Download Agitation After Traumatic Brain Injury

Authors:
Lisa A. Lombard, MD
Ross D. Zafonte, DO
Brain Injury
Affiliations:
From the Department of Physical
Medicine and Rehabilitation,
University of Pittsburgh, The
University of Pittsburgh Medical
Center–Institute for Rehabilitation
and Research, Pittsburgh,
Pennsylvania.
Correspondence:
All correspondence and requests for
reprints should be addressed to Ross
D. Zafonte, DO, University of
Pittsburgh, Rehabilitation, Kaufmann
Medical Building, 3471 Fifth Avenue,
Suite 201, Pittsburgh, PA 15213.
0894-9115/05/8410-0797/0
American Journal of Physical
Medicine & Rehabilitation
Copyright © 2005 by Lippincott
Williams & Wilkins
DOI: 10.1097/01.phm.0000179438.22235.08
INVITED REVIEW
Agitation After Traumatic Brain
Injury
Considerations and Treatment Options
ABSTRACT
Lombard LA, Zafonte RD: Agitation after traumatic brain injury: Considerations
and treatment options. Am J Phys Med Rehabil 2005;84:797– 812.
Posttraumatic agitation is a challenging problem for acute and rehabilitation staff,
persons with traumatic brain injury, and their families. Specific variables for
evaluation and care remain elusive. Clinical trials have not yielded a strong
foundation for evidence-based practice in this arena. This review seeks to
evaluate the present literature (with a focus on the decade 1995–2005) and
employ previous clinical experience to deliver a review of the topic. We will
discuss definitions, pathophysiology, evaluation techniques, and treatment regimens. A recommended approach to the evaluation and treatment of the person
with posttraumatic agitation will be presented. The authors hope that this review
will spur discussion and assist in facilitating clinical care paradigms and research
programs.
Key Words:
Traumatic Brain Injury, Agitation, Delirium, Behavior
O
ne of the more frustrating aspects of care of persons with traumatic brain
injury (TBI) is in the management of the agitated patient; agitated patients may
resist direct care, be disruptive on the unit, or even pose a physical risk to
themselves, family, or staff. A specific definition of agitation remains elusive;
some have described it as a variation of delirium. It may include inappropriate
vocalizing, intolerance of medical management or equipment, and directed or
diffuse aggressive behaviors. Careful consideration of environmental factors
should be given before medicating a person with agitation. When medications
are eventually pursued to modulate behavior, measurement of agitation with an
objective tool is highly recommended in determining the success of treatment.
DEFINITIONS/SCOPE
The Rancho Los Amigos scale1 describes agitation as a component of the
fourth stage of recovery; however, some patients are noted to progress from
localized responses to confusion and consciousness without any stage of aggression. Agitation does seem to correlate with lower cognitive status, as found
by Corrigan and Mysiw2 in an examination of 18 persons with TBI. Ten of the
18 patients were found to be agitated. In a study of 28 persons with brain injury
due to stroke, trauma, or anoxia in a rehabilitation facility, 39% were found to
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Agitation After Traumatic Brain Injury
797
demonstrate some aggressive behaviors within the
first week of admission. There was a significant
correlation between these behaviors and severity of
injury and disorientation to time and place.3 In a
study that used a strict definition of agitation, only
11 of 100 rehabilitation inpatients with severe TBI
were found to be agitated, and 35 were determined
to experience restlessness. In the majority of persons with agitation, the symptoms resolved within
a week.4 In contrast, a more recent study5 examined agitation in a cohort of 158 persons with TBI
in an inpatient rehabilitation setting; 50% of their
sample experienced agitation, but it typically lasted
⬍10 days. No difference was noted in agitation
with regard to sex.
Some of the variation in the reports of frequency of posttraumatic agitation may be a result
of a lack of consensus of the specific definition of
the term. A group in 1997 attempted to determine
clinicians’ definitions of agitation; a survey was
performed of members of the Brain Injury Special
Interest Group of the American Academy of Physical Medicine and Rehabilitation.6 The factors of
physical aggression, explosive anger, increased psychomotor activity, impulsivity, verbal aggression,
disorganized thinking, perceptual disturbances,
and reduced ability to maintain or appropriately
shift attention were noted by ⱖ50% of respondents
to be either “very important” or “essential” to the
definition of agitation. There was no consensus as
to whether agitation was, by its nature, limited to
the period before clearing posttraumatic amnesia
or if it could extend past that time and thus be a
chronic issue. The unification of the definition of
agitation is highly recommended; the ability to
compare or replicate studies depends on a common
language describing this condition.
We suggest that posttraumatic agitation be
defined as a state of aggression during posttraumatic amnesia. This state occurs in the absence of
other physical, medical, or psychiatric causes. It
can be manifested by intermittent or continuous
verbal or physical behaviors and can be identified
by a score of ⱖ22 on the Agitated Behavior Scale.7
Akathisia, which can be seen during recovery
from TBI, carries a more standardized definition.8
It describes a constant sense of inner restlessness,
which may or may not be manifested in motor
activity, ranging from bouncing legs and fidgeting
hands to pacing behaviors. It is not limited to brain
injury specifically; it has been reported as an extrapyramidal side effect from ingestion of neuroleptic
medications.9 As akathisia does not require the
presence of aggression, it is thus not synonymous
with agitation, although certainly could be a component of it.
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PATHOPHYSIOLOGY
Like definitions of agitation, the specific
pathophysiology of posttraumatic aggression remains poorly understood. In determining anatomic
areas associated with this behavior, three specific
subtypes of aggression have been defined: social
aggression, predatory aggression, and defensive aggression.10 In contrast with social and predatory
aggressions, which are associated with more goaldirected acts, defensive aggression is most similar
to behaviors seen in persons with TBI, in which the
response is to a perceived threat, real or otherwise.
In cats, the hypothalamus, periaquaductal gray,
and limbic structures, such as the amygdala, hippocampus, and septal area, have been associated
with this defensive rage.11 In one case report, a
14-yr-old boy with a history of aggression who had
murdered was found to have a cystic lesion lateral
to the right amygdala.12 Temporal lobe epilepsy has
been, on rare occasions, associated with interictal
aggression; a radiographic survey of persons with a
history of both temporal lobe epilepsy and aggression revealed a subgroup of patients with significant amygdala and peri-amygdala atrophy.13 The
importance of subclinical seizures in disorders of
aggression may be underappreciated.14
From a neurochemical perspective, regulation
of aggression seems to be primarily dependent on
the balance of serotonin and dopamine. Exposure
to a confrontational situation results in increased
dopamine and decreased serotonin in normal
rats.15 5HT-1b knockout mice demonstrate disinhibition and increased aggression toward other
mice.16 Apomorphine, a dopamine agonist, can induce aggression in nonaggressive mice, and administration of a D2 inhibitory agent decreases
aggressive behaviors in high-aggressive strains of
mice.17 However, we do not suggest regular use of
potent D2 inhibitors in the treatment of posttraumatic agitation, as it is fraught with the potential
to slow neural recovery (see section on antipsychotic agents below).
In humans, particularly low cerebrospinal
fluid levels of 5-hydroxyindolacetic acid, a major
metabolite of serotonin, were found in male prisoners incarcerated for impulsive, aggressive
crimes.18 Nitric oxide seems to have effects on
aggression, as well; male mice that lack the neuronal nitric oxide synthase gene have significantly
decreased serotonin turnover and clinically demonstrate greater intraspecies aggression.19
Dopamine is also implicated in akathisia,
which, as stated above, often accompanies posttraumatic agitation. Dopamine transporter gene
knockout mice (DAT⫺/⫺) demonstrate increased
extracellular dopamine and locomotion but show
no increase in aggression.20 In a positron emission
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tomographic study in humans, administration of a
potent D1 receptor antagonist resulted in transient
akathisia in both normal controls and schizophrenic patients when receptor occupancy reached
45–59%. Similar results were seen after administration of a D2 receptor antagonist.21
To our knowledge, no study has identified a
specific site or mechanism to account for posttraumatic agitation in humans; it is likely a complicated combination of structural lesions, biochemical deficits, and external factors that lead to this
condition.
MONITORING OF AGITATION
When determining a treatment plan for an
agitated patient, it is necessary to have a measurement tool to determine objectively the effectiveness of treatment. In 1989, Corrigan7 described an
instrument named the Agitated Behavior Scale.
This scale uses a rating of severity from 1 (absent)
to 4 (present to an extreme degree) on 14 different
behaviors and can be completed in 10 mins of
observation. A patient with a score of ⱖ21 is defined to be agitated (Table 1). In follow-up study,
the Agitated Behavior Scale was shown to have
good intrarater and interrater reliability when used
by research assistants and trained nursing staff in
the evaluation of persons with brain injury or dementia.22
Another measurement tool described is the
Overt Aggression Scale (OAS). It was originally
developed in 1986 and proposed to be used as an
evaluation tool for behavioral disturbance in psychiatric patients.23 The OAS focuses on recording
aggressive behavior in four domains of verbal aggression and aggression against self, objects, and
people. A variant of the OAS was designed in 1997
to be more appropriate for neurorehabilitation.24
The OAS-Modified for Neurorehabilitation (OASMNR) added three intervention categories, and included the ability to select from 18 events preceding the aggressive behavior. OAS-MNR was used to
measure the efficacy of treatment in a case series of
three persons in a neurobehavioral program.25
Unfortunately, according to a 1997 survey, less
than half the brain injury specialists use objective
measures of agitation in their practice.26 The potential benefit of quantitative assessment of agitation was highlighted in a study by Angelino et al.27
As a 16-yr-old boy emerged from a vegetative state
to consciousness, an increase in his serial Agitated
Behavior Scale scores was observed; subsequently,
a decrease was noted as his cognitive status improved. A study of 46 persons in a neurobehavioral
program whose aggression was measured with the
OAS-MNR found that those with poor language
function had more severe aggressive outbursts that
were more difficult to control.28
DIFFERENTIAL DIAGNOSIS
Before initiating environmental or pharmacologic management of agitation, it is essential to
TABLE 1 Agitated Behavior Scale
Behaviors scored as:
1. Absent: the behavior is not present
2. Present to a slight degree: the behavior is present but does not prevent the conduct of other,
contextually appropriate behavior. (The individual may redirect spontaneously, or the continuation of
the agitated behavior does not disrupt appropriate behavior).
3. Present to a moderate degree: the individual needs to be redirected from an agitated to an appropriate
behavior, but benefits from such cuing.
4. Present to an extreme degree: the individual is not able to engage in appropriate behavior due to the
interference of the agitated behavior, even when external cuing or redirection is provided.
Behaviors observed:
1. Short attention span, easy distractibility, and inability to concentrate
2. Impulsive, impatient, low tolerance for pain or frustration
3. Uncooperative, resistant to care, demanding
4. Violent and/or threatening violence toward people or property
5. Explosive and/or unpredictable anger
6. Rocking, rubbing, moaning, or other self-stimulating behavior
7. Pulling at tubes, restraints, etc.
8. Wandering from treatment areas
9. Restlessness, pacing, excessive movement
10. Repetitive behaviors, motor and/or verbal
11. Rapid, loud, or excessive talking
12. Sudden changes of mood
13. Easily initiated or excessive crying and/or laughter
14. Self-abusiveness, physical and/or verbal
Total score ranges from 14 to 56.
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799
address other causes of acute mental status
changes. Other factors may either contribute to or
be misdiagnosed as posttraumatic agitation. Infections are very common in trauma patients and may
lead to delirium. Rapid catecholamine release, as
occurs in hypoglycemic or hypoxic states, can result in aggressive behaviors. Although its exact
cause is unclear, “sundowning” may cause increased confusion in afternoons or evenings in
patients with dementia.
Drug and alcohol abuse are common co-morbidities with TBI. Acute alcohol withdrawal, hallmarked by hypertension, tachycardia, hallucinations, disorientation, and agitation, can occur as
late as 72 hrs after the last drink.29 Delirium tremens can be managed with benzodiazepines. The
timing of opioid withdrawal is dependent on the
pharmacology of the agent used. Heroin withdrawal symptoms peak at 24 – 48 hrs after last ingestion, whereas methadone withdrawal can occur
in 3 days. Restlessness, abdominal pain, yawning,
and piloerection may be seen. Although hallucinations and other mental status changes are rare,
persons experiencing these symptoms may become
agitated and violent in attempts to resume their
drug of abuse. Withdrawal from benzodiazepines
may be recognized by hypertension, tachycardia,
diaphoresis, tremors, hyperthermia, and seizures;
symptoms may begin in 2–7 days and can last as
long as 3 wks. A slow taper of a long-acting benzodiazepine can be helpful in reducing symptoms.30
Epilepsy can be a common complication after
TBI, but focal seizures may not be easily recognized; in a study by Vespa et al.,14 22% of persons
with TBI screened with electroencephalography in
the intensive care unit (ICU) setting had seizures,
and 52% of those were not apparent clinically.
Those in a postictal state may be confused and be
misdiagnosed as having intermittent agitation. As
described above, epilepsy arising from the mesial
temporal lobe may be associated with confusion or
anxiety and is typically followed by a confused
postictal period.
Endocrine dysfunction is both a common and,
likely, an underdiagnosed consequence of TBI.31
Hyperthyroidism alone may result in significant
anxiety and agitation;32,33 however, persons with
TBI are more likely to be hypothyroidal after injury.34,35 One case report describes a TBI inpatient
with persistent agitation, hyponatremia, and orthostasis. The patient was diagnosed with primary
adrenal insufficiency, and his ability to participate
in therapies improved after treatment.36 Hyponatremia has, in a few occasions, been associated with
delirium in both ICU37 and elderly hospitalized
populations.37 In persons with TBI, it seems that
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isolated hyponatremia can be seen with a decrease
in cognitive function.38
ENVIRONMENTAL CAUSES AND
TREATMENT
Acute care hospitals, especially in ICU settings,39 can be very noisy, distractible environments. Constant stimulation in the form of frequent assessment of vital signs, audible alarms,
around-the-clock medication administration, constant lighting, and ambient hallway noise can result in “ICU syndrome,” an acute confusional state
seen even in those without primary brain pathology.40 Although many of these distractions are necessary, every attempt should be made to reduce
stimulation, especially at nighttime.
In the rehabilitation setting, there is often
more flexibility in scheduling rest breaks, restoration of day and night patterns, and ensuring a quiet
night environment. Therapies and meals may be
scheduled in an isolated area. Persons with akathisia pose additional needs; many of these patients
benefit from movement and may be calmed by
being wheeled or walked around the unit. Direct
physical restraints, such as vest or wrist restraints,
and intravenous lines may create an additional
source of irritation. When possible, restraints
should be minimized, or changed to noncontact
restraints, such as netted beds to prevent falls and
one-to-one staff supervision to prevent intravenous
lines, gastrostomy tubes, and cervical collars from
being pulled. Protectors or binders should be considered when clinically feasible. Patients with restraints do need to be monitored closely by staff; a
recent recall of a particular brand of netted beds
highlights the potential dangers of equipment
when patients are left unattended.41 Maximal reduction of lines, urinary catheters, and nasogastric
tubes should be attempted as soon as possible, as
potentially hazardous consequences may result
from manipulation of lines by the patient.42 Binders and other covers for lines provide a barrier for
the patient, which may allow for reduction of restraint needs. Simple environmental alterations
may reduce unwanted behaviors; in one study, the
initiation of a staff education program regarding
agitation and the placement of patients on a scheduled toileting program resulted in fewer verbal
outbursts in a heterogeneous population in a longterm care facility.43
In addition to external factors, persons with
TBI have innately disturbed sleep cycles. In one
survey of persons admitted to inpatient rehabilitation after TBI, 50% described difficulty sleeping.44
Interestingly, they found that the more severe the
injury, the less likely the patient reported sleep
disturbance. Sleep-disordered breathing seems to
be the most common disturbance noted in acute
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TBI.45,46 Careful monitoring of sleep cycles and
quality of sleep is indicated in all persons with TBI.
Pain is a well-recognized cause of agitation in
demented elders.47,48 Persons with TBI have many
potential pain generators: musculoskeletal injuries, spasticity, heterotopic bone, and iatrogenic
causes, such as lines, tracheostomies, and gastrostomy tubes. Many associated injuries may be initially undiagnosed.49 The inability to voice pain
complaints may lead to frustration and agitation.
Regular monitoring of pain control, either by patient reports or by observation of behaviors is an
essential component of agitation management.
However, as opioids can be sedating, they should be
used judiciously in this population.
BEHAVIORAL MODIFICATION
In addition to the above environmental alterations, structured behavioral programs may also be
considered. Prigatano et al.50 provided an excellent
model from which to base a behavioral program in
the treatment of psychiatric disorders after TBI.
They introduced the “ICAR” model: information,
whereby patients or families, or both, are provided
with objective information regarding the patient’s
cognitive status; contingencies, whereby patients
may suffer ramifications from engaging in undesirable behaviors; improving self-awareness,
whereby various techniques are suggested to encourage self-monitoring of performance; relationship, whereby the psychotherapeutic relationship
is used in conjunction with cognitive rehabilitation. Although there are aspects of this model that
certainly would be of limited utility in persons with
significant cognitive or communication impairments, there are some aspects that may aide control of behaviors in persons with TBI-related agitation.
MEDICATIONS
As several studies suggest that agitation in
most cases may be time-limited to ⱕ10 days,4,5 a
convincing argument could be made to “ride the
storm” of agitation and wait for the recovery process to resolve the behavioral issues without the
potential risks of medication side effects. However,
with potential risk of injury to the patient or staff
members and the current climate of pressure to
shorten rehabilitation days, pharmacologic measures can be considered in persons with agitation
refractory to environmental or behavioral modifications (as mentioned in “ENVIRONMENTAL
CAUSES AND TREATMENT”). A summary of the
literature of the past 10 yrs (published after 1995)
of medications used for TBI-related agitation can
be found in Table 2.
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Anticonvulsants
One of the more commonly recognized anticonvulsants in the control of behavior is valproic
acid; it has long been used for the treatment of
mania in bipolar disorder.51 Although it has been
suggested by some as a treatment for dementiarelated agitation,52–54 a recent Cochrane database
review suggests that its sedative side effects outweigh any potential benefit in this population.55
Monji et al.56 reported success in the treatment of
a rapid cycling affective disorder with valproic acid
in a 16-yr-old patient with a history of TBI at 4 yrs
of age. In a study of five patients with TBI-related
aggression who failed multiple pharmacologic
treatments, valproic acid did reduce the undesirable behaviors.57 Valproic acid was shown to be
efficacious in the treatment of agitation within a
week of administration in 26 of 29 persons admitted to an inpatient brain injury rehabilitation
unit.58 Although valproic acid has been shown to
have some effects on cognition in epileptics and
normal controls,59 no significant effects on neuropsychological testing were seen in a double-blinded
study of 279 persons with TBI who were given the
medication for posttraumatic seizure prophylaxis.60 One of the benefits of valproic acid is the
potential for a rapid load (10 –20 mg/kg/day). Its
maximum dose is limited mainly by hepatotoxicity,
thrombocytopenia, and medication toxicity. One
study does suggest that persons with TBI may
demonstrate increased metabolism of valproic acid,
and thus this population may require higher doses.61
Another anticonvulsant used in the TBI population is carbamazepine, which although may
cause some motor slowing, has effects of questionable clinical significance on cognitive tasks in one
study.62 Chatham-Showalter63 described the successful use of carbamazepine in a series of seven
acute inpatients with combativeness after TBI refractory to other medications. In another study,
carbamazepine was found to significantly improve
Agitated Behavior Scale scores without alteration
of Mini-Mental Status Examination scores in eight
of ten patients treated; particular areas of improvement cited were in irritability and disinhibition.64
Its major side effects include hyponatremia, renal
failure, and in rare cases, aplastic anemia. Although dosing level is to therapeutic effect, serum
levels should be monitored to avoid toxicity. Gabapentin has been reported to be helpful in modulating agitation related to dementia.65,66 However, a
case series reported paradoxical effects in two persons with TBI treated with gabapentin for neuropathic pain.67 Other similar membrane-stabilizing
agents, such as lamotrigine,68 may be of use in
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Antidepressants
Anticonvulsants
Medication Class
Paroxetine and
citalopram
Sertraline
Lamotrigine
Carbamazepine
Valproic Acid
Agent
Case report
Prospective
open-label
trial
Single-blind
placebo
controlled
Randomized
placebo
controlled
Prospective
controlled
trial
Pachet et al., 200368
Kant et al., 199881
Fann et al., 200077
Muller et al., 199978
Meythaler et al.,
200179
Prospective,
open label
Randomized,
case control
Dikmen et al., 200060
Azouvi et al., 199964
Retrospective
Chatham-Showalter
et al., 200058
Case series
Case report
Monji et al., 199956
Chatham-Showalter,
199663
Case series
Design
Wroblewski et al.,
199757
Study
7 patients with TBI
and agitation in
acute care
10 patients with TBI
and significant
anger outbursts
A 40 yr old with
severe TBI and
aggression
13 persons with TBI
and posttraumatic
aggression and
irritability
15 outpatients after
TBI with severe
depression
11 patients with DAI
in acute inpatient
rehabilitation
26 persons with TBI
and pathological
crying
29 persons with
posttraumatic
agitation in acute
rehabilitation
279 persons with TBI
5 patients with TBIassociated
aggression
16 yr old with history
of TBI at 4 yrs old
Sample
Treatment with
sertraline, amnesia and
agitation scores
Treatment with either
paroxetine (n ⫽ 13) or
citalopram (n ⫽ 13)
Treatment with sertraline
8-wk trial of sertraline
Treatment with
carbamazepine,
behavior testing
Treatment with
lamotrigine
Seizure prophylaxis with
valproic acid in half,
neuropsychological
testing
Treatment with
carbamazepine
Valproic acid given for
rapid-cycling affective
disorder
Treatment with valproic
acid
Treatment with valproic
acid
Intervention
Outcome
(Table continues)
Both groups experienced
improvements in symptoms
No difference noted in cognition,
alertness or agitation
Decreased depression and aggression
Decrease in aggressive behaviors,
improved neurobehavioral
functioning
Reduced aggression and irritability, no
effect on depression
Good improvement seen in 5 cases,
modest in 3, no response seen in 2
Reduced combativeness within 4 days
of administration
No significant differences in
performance in neuropsychological
tests
90% of sample responded with
decreased agitation within 7 days
Improved behavioral control
Decreased aggression 1–2 days after
initiation of the medication
TABLE 2 Recent literature (after 1995) on the pharmacologic management of agitation in persons with traumatic brain injury (TBI)
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Perino et al., 200176
NA, not applicable.
Multiple
Database
review
Prospective
Bellus et al., 1996125
Fleminger et al.,
2003121
Case series
Stanislav, 199795
Various
Citalopram and
carbamazepine
Prospective
Silver et al., 2003102
Risperidone
Multiple
medications
Case report
Maryniak et al.,
200192
Methotrimeprazine
NA
Prospective
intervention
with
retrospective
comparison
Case series
Design
Stanislav and Childs,
200091
Study
Droperidol
Agent
Lithium
Antipsychotics
Medication Class
TABLE 2 Continued
56 TBI inpatients with
agitation in
comparison with 64
TBI patients without
agitation
Adolescent patient with
anoxic brain injury
and significant motor
restlessness
Persons with TBI
chronically on
antipsychotic
medications
2 persons with chronic
aggressive behaviors
in a state psychiatric
facility
20 persons with TBI
referred for treatment
of depression and
behavioral disturbance
Evaluation of
randomized,
controlled trials
performed 1980–2002
27 persons with TBI and
significant agitation
Sample
NA
Treatment with both
agents, follow-up at 12
wks
Treatment with lithium
Administration of
risperidone in addition
to amantadine and
methylphenidate
Neuropsychological
testing before and after
taper off medications
Treatment of agitation
with
methotrimeprazine
Episodic agitation treated
with intramuscular
droperidol
Intervention
Beta-blockers have the best evidence for
efficacy in the treatment of agitation
in TBI patients
Reduction in depression and behavioral
disturbance
Decreased aggression and need for
behavioral control techniques
Improvement in performance after
discontinuation of antipsychotics
Reduced restlessness, allowing for
wound healing
2 cases of extrapyramidal symptoms,
longer lengths of stay with treated
group
Time to calming shorter with
droperidol in comparison with other
medications
Outcome
TBI-related agitation; however, no studies beyond
case reports have been reported.
Antidepressant Agents
Before the advent of selective-serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants
were the most commonly used medication in the
pharmacological treatment of both idiopathic depression and mood disorders related to organic
brain disease.69,70 In TBI, specifically, tricyclic antidepressants with predominantly noradrenergic
action (e.g., protriptyline and desipramine) have
shown some efficacy in the treatment of hypoarousal.71,72 Other tricyclic antidepressants that
demonstrate greater affinity for serotonergic receptors (e.g., amitriptyline and imipramine) have a
significant sedative side effect profile and thus have
some potential to reduce aggression. An early case
report described the successful treatment of a patient with frontal lobe damage and aggression with
amitriptyline.73 It seems that the cause of the agitation may determine success with this medication; in a study by Mysiw et al.,74 12 out of 17
agitated persons with TBI in posttraumatic amnesia responded well to amitriptyline, whereas two of
three patients out of posttraumatic amnesia failed
to respond. Despite these successes, due to its
sedative and cardiac effects and potential reduction
of seizure threshold,75 its utility is limited in the
TBI population.
SSRIs offer the appeal of a more benign sideeffect profile than with tricyclic antidepressants.
They have been shown to be efficacious in the
treatment of depression in persons with TBI.76,77
An additional use for this class is in the treatment
of emotional lability.78 Equivocal results were obtained in a small study of sertraline for hypoarousal
in TBI patients.79 A case series of two patients with
agitation associated with Huntington’s disease
showed that sertraline was helpful in reducing irritability and aggressive behaviors.80 In 13 outpatients with TBI, treatment with sertraline for 8 wks
reduced irritability and aggression, but it had no
effect on depressive symptoms.81 One major drawback of this class is that, at least for its antidepressant effects, ⱖ2 wks is needed for effectiveness; this
would be an unacceptable amount of time to wait
for the control of severe agitation. Unlike the tricyclic agents, it seems that SSRIs may not have as
significant of an effect on seizure frequency; in a
study of 100 persons with epilepsy, five developed
increased seizure frequency, but all returned to
baseline with adjustments in seizure medications.82
A newer phenylpiperazine serotonergic agent
commonly used for sleep-cycle regulation in TBI is
trazodone. It has been shown in some studies to
decrease agitation and aggressive behaviors in both
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Lombard and Zafonte
persons with dementia83,84 and progressive supranuclear palsy.85 However, a recent Cochrane
Database Study questions its efficacy in elderly
demented patients.86 Starting dose can be 50 –100
mg, with results of increased sleep usually seen by
150 mg. Care must be given when using this medication in those who are also taking SSRIs to avoid
potential serotonin syndrome. Other side effects
attributed to this medication include anticholinergic symptoms and priapism.87
Buspirone, as a serotonergic and weak dopaminergic agent, is known to have significant anxiolytic properties without sedation. Levine88 initially reported incidental findings of improvement
in agitation in three persons with TBI who were
given this medication; this has been supported in
later studies.89,90 As buspirone may induce seizures, care should be taken in its use with persons
with TBI.
Antipsychotic Agents
Typical antipsychotic agents have often been
used for the immediate control of aggression or
agitation in TBI patients; in the case of haloperidol,
it can be given intravenously, intramuscularly, or
orally, and it has a rapid onset of action. Intramuscular administration of droperidol, another member of the butyrophenone class, was found to be
faster and superior in controlling acute episodes of
agitation when compared with haloperidol, diphenhydramine, or lorazepam.91 Maryniak et al.92 describe their successful use of scheduled oral
methotrimeprazine, from the older phenothiazine
class of antipsychotics, in persons with TBI admitted to their inpatient rehabilitation unit; it had
been used in almost half of their agitated inpatients
(n ⫽ 56), with only two persons experiencing side
effects of extrapyramidal symptoms and paradoxical akathisia. Although those treated with methotrimeprazine had longer periods of posttraumatic
amnesia and lengths of stay, the authors assert that
the patients with agitation as a group are typically
more seriously injured than those without behavioral issues.
There is, however, some concern with the use
of typical antipsychotic agents in persons with TBI.
Research by Feeney et al.93 showed that haloperidol
slowed motor recovery in an animal model of TBI.
In a study of humans, although haloperidol did not
change eventual rehabilitation outcome, its use
was associated with a longer period of time in
posttraumatic amnesia.94 Improvements in neuropsychological test results were seen in a population
of adults with TBI after a taper off chronic typical
antipsychotic agents.95 As with any patient group,
neuroleptic malignant syndrome has been reported
in the administration of antipsychotic agents to
persons with TBI;96 –98 presenting symptoms can
Am. J. Phys. Med. Rehabil.
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include significant fever, leukocytosis, and muscle
stiffness and can carry a mortality rate of ⬎10%.99
Treatment is with dantrolene and beta-blockers.
Persons receiving these medications are also subject to extrapyramidal side effects of tardive dyskinesia and Parkinsonism, which could form lifelong
sources of disability.
The source of these adverse effects seems to be
the typical antipsychotics’ particular affinity for
blocking the D2 dopamine receptor; a newer generation of neuroleptics, termed atypical antipsychotics, has less D2 receptor activity and more
5HT-2a activity, theoretically reducing some of the
undesirable effects and alpha adrenergic blockade.
In an animal study evaluating the effects of antipsychotic agents on cognitive function after TBI,
haloperidol was shown to increase Morris water
maze time, whereas olanzapine did not.100 In an
early study of the oldest atypical antipsychotic,
clozapine, nine persons with TBI demonstrating
rage and aggression were given this medication;
three responded favorably and three had mild improvements in behavior, but two patients developed seizures.101 Frequent blood draws for evaluation of agranulocytosis are required for patients on
clozapine. Risperidone, in combination with methylphenidate and amantadine, was shown to decrease restlessness in a 15-yr-old patient with anoxic brain injury.102 However, the powerful
adrenergic and D2 blockade of this agent may raise
concerns. In addition, a recent study in an animal
model of TBI has suggested that at high doses,
risperidone has a cognitive effect similar to haloperidol (A. Kline, personal communication, unpublished data, 2005).
Benzodiazepines
Benzodiazepines remain a core medication for
sedation in the ICU and for surgical procedures.
Short-acting agents (e.g., midazolam, lorazepam)
and long-acting agents (e.g., diazepam, clonazepam) exist in both enteral and parenteral forms,
allowing for a range of administrations. Shortacting benzodiazepines are commonly used in the
treatment of acute mania and other psychiatric
emergencies and, in one study, have been shown to
be superior to haloperidol in the treatment of motor agitation in this population.103 Their utility in
the treatment of acute alcohol withdrawal has been
discussed earlier. In addition, benzodiazepines
have been shown to be efficacious in the treatment
of neuroleptic-induced akathisia.104,105
In brain injury, the effects of benzodiazepines
are more complex. Early and daily administration
of diazepam significantly impaired motor recovery
in rats with cortical lesions; later administration in
diazepam-naı̈ve injured rats produced a transient
October 2005
reoccurrence of hemiparesis.106 In eight persons
with a distant history of stroke, light sedation with
midazolam resulted in reemergence of stroke
symptoms.107 Benzodiazepines are thus considered
by some to be in the group of potentially detrimental medications in persons with stroke108 and brain
injury.109,110 Benzodiazepine administration may
result in paradoxical agitation in a small subpopulation of patients, particularly in the elderly; it can
be successfully treated with flumazneil.111,112 Elderly patients who take benzodiazepines regularly
have lower functional status than those who do
not.113 By its nature, this class of medications
causes an amnestic effect and may increase confusion in those emerging from posttraumatic amnesia. It is not without any utility in this population;
as an agent that potentiates the GABAA receptor, it
also can be used as a treatment for spasticity. In
addition, a case report by Caradoc-Davies114 suggested it has potential use in the treatment of
mutism in persons with TBI. It is the authors’
opinion that, outside of their utility in the treatment of alcohol withdrawal, benzodiazepines
should be used in emergency situations only and
not be utilized in frequent dosing for the treatment
of agitation.
Beta-Blockers
As a frequently used medication for the treatment of hyperadrenergic states after TBI, betablockers may also help in the reduction of agitation. Early studies suggest that atenolol can be
helpful in the treatment of alcohol withdrawal,
with reduction of agitation and anxiety and in more
rapid normalization of vital signs.115 Beta-blockade
has also been shown to be efficacious in managing
akathisia due to either neuroleptic agents116 –118 or
to Parkinson’s disease;116 lipophilic beta-blockers,
such as propranolol and metoprolol, were particularly effective, suggesting a central mode of action.116,118 In persons with dementia, low-dose propranolol monotherapy was shown to decrease
agitation, aggression, and wandering behaviors.119
Pindolol was reported to reduce violent behaviors
in 8 of 13 inpatients with TBI in a double-blind,
placebo-controlled trial, and in some, it reduced
care needs due to improved behavioral management.120 A Cochrane database review of studies
examining medications in the treatment of posttraumatic agitation found that beta-blockers had
the best evidence for efficacy.121 The major limiting factor in the administration of beta-blockers is
hypotension and bradycardia, but as many patients
may present with aspects of hyperadrenergia, these
medications may serve to treat two clinical problems at once.
Agitation After Traumatic Brain Injury
805
Lithium
Lithium carbonate has long been a mainstay
treatment of mania and bipolar disease.122 Although specific details of its method of action are
unknown, it is recognized to primarily alter sodium transport and increase intracellular metabolism of catecholamines. However lithium does
seem to have some dopamine blocking effects, as it
seems to inhibit the response to apomorphine in an
animal model.123 Cohn et al.124 published one of
the earliest reports of its use in persons with brain
injury; they successfully treated a 12-yr-old boy
who exhibited agitated and hypomanic behaviors
with a 6-mo course of lithium. Two adults with
brain injury–related aggression so severe they were
admitted to a state psychiatric facility displayed
reductions in frequency of outbursts and in other
medication needs when placed on lithium.125 In
the rehabilitation setting, a group of ten TBI patients with severe aggression were administered
lithium; although five of these persons had significant improvement measured by improved participation in rehabilitation, three had significant side
effects that required discontinuation.126 Silver et
al.127 have suggested that lithium use in TBI be
reserved for those whose aggression is related to
manic effects and for those whose recurrent irritability is related to cyclic mood disorders.
Lithium should be started at 300 mg twice a
day and titrated by serum levels and side effects. Its
toxicity level (⬎1.4 mEq/liter) is very close to its
therapeutic range (0.6 –1.2 mEq/liter), and thus,
levels should be closely monitored. Significant adverse reactions to lithium are often related to high
serum levels and may include movement disorders,
ranging from tremor to dystonia, seizures, hypothyroidism, bradycardia, and vomiting. Those with
central nervous system dysfunction may be
uniquely sensitive to lithium’s side effects;128 thus,
the difficulties in managing this medication often
detract from its potential utility in the treatment of
agitated TBI patients.
Neurostimulants
Although it would seem that the administration of neurostimulant medications might be
counterproductive in the management of agitated
TBI patients, it seems that they do have a role. In
humans, dopaminergic agents, such as amantadine
and bromocriptine, have been shown to be efficacious in the treatment of low-level states129,130 and
in increasing the rate of both motoric and cognitive recovery.131,132 Bromocriptine has been suggested as a treatment of TBI-induced akathisia in
two case reports;133,134 however, it may cause
movement disorders as a side effect. In an early
study, amantadine was shown to reduce agitation
in 7 of 19 persons with dementia. However, adverse
806
Lombard and Zafonte
effects of overactivity, anxiety, and visual hallucinations were seen in eight of the test subjects.135
Studies performed on the brain injury population
have demonstrated its utility in the treatment of
severe impairments of consciousness129,136,137 and
in the enhancement of higher-level cognitive function.131,138,139 Amantadine’s utility as a mood-stabilizing agent was shown in several small case
series in persons with agitation due to
TBI.137,140,141 Because of this potential to both enhance recovery and control undesirable behaviors,
it has been identified by experts in brain injury
rehabilitation as a preferred agent for the treatment of agitation.26 Methylphenidate has been
shown to help with concentration and processing
deficits after TBI.142,143 In one randomized, placebo-controlled study of 38 persons with chronic
TBI-related anger, 30 mg daily of methylphenidate
significantly reduced these behaviors.144
Other Agents and Modalities
There are a number of promising treatment
avenues that merit further study. As stated above,
there is a paucity of literature examining the potential benefits of newer anticonvulsant agents,
such as lamotrigine and levetiracetam. As a combination SSRI and norepinephrine reuptake inhibitor, duloxetine may also have benefits as both a
neurostimulant and a mood-stabilizing agent.
A 1995 case report described the successful
treatment of severe agitation unresponsive to pharmacologic measures with electroconvulsive therapy. A course of six brief-pulse treatments resulted
in improved participation in self-care skills and
response to medication.145 Although this treatment certainly should not be first-line management, further studies to investigate its potential
use in intractable posttraumatic agitation are in
order.
An additional treatment that has demonstrated
promise in other arenas is magnesium. It has been
shown as an effective treatment for mania in persons with bipolar disorder.146 –148 It may have benefits beyond behavioral management; magnesium
has been shown to have neuroprotective properties
in acute TBI. Three studies in rats showed improved behavioral149 and motoric150,151 recovery
when magnesium was administered acutely after
injury. A potential mechanism was suggested by
Ustun et al.;152 magnesium reduced the typical
decline of the antioxidants superoxide dismutase
and glutathione peroxidase in a model of brain
injury in rabbits.
Alternative medications also remain under-examined treatments in persons with TBI. Lavender
oil as aromatherapy has been suggested as an agent
to reduce anxiety and agitation. In one study of
normal subjects in a randomized, controlled deAm. J. Phys. Med. Rehabil.
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Vol. 84, No. 10
sign, lavender oil added to bath water reduced
anger and frustration levels.153 In persons with
agitation related to dementia, the literature examining lavender has been equivocal; although one
study found modestly positive results,154 two others found no improvement in behavior.155,156
APPROACH TO AGITATION
ICU
As we have now introduced the substantial
array of medications investigated in the treatment
of agitation in persons with TBI, we suggest a
systematic approach to the problem. The patient’s
general treatment goals and location often dictate
initial management. With a person in the ICU setting who may have unstable fractures, endotracheal intubation, and increased intracranial pressure, use of significantly sedating medications such
as the lipid-soluble agent propofol are indicated
(Fig. 1). Agents that address the person’s pain are
also of importance during this time frame. Shortacting benzodiazepines may be needed to accomplish required testing once more generally sedating
agents have been weaned. As the patient becomes
more stable, and the treatment goals move toward
increased mobility and participation in therapies,
behavioral management is necessary. We advocate
for an early approach to the patient who may need
longer-term therapy for his or her agitation, thus
beginning potential evaluations and treatment regimens as previously described.
Systematic Evaluation in the Post-ICU
and Rehabilitation Setting
The assessment of an agitated patient starts
with an evaluation of the safety of the patient and
staff members. Those persons who pose a significant and immediate risk of harm to themselves or
FIGURE 1 Agitation management flow sheet. ABS, Agitated Behavior Scale; SSRI, selective-serotonin reuptake
inhibitor.
October 2005
Agitation After Traumatic Brain Injury
807
others and who cannot be redirected will need to be
managed with rapidly acting pharmacologic
agents, such as lorazepam. If there is no urgent
safety issue, some consideration can be given to the
possible differential diagnosis of the behavioral disturbance. A detailed patient history should be performed, with special attention to drug and alcohol
use and psychiatric conditions. Vital signs, laboratory values, electroencephalograms, and radiologic
evaluation should be performed as appropriate. The
importance of reducing sensory stimulation in an
acutely agitated patient cannot be overemphasized;
excess staff members should be excused from the
nearby area, television sets should be turned off,
and lighting should be dimmed as possible. Evaluation of sleep-cycle regulation should be given
careful consideration; in our acute inpatient TBI
unit, the nursing staff records the number of hours
slept for all patients. If the sleep cycle is disrupted,
and environmental interventions (such as reducing
caffeine intake and minimizing naps during the
day) are ineffective, trazodone should be considered. Adequate pain medication should be given as
appropriate.
Treatment in the Post-ICU and
Rehabilitation Setting
In the absence of response to behavioral and
environmental modification, pharmacology for the
management of agitation may be considered. The
class of medication initially selected partially depends on potential secondary benefits. If the patient is also experiencing hyperadrenergia, betablockers are likely to be a good choice. Persons
with deficits in attention and concentration may
benefit from amantadine. Anticonvulsants, particularly carbamazepine and valproic acid, are effective for severe agitation. Other agents, such as
atypical antipsychotics and SSRIs also may be considered, particularly if the patient has additional
psychiatric co-morbidities. Frequent use of “emergency” medications is an indication of poor general
control of agitation. Lastly, it is important to use
objective measures, such as the Agitated Behavior
Scale, to monitor success of treatment.
CONCLUSIONS
This review represents the thoughts of the
authors based on their experiences and review of
the literature. Additional research is certainly
needed to elucidate many aspects of agitation after
TBI. The pathophysiology of agitation in both an
anatomic and a neurochemical basis remains
largely a mystery. Likewise, more investigation
into the safety of atypical antipsychotic agents
needs to be pursued, starting with further animal
studies. As mentioned above, several other medications, such as newer antiepileptics and antidepres-
808
Lombard and Zafonte
sant therapies, show some initial promise for the
treatment of agitation. There is a general paucity of
randomized, controlled clinical trials even for the
most commonly used medications. Finally, the validity and applicability of human studies depend on
a common language describing agitation and common objective measurement tools. The importance
of effective management of persons with agitation
after TBI has the potential to reduce morbidity and
staffing needs and to improve safety, participation
in rehabilitation, and overall function.
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