Management of Severe TBI-A Review of Recent Literature
Management of Severe TBI - A Review of Recent Literature
M. Kamran Athar
0 Sidney Kimmel Medical College, Thomas Jefferson University
Traumatic Brain Injury (TBI) is the result of sudden trauma causing damage to the brain.
TBI can occur when the head strongly and abruptly changes direction or contacts an
object, or when an object penetrates the skull and brain tissue. (Figure 1 – TBI). CDC
estimated that in 2010, TBI, alone and in conjunction with other injuries, accounted for
approximately 2.5 million ED visits, hospitalizations, and deaths in the United States.
Children aged 0–4 years, adolescents aged 15–19 years, and, most significantly, adults
aged 75 years and older are the most likely to sustain a TBI and seek medical care1. The
leading cause of non-fatal TBI in the U.S. is falls and the leading cause of TBI-related
fatalities is motor vehicle accidents2.
As a heterogeneous condition, TBI is conventionally categorized as mild, moderate, or
severe. The most useful classification system is the Glasgow Coma Scale (GCS) which
is based on level of consciousness as assessed by eye, motor, and verbal performance.
A GCS score of 13 to 15 classifies a mild TBI, 9 to 12 a moderate TBI, and a score of 3
to 8 defines a severe TBI (sTBI). Each year, the direct and indirect medical cost of TBI
is nearly $76.5 billion, with 90% directed at severe TBI3.
Although little can be done to reverse the initial, or primary, brain injury caused by
trauma, care is directed at stabilizing the patient and preventing further, or secondary,
brain injury. Concerns of delayed non-mechanical damage include swelling,
inadequate oxygenation, lack of autoregulation, and metabolic dysfunction. Elevated
intracranial pressure (ICP), often the result of increasing mass effect from hematomas
and contusions, diffuse cerebral edema, or hydrocephalus, is an important promoter
of secondary brain injury and is associated with worse neurological outcomes in
patients after TBI. Consequently, medical and surgical efforts attempt to normalize
ICP in order to maintain cerebral blood flow and prevent parenchymal death. (Figure
2 and 3– ICPmonitor1 and 2). In the past 5 years, three landmark trials have explored
the beneficence of three individual techniques for mitigating secondary brain injury
associated with intracranial hypertension. Although the following investigations do
not isolate and then evaluate ICP treatment, they do smear the guidelines of practice
for approach and management of sTBI.
BEST TRIP: A call for greater investigation into the efficacy of ICP Monitoring
For decades, ICP monitoring has been considered the gold standard for steering
treatment in patients with sTBI. Despite guidelines, there is a great deal of variation
in its use and patients may undergo ICP modification without the use of a monitor.
(Figure 4 – ICP monitor 3). Only recently has the efficacy of direct monitoring on
outcome improvement been explored by more than observational and nonrandomized
studies. The Benchmark Evidence from South American Trials: Treatment of
Intracranial Pressure (BEST TRIP) trial was a multicenter, prospective RCT that enrolled 324 sTBI
patients 13 years of age or older from four ICU’s in Bolivia and Ecuador. Participants
were randomized to one of two management strategies determined either by ICP
monitoring maintaining ≤20mmHg or by
clinical examination and serial computed
tomography (CT) imaging4. The overall
composite outcome was calculated
as the average of percentiles from 21
measures, including survival time,
duration and level of impaired consciousness,
functional status at 3 and 6 months,
and cognitive status at 6 months, with
lower percentiles representing worse
outcome. This five-year investigation
demonstrated no statistical difference
in overall outcome between the two
groups (56% composite for pressure
monitoring group vs. 53% composite for
imaging-clinical exam group; p = 0.49).
Six-month mortality, median length
of stay in the ICU, and distribution of
serious adverse events were also not
significantly different.5 These results
suggest that clinical findings and imaging
are sufficient for practitioners to
determine a treatment regimen.
However, the ability to generalize these
findings and extend them to practice
in developed countries is questionable.
BEST TRIP was conducted in Bolivia
and Ecuador; prehospital care is not as
advanced as in higher income countries
and rehabilitation is essentially
nonexistent. Severely injured patients in the
sampled nations do not survive long
enough to reach a care facility;
consequently, sTBI cases represented in this
trial are likely less severe than those seen
in the U.S.6 ICP monitoring may in fact
assist in approaching treatment of more
severe patients and this study could not
include that population. Elderly patients,
the largest contributors to sTBI care in
the U.S., were also missed. Accurate
information on prehospital interventions
or early secondary insults such as
hypothermia and hypoxia were not recorded
or assessed in both transfer patients and
It is important to note that the BEST
TRIP study did not intend to question
the value of knowing the ICP and actively
managing brain edema. What this trial
did reveal was that our understanding of
ICP manipulation is oversimplified and
does not produce improved recovery in a
general sTBI population8. For instance, a
universal threshold of 20mmHg was used
as recommended; in light of the study’s
findings, monitoring may be productive
if this number could be personalized
beyond the current standardized value.
Overall, the strongest clinical implication
stemming from the BEST TRIP trail is the
need to refine the role of ICP monitoring
in sTBI management, determining when
it is efficacious and how to guide therapy
based on its findings.
DECRA: Questioning the putative benefits of decompressive craniectomy
When patients with severe head injury
have raised ICP that is refractory to
first-tier therapies such as
hyperosmolar infusions, surgical decompressive
craniectomy (DC) is recommended.
This procedure has been increasingly
performed in the last 15 years and only
recently has a randomized control trial
taken place to explore its efficacy. The
Decompressive Craniectomy (DECRA)
Trial was conducted over eight years in
fifteen ICUs in Australia, New Zealand,
craniotomy with standard care or
standard care alone. The clinical outcomes
were measured 6 months after injury
using the Extended Glasgow Outcome
Scale (GOS-E). Although the surgical
group did demonstrate a significant
decrease in ICP, fewer interventions,
IP mS Device
(1 mm in diameter)
20mmHg for over 15 minutes despite
medical therapy. Decompressive
craniectomy is used as a last resort and
DECRA may have included patients that
are not typical candidates. There were
also two exclusion criteria that may
serve as points of contention: patients
needing a unilateral DC and patients with
previous evacuation of a mass lesion; in a
multicenter study of 729 patients, it was
found that about one third of patients
receiving removal of an intracranial
hematoma also required a typically
unilateral decompressive craniectomy10.
An important patient type was neglected
from this evaluation.
Regardless of potential limitations,
the DECRA study offered convincing
support that early neuro-protective
bifrontal DC is not superior to medical
management for patients with severe
diffuse TBI. Two more trials are currently
u n d e r w a y – R E S CU E- A S D H – a n d
RESCUEicp – evaluating the efficacy of
primary and secondary DC, respectively,
and the parameters outlined seem more
accurate and applicable11. In light of
the currently available findings and the
potential complications associated with
DC, use of DC for patients with severe
diffuse TBI should continue to remain
Eurotherm3235: An unexpected response to therapeutic hypothermia
Elevated body temperature following
brain trauma is associated with increased
cytokine release and worsening of
outcome. Given this as well as the
neuro-protective effect of induced
hypothermia after global brain
ischemia caused by cardiac arrest, neonatal
asphyxia, or drowning in cold water,
hypothermia has become routinely
used in some ICUs to treat elevated
ICP in patients with TBI. However, its
effect on outcome in this context has
limited evaluation. The European Study
of Therapeutic Hypothermia (32–35°C)
for Intracranial Pressure Reduction after
Traumatic Brain Injury (Eurotherm3235)
randomized 387 patients at 47 centers
in 18 countries to receive standard
care or standard care plus therapeutic
hypothermia. Temperature was adjusted
to maintain ICP at or below 20mmHg,
and treatment continued for at least 48
hours as needed. The primary outcome
measure was the score on the Extended
Glasgow Outcome Scale (GOS-E) at 6
months after injury. GOS-E score of 5
to 8, indicating moderate disability or
good recovery, occurred less often in the
hypothermia group than in the control
group (25.7% vs. 36.5%; P=0.03)12. The
occurrence of serious adverse events
and mortality also favored the control
hypothermiainduced reduction of ICP had a similar
efficacy as standard medical protocols.
The study’s findings are implying a
contraindication of active hypothermia
in ICP management. However, there
are important considerations raised
by study critics. The Eurotherm3235
trial was terminated early due to safety
concerns. Additionally, a lack of blinding
to the intervention, problematic in any
trial involving therapeutic hypothermia,
may have introduced bias13.
Participants receiving hypothermia treatment
may have more often reported serious
adverse events, while control group
participants expected these results. In
regards to study design, investigators
used an intracranial pressure of 20 mm
Hg as a treatment threshold, but many
protocols also measure cerebral
perfusion pressure; intracranial pressures of
up to 25 mm Hg may be safe provided
that cerebral perfusion pressure is
Although it would be difficult to
appreciate an effect of hypothermia alone
on outcome, Eurotherm3235
demonstrated a lack of evidence supporting
the benefit of therapeutic hypothermia
in decreasing ICP and improving patient
outcome 6 months after treatment.
Interestingly, hypothermia resulted in a
largely decreased need for
pentobarbital-induced coma14. This may suggest
that barbiturates provide similar or better
metabolic suppression and
neuroprotection as compared with hypothermia.
The overall goal of medical and surgical
treatment for severe TBI is to prevent
secondary injury by maintaining blood
flow and oxygen delivery to the brain
and minimizing swelling and
pressure. The trials assessed in this review
were not concerned with the
challenge of isolating the effect of a single
treatment, nor could they establish if
successful treatment of intracranial
hypertension improved outcomes. The
collective effect of these investigations
is to increase awareness of the lack of
evidence supporting commonly used
approaches for the management of
patients with sTBI. It has become unclear
how beneficial ICP monitoring,
decompressive craniectomy, and therapeutic
hypothermia are when compared to
other standard treatment regimens. The
unpredictable nature of the
pathophysiology of traumatic brain injury demands
guidelines for a pressure-focused
approach to be more firmly established
in order to effectively tailor treatment to
A recently completed study, BOOST
2 – Brain Tissue Oxygen Monitoring in
Traumatic Brain Injury, is a multi-center
randomized control phase 2 trial which
uses a newly approved device to
maintain continuous monitoring of the partial
pressure of oxygen in brain tissue (pBrO2).
182 patients requiring ICP monitoring
received both an ICP monitor and a pBrO2
monitor; patients in the control group
had pBrO2 monitors masked by opaque
tape in order to manage treatment based
on ICP alone. Patients in the treatment
group were managed based on results
from both. Level of recovery was assessed
6 months after injury using GOS-E.15 As
the results of this trial are awaited, it can
be noted that the treatment group
incorporated two modalities to direct care
for patients with sTBI. Although there is
contention to the efficacy of some of
these techniques individually, there may
be a benefit in determining care based on
evaluating and balancing more than one
parameter. A multi-modal monitoring
approach is a likely direction for future
research into the management of patients
with severe TBI.
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