Management of acute severe traumatic brain injury

Author:
J Claude Hemphill, III, MD, MAS
Section Editors:
Michael J Aminoff, MD, DSc
Maria E Moreira, MD
Deputy Editor:
Janet L Wilterdink, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Feb 2018. | This topic last updated: Dec 20, 2017.

INTRODUCTION — Traumatic brain injury (TBI) is the leading cause of death in North
America for individuals between the ages of 1 to 45 [1,2]. Many survivors live with
significant disabilities, resulting in major socioeconomic burden as well. In 2000, the
economic impact of TBI in the United States was estimated to be $9.2 billion in lifetime
medical costs and $51.2 billion in productivity losses.

One of the major advances over the past two decades in the care of patients with severe
head injury has been the development of standardized approaches that follow international
and national guidelines [3-6]. The intent of these guidelines has been to use existing
evidence to provide recommendations for current care in order to lessen heterogeneity and
improve patient outcomes. Unfortunately, the lack of randomized clinical trials addressing
many aspects of care of the severe TBI patient has meant that the strength of supporting
data for most treatment concepts is relatively weak. Despite this caveat, there is evidence
that treatment in centers with neurosurgical support, especially in settings where protocol-
driven neurointensive care units operate based on the above-referenced guidelines, is
associated with better patient outcomes [7-14]. Many expert panels recommend that
treatment of severe TBI should be centralized in large trauma centers that offer
neurosurgical treatment and access to specialized neurocritical care.

Patients with severe head injury may frequently have other traumatic injuries to internal
organs, lungs, limbs, or the spinal cord. Thus, the management of the patient with severe
head injury is often complex and requires a multidisciplinary approach and lends itself to
protocol-based treatment and standardized hospital order sets derived from the previously
referenced guidelines.
This topic discusses the management of acute severe TBI. The epidemiology and
pathophysiology of TBI, the management of mild TBI, acute spinal cord injury, and other
aspects of care of the trauma patient are discussed separately. (See "Traumatic brain
injury: Epidemiology, classification, and pathophysiology" and "Acute mild traumatic brain
injury (concussion) in adults" and "Acute traumatic spinal cord injury" and "Skull fractures in
adults".)

INITIAL EVALUATION AND TREATMENT

Prehospital — The primary goal of prehospital management for severe head injury is to
prevent hypotension and hypoxia, two systemic insults known to be major causes of
secondary injury after TBI [15-20]. In a meta-analysis of clinical trials and population-based
studies, hypoxia (PaO 2<60 mmHg) and hypotension (systolic blood pressure [BP] <90
mmHg) were present in 50 and 30 percent of patients, respectively, and were each
associated with a higher likelihood of a poor outcome: hypoxia (OR 2.14), hypotension (OR
2.67) [16]. Changes in prehospital management that aim to normalize oxygenation and BP
have improved outcomes [21-25]:

●Early endotracheal intubation is generally recommended for patients with a Glasgow

Coma Scale (GCS) score of 8 or less if performed by well-trained personnel (table 1).
The value of prehospital intubation is controversial, with studies finding conflicting
results [26]. In one randomized trial of 312 patients with severe TBI performed in
Australia, prehospital rapid sequence intubation by paramedics was associated with
better functional outcome at six months compared with intubation in hospital (51 versus
39 percent of patients with favorable outcome on GCS) [27]. However, another study in
San Diego, California found that prehospital intubation was associated with an
increased mortality, perhaps due to inadvertent hyperventilation, transient hypoxia, or
longer time at scene prior to transport [28]; hemodynamic instability induced during
intubation is another potential explanation for adverse outcome [29]. A benefit from
prehospital intubation by paramedics requires extensive training and is not widely
generalizable [30]. If this expertise is not available, bag-mask ventilation is
recommended.
●Prevention of hypotension in the prehospital setting is best accomplished by
adequate fluid resuscitation using isotonic crystalloids. Studies of hypertonic saline in
the prehospital setting have not suggested benefit [31,32]. Saline is preferred over
albumin; the latter was associated with increased mortality in one randomized study of
patients with TBI [33].
Patients with TBI should be assumed to have a spinal fracture and appropriate precautions
taken to stabilize and immobilize the spine during transport. (See "Acute traumatic spinal
cord injury".)

A prehospital assessment of the GCS can be helpful for early triage decisions (table 1).

The prehospital management of the trauma patient is discussed in detail separately.

(See "Prehospital care of the adult trauma patient".)

Emergency department — In the early hospital admission phase of patients with severe
head injury, treatment and diagnostic assessment is done according to the Advanced
Trauma Life Support (ATLS) protocol:

●Adequate oxygenation (PaO 2 >60 mmHg) and BP support (systolic BP >90 mmHg)
continue to be priorities [15]. (See "Emergency airway management in the patient with
elevated ICP".)
●Vital signs including heart rate, BP, respiratory status (pulse oximetry, capnography),
and temperature require ongoing monitoring.
●A neurologic examination should be completed as soon as possible to determine the
clinical severity of the TBI. The GCS is commonly used to assess and communicate
neurologic status in this setting (table 1). A GCS score of 8 or lower is considered a
severe TBI. Neurologic status should be continuously assessed. Deterioration is
common in the initial hours after the injury.
●The patient should be assessed for other systemic trauma.
●A complete blood count, electrolytes, glucose, coagulation parameters, blood alcohol
level, and urine toxicology should be checked. Coagulopathy is common in patients
with severe TBI, either resulting from patient medications or as a consequence of the
trauma itself. When the international normalized ratio (INR) is elevated, then efforts to
reverse the coagulopathy should begin immediately. (See 'Hemostatic therapy' below
and "Coagulopathy associated with trauma".)

Efforts to evaluate and manage increased intracranial pressure (ICP) should begin in the
emergency department. Patients with severe TBI (GCS ≤8) and clinical symptoms
suggesting possible impending herniation from elevated ICP (unilaterally or bilaterally fixed
and dilated pupil[s], decorticate or decerebrate posturing, bradycardia,
hypertension, and/or respiratory depression) should be treated urgently, with head elevation
and osmotic therapy (mannitol 1 g/kg IV) concurrently with neuroimaging and other
assessments. The evaluation and management of increased ICP are discussed in detail
below. (See 'Intracranial pressure' below.)
Patients with TBI should be transferred to a hospital with neurosurgical services as soon as
they are hemodynamically stable [7-11].

Neuroimaging — Computed tomography (CT) is the preferred imaging modality in the

acute phase of head trauma and should be performed as quickly as possible. CT scan will
detect skull fractures, intracranial hematomas, and cerebral edema (image 1A-D). Current
guidelines recommend head CT in all TBI patients with a GCS score of 14 or lower (table
1).

Follow-up CT scanning should be performed if there is any clinical deterioration. Evolution

of CT findings is common and may indicate an alternative treatment approach in a
significant number of patients [34-38]. While there is no clear indication for routine follow-up
CT scans in the absence of clinical change or changes in physiologic parameters such as
ICP, practice varies considerably in this regard [39,40]. Many centers do routinely order
follow-up imaging. Of note, parenchymal contrast extravasation, as with spontaneous
intracerebral hemorrhage (ICH), may predict a higher risk of hemorrhage progression [41].
(See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and
diagnosis", section on 'Hemorrhage enlargement'.)

SURGICAL TREATMENT — Indications for emergency surgery after severe head injury
are based upon neurologic status, usually defined by the Glasgow Coma Scale (GCS)
(table 1), and findings on head computed tomography (CT) criteria such as large hematoma
volume or thickness and evidence of mass effect including midline shift (image 1A).

Epidural hematoma — Surgical guidelines recommend evacuation of an epidural

hematoma (EDH) larger than 30 mL in volume regardless of a patient's GCS score; urgent
surgical evacuation is recommended for patients with acute EDH and coma (GCS score ≤8)
who have pupillary abnormalities (anisocoria) [42]. (See "Intracranial epidural hematoma in
adults", section on 'Management'.)

Subdural hematoma — Acute subdural hematomas (SDH) >10 mm in thickness or

associated with midline shift >5 mm on CT should be surgically evacuated, regardless of
the patient's GCS score [43]. In addition, surgery is recommended if the GCS score is ≤8 or
if the GCS score has decreased by ≥2 points from the time of injury to hospital
admission, and/or the patient presents with asymmetric or fixed and dilated
pupils, and/orintracranial pressure (ICP) measurements are consistently >20 mmHg.
(See "Subdural hematoma in adults: Prognosis and management", section on 'Acute SDH'.)

Intracerebral hemorrhage — Surgical evacuation of a traumatic intracerebral hemorrhage

(ICH) in the posterior fossa is recommended when there is evidence of significant mass
effect (distortion, dislocation, obliteration of the fourth ventricle, compression of the basal
cisterns, or obstructive hydrocephalus) [44].

For traumatic ICH involving the cerebral hemispheres, surgical indications are not as clearly
defined. Consensus surgical guidelines recommend craniotomy with evacuation if the
hemorrhage exceeds 50 cm 3 in volume, or if the GCS score is 6 to 8 in a patient with a
frontal or temporal hemorrhage greater than 20 cm 3 with midline shift of at least 5
mm and/or cisternal compression on CT scan [45].

Penetrating injury — Superficial debridement and dural closure to prevent cerebrospinal

fluid (CSF) leak is generally recommended [46]. Small entry wounds can be treated with
simple closure. Aggressive debridement and removal of deep foreign bodies such as bone
or bullet fragments have not been shown to be effective in preventing delayed infection. The
use of prophylactic broad-spectrum antibiotics (usually a cephalosporin) is routine in this
setting and is believed to have contributed to the reduced incidence of infection in this
setting [47].

Depressed skull fracture — Elevation and debridement are recommended for open skull
fractures depressed greater than the thickness of the cranium or if there is dural
penetration, significant intracranial hematoma, frontal sinus involvement, cosmetic
deformity, wound infection or contamination, or pneumocephalus [48]. (See "Skull fractures
in adults" and "Skull fractures in children: Clinical manifestations, diagnosis, and
management".)

Decompressive craniectomy — In a decompressive craniectomy, a substantial portion of

the skull is removed in order to reduce increased ICP. This can be done in combination with
an evacuation procedure or as a primary treatment for increased ICP [49]. Use of this
technique is controversial and its efficacy in TBI is uncertain [50-55]. Clinical trials are in
progress, with a pilot study in children suggesting favorable results on both ICP and clinical
outcome [56].

A randomized trial in 155 adults with severe diffuse TBI with elevated ICP refractory to other
therapies compared bifrontal decompressive craniectomy with continued standard care [57].
Surgery was associated with decreased ICP and shorter stays in the intensive care unit
(ICU), but worse outcome on the extended GCS at six months. The study has been
criticized for having a baseline imbalance in TBI severity between the treatment groups, a
relatively low threshold for elevated ICP, and a short time window for defining it to be
treatment resistant [58]. Also, the surgical procedure used in this study is not representative
of that most often performed in clinical care. Other clinical trials are in progress.
This procedure, its complications, and its efficacy in settings other than TBI are discussed in
detail separately. (See "Evaluation and management of elevated intracranial pressure in
adults", section on 'Decompressive craniectomy' and "Decompressive hemicraniectomy for
malignant middle cerebral artery territory infarction".)

INTENSIVE CARE MANAGEMENT — The principal focus of critical care management for
severe TBI is to limit secondary brain injury. In general, treatment efforts are aimed at
intracranial pressure (ICP) management and maintenance of cerebral perfusion as well as
optimizing oxygenation and blood pressure (BP) and managing temperature, glucose,
seizures, and other potential secondary brain insults.

General medical care — Maintenance of BP (systolic >90 mmHg) and oxygenation

(PaO2 >60 mmHg) remain priorities in the management of TBI patients in the intensive care
unit (ICU) [15]. These should be continuously monitored. Isotonic fluids (normal saline)
should be used to maintain euvolemia. A subgroup analysis in the large Saline versus
Albumin Fluid Evaluation (SAFE) study found that for patients with TBI, fluid resuscitation
with albumin was associated with a higher mortality as compared with normal saline (33
versus 20 percent); this risk was even more pronounced in those with severe TBI (42
versus 22 percent) [33]. Electrolyte imbalances are common in patients with TBI and should
be regularly assessed along with other laboratory parameters.

Other extracranial traumatic injuries are managed simultaneously. (See appropriate topic
reviews.)

The prevention of deep venous thrombosis (DVT) is a difficult management issue in TBI.
Patients with TBI are at increased risk of DVT, which can be reduced by the use of
mechanical thromboprophylaxis using intermittent pneumatic compression stockings
[59,60]. While DVT risk can be further reduced with antithrombotic therapy, this has to be
weighed against the potential risk of hemorrhage expansion, which is greatest in the first 24
to 48 hours [61-63]. The use and timing of antithrombotic agents in patients with TBI must
therefore be individualized according to the degree of intracranial bleeding and the
perceived risk of DVT. No randomized studies have examined the risks and benefits of
antithrombotic agents in this setting. While some observational studies suggest that
antithrombotic therapy may not be associated with the increased risk of intracranial
hemorrhage expansion [64-66], others have found a higher rate of hemorrhage progression
with the use of low molecular weight heparin [67]. One pilot study randomly assigned 62
patients with low-risk TBI to enoxaparin or placebo [68]. Subclinical, radiographic
progression of intracranial hemorrhage was nonsignificantly more common in the treated
patient group; no patient suffered a clinical progression; one patient in the placebo group
had a DVT. (See "The use of antithrombotic therapy in patients with an acute or prior
intracerebral hemorrhage", section on 'Prevention' and "Prevention of venous
thromboembolic disease in surgical patients".)

Nutritional support should not be neglected in patients with TBI. Undernutrition is associated
with higher mortality [69,70]. Patients should be fed to full caloric replacement by day 7
postinjury [71]. (See "Nutrition support in critically ill patients: An overview".)

TBI patients are at risk for other complications (eg, infection, gastrointestinal stress
ulceration), which can be reduced by appropriate interventions. Other aspects of the
general medical care of the trauma patient are discussed in detail separately.
(See "Overview of inpatient management in the adult trauma patient".)

Intracranial pressure — Elevated ICP is associated with increased mortality and worsened
outcome [72-74].

Specific measures regarding ICP management in the setting of TBI are discussed here. The
evaluation and management of elevated ICP in other settings are discussed in detail
separately. (See "Evaluation and management of elevated intracranial pressure in adults".)

Initial treatment and ICP monitoring — Several approaches are used in the intensive
care setting to prevent and treat elevated ICP. Simple techniques should be instituted as
soon as possible:

●Head of bed elevation to 30 degrees

●Optimization of venous drainage: keeping the neck in neutral position, loosening neck
braces if too tight
●Monitoring central venous pressure and avoiding excessive hypervolemia

Indications for ICP monitoring in TBI are a Glasgow Coma Scale (GCS) score ≤8 and an
abnormal computed tomography (CT) scan showing evidence of mass effect from lesions
such as hematomas, contusions, or swelling [75]. ICP monitoring in severe TBI patients with
a normal CT scan may be indicated if two of the following features are present: age >40
years, motor posturing, systolic BP <90 mmHg. A ventricular catheter connected to a strain
gauge transducer is the most accurate and cost-effective method of ICP monitoring and has
the therapeutic advantage of allowing for cerebrospinal fluid (CSF) drainage to treat rises in
ICP (figure 1) [75]. Other monitor types are discussed separately. (See "Evaluation and
management of elevated intracranial pressure in adults", section on 'Types of monitors'.)

While ICP monitoring has long been central to the management of patients with severe
head injury, the strength of this recommendation has been limited by the lack of large
randomized trials examining the effect of ICP monitoring and treatment on outcome [76-78].
One randomized study of 324 patients with severe TBI hospitalized in Bolivia or Ecuador
found no differences in outcomes among those patients assigned to a protocol for
monitoring ICP and focusing treatment on maintaining pressures at 20 mmHg or less
compared with patients assigned to a treatment protocol based on imaging and clinical
examination [79]. The results of this study suggest that further research is needed to assess
the role of ICP monitoring as well as targeted treatments of ICP in the management of
severe TBI.

Most guidelines and clinical protocols recommend that treatment for elevated ICP should be
initiated when ICP rises above 20 mmHg [80]. Ventricular drainage is generally attempted
first. CSF should be removed at a rate of approximately 1 to 2 mL/minute, for two to three
minutes at a time, with intervals of two to three minutes in between until a satisfactory ICP
has been achieved (ICP <20 mmHg) or until CSF is no longer easily obtained. Slow
removal can also be accomplished by passive gravitational drainage through the
ventriculostomy.

If ICP remains elevated, other targeted interventions include osmotic therapy,

hyperventilation, and sedation. In refractory cases, barbiturate coma, induced hypothermia,
and decompressive craniectomy may be considered [81].

Osmotic therapy — The intravascular injection of hyperosmolar agents (mannitol,

hypertonic saline) creates an osmolar gradient, drawing water across the blood-brain barrier
[82]. This leads to a decrease in interstitial volume and a decrease in ICP.

●Mannitol is the agent used most consistently to achieve ICP control in various
settings, and it has also been shown to improve cerebral blood flow (CBF) [77,83-87].
Mannitol is administered in boluses of 0.25 to 1 g/kg every four to six hours as needed.
Monitoring of serum osmolality (maintained <320 mmol/L), fluid balance, renal function,
and electrolytes is required. (See "Evaluation and management of elevated intracranial
pressure in adults", section on 'Mannitol'.)
●Hypertonic saline is being used increasingly in this setting, but with varying volumes
and tonicity (3 to 23.4 percent) and either as a bolus or continuous infusion [88,89].

Two small studies have compared mannitol and hypertonic saline in patients with TBI:

●In one study, nine patients received two treatments each of 200 mL 20
percent mannitol and 100 mL of 7.5 percent saline with 6 percent dextran-70 solution
(HSD) in a random order [90]. Median ICP reductions were greater with HSD than
mannitol infusion (13 versus 7.5 mmHg).
 ●In another study, 20 patients were randomly assigned treatment with either 20
percent mannitol or 7.5 percent hypertonic saline solution, each given as a dose of
2 mL/kg [91]. The mean number and duration of recurrent elevated ICP episodes were
higher in patients treated with mannitol than with hypertonic saline.

Clinical outcomes were not a focus of either of these studies. Further work is required to
clarify what role hypertonic saline infusion has in the management of elevated ICP [77,92].

Hyperventilation — Most patients with severe TBI are sedated and artificially ventilated
during the first several days [93]. Regarding ICP management, control of ventilation helps
prevent increases in intrathoracic pressure that may elevate central venous pressures and
impair cerebral venous drainage.

Hyperventilation can be used to reduce ICP. With hyperventilation, PaCO 2 decreases,

thereby leading to cerebral vasoconstriction, which then results in decreased cerebral blood
volume and ICP. However, hyperventilation-induced vasoconstriction may also cause
secondary ischemia and may thereby worsen outcomes [94-96]. Hyperventilation can also
increase extracellular lactate and glutamate levels that may contribute to secondary brain
injury [97]. In one randomized study, patients hyperventilated to a PaCO 2 of 25 mmHg for
five days had a worse clinical outcome than nonhyperventilated controls [98].

Based upon these competing concerns, guidelines recommend avoiding hyperventilation,

especially in the acute phase (the first 24 to 48 hours) following TBI. Mild to moderate
hyperventilation can be considered at later stages, but PaCO 2 of less than 30 mmHg should
be avoided [99]. Multimodality monitoring of cerebral oxygenation and metabolism
(see 'Advanced neuromonitoring' below) should also be used where available with
therapeutic hyperventilation to monitor its effects and prevent ischemic episodes
[95,96,100].

Sedation — Sedative medications and pharmacologic paralysis are often used in patients
with severe head injury and elevated ICP. The rationale is that appropriate sedation may
lower ICP by reducing metabolic demand. Sedation may also ameliorate ventilator
asynchrony and blunt sympathetic responses of hypertension and tachycardia. These
possible beneficial effects are counterbalanced by the potential for these drugs to cause
hypotension and cerebral vasodilation that in turn may aggravate cerebral hypoperfusion
and elevate ICP.

While there are a number of agents that can be used, we prefer to use propofol because of
its short duration of action that allows intermittent clinical neurologic assessment [101].
Anecdotally, propofol sedation can produce ICP reductions. Propofol also has putative
neuroprotective effects [102]. In one trial, propofol appeared to be associated with better
ICP control and a trend toward better outcomes compared with morphine sedation [103].
However, some reports suggest that patients with TBI are at particular risk of developing the
rare, but potentially fatal, propofol infusion syndrome (severe metabolic acidosis,
rhabdomyolysis, hyperkalemia, renal failure, and cardiovascular collapse) [104,105]. As a
result, it is suggested that when used in TBI, the infusion rate of propofol not exceed
4 mg/kg per hour and patients be monitored for electrocardiogram (ECG) changes, lactic
acidosis, and elevations in creatinine kinase and myoglobin. (See "Sedative-analgesic
medications in critically ill adults: Selection, initiation, maintenance, and withdrawal", section
on 'Available agents'.)

Barbiturate coma has been used traditionally in this setting. However, there are few clinical
data to support its use [106]:

●In a randomized trial of 73 patients with severe TBI, pentobarbital coma was
associated with more effective ICP control compared with control treatment, but not
improved 30-day mortality [107].
●Thiopental was compared with pentobarbital in a small study of 44 patients with TBI
[108]. While thiopental appeared more effective in terms of ICP control, conclusions
drawn from this study are limited by its small size and an imbalance in baseline CT
characteristics in the treatment groups [108].

In addition, high-dose barbiturates often cause hypotension necessitating treatment with

pressor agents [106,109].

Pentobarbital remains a treatment option for elevated ICP refractory to other therapies
[110]. A loading dose of 5 to 20 mg/kg is given as a bolus, followed by 1 to 4 mg/kg per
hour. Continuous electroencephalography (EEG) monitoring is used, with the pentobarbital
infusion titrated to produce a burst-suppression pattern.

Other sedative agents may also be used, although none have been well studied in patients
with severe TBI. These may include benzodiazepines or opiates
(eg, midazolam, morphine, fentanyl) individually or in combination with
barbiturates and/or neuromuscular blockade [110-112]. A systematic review of trials of
sedative agents in this setting found no convincing evidence to support the use of one agent
over another [113]. However, high bolus doses of opioids were found to cause transient
increases in ICP, which may warrant avoidance of that treatment approach. (See "Sedative-
analgesic medications in critically ill adults: Selection, initiation, maintenance, and
withdrawal".)

In the absence of clinical trial data to support the use of any specific protocol, we suggest
that the use of sedation be individualized according to specific clinical circumstances and
that the choice of agent(s) be similarly individualized, considering also the specific
institutional expertise. Monitoring of cerebral perfusion pressure (CPP) is advised
(see 'Cerebral perfusion pressure' below) to evaluate the somewhat unpredictable effects of
these agents on BP and ICP.

Cerebral perfusion pressure — Through autoregulation, the normal cerebral vasculature

maintains an adequate CBF across a wide range (50 to 150 mmHg) of mean arterial blood
pressure (MAP). Cerebral autoregulation is disrupted in approximately a third of patients
with severe TBI [114-116]. In these patients, a rise in MAP can lead to elevated ICP due to
increased cerebral blood volume and hyperemia, while drops in MAP may be associated
with hypoperfusion and ischemia. Patients with impaired cerebral autoregulation are
described as "pressure passive."

While optimization of CBF is a foundation of TBI treatment, bedside measurement of CBF is

not easily obtained. CPP, the difference between the MAP and the ICP (CPP = MAP - ICP),
is a surrogate measure. Episodes of hypotension (low MAP), raised ICP, and/or low CPP
are associated with secondary brain injury and worse clinical outcomes [21,22,117].

An early approach to induce hypertension to target CPP >70 mmHg using volume
expansion and vasopressor agents appeared to reduce mortality and morbidity [118,119].
However, subsequent studies have suggested that this strategy does not improve outcome
and rather risks severe extracerebral complications such as acute respiratory distress
syndrome [119-121]. According to guidelines published in 2007, the recommended CPP
target is 60 mmHg, avoiding levels below 50 mmHg and above 70 mmHg [122-124]. In
children these thresholds may be lower, 40 to 65 mmHg [125]. Efforts to optimize CPP
should first treat and maintain ICP at low levels when possible [126]. This may have a more
substantial effect on CBF and obviate the use of fluids and inotropic agents. Patients with
more severely impaired autoregulation in particular may be more likely to respond to efforts
to lower ICP than to hypertensive-focused CPP therapy [120].

Antiepileptic drugs — Overall, the incidence of early post-traumatic seizures (within the
first week or two) is approximately 6 to 10 percent but may be as high as 30 percent in
patients with severe TBI [127-129]. In addition, case series suggest that approximately 15 to
25 percent of patients with coma and severe head injury will have nonconvulsive seizures
identified on continuous monitoring with EEG [129,130]. However, the clinical significance of
clinically silent electrographic seizures and whether they should be treated is unclear.

The use of antiepileptic drugs (AEDs) in the acute management of TBI has been shown to
reduce the incidence of early seizures, but does not prevent the later development of
epilepsy [131,132]. Reasons to prevent early seizures include the risk of status epilepticus,
which has a high fatality rate in this setting, and the potential of convulsions to aggravate a
systemic injury [129]. In addition, recurrent seizures may increase CBF and could thereby
increase ICP. Another potential concern is that seizures place a metabolic demand on
damaged brain tissue and may aggravate secondary brain injury.

Based upon the available information, we use the following approach to seizure
management in patients with severe TBI:

●Use a seven-day course of prophylactic phenytoin or valproic acid. Levetiracetam can

be considered as an alternative.
●Do not use AED prophylaxis long term.
●Consider EEG and/or EEG monitoring in patients with coma.
●Treat both clinical and electrographic-only seizures with AEDs.

Post-traumatic seizures and epilepsy are discussed in detail separately. (See "Post-
traumatic seizures and epilepsy".)

Temperature management

Normothermia — Fever worsens outcome after stroke and probably severe head injury,
presumably by aggravating secondary brain injury [21]. Current approaches emphasize
maintaining normothermia through the use of antipyretic medications, surface-cooling
devices, or even endovascular temperature management catheters. However, this
approach has not been systematically tested with regard to clinical outcome.

Similarly, noninduced hypothermia has been associated with an increase in mortality after
TBI [133], but the efficacy of efforts to avoid this complication has not been evaluated.

Induced hypothermia — Induced or therapeutic hypothermia has been a proposed

treatment for TBI based upon its potential to reduce ICP as well as to provide
neuroprotection and prevent secondary brain injury [134]. Induced hypothermia has been
shown to be effective in improving neurologic outcome after ventricular fibrillation cardiac
arrest. (See "Hypoxic-ischem ic brain injury in adults: Evaluation and prognosis", section on
'Therapeutic (induced) hypothermia'.)

A systematic review of 22 randomized controlled trials of mild to moderate hypothermia (32

to 35ºC) following TBI noted a small but significant decrease in the risk of death (RR 0.76,
95% CI 0.60-0.97) or poor neurologic outcome (RR 0.69, 95% CI 0.55-0.86) among more
than 1300 patients treated, but noted that significant benefit was seen only in low-quality
trials [135]. Other systematic reviews and meta-analyses found similar but more borderline
benefits for death and neurologic outcome as well as an increased risk for pneumonia
[134,136-139]. Substantial variability among studies in the depth and duration of
hypothermia, as well as the rate of rewarming, limit the ability to draw conclusions from
these studies. Two subsequently published trials have also found no benefit of induced
hypothermia in specific subgroups of patients with TBI; in one, hypothermia was not
beneficial when initiated within two to five hours of TBI in a selected group of younger
patients (age 16 to 45 years) [140]. In another trial, there was no benefit for induced
hypothermia when added to other standard-of-care measures in patients with intracranial
hypertension refractory to initial treatment within 10 days of TBI [141].

Two trials of hypothermia therapy in children with TBI have shown no improvement in
neurologic or other outcomes; one showed a nonsignificant increase in mortality [142,143].
(See "Elevated intracranial pressure (ICP) in children: Management", section on
'Temperature control'.)

Given the uncertainties surrounding its appropriate use, therapeutic hypothermia treatment
should be limited to clinical trials, or to patients with elevated ICP refractory to other
therapies [135,144,145].

Glucose management — Both hyper- and hypoglycemia are associated with worsened
outcome in a variety of neurologic conditions including severe TBI [146-148]. In a
retrospective cohort study of 77 patients with severe TBI, hyperglycemia (blood glucose
≥170 mg/dL [9.4 mmol/L]) at the time of ICU admission was an independent predictor of a
poor GCS score five days later [147]. This has been presumed to be at least in part related
to aggravation of secondary brain injury. Several mechanisms for this are proposed,
including increased tissue acidosis from anaerobic metabolism, free radical generation, and
increased blood-brain barrier permeability.

Increased use of insulin infusions to maintain tight glucose control in critically ill patients has
been studied, but the optimal glucose target and best treatment regimen are uncertain. One
case series using cerebral microdialysis found that tight glycemic control was associated
with reduced cerebral glucose availability and elevated lactate/pyruvate ratio, which in turn
was associated with increased mortality [149].

At present, avoidance of both hypo- and hyperglycemia is appropriate, but further studies
are needed to clarify the optimal serum glucose target range and duration of therapy. To
avoid extremes of very high or low blood glucose levels, a broad target range of up to
140 mg/dL or possibly even 180 mg/dL may be appropriate. (See "Glycemic control and
intensive insulin therapy in critical illness".)

Hemostatic therapy — Approximately one-third of patients with severe TBI develop a

coagulopathy, which is associated with an increased risk of hemorrhage enlargement, poor
neurologic outcomes, and death [150-155]. The coagulopathy may result from existing
patient medications such as warfarin or antiplatelet agents. Acute TBI is also thought to
produce a coagulopathy through the systemic release of tissue factor and brain
phospholipids into the circulation leading to inappropriate intravascular coagulation and a
consumptive coagulopathy, but this is unproven [155-157]. Coagulation parameters should
be measured in the emergency department in all patients with severe TBI and efforts to
correct any identified coagulopathy should begin immediately.

●Patients taking warfarin may be managed with prothrombin complex concentrate

(PCC), fresh frozen plasma (FFP), and/or vitamin K as recommended for patients with
warfarin-associated intracerebral hemorrhage (ICH). (See "Reversal of anticoagulation
in warfarin-associated intracerebral hemorrhage".)
●In patients with thrombocytopenia, many centers choose to maintain a platelet
count >75,000/microL with platelet transfusions if necessary. In one cohort analysis, a
platelet count of <135,000/microL was associated with a 12.4 times higher risk of
hemorrhage expansion, while a platelet count of <95,000/microL identified patients who
were 31.5 times more likely to require neurosurgical intervention [158].
The utility of platelet transfusions in TBI patients who arrive on antiplatelet medications
is not known, although the incidence of neurologic worsening is greater in such
patients [158,159]. (See "Use of blood products in the critically ill", section on
'Platelets'.)

Recommendations for hemostatic therapy in other categories of patients with severe TBI
are limited by lack of evidence [160]. When a coagulopathy is identified, it is reasonable to
use FFP, PCC, and/or vitamin K as for warfarin reversal. A reasonable, if somewhat
arbitrary target is an international normalized ratio (INR) <1.4. A phase II dose-escalation
clinical trial of recombinant factor VIIa in TBI patients demonstrated a nonsignificant trend
towards limiting hematoma expansion but no mortality benefit, although this was not
directed exclusively at patients with TBI-related INR elevation [161]. Similarly, hemostatic
therapy has not been shown to be of overall benefit in patients with nontraumatic ICH,
including those that are warfarin associated (see "Spontaneous intracerebral hemorrhage:
Treatment and prognosis", section on 'Hemostatic therapy'). There is no evidence that
hemostatic therapy benefits noncoagulopathic patients with severe TBI [162,163].

Coagulopathy associated with trauma is discussed in detail separately. (See "Coagulopathy

associated with trauma".)

Glucocorticoids — The use of glucocorticoid therapy following head trauma was found to
be harmful rather than beneficial in a large trial of patients with moderate to severe TBI
[164]. More than 10,000 patients within eight hours of presentation were randomly assigned
to treatment with methylprednisolone or to placebo. Treated patients had increased
mortality at two weeks (21 versus 18 percent; RR 1.18) and at six-month follow-up (26
versus 22 percent; RR 1.15) [165].

Neuroprotective treatment — The use of a wide range of agents targeting various aspects
of the TBI injury cascade has been tested in clinical trials. To date, no neuroprotective
agents or strategies (including induced hypothermia) have been shown to produc e
improved outcome [50]. No benefit was found for intravenous progesterone administration
in two randomized trials in acute severe TBI [166,167]. Citicoline was not found to be
effective at improving outcomes in a randomized trial of 1213 patients with TBI [168].

Erythropoietin has been postulated to have neuroprotective effects. However, two

randomized clinical trials have not demonstrated a benefit in patients with TBI [169,170]. In
the larger study of 606 patients with TBI, neurologic outcome at six months was not
improved, while mortality was nonsignificantly lower (11 versus 16 percent) in patients who
received erythropoietin [170].

Other agents being investigated include magnesium [171], hyperbaric oxygen [172],
and cyclosporine [173], among others [174].

ADVANCED NEUROMONITORING — In order to supplement intracranial pressure (ICP)

monitoring, several technologies have been developed for the treatment of severe TBI.
These techniques allow for the measurement of cerebral physiologic and metabolic
parameters related to oxygen delivery, cerebral blood flow (CBF), and metabolism, with the
goal of improving the detection and management of secondary brain injury.

Current monitoring techniques include:

●Jugular venous oximetry: retrograde cannulation of the internal jugular vein that
allows measurement of oxygen saturation in the blood exiting the brain [175]. Normal
jugular venous oxygen saturation (SjVO 2 ) is approximately 60 percent. SjVO2 <50
percent for 10 minutes is considered an "ischemic desaturation" and is associated with
impaired cerebral perfusion pressure (CPP) and worsened outcome [176].
●Brain tissue oxygen tension (PbtO 2 ) monitoring: intraparenchym al oxygen electrode
placed in a manner similar to a fiberoptic ICP probe that measures PbtO 2 in the white
matter [177]. Normal PbtO 2 is >20 mmHg; duration and depth of PbtO 2 below 15
mmHg are associated with worsened outcome [176]. One case series used oxygen
supplementation to maintain PbtO 2 above 25 mmHg and found better outcomes
compared with historical controls [178].
●Cerebral microdialysis: intraparenchymal probe placed in a manner similar to a
PbtO2 probe that allows measurement of extracellular glucose, lactate, pyruvate,
 glutamate [179,180]. A lactate:pyruvate ratio >40 is suggestive of anaerobic
metabolism, which is believed to exacerbate secondary brain injury.
●Thermal diffusion flowmetry: intraparenchym al probe placed in a manner similar to a
PbtO2 probe that allows continuous measurement of CBF, usually in the white matter.
Correlation with CBF from neuroimaging and outcome data is very preliminary at
present.

Observational data suggest that these monitoring tools provide unique information that may
help to individualize severe head injury management for patients. Clinical trials are currently
in the planning phases for use of these multimodality advanced neuromonitoring
approaches.

PROGNOSIS — Outcome from severe head injury is dependent on a range of factors

including baseline patient characteristics, severity of TBI, and the occurrence of medical
complications and secondary brain insults. Specific negative outcome predictors that have
been identified from these factors include [16,19-21,50,73,154,181-190]:

●Glasgow Coma Scale (GCS) score at presentation (especially the GCS motor score)
(table 1)
●Full Outline of Unresponsiveness (FOUR) score (table 2)
●Presence and severity of computed tomography (CT) abnormalities (subarachnoid
hemorrhage, cisternal effacement, midline shift, leukoaraiosis)
●Pupillary function
●Age
●Associated injuries and complications
●Hypotension
●Hypoxemia
●Pyrexia
●Elevated intracranial pressure (ICP)
●Reduced cerebral perfusion pressure (CPP)
●Bleeding diathesis (low platelet count, abnormal coagulation parameters)

Other studies are evaluating the potential of biomarkers, such as the levels of S-100β
protein, neuron-specific enolase, and α-synuclein in the blood and/or cerebrospinal fluid
(CSF), to predict neurologic outcome [191-193].

While some have attempted to develop outcome prediction models to guide decisions about
withholding early treatment, the heterogeneity of severe head injury makes this difficult to
apply to clinical decision making in individual patients [182,194,195]. Thus, except in the
most extreme cases, a trial of early aggressive neurosurgical and neurocritical care
management, including surgical removal of evacuable lesions and ICP monitoring, should
be undertaken.

Cohort studies have suggested that patients with severe head injury (GCS ≤8) have
approximately a 30 percent risk of death. At least one cohort study found that survivors of
TBI continue to have a substantially increased risk of mortality for at least 13 years after
hospitalization [196].

Only approximately 25 percent of survivors of severe TBI achieve long-term functional

independence [73,181,197]. Approximately 5 to 15 percent of patients with severe TBI are
discharged from acute care in a vegetative state [181,197,198]. Only half of these patients
regain consciousness over the next year and virtually all of these patients remain severely
disabled. Outcomes are somewhat better for those in the minimally conscious state. The
persistent vegetative and minimally conscious states are described separately. The use of
prognostic indicators for these outcomes is better defined for hypoxic-ischemic brain injury
than for TBI [199]. (See "Hypoxic-ischemic brain injury in adults: Evaluation and prognosis",
section on 'Persistent vegetative state' and "Hypoxic-ischemic brain injury in adults:
Evaluation and prognosis", section on 'Minimally conscious state'.)

A randomized trial of amantadine (starting at 100 mg twice daily) in 184 patients admitted to
inpatient rehabilitation in a vegetative or minimally conscious state after severe TBI found
that amantadine treatment was associated with accelerated recovery during the four-week
active treatment phase [200]. Rates of improvement subsequently slowed after treatment
withdrawal in the amantadine group, and at week 6, disability scores in the two groups were
similar. Further study is needed to determine a benefit for amantadine on long-term
prognosis and its role in the treatment of patients with severe TBI. The mechanism of action
for amantadine's putative effect is unclear; it is speculated that antagonism of N-methyl-D-
aspartate and/or indirect agonism of dopamine may be involved.

Among patients with more moderate TBI, educational attainment is associated with an
increased odds of disability-free recovery [201].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education

materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer, more sophisticated, and more detailed.
These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Closed head injury (The Basics)")

SUMMARY AND RECOMMENDATIONS — Patients with severe traumatic brain injury

(TBI) are most optimally managed in a specialized neurotrauma center with neurosurgical
and neurocritical care support and the use of guidelines-based standardized protocols.

●Prevention of hypoxia (PaO 2 <60 mmHg) and hypotension (systolic blood pressure
[BP] <90 mmHg) are priorities in the management of patients with severe TBI
beginning with their prehospital care. (See 'Initial evaluation and treatment' above.)
●Emergency department evaluation should include frequent clinical neurologic
assessments and a computed tomography (CT) scan of the head.
When impending herniation due to elevated intracranial pressure (ICP) is suspected in
a patient with severe TBI, we recommend treatment with head of bed elevation and
intravenous mannitol pending the results of the CT and measurement of ICP (Grade
1B). (See 'Emergency department' above.)
●Surgical evacuation of epidural, subdural, and intracerebral hematomas are
performed based upon blood volume and associated mass effect, in conjunction with
the patient's neurologic status. (See 'Surgical treatment' above.)
●We recommend ventriculostomy placement with ICP monitoring in patients with
severe TBI and an abnormal CT scan showing evidence of mass effect from lesions
such as hematomas, contusions, or swelling. (See 'Intracranial pressure' above.)
●We recommend treatment of elevated ICP to target pressures below 20 mmHg
(Grade 1B). Appropriate first measures include removal of cerebrospinal fluid (CSF)
through the ventriculostomy, head of bed elevation, followed by osmotic therapy
with mannitol. (See 'Initial treatment and ICP monitoring' above and 'Osmotic
therapy' above.)
For patients with elevated ICP refractory to initial therapy, treatment options include
hyperventilation, barbiturate coma, induced hypothermia, and decompressive
craniectomy. Hyperventilation should be avoided in the first 24 to 48 hours and should
not exceed PaCO 2 <30 mmHg. (See 'Hyperventilation' above and 'Sedation' above
and 'Temperature management' above and 'Decompressive craniectomy' above.)
●We recommend using normal saline to maintain euvolemia (Grade 1B). (See 'General
medical care' above.)
●Cerebral perfusion pressure (CPP; the difference between mean arterial pressure
[MAP] and ICP) should be continuously assessed. The suggested CPP target is 60
mmHg, avoiding CPP >70 mmHg and <50 mmHg, which should be achieved by
 optimizing ICP first and then MAP (with volume expansion, pressors) second.
(See 'Cerebral perfusion pressure' above.)
●We recommend short-term (one-week) use of antiepileptic drugs
(AEDs; phenytoin, valproate) for the prevention of early seizures (Grade 1B).
(See 'Antiepileptic drugs' above and "Post-traumatic seizures and epilepsy".)
●We suggest that fever and hyperglycemia be avoided for their potential to exacerbate
secondary neurologic injury. Coagulopathy should be corrected to maintain an
international normalized ratio (INR) <1.4 and a platelet count >75,000/mm 3.
(See 'General medical care' above and 'Temperature management' above
and 'Glucose management' above and 'Hemostatic therapy' above.)
●We recommend thromboprophylaxis for the prevention of venous thromboembolism
(Grade 1A). The use and timing of antithrombotic agents is individualized based upon
an assessment of the competing risks of venous thrombosis and intracranial
hemorrhage expansion. Patients not receiving antithrombotic therapy should wear
pneumatic compression stockings. (See 'General medical care' above.)
●We recommend not using glucocorticoids for the management of patients with severe
TBI (Grade 1A). (See 'Glucocorticoids' above.)
●The use of sedative medications should be individualized. Options include
barbiturates, propofol, fentanyl, benzodiazepines, and morphine. These can be used
individually, in combination, and/or with neuromuscular blockade. BP, ICP, and CPP
should be monitored, as these are somewhat unpredictably affected by these
medications. (See 'Sedation' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge

Nicholas Phan, MD, FRCSC, FACS, who contributed to an earlier version of this topic
review.