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Neuroprotection and Traumatic Brain Injury
The Search Continues
Alan I. Faden, MD
Arch Neurol. 2001;58:1553-1555.
INTRODUCTION
During the last decade, experimental studies of traumatic brain injury
(TBI) have provided important new insights into the pathophysiological mechanisms
leading to posttraumatic tissue damage and associated neurological dysfunction.
The concept of delayed or secondary tissue injury has strong experimental
support and a cascade of secondary injury factors has been delineated.1, 2 These observations have led to the
application of targeted pharmacotherapies, whose aim is to block specific
pathobiological pathways.2, 3 Such
research has been aided by the development of rodent models of head injury
that simulate critical components of clinical neurotrauma, as well as by the
development of novel neuroprotective agents.3, 4
These experimental studies have identified mechanisms of delayed tissue damage
and have demonstrated the effectiveness of a number of pharmacological treatment
strategies.1, 2, 3, 4
However, despite this enormous experimental promise, the clinical studies
to date have been disappointing.5, 6
Here we explore the conceptual and methodological issues that have contributed
to this discrepancy between preclinical and clinical studies.
SECONDARY INJURY AND NEUROPROTECTION: PRECLINICAL STUDIES
Although earlier studies focused on brain injury models in higher species
such as the sheep, cat, and primate, most studies during the past decade have
used rodent models.7 Such models have been
designed to reflect certain components of clinical head injury, such as contusion,
hematoma, and/or diffuse axonal injury.6, 7
Nonetheless, there are significant questions as to how adequately these animal
models reflect human brain injury, which is a highly heterogeneous disorder.
Moreover, rodent models generally use highly inbred strains of one sex in
an effort to minimize intersubject variability. Despite these limitations,
a variety of biochemical changes have been consistently identified across
experimental models and across laboratories; these include changes in ionic
homeostasis (calcium, potassium, sodium, magnesium), release of excitatory
amino acids, induction of free radicals, inflammatory/immune changes, and
alterations of multiple neurotransmitter systems,1, 2
among others. It has also been established that TBI leads to apoptotic as
well as necrotic cell death, and that both forms of cell death may be pharmacologically
modulated.8, 9, 10
These observations have led to the evaluation of numerous pharmacological
strategies, including calcium channel blockers, corticosteroids and other
antioxidants, glutamate receptor antagonists, opioid receptor antagonists,
thyrotropin-releasing hormone analogs, and magnesium administration, as well
as various anti-inflammatory and immune modulatory treatments.3, 4
Some of these approaches, such as the use of N-methyl-D-aspartate
receptor antagonists, have particularly strong experimental support.8, 11 More recently, it has also been shown
that modulation of apoptotic cell death by inhibiting caspases also improves
outcome after TBI.9 Another strategy that has
gained increasing experimental support but that has not yet been translated
into well-designed clinical trials is the use of either combination therapies
that block different components of the secondary injury cascade or administration
of single agents (such as thyrotropin-releasing hormone or HU-211) that modulate
multiple components of the cascade.12, 13
NEUROPROTECTION AND TBI: CLINICAL STUDIES
During the past 50 years, numerous clinical trials of neuroprotective
agents have been conducted. In general, these have not shown significant beneficial
effects.5, 6 Negative trials have
included evaluation of corticosteroids, barbiturates, calcium channel antagonists,
antioxidants/free radical scavengers, and glutamate antagonists, among others.5, 6, 14, 15 Why
has it been so difficult to demonstrate effective drug treatments for clinical
head injury in contrast to recent studies of stroke or spinal cord injury?
Moreover, why are there such substantial discrepancies between animal head
injury studies and related clinical studies? There are various potential explanations
for such failures.
HETEROGENEITY OF POPULATIONS BEING STUDIED
As noted above, patients with severe brain trauma include a heterogeneous
population with regard to underlying mechanisms of secondary injury, with
the latter including varying degrees of hypoxia, ischemia, contusion, diffuse
axonal injury, edema, and the presence of associated hematoma.6
Therefore, in evaluating potential therapeutic strategies, investigators may
need to better define or stratify subpopulations of patients being studied.
For example, although 2 earlier clinical trials of nimodipine treatment in
head injury were negative,16, 17
subgroup analysis suggested a potential benefit in patients demonstrating
traumatic subarachnoid hemorrhage. A subsequent small study that focused on
patients with traumatic hemorrhage did report a significant treatment effect.18 The latter will need to be repeated with larger numbers
of patients but it does suggest the possibility that clearer delineation of
classes of patients with head injuries may increase the likelihood that significant
neuroprotective effects may be observed.
INJURY SEVERITY
Clinical trials have generally included patients with severe head injuries.
However, animal studies have shown that moderate head injury may provide a
better target for evaluation of neuroprotective treatments. Subjects with
severe injuries may be incapable of demonstrating a treatment effect because
of the severity of the primary insult or associated injuries. On the other
hand, inclusion of only mildly injured patients may lead to a ceiling effect,
in which case it is unlikely that a treatment effect can be observed unless
very large populations are studied.
RELEVANCE OF ANIMAL MODELS
Animal models are usually designed to model a component of clinical
head injury, such as concussion or contusion, to improve consistency across
subjects and reduce outcome variability. Despite inherent difficulties, it
would be desirable to develop more complex animal models that may include
hypoxia, ischemia, or other potentially relevant components of clinical head
injury (hemorrhage, hematoma, etc).
END POINTS
End points in clinical and experimental studies often differ significantly.
Experimental studies generally use behavioral assessment and lesion volume
measurements, whereas clinical studies may examine combined death/disability
or use surrogate markers such as intracranial pressure changes.
TIME POINTS/THERAPEUTIC WINDOWS
In experimental studies, pharmacotherapies are often administered either
as pretreatment or as very early posttreatment (ie, 15-30 minutes). In contrast,
clinical studies can rarely enter a brain trauma patient into a study sooner
than 3 to 6 hours after injury, particularly in view of difficulties in obtaining
informed consent. More clinically relevant treatment times should be examined
in animal studies before they are moved into the clinic. It is also important
to develop clinical treatment approaches that permit earlier treatment times.
PHARMACOLOGY IN EXPERIMENTAL MODELS
In animal studies, it is rare that pharmacokinetic or pharmacodynamic
studies are performed. Moreover, studies examining central penetration of
systemically administered compounds are rarely conducted. More detailed pharmacological
profiles, as well as optimization of treatment protocols, should be conducted
in animals before moving such studies into clinical trials.
COMBINATION OR MULTIPOTENTIAL TREATMENT STRATEGIES
Experimental studies have established that both necrotic and apoptotic
cell death occur after TBI.8, 9, 10
Moreover, it has been shown that treatment strategies aimed at necrosis may
enhance apoptotic cell death.19 Importantly,
combination treatment with agents directed to each type of cell death have
shown additive, if not synergistic, treatment effects.20
Further studies are needed to examine whether such combination treatment strategies
can improve outcomes in more clinically relevant animal model systems.
OTHER METHODOLOGICAL DIFFERENCES
Another major difference between clinical and preclinical studies is
that the former generally use an intent-to-treat methodology; that is, patients
are included in the treatment group even if by mistake they did not receive
the effective treatment dose. In contrast, with animal experimentation, investigators
routinely exclude an animal that fails to receive adequate treatment; in many
cases, subjects are excluded based on other criteria, such as inadequacy of
trauma, etc.
LESSONS LEARNED: CAN THEY BE APPLIED?
Many important lessons have been learned during the past few years regarding
clinical trial design in head injury/neuroprotection studies. In many reported
studies there has been concern about adequacy of sample size and some recent
studies suggest substantial increases in proposed sample size.21
Future clinical studies should identify more appropriate target populations,
ideally focusing on moderate as opposed to mild or severe injury. It will
be important to better stratify these populations, for example, with regard
to the presence or absence of significant hemorrhage or other confounding
factors. Future trials should also await more complete preclinical investigation,
in particular with regard to such issues as therapeutic window, pharmacokinetics,
and central nervous system drug penetration. Finally, more emphasis should
be placed on evaluating either drugs with multipotential treatment actions
(ie, altering multiple components of the secondary injury cascade) or combination
treatment strategies.
AUTHOR INFORMATION
Accepted for publication June 7, 2001.
From the Departments of Neuroscience, Neurology, and Pharmacology,
Georgetown University, Washington, DC.
Corresponding author: Alan I. Faden, MD, Department of Neuroscience,
EP-12 Research Bldg, 3970 Reservoir Rd NW, Washington, DC 20007 (e-mail:
fadena{at}giccs.georgetown.edu).
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