cellular
structures such as the cytoskeleton and cytosolic
proteins. As calcium concentrations increase inside the cell, calpains are unleashed, leading to
proteolysis of spectrin and neurofilament proteins.[53] In addition to destabilizing cellular
structure, calpain activation may also impair
axonal transmission and neuronal plasticity. As
such, cells that survive the secondary injury process may be dysfunctional long-term, which may
translate to clinical residual deficits during TBI
recovery.[53] Cytoskeletal proteins, DNA repair
enzymes and a host of other intracellular proteins
may be lysed by various caspases.[54] Caspases
also interact with TNF and Fas ligand receptors
in the cell membrane, which when stimulated,
produce an irrevocable apoptosis response. Intracellular caspases (specifically caspase-3) also
combine with mitochondria-derived cytochrome
C to create an ‘apoptosome’, which indirectly
promotes cell lysis and inhibits repair of DNA.
Poly (adenosine diphosphate [ADP]-ribose)
polymerase (PARP) is a DNA repair enzyme
that uses nicotinamide adenosine dinucleotide as
a substrate to add ADP-ribose molecules to damaged DNA. This ubiquitous enzyme becomes
overactive in TBI, resulting in high rates of ATP
CNS Drugs 2012; 26 (7)
Neuroprotection in TBI
consumption. Ultimately, in severe TBI, the intracellular ATP supply is depleted and the cell is
predisposed to energy failure.[55] PARP also appears to be integral to apoptosis via activation of
calpains and movement of cytochrome C and
apoptosis-inducing factor into the nucleus.
Endogenous mediators with potential benefit
to the injured brain continue to be of interest as
pharmacological targets for intervention. Insulinlike growth factor (IGF)-1 was investigated
as a modulator of both central and systemic responses following TBI.[56] IGF-1 has neurotrophic effects on many CNS cell types and has
recently shown promise in synaptic plasticity.[57-59]
Through influences on neurotransmitters, CNS
cellular growth and differentiation, metabolic
and energy dynamics, and vascular reactivity,
this agent has demonstrated a multitude of potential mechanisms for improved neurological
outcome following TBI.[60,61] Fluid percussion
models of TBI in rats have demonstrated that
IGF-1 improves cognitive and motor outcomes,
whereas a penetrating brain injury model also
suggests benefit of IGF-1 supplementation (increasing brain-derived neurotrophic factor).[62,63]
Clinical exposure to this investigational agent is
limited in TBI patients but preliminary evidence
demonstrated improved systemic metabolic responses and no safety concerns when IGF-1 was
combined with aggressive nutrition support and
growth hormone in this population.[56] Studies in
human TBI were affected by the altered pharmacokinetic disposition of IGF-1 that limited both
blood and brain concentrations of the exogenous
investigational formulation.[64] Recent advances
in drug formulations for IGF-1 may provide opportunity for renewed clinical trials of this agent
in patients with TBI.[65]
It is evident that the interdigitation of these
processes is quite complex. Several excellent reviews focusing on the secondary injury process
and the various mediators involved are available
for the reader to acquire more depth of information in this area.[16,21,66,67] What is more difficult
for clinicians and scientists to discern is how much
of this interwoven process must be disrupted (or
at what critical juncture) in order to have an impact on maintaining homeostasis and the overall
Adis ª 2012 Springer International Publishing AG. All rights reserved.
619
process of cell damage and death. This is made
more difficult by challenges encountered in the
pre-clinical and clinical models employed to evaluate agents for utility in neuroprotection.
3. Translating Neuroprotective Agents
from the Bench to the Bedside
The pathophysiology of TBI is multi-faceted
and rich with pharmacological targets. To date,
most of the studies of putative neuroprotective
agents have been focused on a single component
of a complex cascade of injury. All of these agents
showed potential in laboratory and/or animal
models. However, failure has been consistent
as the agents are transitioned from animals to
humans with TBI. The disconnect between the
bench and the bedside has been well described in
a number of recent reviews.[68,69] There are potential problems with various aspects of the
animal models utilized to evaluate TBI in addition to the clinical trial design approach and
various other factors related to the variability of
care and patient-specific response that may have
impacted the success.
First, the injury models used to simulate TBI
represent a relatively homogenous injury type.
For instance, weight drop or controlled cortical
impact involves the use of a defined impact on
exposed brain to generate a contusion-type injury
accompanied by subdural or epidural haematoma.[70] This model is useful because it is reproducible and predictable with regard to the extent
and type of injury it inflicts. However, the
heterogeneity of TBI in reality is difficult to replicate.[71] Patients often present with more than
one abnormality or injury type due to neurotrauma. For instance, two patients may be admitted with severe TBI and an identical GCS.
However, if one patient has DAI and scattered
subarachnoid haemorrhage, and the other has a
subdural hematoma with a contralateral contusion, the nature of those injuries are distinctly
different. In many respects, their response to injury and subsequent treatment may be quite dissimilar. Yet, in large clinical trials, the severity
of these injuries may be considered equivalent.
The interplay among different injury types when
CNS Drugs 2012; 26 (7)
620
simultaneously present is ill-defined and may be a
factor in the difficulty in translating experimental
findings to clinical trials.
Second, a robust description of the therapeutic
window, the pharmacokinetics, and the pharmacodynamics for each agent is often not available.
It is increasingly evident that there exists a window of opportunity for specific agents, depending on their onset of action, ability to access the
central compartment and the mechanism of action. Timing is of the essence for most therapies in
TBI. Administration of the agent when the brain
penetration is suboptimal (i.e. during a time when
the blood-brain barrier is likely closed) or after
the process targeted by the agent has begun in
earnest is likely to lead to failure.[72] Drug efflux
pumps may also diminish the brain concentrations
of many agents used for neuroprotection.[73,74]
Optimization of retaining the pharmacological
agent in the brain would be helpful in achieving
satisfactory concentrations of the agent for prolonged durations. The increased use of the exception from informed consent (EFIC) process
or developing agents with broad therapeutic
windows may facilitate more timely administration of neuroprotective agents within a desirable
timeframe.
Third, TBI is commonly associated with pharmacokinetic alterations in drug distribution, metabolism and elimination.[75] Consequently, the
pharmacokinetics of neuroprotective agents may
vary among TBI patients. Alterations in bloodbrain barrier integrity, albumin and other serum
protein concentrations, and the metabolic capacity of the cytochrome P450 (CYP) and other hepatic enzyme systems related to the systemic
stress and immune response after TBI may
change the concentration-time profile or tissue
concentrations that might be typical of a non-TBI
patient.[75,76] For instance, the pharmacokinetic
profile of ciclosporin, a commonly used immunosuppressant in transplant and autoimmune disease, has been modelled in a number of different
populations.[77-80] Ciclosporin pharmacokinetics
in the normal individual are complex due to high
protein binding, dependence upon CYP3A4
metabolism, and the fact that not only is it a
substrate for efflux transporters, but it is also an
Adis ª 2012 Springer International Publishing AG. All rights reserved.
McConeghy et al.
inhibitor of these same transporters. Certainly,
the pharmacokinetics of ciclosporin in TBI merit
consideration. As demonstrated in phase II studies,
the volume of distribution of ciclosporin may be
slightly elevated (although quite variable) in TBI
patients compared with normal individuals, possibly due to increased CNS penetration.[81,82]
Ciclosporin is usually not detectable in the brain
due to high plasma binding and efflux transporters in the brain. However, after TBI, ciclosporin
is detectable in the brain, suggesting that the
blood-brain barrier may have enhanced permeability post-injury or that high doses or continuous infusions of ciclosporin may yield a brain
concentration sufficient to inhibit the efflux
pumps. Clearance of ciclosporin is also elevated
in the TBI patient, which is reflective of the hepatic enzyme induction commonly seen in the
days and weeks after TBI.[76] Dramatic changes
in serum or tissue drug exposure may impact the
efficacy and safety of investigational agents for
TBI and should be considered in the context of
TBI during clinical trial evaluation.
Fourth, several clinical trials have included
patients with a spectrum of TBI severity, ranging
from mild to severe.[9,83-85] Certainly, the need for
neuroprotection may be more desperate in severely injured patients, whereas patients with
mild TBI may have less obvious benefits. Patients
with severe TBI may be assessed by mortality rate
and broader outcomes measures like the Glasgow
Outcome Score (GOS) or the Disability Ratings
Scale. In contrast, mild to moderate TBI patients
have a relatively low mortality rate, making this
a less desirable target for a clinical trial. The
focus for outcomes in these patients needs to be
on functional outcomes and subtle cognitive
findings, for which there are numerous tests
(although some of them are onerous and time
consuming).[86,87] Fundamentally, a method of
precise definition and classification of TBI that
incorporates all of the factors related to the underlying pathology of the injury including patientspecific biomechanics and neurochemical factors
has yet to be developed. Biomarkers of TBI may
also play a role in screening or determining severity early after injury, although specific applicable examples are only now emerging.[88-91]
CNS Drugs 2012; 26 (7)
Neuroprotection in TBI
Finally, the variety of supportive care and
treatment approaches within TBI may impact the
outcome of previous studies. Disparities in fluid
resuscitation, evaluation and treatment of elevated ICP, CPP targets, timing to nutrition provision and numerous other aspects of therapy
may combine to sway the results of a trial in one
direction or another. If the studies do not randomize within centre strata, or if the study is not
large enough to account for heterogeneity, then
bias could be introduced. In addition, centres
with high enrolment rates or TBI volume may
have different outcomes in large multicentre
studies than lower volume centres or slow enrollers.[92] Areas with high concentrations of
specific age groups or ethnicities may exhibit
different outcomes or pharmacokinetic variability with the neuroprotective agent. Consensus on
key points in treatment, adherence to studyendorsed treatment protocols and limiting the
heterogeneity of injury type may all be methods
to limit the variability that has plagued many of
the TBI trials to date.
4. Pharmacotherapeutic Agents Used for
Traumatic Brain Injury
Any investigational agent for neuroprotection
faces an incredibly difficult challenge in becoming
an effective clinical therapy with proven benefit
in neurological outcome. The ideal therapy would
have a significant clinical impact outside a narrow window of the acute injury to avoid the
practical limitations of clinical trials. It would be
administered systemically via infusion or by enteral administration, while achieving an elevated
concentration at the site of injury, including penetration of the blood-brain barrier, and limiting
toxicity in other areas of the body or activation/
inhibition of other cellular receptors. It is possible
that our current research strategy of a single targeted therapy may be inadequate. Any effective
therapy would most likely need to be pluripotent
to ameliorate the multiple pathways of ischaemia
and cell death in TBI rather than affecting one
target in the complicated cascade of events. The
National Institutes of Health even issued a request
for applications #RFA-HD-08-003, to promote
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621
pre-clinical research for multi-drug combinations
in treating TBI.[93] Moving forward, one might
consider if there are numerous agents that have
been abandoned, which if combined with other
agents with different mechanisms of action, might
potentially yield a comprehensive therapeutic inhibition of calcium dysregulation, oxidative stress,
apoptosis and cell death. Table II reviews published clinical trials of neuroprotective agents in
TBI; table III describes clinical trials of neuroprotective agents currently ongoing; and table IV
highlights other trials of neuroprotective agents
in animal models.
4.1 Calcium-Channel Antagonists
Numerous randomized controlled trials have
evaluated nimodipine and nicardipine in TBI.[35]
Antagonism of the calcium channel would theoretically abrogate the harmful effects of excitatory neurotransmitters and the initiation of the
apoptosis cascade. Nimodipine has shown benefit in other acute neurological injuries such as
aneurysmal subarachnoid haemorrhage due to a
reduction in vasospasm and possible neuroprotective role.[199] However, calcium channel blockers are also active systemically and can cause a
reduction in systemic blood pressure (and subsequently, CPP), which may complicate supportive
care efforts in the acutely brain-injured patients.
An extensive Cochrane meta-analysis demonstrated that the only subgroup with a significant
reduction in death or severe disability were patients with traumatic subarachnoid haemorrhage
(odds ratio [OR] 0.67; 95% CI 0.46, 0.98).[35]
Based on these data, these medications are not
recommended for the general TBI population.
4.2 Corticosteroids
The role of corticosteroids has been extensively studied in TBI. Attenuation of the vasogenic oedema and ‘swelling’ after TBI generally
seems like a prudent target. However, the risks
attendant with high doses of corticosteroids (e.g.
bleeding, hyperglycaemia) may outweigh the benefits.[200-203] In addition, the resulting increase in
cerebral metabolic rate may exacerbate the metabolic derangements that are typical of the
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McConeghy et al.
622
Table II. Clinical trials for neuroprotection in traumatic brain injury (TBI)
Agent
Study type
Population and
sample size
Primary outcome
Notes
References
Clinical trials with possible or proven benefit
Anatibant
Phase I, pc
Severe TBI, n = 25
Safety
No adverse drug events noted,
achieves good CSF penetration,
GOS outcomes numerically better
in treatment arm
94
Ciclosporin
Phase II, pc
Severe TBI, n = 40
Safety
No significant difference in adverse
events compared with placebo,
possible improvement in GOS
at 6 mo
95
Deltibant
Phase II, pc
Severe TBI, n = 139
Elevation in ICP
Less time with ICP >15 mmHg in
deltibant group, non-significant
improvement in mortality and GOS
96
Pegorgotein
(PEG-SOD)
Phase II, III, pc
Phase II: severe TBI,
n = 104
Phase III: severe TBI,
n = 463
GOS at 3 mo
Phase II: 44% vegetative state/dead
in placebo group vs 20% pegorgotein
group (p < 0.03)
Phase III: No statistically significant
differences, but favourable GOS
scores higher in treatment groups
97,98
Progesterone
Phase II, III, pc
ProTECT study:
moderate to severe
TBI, n = 100
Xiao study: severe
TBI, n = 159
ProTECT study: safety
Xiao study: GOS at 3 and
6 mo
No significant difference in adverse
events compared with placebo,
significant reduction in mortality in
and improvement in GOS at 3 and
6 mo
85,99
Traxoprodil
Phase III, pc
Severe TBI, n = 404
GOS at 6 mo
No statistically significant difference,
but percentage of patients with
favourable outcomes was higher in
treatment group, and mortality was
lower
100,101
Clinical trials demonstrating no significant benefit
Dexanabinol
Phase III, pc
Moderate or severe
TBI, n = 861
GOSE at 6 mo
No difference noted
102
Magnesium
sulphate
Phase III, pc
Moderate or severe
TBI, n = 499
Composite outcome of
mortality, seizures,
functional measures
No significant improvements on any
measure, and possibly increased risk
of mortality with magnesium
84,103
Nimodipine
Multiple
randomized
controlled
trials
Cochrane review
includes 6 trials with
1862 patients
Death or severe disability
No significant differences except in
patients with concomitant
subarachnoid haemorrhage where
risk of death may be lower
104-109
Rosuvastatin
Phase II, pc
Moderate TBI, n = 22
GOAT at 3 mo
Possible early benefit in amnesia
resolution, no differences found at
3 mo
110
Selfotel
Phase III, pc
Severe TBI, n = 693
GOS at 6 mo
Trial terminated early, no significant
differences found
111
Tirilazad
Phase III, pc
Moderate and severe
TBI, n = 1120
GOS at 6 mo
No statistically significant difference
in GOS, but post hoc mortality benefit
in trauma-related subarachnoid
haemorrhage
112
CSF = cerebrospinal fluid; GOAT = Galveston Orientation and Amnesia Test; GOS = Glasgow Outcome Score; GOSE = Glasgow Outcome
Score Extended; ICP = intracranial pressure; pc = placebo controlled; PEG-SOD = polyethylene glycol-conjugated superoxide dismutase;
severe TBI = Glasgow Coma Scale <8.
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CNS Drugs 2012; 26 (7)
Neuroprotection in TBI
623
secondary injury response.[200,204] The Corticosteroid Randomization After Significant Head
Injury (CRASH) study demonstrated an increase
in mortality in TBI patients receiving high doses
of methylprednisolone compared with placebo
(particularly for moderate to severe injuries).[9] A
later Cochrane meta-analysis including 12 203
randomized patients demonstrated that corticosteroids may be associated with an increased risk
of gastrointestinal bleeding, although not statistically significant (OR 1.23; 95% CI 0.91, 1.67).
However, death was significantly increased relative to placebo (OR 1.15; 95% CI 1.07, 1.24).[205]
These data support one of the few level I recommendations in the TBI guidelines, suggesting that
high doses of corticosteroids for the purposes of
treating or preventing secondary injury after TBI
should be avoided.[18]
4.3 Ciclosporin A
Since calcium dysregulation has been strongly
linked with TBI, the regulation of intracellular
calcium by mitochondria is a strong area of scien-
tific research. Ciclosporin A, a well known immunosuppressant in solid organ transplant, has
been demonstrated to inhibit cyclophilin A via
calcineurin inhibition, which results in immunosuppression. Ciclosporin also inhibits mitochondrial
permeability transition pore opening (cyclophilin
D binding) and the combination of these actions
likely prevents organelle swelling and cell death.[52]
Ciclosporin has been investigated for use in TBI
through several phase II clinical trials. Thus far,
these trials have demonstrated that ciclosporin is
safe in the TBI population and may suggest the
possibility of good outcomes.
Hatton and colleagues completed a phase IIb
single-centre study that compared placebo with
ciclosporin in patients with severe TBI within
8 hours of injury.[95] This was primarily a doseescalation study that described the pharmacokinetics of ciclosporin in the TBI population
and provided information on safety.[82] Overall,
40 subjects were enrolled (32 ciclosporin and 8
placebo). No differences in safety measures such
as renal dysfunction, infection or seizure were
found. The mortality rate was similar between
Table III. On-going clinical trials for neuroprotection in traumatic brain injury (TBI)
Agent
Outcome
Amantadine
Disability rating scale and coma recovery
ClinicalTrials.gov identifier
NCT00970944
Citicoline
Composite endpoint including GOSE and other
neuropsychological evaluations
NCT00545662
Darbepoetin-a
Surrogate markers
NCT00375869
Estrogen
Neurological outcome
RESCUE-TBI NCT00973674
Glibenclamide (glyburide)
Safety
NCT01454154
hCG and rhEPO (NTx 265)
Safety study
NCT01239706
Minocycline
Disability rating scale, safety
NCT01058395
NNZ-2566
Safety study, GOSE
NCT00805818, INTREPID study
NCT01366820
N-acetyl-cysteine
Hearing loss and balance in mild TBI
NCT00822263
Oxycyte perfluorocarbon
emulsion
Safety, GOSE, brain oxygenation
NCT00908063, NCT00174980
Progesterone
GOSE
NCT00822900, NCT01143064
Propranolol
Bradycardia, cerebral perfusion pressure
EPAT phase II safety study;
NCT01202110
Propranolol and clonidine
Plasma noradrenaline (norepinephrine) levels, GOSE
NCT01322048
rhEPO
GOSE
NCT00313716, NCT00987454
SLV334
Safety study
NCT00735085, study terminated
GOSE = Glasgow Outcome Score Extended; hCG = human chorionic gonadotropin; rhEPO = recombinant erythropoietin.
Adis ª 2012 Springer International Publishing AG. All rights reserved.
CNS Drugs 2012; 26 (7)
McConeghy et al.
624
Table IV. Experimental agents with positive in vivo or in vitro evidence without published clinical evidence of efficacy
Investigational drug
Proposed mechanism
Model
Global outcome measuresa
References
GPI 6150
PARP inhibition
Fluid percussion injury
Molecular, cellular,
histological
113
Nicotinamide
PARP inhibitor,
anti-oxidant
Controlled cortical impact
Cellular, histological,
behavioural
114-119
Ethyl pyruvate
TLR4/NF-kB pathway
Controlled cortical impact
Histological, behavioural
120
N-acetyl cysteine
NF-kB inhibitor,
anti-oxidant
Controlled cortical impact
Cellular, histological
121,122
S-nitrosoglutathione
NF-kB inhibitor
Controlled cortical impact
Histological, behavioural
123,124
Bortezomib
NF-kB inhibitor
Controlled cortical impact
Cellular, histological,
behavioural
125
Glyceryltriacetate
Increases energy
Controlled cortical impact
Cellular, behavioural
126
Ketogenic diet
Alternative energy
source
Controlled cortical impact
Behavioural
127
BIBN 99
Muscarinic antagonist
Fluid percussion injury
Behavioural
128
Lazaroid U-83836E
Lipid peroxidase
inhibitor
Controlled cortical impact
Cellular, histological
129,130
NNZ-2566
Glycine-prolineglutamate analogue
Penetrating ballistic-type brain
injury
Cellular, histological,
behavioural
131,132
Ziconotide (SNX 111/
CI 1009)
N-type calcium channel
blockade
Controlled cortical impact, fluid
percussion injury
Cellular, histological,
behavioural
133,134
mGlu Antagonists
Calcium regulation
Fluid percussion injury
Cellular, histological,
behavioural
135,136
Riboflavin
Anti-oxidant
Controlled cortical impact
Molecular, cellular,
histological, behavioural
137,138
Stilbazulenyl nitrone
Anti-oxidant
Fluid percussion injury
Histological, behavioural
139
Insulin-like growth factor-1
Neurotrophic hormone
Fluid percussion injury
Behavioural, cellular
56,63
Basic fibroblast growth factor
Neurotrophic hormone
Fluid percussion brain injury
Histological, behavioural
140-143
Nimesulide
COX-2 inhibition
Closed head injury
Behavioural
144
Enoxaparin ENREF_21
Multi-modal
Fluid percussion injury
Cellular, histological,
behavioural
145,146
Minocycline
Multi-modal
anti-inflammatory
Closed head injury
Molecular, cellular,
histological,
121,147-150
Riluzole
Multi-modal
Fluid percussion injury
Cellular, histological
151,152
Erythropoetin
Multi-modal
Controlled cortical impact
Molecular, cellular,
histological, behavioural
153-164
Pyridoxine
Multi-modal
Controlled cortical impact
Histological, behavioural
165
S100B
Multi-modal
Fluid percussion injury
Cellular, histological,
behavioural
166,167
Bromocriptine
Dopamine agonism
Controlled cortical impact,
fluid-percussion injury
Behavioural
168
BAY 38-7271 (cannabinoid
agonist)
Glutamate excitotoxicity
Subdural haematoma
Histological, intracranial
pressure
169,170
Nitric oxide synthase
Inhibitors
Glutamate excitotoxicity
Closed head injury
Behavioural
171
Edavarone (NMDA
antagonist) ENREF_95
Glutamate excitotoxicity
Controlled cortical impact, fluid
percussion injury
Cellular, histological,
behavioural
172-184
AMPA antagonists
Glutamate excitotoxicity
Fluid percussion brain injury
Histological
185
Continued next page
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CNS Drugs 2012; 26 (7)
Neuroprotection in TBI
625
Table IV. Contd
Investigational drug
Proposed mechanism
Model
Global outcome measuresa
References
Repinotan (serotonin
agonist)
Glutamate excitotoxicity
Subdural haematoma
Histological
186,187
8-OH-DPAT (serotonin
agonist)
Glutamate excitotoxicity
Controlled cortical impact
Behavioural
188-193
Neuronal stem cells
Neurogenesis
Controlled cortical impact
Histological, behavioural
194-196
Pentoxifylline
TNFa inhibition
Closed head injury
Cellular, histological,
behavioural
197
Etanercept
TNFa inhibition
Penetrating injury
Cellular, behavioural
198
a
Classification of different outcomes. Molecular: up- or downregulation of different genetic markers. Cellular: surrogate markers such as
concentrations of neurochemicals. Haemodynamic: cerebral blood flow, arterial pressures, oxygenation. Histological: quantified or
subjective measurement of tissue injury, oedema. Behavioural: animal models with either cognitive or neurological evaluations including
agility tests, mazes, beam walking, etc. All studies demonstrated a positive result in the global outcomes studied.
AMPA = 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid; COX-2 = cyclo-oxygenase 2; NF-jB = nuclear factor-kappa B; PARP =
poly (adenosine diphosphate ribose) polymerase; TLR4 = toll-like receptor 4; TNFa = tumour necrosis factor-a.
the two groups, although patients who received a
higher dose (and continuous infusion) of ciclosporin appeared to have a greater probability
of favourable outcome as measured by GOSextended. This is notable from a pharmacokinetic
standpoint, since it is likely that higher serum ciclosporin concentrations increased drug exposure
in the brain. CNS concentrations of ciclosporin
may be maximized in TBI due to inhibition of
efflux transporters that would ordinarily eliminate ciclosporin from the CNS compartment.
Mazzeo and colleagues performed another
phase II prospective trial to evaluate safety, haemodynamics and pharmacokinetics in a population with severe TBI.[206] They administered a
continuous intravenous infusion of 5 mg/kg/day
for 24 hours of ciclosporin or placebo in a 3 : 1
fashion to 50 adult TBI patients. There was no
statistical difference in the lactate/pyruvate ratio
in the brain. Mean arterial pressure (MAP), ICP
and CPP were all significantly elevated in the ciclosporin group versus placebo, which the authors
hypothesize was due to a ciclosporin hypertensive
effect. Ciclosporin appears to have little effects
on T-lymphocyte counts or incidence of infection
in the acute phases of TBI.[81,95,207]
4.4 Deltibant
Marmarou et al. evaluated the bradykinin
antagonist, deltibant, in a phase II, randomized
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controlled trial for severe TBI (GCS 3–8).[96]
Subjects (n = 115) were randomized to either
3 mg/kg/min or placebo for 5 days and assessed by
mortality and GOS at 3 and 6 months. Mortality
was numerically lower at 6 months but not statistically significant (20% vs 28%, respectively;
p = 0.31). Favourable outcomes were also more
common at 3 months but not statistically different
in the deltibant group (40.3% vs 30%). A post hoc
analysis demonstrated a significant reduction in
mean time with ICP >15 mmHg. The trial was
stopped prematurely by the company based on
emergent toxicity demonstrated in animal models, despite no demonstrated increased risk of adverse events in the study. There are no ongoing
trials evaluating deltibant. Marmarou et al. also
conducted a small phase I study with another
bradykinin antagonist Anatibant (LF16-06087),
with favourable safety and pharmacokinetic
outcomes, but no other trials have been published
with this agent.[94]
4.5 Modulation of Excitotoxicity and Glutamate
Dexanabinol is a synthetic cannabinoid receptor agonist with NMDA antagonist properties.
Knoller et al. studied dexanabinol in a small, randomized, phase II safety trial where 67 patients
with severe brain trauma were randomized to a
single dose of 150 mg of dexanabinol or placebo,
and monitored for primary endpoints of ICP and
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McConeghy et al.
626
CPP.[208] Secondary endpoints included the disability rating scale and GOS. Mean GCS was 6 in
both groups, although the groups were not entirely comparable (basal cistern compression was
more common in the placebo group than the dexanabinol group). Drug-treated patients achieved
significantly higher MAP, lower ICP and higher
CPP than control patients. At 1 month the number of patients achieving good recovery was
higher in the treatment arm (20% vs 2.7%), but
did not remain statistically different at 6 months
(47% vs 32.4%; p = 0.1). The results of this trial
led to a phase III efficacy study where 861
patients were randomized to either dexanabinol
or placebo, with the primary endpoint being GOS
6 months after injury, with early and late mortality, ICP and CPP as secondary endpoints.[102]
Dexanabinol had no clinical or statistical effect
on the 6-month extended GOS assessment, mortality, ventilator duration or ICP/CPP values.
Temkin et al.[84] investigated the use of magnesium sulphate for neuroprotection in TBI.
Magnesium had been previously demonstrated to
be deficient in TBI, and several animal models
demonstrated benefit, likely due to the ability of
magnesium to inhibit calcium influx at the NMDA
receptor.[209-211] A loading dose of 0.30 mmol/kg
followed by an initial infusion of 0.05 mmol/kg/h
of magnesium sulphate or placebo was administered within 8 hours of moderate or severe head
injury. The composite endpoint score included:
survival, seizure occurrence and neurobehavioural
functioning. Subjects were stratified by GCS and
age. After interim safety data demonstrated
increased risk of death and lower blood pressures, the target magnesium level was lowered
from 1.25–2.5 to 1.0–1.85 mmol/L. The authors
demonstrated that magnesium sulphate was not
associated with any positive outcome, and may
possibly increase mortality (28% vs 14%; p = 0.05)
in the high target range group.
Morris et al. investigated the competitive
NMDA antagonist selfotel (CGS 19755) for the
treatment of severe TBI.[111] Two separate doubleblind, randomized, phase III trials were conducted comparing 5 mg/kg of selfotel to placebo
with a primary outcome of GOS at 1, 3 and
6 months post-injury. At 6 months, favourable
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outcomes were achieved in 185 (55%) of the 338
patients who had received selfotel and in 204
(58%) of the 352 patients in the placebo group
(p > 0.25). Mortality rates were 23% in the selfotel
and 21% in the placebo group (p > 0.25). The
study was discontinued early due to futility, as
well as because of concomitant stroke trials,
which were indicating increased risk of mortality
in the selfotel arms. The authors hypothesized
that selfotel had no effect on outcome because it
was unable to overcome the excessive glutamate
levels found in severe TBI.
Based on in vitro and in vivo evidence demonstrating the benefit of glutamate antagonism in
experimental TBI, numerous other clinical trials
have been conducted with NMDA antagonists.
Some agents were competitive NMDA inhibitors,
while others were bound to the post-synaptic region of the glutamate receptor. Generally, these
agents were safe, except traxoprodil, which did
exhibit some QTc prolongation.[100,101,212,213] None
of these therapies had statistically significant
effects on GOS or mortality. Failures of therapies
notwithstanding, glutamate continues to be widely
implicated in the secondary injury process and
the NMDA receptor remains a target for novel
agents.
4.6 Progesterone
The serendipitous discovery that gender and
menstrual cycle may have an effect on animal
response to experimental TBI has ultimately led
to the development of progesterone as an intravenous product (solubilized in egg phospholipid emulsion, much like propofol). Progesterone
appears to have pluripotent activity in the injured
brain by limiting cerebral oedema through reducing lipid peroxidation, aquaporin expression,
pro-inflammatory cytokine release and complement activation.[214] Progesterone is one of the
most promising agents currently being investigated and two previous phase II studies have already demonstrated safety and suggested efficacy
in TBI.[85,99]
The Progesterone for the Treatment of Traumatic Brain Injury (ProTECT) study was a phase
II, single-centre study where moderate to severe
CNS Drugs 2012; 26 (7)
Neuroprotection in TBI
TBI patients were randomized to receive progesterone or lipid vehicle within 11 hours of
injury.[85] The study was powered to detect predetermined safety measures such as hypotension,
pneumonia and hepatotoxicity. Other functional
measures such as duration of coma, duration of
post-traumatic amnesia and mortality were also
recorded. Overall, 100 subjects were enrolled.
Among the safety measures, no differences between progesterone and placebo were noted.
However, death within 30 days of injury was
lower in the progesterone group (13% vs 30.4%;
relative risk [RR] 0.43; 95% CI 0.18, 0.99),
primarily in the severe TBI subpopulation.
Another phase II, single-centre, study included
only severe TBI patients who were randomized to
receive progesterone or matching placebo within
8 hours of injury.[99] The power analysis for this
study was not reported, but the primary endpoint
was 3-month GOS. Overall, 159 subjects were
enrolled in this Chinese trial. Patients who received progesterone had a higher incidence of
favourable outcome, as measured by GOS compared with the placebo group at 3 months (47%
progesterone vs 31% placebo; p = 0.034). Interestingly, the mortality rate was also different in
the progesterone group in this study (18% progesterone vs 32% placebo; p = 0.039), despite the
different time window, a more severely injured
population and a different dosing regimen (1 mg/kg
intramuscularly every 12 hours for 96 hours)
when compared with ProTECT.
Currently, the ProTECT III study and the
Study of the Neuroprotective Activity of Progesterone in Severe Traumatic Brain Injuries
(SyNAPSe), two large, phase III trials, are underway to evaluate the efficacy of progesterone in
moderate to severe TBI.[83,215] ProTECT III patients are moderate to severe TBI patients randomized to receive a loading dose of 0.714 mg/kg
within 4 hours after injury, then a continuous
intravenous infusion at 0.5 mg/kg/h for 71 hours,
which is then tapered over an additional 24 hours
for a total 96-hour infusion (or matching intralipid vehicle control). The SyNAPSe trial uses
a similar loading and continuous infusion dosing,
but differs slightly in that the time window for
initial dosing is 8 hours and the duration of the
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627
infusion is 120 hours. The SyNAPSe trial is also
only including patients with severe TBI.
4.7 Statins
HMG-CoA reductase inhibitors (‘statins’) are
commonly used in patients with cardiovascular
disease and include agents such as simvastatin,
atorvastatin and rosuvastatin among others. More
recent reports have also focused on the pleiotropic nature of these drugs.[216] Specifically,
statins appear to attenuate inducible nitric oxide
synthetase (iNOS) activity and stabilize endothelial nitric oxide synthetase (eNOS) activity, as
well as exhibiting some immune neutralizing
properties. Although a significant amount of
in vitro and animal data exist, so far only rosuvastatin has been studied in a small (n = 22) phase II
trial for moderate TBI.[110] Patients with moderate
TBI (GCS of 9–13) were randomized to rosuvastatin 20 mg or placebo. The primary outcome
was a change on the Galveston Orientation Amnesia Test (GOAT) up to 3 months after TBI.
Disability rating score upon discharge and at
3 months was also assessed, along with a panel of
immunomodulatory cytokines that might be affected by rosuvastatin (IL-6 and TNFa). The
treatment group only included eight patients so it
is difficult to draw definitive conclusions but rosuvastatin seemed to be associated with improved
amnesia scores within the first 2–3 weeks, although scores were similar at 3 months follow-up.
Further investigation is warranted before these
medications can be applied to clinical practice.
4.8 Pegorgotein (PEG-SOD)
Neutralization of reactive oxygen species (ROS)
was investigated as a therapy to prevent neurotoxicity after severe TBI in the 1996 study involving pegorgotein (also known as polyethylene
glycol-conjugated superoxide dismutase or PEGSOD).[97] This was a prospective, double-blind,
placebo-controlled, multicentre study that compared two doses of pegorgotein with placebo. The
study agents were given within 8 hours of injury
and patients were followed for as long as 6 months
after TBI. The primary outcome was good outcome as measured by GOS. A total of 463
CNS Drugs 2012; 26 (7)
McConeghy et al.
628
patients were randomized to the three study
arms, with baseline data essentially comparable
among the different groups. Overall, there was no
difference between either dose of pegorgotein and
placebo on the 3- or 6-month GOS. However,
when patients admitted with a GCS of 3 were
excluded, more patients who received the lower
dose of pegorgotein (10 000 units/kg) had a favourable outcome (good recovery or moderate
disability) than did patients who received placebo
(63% vs 51%, respectively; p = 0.06), although this
post hoc analysis was not statistically significant.
The study had an a priori power design to detect a
14% absolute improvement in good outcome on
the GOS (whereas many other TBI clinical trials
have been powered to detect a 10% difference).
However, only a 9.4% improvement was demonstrated with pegorgotein, which may have affected statistical significance. Interestingly, to
further support the putative benefit of ROS scavenging, the incidence of acute respiratory distress
syndrome (ARDS) was significantly lower in
patients receiving the lower pegorgotein dose
compared with placebo (0% vs 4%; p = 0.015).
The mortality rate was not significantly different
among the three groups and ranged from 22% to
25%. The potential of pegorgotein was ultimately
not pursued for TBI, despite the potentially encouraging results of this under-powered trial.
4.9 Tirilizad
Marshall and colleagues conducted a large,
multicentre TBI study on the use of tirilizad, a
21-aminosteroid with antioxidative and lipid
peroxidation inhibitor effects.[112] Tirilizad had
been previously studied in spinal cord injury,
with possible benefit. Primary outcome was GOS
score at 6 months. Patients were stratified by
GCS and randomized within 4 hours to 10 mg/kg
every 6 hours for 5 days or placebo. Baseline hypotension and hypoxia was significantly higher in
the tirilizad-treated group despite the large sample size (n = 1131), introducing possible bias. In
the severe injury group at 6 months, there was no
difference in favourable outcome (35% vs 38%) or
mortality (29% or 28%) in the tirilizad or placebo
groups, respectively. Although post hoc analysis
Adis ª 2012 Springer International Publishing AG. All rights reserved.
demonstrated mortality benefit in patients with
traumatic subarachnoid haemorrhage, there was
no overall benefit of tirilizad demonstrated in the
study.
4.10 Zinc Supplementation
Young and colleagues investigated supplementing severe closed-head injury patients (n = 68) with
either standard 2.5 mg of zinc or 12.5 mg of zinc
in their parenteral nutrition for 15 days.[217] Mean
GCS scores in the zinc-supplemented group exceeded the mean GCS score of the standard
group at day 28 (p = 0.03). The groups did not
have statistically different serum zinc concentrations, weight, energy expenditure or total urinary
nitrogen excretion. Mean prealbumin concentrations were significantly higher in the zincsupplemented group (p = 0.003) at 3 weeks after
injury. However, more patients in the standard
group underwent craniotomies than the supplementation group possibly creating a bias towards
worse GCS scores. It is currently unknown whether
zinc supplementation improves outcome in TBI.
5. The Future of Treatment for Patients with
Traumatic Brain Injury
Although the secondary neurological injury
process after TBI is complex, the opportunities
for pharmacological intervention are robust. The
frustrations of limited progress over the last decade have actually provided improved understanding of the obstacles and limitations existing
in early study designs and unrecognized drug
delivery challenges. Creative intervention strategies based on sound pharmacokinetic and pharmacodynamic principles integrated into clinical
trials along with possible combination strategies
based on pharmacology are reasonable expectations for future advances in the treatment of TBI.
Recognizing that numerous challenges may exist
in translating the pre-clinical studies into clinical
practice where TBI injury severity and clinical
course is highly variable, the knowledge acquired
to date will afford improved monitoring using
alternative measures such as biomarkers to more
closely define drug effect. A more detailed underCNS Drugs 2012; 26 (7)
Neuroprotection in TBI
standing of the permeability of the blood-brain
barrier, effect of drug transporters (for both CNS
penetration and efflux) and specific pharmacological target regulation over the injury time-course
will further refine the optimal treatment approach.
Innovative trial designs and statistical methods
incorporating TBI-specific outcome assessment
tools that target behavioural and cognitive changes,
as well as further definition of surrogate markers
of therapy to improve study population enrolment, will facilitate future success of clinical trials
for TBI.[91,218-220]
Acknowledgements
629
10.
11.
12.
13.
14.
15.
The authors have no potential conflicts of interest or sources
of funding related to the preparation of this manuscript.
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Correspondence: Dr Aaron Cook, Pharm.D., 800 Rose St.
H112, Lexington, KY 40536-0293 USA.
E-mail: amcook0@email.uky.edu
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