Traumatic brain injury (TBI) can be a devastating life-long condition that may significantly reduce quality of life and is associated with significant morbidity and mortality.1-3 Traumatic brain injury is defined as an alteration in brain function or other evidence of brain pathology caused by an external force.4 The majority of injuries are classified as mild (80%), with moderate and severe injuries each accounting for approximately 10% of head injuries.5,6 It is estimated that 10 million people worldwide are affected annualy by TBI,3 with incidence rates of 790 in 100,000 in New Zealand,7 558 in 100,000 in the USA,8 and 262 per 100,000 in Europe.9 Groups at risk for TBI include males, individuals living in regions characterized by socioeconomic deprivation, the very young, adolescents, young adults, and the elderly.5-11 Traumatic brain injury is associated with significant and ongoing cognitive difficulties,12,13 functional disability,13 neurological symptoms,13 and neurobehavioral symptoms (NBS).14,15 Neurobehavioral symptoms are particularly prominent in the early stage of recovery after TBI, during the period termed “post traumatic amnesia” (PTA).16-18 There is no universally accepted definition of PTA,18,19 however, most focus on disorientation in time, place and person, and the inability to remember new experiences.20 Post traumatic amnesia duration is measured from the time of injury to the return of continuous memory for ongoing events, and is generally taken to include the full period of coma.21,22 Although it is brief in the majority of cases, lasting 1 to 14 days, it can extend to weeks or months.21,23 A number of standardized scales have been developed for measuring PTA, including the Galveston Orientation and Amnesia Test (GOAT24), the Westmead PTA Scale (WPTAS25), and the Orientation Log (O-Log26). The duration of PTA is recognized as both an indicator of injury severity and a reliable predictor of long term outcomes.21,27,28
Many individuals in PTA experience significant and varied NBS,16-18 including akathisia (i.e. motor restlessness), impulsiveness, disinhibition, low frustration tolerance, emotional lability, agitation, physical and verbal aggression, confusion, disorientation, motor and verbal perseveration, wandering, delusions and hallucinations.17,21,22,29 Agitation has received the most empirical study, and is estimated to occur in approximately 50% of patients with severe TBI.30 Many factors may contribute to NBS during PTA including premorbid conditions, pain, medical comorbidities, seizure activity, altered sensory input, alcohol or drug withdrawal, anxiety, problems with arousal and attention, poor memory, poor impulse control and impaired judgment.16,17,29,31-33 Neurobehavioral symptoms during PTA may be of significant concern, given their association with increased length of stay in rehabilitation, low engagement with rehabilitation, delayed progress towards functional goals, falls, self-inflicted harm, destruction of hospital equipment, risks of physical violence towards healthcare professionals and loved ones, physical and mental burn out in family members, and increased burden on health care providers.29,30,34-36
Management of NBS in PTA includes both pharmacological and non-pharmacological interventions, however, evidence in support of specific management strategies is weak.22 Environmental modifications are often considered a crucial first step in managing individuals in PTA,17,21,29,31-33 and include reducing noise and over stimulation, and providing orientation cues.17,21,29 Research suggests that the most common drugs prescribed for TBI survivors with NBS in PTA are carbamazepine, tricyclic antidepressants, trazodone, amantadine, beta-blockers,37 narcotics, benzodiazepines and neuroleptics.17,38 Because of the lack of good quality evidence regarding pharmacological management of NBS in PTA,23,29,33,39-42 management is often based on empirical assumptions of how similar or related conditions, as primary disorders, are managed pharmacologically.29,43,44 However, both TBI and PTA affect how medications are tolerated,45 with evidence demonstrating the need for extremely large or conversely small doses, long periods for titration and discontinuation,29,44 and paradoxical exacerbation of the behavior that is targeted.31 Certain agents may also introduce adverse effects contrary to recovery. For instance, evidence from human and animal studies suggests that use of neuroleptics is associated with impairments in both cognitive and motor functioning,38,46-48 as well as sedation.31 Use of pharmacological agents must be continually re-assessed as NBS in PTA are often transient,32 and it is recommended that clinicians start with low doses and progress slowly.22,29,45,49
There are a number of guidelines that include recommendations for management of NBS in the acute period post TBI.22,49,50 Of those making specific reference to the PTA period, both made only one recommendation, namely, to minimize benzodiazepines and neuroleptic medications.22,49 Previous reviews of the pharmacological management of NBS post TBI have consistently concluded that there is limited quality evidence to accurately guide clinicians,23,29,33,39-42 and most did not include PTA in their scope.39,43-45 A small number of reviews have examined pharmacotherapy for NBS early post injury.23,29,33,41,51 However, many of the studies included in the reviews did not specify if patients were in PTA, or indeed report the time post injury. As such, reviews could only draw conclusions about the “acute” phase post injury and no direct conclusions about NBS in PTA could be drawn.23,29,33,41,51 Further, many are now over a decade old,23,33,41 did not include a formal systematic synthesis of the literature,33,50 and an analysis of methodological quality,39,41 or failed to grade the quality of evidence.41,51
Only one review has included a specific focus on the PTA period.40 A Cochrane review of randomized controlled trials up to 2006 examined pharmacological management of agitation and aggression during the PTA period.40 However, no reviewed studies fulfilled the criteria used to classify PTA; patients were to be described as being in a confused state, Rancho Los Amigos Scale level IV (confused-agitated response) or in PTA.40 As such, no conclusions could be drawn regarding management of agitation and aggression during the PTA period.
There is a need for an updated systematic review of the literature that critically includes only those studies in which all, or the majority of participants, were in PTA. Further, such a review should include a comprehensive search of the literature, an evaluation of methodological quality, and clinical grading of the literature where possible. The primary outcomes for this review will be the efficacy and harms of pharmacological therapies, as compared to all types of comparators, for NBS in PTA. This review will also examine, as secondary outcomes, associated symptoms in PTA, length of stay, duration of PTA, functional outcomes and cognition.
A preliminary search (performed in February 2017) of PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), JBI Database of Systematic Reviews and Implementation Reports, PROSPERO and Epistemonikos found that there were no recent systematic reviews or systematic review protocols exploring the precise review objective and questions, with the inclusion criteria of interest for this review.
This review will be conducted in accordance with the Joanna Briggs Institute guidance for systematic review protocols and reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines.52
Types of participants
This review will consider studies of any sample size that include participants who have sustained a TBI, are currently in PTA, and are exhibiting NBS. Participants must be adults, of either gender, aged 16 years and over. Studies where greater than 80% of the sample is within this age range will be included.
Studies will be included regardless of TBI severity or mechanism, with both penetrating and non-penetrating injuries accepted. There will be no restrictions regarding age at injury or time since injury. Participants must have definite medical evidence of TBI, such as findings from brain imaging (e.g. CT scan, MRI), loss of consciousness, PTA, Glasgow Coma Scale (GCS) score, as documented in medical/health records and sighted by the research team associated with the published article. Self-report of TBI from either the individual or an informant, in the absence of other medical evidence regarding the head injury, will be excluded. Studies of acquired brain injury populations will only be included if data for the TBI group are reported separately.
Participants must be deemed as being in PTA at study entry/baseline. To determine whether patients were in PTA we will consider use of terms such as post traumatic amnesia, delirium, or post confusional state; descriptions of patients using terms such as confusion, disorientation, agitation, or amnestic; use of Rancho Los Amigos Scales or a PTA monitoring scale including the GOAT, WPTAS, or O-Log; time post injury (particularly where this is noted to be close to emergence from coma); setting (ICU, rehabilitation ward). Where PTA has been formally assessed, both retrospective and prospective measurement tools will be accepted. If the sample appears to contain both participants in PTA and out of PTA at baseline, studies will be included if the participants in PTA constitute >50% of the sample or if the data can be disaggregated.
Neurobehavioral symptoms in PTA will include agitation, psychotic symptoms such as hallucinations and delusions, akathisia (i.e. motor restlessness), low frustration tolerance, emotional lability, physical and verbal aggression, impulsivity, disinhibition, motor and verbal perseveration, wandering, confusion and disorientation. There will be no exclusion of participants based on the diagnostic and/or assessment criteria used for NBS. We will include studies where the NBS during PTA were not the presenting symptom but were measured as an outcome variable (e.g. in studies examining alertness, arousal, sleep wake cycles, pain), however, these will be analysed separately. We will exclude studies that report on clusters of individuals rather than individuals themselves (e.g., inpatients in a specific hospital in a multi-site trial).
Types of Interventions
This review will consider all studies that have evaluated the use of pharmacotherapy interventions, with no limitation as to the pharmacotherapeutic agent. Pharmacotherapy must be prescribed by a health provider and the names of the drugs must be specified. There will be no restriction on dose, duration, frequency, timing of delivery or combination of drugs.
Pharmacological interventions will include beta blockers (propranolol); typical and atypical antipsychotics (clozapine); neuroleptics (haloperidol); cholinergic agents (donezepil); anticonvulsants (valproic acid, carbamazepine, oxcarbazepine, levetiracetam, gabapentin, divalproex sodium, lamotrigine); anxiolytics (busiprone, benzodiazepine); dopaminergic agents (amantadine); psychostimulants (methylphenidate); antidepressants (selective serotonin reuptake inhibitors [SSRI], serotonin and norepinephrine reuptake inhibitors [SNRI], norepinephrine and dopamine reuptake inhibitors [NDRI], tricyclic antidepressants [TCA]); alpha-2-adrenergic agonists (clonidine, dexmedetomidine); alkylphenols (propofol); and lithium.
Studies reporting mixed interventions (e.g. pharmacotherapy and psychological therapy) will be included if the data for the pharmacotherapeutic intervention are reported separately. This review will exclude studies of complementary medicines and over the counter medicine unless these were a co-intervention to the pharmacotherapy.
This review will include studies that compare the intervention with all types of comparators including placebo (dummy or active), supportive or standard care, other non-pharmacological therapeutic intervention, and comparison of drugs within the same pharmacological class.
For both primary and secondary outcomes, this review will preferentially report on validated measurement tools, however, where these are not available, information on outcomes will be reported as presented in the included study.
The primary outcomes of interest for the review are:
- Reduction in the severity of NBS in PTA (including agitation, psychotic symptoms such as hallucinations and delusions, akathisia, low frustration tolerance, emotional lability, verbal and physical aggression, impulsivity, disinhibition, motor and verbal perseveration, confusion, disorientation). This may be measured as acute episodes, change in severity on continuous measures or dichotomous diagnosis. Validated measurement instruments may include the Agitated Behaviour Scale (agitation), Overt Aggression Scale, Neurobehavioral Rating Scale (aggression, low frustration tolerance, impulsivity), WPTAS, GOAT and O-Log (disorientation, and confusion). Reduction in the severity of NBS in PTA may also be measured by change in use of physical restraints or restraint alternatives (as described by study authors), change in the amount of direct supervision/observation needed (e.g. hours of supervision, number of nursing staff needed), and change to environmental modifications (e.g. use of modular rehabilitation enclosure bed [CraigBed], change in setting).
- Harms and adverse events:Adverse events will be documented either qualitatively or where possible using Medical Dictionary for Regulatory Activities (MEDRA), or WHO Adverse Reaction Terminology (WHO-ART), or other classification systems.The need for medication to manage adverse effects will be documented if reported.Examples of harms include paradoxical increases in neurobehavioral symptoms (e.g. increased confusion, agitation or impulsiveness); cognitive difficulties; psychiatric symptomatology (e.g. hypomania, psychotic symptoms); reduced energy/lethargy; and physical/medical complaints including tremor, extrapyramidal effects, seizures, neuroleptic malignant syndrome, bradycardia or tachycardia, arrhythmia, hypotension or hypertension, respiratory issues, nausea and vomiting, difficulty swallowing, constipation, urinary retention and dizziness.Study dropouts will also be reported (loss to follow-up and leaving the study early due to adverse events, inefficacy of treatment, death, or any other reason).
The secondary outcomes of interest for the review are:
- Changes in associated symptoms including arousal/alertness, awareness, mood (e.g. anxiety), speech changes/incoherent speech, perceptual difficulties, fatigue, sleep wake cycles. This may be measured as change on continuous measures or dichotomous diagnosis. Validated measurement instruments may include Hospital Anxiety and Depression Scale (HADS); Fatigue Severity Scale (FSS).
- Length of stay:ICU for acute phase and hospital for rehabilitation phase.
- Duration of PTA (if PTA cleared by end of study period) (as described by study authors including both retrospective and prospective measurement tools).
- Functional outcome (as defined by study authors, measured on such scales as the Functional Independence Measure [FIM]).
- Cognitive functioning (using validated measurement instruments as defined by study authors).
Types of studies
This review will consider the following study types: randomized controlled trials, controlled non-randomized clinical trials, quasi-randomized controlled trials, controlled before and after studies, interrupted time series with a control group, interrupted time series without a parallel concurrent control group, analytical observational studies (including cohort and case-control studies), case series with pre-test/post-test outcomes and single arm studies.
The following study types will be excluded from the review: case reports (including studies with multiple case reports), case series with only post-test outcomes, qualitative research, protocols, methodological papers, descriptive cross sectional studies, mechanism based reasoning studies (animals, physiology, laboratory), comparative studies without concurrent controls (e.g. historical controls), cluster clinical trials where the unit of analysis is the cluster not the person, epidemiological studies of incidence and prevalence, and studies of treatment preferences.
The search strategy aims at identifying all eligible human studies regardless of publication status or year of publication. The search strategy will, however, be restricted to studies published or available in the English language only. If potentially relevant titles in any other language are identified, they will be provided as an appendix to the review.
The search strategy will be developed by an information specialist with extensive experience in systematic reviews. Oversight and consultation will be provided by the study team. To develop the search strategy, the information specialist will use CENTRAL and PubMed to source key words from the titles, abstracts and search strategies of previous systematic reviews in this area. Both key words (linked with Boolean operators) and controlled vocabulary will be used. The search strategy will include terms relating to the population (traumatic brain injury) and intervention (pharmacotherapy) (PTA will not be specified as this review forms part of a large project that will review current evidence on a range of NBS post TBI). We will search the following databases: MEDLINE, OVID SP interface; PubMed excluding MEDLINE; CINAHL (Cumulative Index to Nursing and Allied Health Literature); Embase (Excerpta Medica Database) excluding MEDLINE, OVID SP interface; PsycINFO, OVID SP interface; and CENTRAL. The search strategy will be initially developed for PubMed and adapted for each database in accordance with the specific requirements. A full search strategy for MEDLINE is provided in Appendix I. We will supplement the formal database search by undertaking keyword searches in Google Scholar, Research Gate and PsychBite. If the review takes more than six months to produce from the date of the literature searches, we will re-run searches immediately prior to final analyses to identify any recent studies that meet inclusion criteria.
Hand searching will be completed for key journals in this area; Brain Injury, Neuropsychology, Journal of Neurotrauma, and Journal of Head Trauma Rehabilitation. Clinical trials registries will be searched for ongoing or recently completed trials using the terms “traumatic brain injury” and “pharmacotherapy”. The trial registries to be searched are the International Clinical Trials Registry Platform Search Portal and ClinicalTrials.gov. The international drug regulators, the Food and Drug Administration (FDA), European Medicine Agency (EMA) and the Medicines and Healthcare Products Regulatory Agency (MHRA), will be searched to identify unpublished studies. Experts in the field and key authors will be contacted to identify additional published and unpublished studies. Finally, for all included studies, reference lists, citations and related articles will be reviewed. Endnote (Clarivate Analytics, PA, USA) will be used to manage all reference retrieved, and duplicate entries will be deleted.
The titles and abstracts of all identified publications will be screened by two independent reviewers for eligibility. Discrepancies will be adjudicated by a third team member. Eligible citations will be retrieved in full and assessed by pairs of two independent team members. Inclusion will be decided by referring in detail to the eligibility criteria. Disagreements regarding eligibility will be resolved through discussion with a third reviewer. The discussions will be well documented, including reasons for final decisions. Where necessary, additional information will be sought from study authors to determine eligibility. All reviewers will record a specific reason for excluding studies, along with an explanatory note for their determination. Inter-rater reliability statistics using percent agreement and Cohen's kappa will be produced and reported. The results of the search will be reported in full in the final report and presented in a PRISMA flow diagram. Throughout the study selection process, reviewers will not be blinded to the journal titles, study authors or their institutions.
Assessment of methodological quality
The assessment of methodological quality will involve the evaluation of the impact of bias on the findings and will contribute to an evaluation of the overall quality of the evidence. No studies will be excluded based on the assessment of methodological quality. We will assess and report methodological quality according to the Joanna Briggs Institute critical appraisal instruments.53 Independent critical appraisal will be conducted by two reviewers. Disagreements will be resolved by consensus and discussion with a third reviewer. Inter-rater reliability statistics using percent agreement and Cohen's kappa will be produced and reported. A table will be used to document scores for methodological quality, with supporting comments to explain and justify scores. Scores will be presented and analysed in the results section of the final publication.
Data extraction will be conducted by two independent study team members. Data will be extracted from included studies using a customized data extraction tool (draft tool is provided in Appendix II) based on the standardized data extraction tool from the Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information (JBI-SUMARI).53 The tool will be piloted and refined early in the data extraction phase to accurately capture all of the data required for analysis. The specific data items that will be collected are listed below and grouped for ease of use as: basic study identifying information; study methodology; study sample and findings. We will contact authors where substantial outcomes of interest are not reported or to clarify uncertainty about study characteristics.
Basic study identifying information:
- Study title
- Name of first author
- Year of publication
- Financial support received to carry out the study
- Country where study carried out.
- Study design
- Study setting
- Study population
- Main inclusion and exclusion criteria
- Traumatic brain injury: definition, measurement scales used, severity, time post injury, other injuries
- PTA: definition, measurement scales used
- NBS in PTA: definition/description/characterisation, measurement scales used, severity
- Pharmacotherapy: compound, dose, frequency, duration, drug class
- Comparator conditions
- Outcomesoutcome measuresprimarysecondaryothertiming of measurement
- Statistical analysis methods.
Study sample and findings:
- Participant demographics: age, gender, time since injury, TBI severity
- Recruitment and study completion rates
- Extent of missing data
- Main results
- Treatment harms and adverse events.
We will provide a narrative descriptive synthesis of the findings from the included studies. The focus of this synthesis will be to present, integrate and compare findings within and across studies with respect to the primary and secondary outcomes.
This summary will include a description of the included studies, with the aid of tables and a summary of methodological quality, with tabulated JBI critical appraisal scores. Where data is available, we will provide statistical summaries of pharmacotherapeutic effects for each study. For continuous data, we will calculate the mean difference or standardised mean difference; dichotomous data will be analyzed using risk ratio estimates; ordinal data will be analyzed as continuous data (for long ordinal scales) or dichotomous data (when it is appropriate to combine adjacent categories together); count data will be analyzed as dichotomous (where appropriate to categorize data as “no events” versus “one or more events”) or as rate ratios using members of the Poisson regression family such as poisson, negative binomial and zero inflated poisson.
We anticipate that there will be limited scope for a meta-analysis due to the range of study designs and outcome measures used across the included studies. To determine heterogeneity among studies, we will qualitatively evaluate the studies by comparing patient characteristics, pharmacological classes, drug doses, co-therapies and clinical setting. We will also evaluate methodological heterogeneity by reviewing study design, outcome measures, risk of bias and type of control group. The meta-analysis will go ahead if at least five studies are available. Should a meta-analysis prove feasible, two review authors will independently review all studies for inclusion in meta-analysis. Where there is disagreement, a third team member will review the article and adjudicate.
We will use a random-effects model to calculate the effect measures (as detailed above) with their 95% confidence intervals and two-sided p values. Results will be presented in a forest plot. Heterogeneity will be assessed using prediction intervals (generated from the T statistic), and the I-squared statistic.54 Procedures to assess publication bias will be applied if there are a sufficient number of studies (e.g. funnel plot, Egger's regression, trim and fill procedure, fail-safe N). If there are sufficient data, subgroup analyses will be conducted on the following: gender (male and female); age (<20, 20–30, 30–40, >40 years); severity of TBI (mild, moderate, severe); medications dosage; adverse effects (serious versus non serious); single or more than one pharmacological regimen; and medication type.
Sensitivity analyses will be performed to examine whether the results of the meta-analysis are robust to changes in criteria used during the systematic review process. Specifically, we will repeat the meta-analysis substituting alternative decisions or ranges of values when we feel the original decision could be considered arbitrary or unclear. For example, excluding studies with “high” and “unclear” risk of bias. It is anticipated that further issues suitable for sensitivity analysis may be identified during the review process and are not pre-specified in this protocol. We will report sensitivity analyses by producing a summary table. Where sensitivity analyses suggest that the overall results may have been greatly influenced by certain decisions made during the review, we will attempt to address this by sourcing further information from authors and study coordinators.
This review will be reported in accordance with the PRISMA guidelines,52 and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.55 Any protocol amendments will be documented in the final systematic review report, including the date of each amendment, an explicit description, and a justification for the deviation.
If sufficient information is found in the research literature, we will use the Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) approach to define the quality of the evidence.56 The quality of evidence will be assessed across the domains of risk of bias, consistency, directness, precision and publication bias. Quality will be adjudicated as: high (further research is very unlikely to change our confidence in the estimate of effect); moderate (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate); low (further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate); or very low (very uncertain about the estimate of effect).
We will use the GRADE profiler GRADEpro to create “Summary of findings” tables. Summary of findings tables provide outcome-specific information concerning the overall quality of evidence from each included study. It also presents the magnitude of effect of the interventions examined and the sum of available data on all outcomes rated as important to patient care and decision making. All decisions will be recorded and provided as supplementary data to allow readers to appreciate the degree of any uncertainty, as well as provide greater transparency. If the data are sufficient, summary of findings tables will be prepared on the following outcomes: treatment efficacy; harms and adverse events; changes in associated symptoms; and changes in non-pharmacological management (use of physical restraints, environmental modifications, direct supervision/observation needed).
The authors acknowledge with thanks the input of our information specialist Farhad Shokraneh in the design of search strategies. The Institute for Safety, Compensation and Recovery Research (ISCRR), Monash University, provided funding for this review through the Neurotrauma strategy 2010–2015. ISCRR is a research-policy partnership established in 2009 via an agreement between WorkSafe Victoria, the Transport Accident Commission (TAC) and Monash University. The funder will not be involved in any other aspect of the project. This includes the preparation and submission of the protocol, all aspects of the proposed review method and the preparation of the review manuscript for submission.
Appendix I: Search strategy
- Exp Brain Hemorrhage, Traumatic/OR Brain Injuries/OR Brain Injury, Chronic/OR Cerebral Hemorrhage, Traumatic/OR Cerebrovascular Trauma/OR Craniocerebral Trauma/OR Diffuse Axonal Injury/OR Exp Head Injuries, Closed/OR Head Injuries, Penetrating/OR Exp Intracranial Hemorrhage, Traumatic/OR Exp Pneumocephalus/OR (((Brain OR Cerebr$ OR Crani$ OR Crushing Skull OR Diffuse Axonal OR Head OR Hemisphere?) adj1 (Injur$ OR Trauma$)) OR ((Cerebr$ OR Crani$ OR Head) adj (Lesion? OR Wound?)) OR ((Posttraumatic OR Traumatic) adj Encephalopath$) OR (Traumatic adj (Brain OR Cerebr$)) OR Concuss$ OR DAI OR DAIs OR Pneumocephalus OR TBI OR TBIs).ti,ab.
- “Anti-Anxiety Agents”/OR “Anticonvulsants”/OR “Antidepressive Agents”/OR “Antipsychotic Agents”/OR “Benzodiazepines”/OR “Adrenergic Beta-Antagonists”/OR Alprazolam/OR Amitriptyline/OR Amoxapine/OR Aripiprazole/OR Atenolol/OR Atomoxetine Hydrochloride/OR Benztropine/OR Bromazepam/OR Bupropion/OR Buspirone/OR Carbamazepine/OR Chlordiazepoxide/OR Chlorpromazine/OR Citalopram/OR Clomipramine/OR Clonazepam/OR Clopenthixol/OR Clorazepate Dipotassium/OR Clozapine/OR Desipramine/OR Desvenlafaxine Succinate/OR Dextroamphetamine/OR Diazepam/OR Valproic Acid/OR Domperidone/OR Dothiepin/OR Doxepin/OR Droperidol/OR Duloxetine Hydrochloride/OR Estazolam/OR Eszopiclone/OR Flunitrazepam/OR Fluoxetine/OR Flupenthixol/OR Fluphenazine/OR Fluvoxamine/OR Guanfacine/OR Haloperidol/OR Imipramine/OR Isocarboxazid/OR Methotrimeprazine/OR Lithium/OR Lithium Carbonate/OR Lorazepam/OR Loxapine/OR Lurasidone Hydrochloride/OR Methylphenidate/OR Mianserin/OR Midazolam/OR Moclobemide/OR Molindone/OR Nitrazepam/OR Nortriptyline/OR Oxazepam/OR Paliperidone Palmitate/OR Paroxetine/OR Phenelzine/OR Phenobarbital/OR Pindolol/OR Prazepam/OR Pregabalin/OR Prochlorperazine/OR Promazine/OR Promethazine/OR Propranolol/OR Protriptyline/OR Quetiapine Fumarate/OR Remoxipride/OR Risperidone/OR Selegiline/OR Sertraline/OR Sulpiride/OR Temazepam/OR Thioridazine/OR Thiothixene/OR Tranylcypromine/OR Trazodone/OR Triazolam/OR Trifluoperazine/OR Trimipramine/OR Venlafaxine Hydrochloride/OR Vigabatrin/OR ((Adrenergic adj Beta adj2 (Antagonist OR Block$)) OR Anti Anxiety OR Anti Convuls$ OR Anti Depress$ OR Anti Epilep$ OR Anti Psychotic? OR Antianxiety OR Anticonvuls$ OR Antidepress$ OR Antiepilep$ OR Antipsychotic$ OR Anxiolytic$ OR Benzodiazepine$ OR (Beta adj Block$) OR (Beta adj1 Adrenergic adj2 Block$) OR Thymoanaleptic$ OR Thymoleptic$ OR Agomelatine OR “S 20098” OR S20098 OR Thymanax OR Valdoxan OR “AGO 178” OR AGO178 OR Alprazolam OR Alprazolan OR “Apo Alpraz” OR ApoAlpraz OR Cassadan OR “D 65MT” OR D65MT OR Xanax OR Tafil OR Trankimazin OR “Novo Alprazol” OR NovoAlprazol OR “Nu Alpraz” OR NuAlpraz OR Ralozam OR “U-31,889” OR “U31,889” OR Alprox OR Esparon OR Kalma OR Amisulpride OR Sultopride OR Barnetil OR “DAN 2163” OR Solian OR “LIN 1418” OR Amitriptyline OR Amineurin OR Amitrip OR Amitriptylin OR Amitrol OR Tryptine OR ApoAmitriptyline OR Damilen OR Domical OR Laroxyl OR Endep OR Lentizol OR Novoprotect OR Saroten OR Sarotex OR Syneudon OR Triptafen OR Tryptizol OR Tryptanol OR Elavil OR Anapsique OR Amoxapine OR Desmethylloxapine OR “CL 67,772” OR “CL67,772” OR Demolox OR Asendin OR Defanyl OR Asendis OR Aripiprazole OR Aripiprazol OR “OPC 14597” OR Abilify OR Asenapine OR Saphris OR “ OR G 5222” OR Atenolol OR Tenormine OR Tenormin OR “ICI 66082” OR ICI66082 OR Atomoxetine OR Tomoxetine OR Strattera OR “LY 139603” OR Benztropine OR Benzatropine OR Bensylate OR PMSBenztropine OR Cogentin OR Cogentinol OR Methylbenztropine OR ApoBenztropine OR Brexpiprazole OR Bromazepam OR BromaLich OR “Bromaz 1A Pharma” OR Bromazanil OR “Bromazep von CT” OR Durazanil OR Lexotan OR Lexotanil OR Lexatin OR Lexomil OR “Ro 5–3350” OR “Ro 53350” OR Anxyrex OR Bupropion OR Amfebutamone OR Zyntabac OR Quomen OR Wellbutrin OR Zyban OR Buspirone OR “MJ 9022 1” OR MJ90221 OR Neurosine OR Busp OR Anxut OR Buspar OR Bespar OR Carbamazepine OR Tegretol OR Carbazepin OR Epitol OR Finlepsin OR Neurotol OR Amizepine OR Cariprazine OR “RGH 188” OR Chlordiazepoxide OR Methaminodiazepoxide OR Librium OR Chlozepid OR Elenium OR Chlorpromazine OR Thorazine OR Aminazine OR Largactil OR Chlordelazine OR Contomin OR Fenactil OR Propaphenin OR Chlorazine OR Citalopram OR Cytalopram OR “Lu 10 171” OR Lu10171 OR Escitalopram OR Lexapro OR Clobazam OR “HR 376” OR Onfi OR “LM 2717” OR Frisium OR Urbanyl OR Clomipramine OR Chlomipramine OR Chlorimipramine OR Hydiphen OR Anafranil OR Clonazepam OR “Ro 5 4023” OR “Ro 54023” OR Antelepsin OR Rivotril OR Clopenthixol OR Zuclopenthixol OR Cisordinol OR Clorazepate OR Chlorazepate OR Tranxene OR Tranxilium OR “4306 CB” OR Clozapine OR Clozaril OR Leponex OR Desipramine OR Desmethylimipramine OR Demethylimipramine OR Norpramin OR Pertofrane OR Pertrofran OR Pertofran OR Petylyl OR Desvenlafaxine OR “O Desmethylvenlafaxine” OR “WY 45,233” OR “WY 45,233” OR “WY45,233” OR “WY 45233” OR WY45233 OR Pristiq OR Dextroamphetamine OR Dexamphetamine OR Dexamfetamine OR “Dextro Amphetamine” OR “D Amphetamine” OR Dexedrine OR DextroStat OR Oxydess OR Diazepam OR Diazemuls OR Faustan OR Valium OR Seduxen OR Sibazon OR Stesolid OR Apaurin OR Relanium OR “Valproic Acid” OR Divalproex OR “Propylisopropylacetic Acid” OR “2 Propylpentanoic Acid” OR Convulsofin OR Depakene OR Depakine OR Depakote OR Vupral OR Valproate OR Ergenyl OR “Dipropyl Acetate” OR Domperidone OR Domperidon OR Domidon OR Gastrocure OR Motilium OR Nauzelin OR Peridys OR “R 33,812” OR “R33,812” OR “R 33812” OR R33812 OR Dothiepin OR Dosulepin OR Prothiaden OR Doxepin OR Deptran OR Desidox OR Doneurin OR Doxepia OR Espadox OR Mareen OR Prudoxin OR Quitaxon OR Sinequan OR Sinquan OR Zonalon OR Xepin OR Aponal OR ApoDoxepin OR Droperidol OR Inapsine OR Dehidrobenzperidol OR Dehydrobenzperidol OR Droleptan OR Duloxetine OR “LY 248686” OR LY248686 OR “LY 227942” OR LY227942 OR Cymbalta OR Estazolam OR Tasedan OR ProSom OR “D 40TA” OR D40TA OR Nuctalon OR Eszopiclone OR Lunesta OR Estorra OR Flunitrazepam OR Fluridrazepam OR Flunibeta OR Flunimerck OR Fluninoc OR Rohypnol OR Rohipnol OR Narcozep OR “Flunizep von CT” OR “RO 5 4200” OR RO54200 OR Fluoxetine OR Fluoxetin OR “Lilly 110140” OR Lilly110140 OR Sarafem OR Prozac OR Flupenthixol OR Flupentixol OR Emergil OR Fluanxol OR Fluphenazine OR Flufenazin OR Lyogen OR Prolixin OR Fluvoxamine OR Fluvoxadura OR Fluvoxamin OR Fluvoxamina OR Luvox OR Fevarin OR Floxyfral OR Dumirox OR Faverin OR Desiflu OR “DU 23000” OR DU23000 OR Guanfacine OR Tenex OR Lon798 OR “BS 100 141” OR BS100141 OR Estulic OR Haloperidol OR Haldol OR Iloperidone OR Zomaril OR Fanapt OR “HP 873” OR Imipramine OR Imizin OR Norchlorimipramine OR Imidobenzyle OR Tofranil OR Melipramine OR Pryleugan OR Janimine OR Isocarboxazid OR Lamotrigine OR Crisomet OR Lamictal OR Lamiktal OR “BW 430C” OR Labileno OR Methotrimeprazine OR Levomepromazine OR Levopromazine OR Levomeprazin OR Tisercin OR Tizercine OR Tizertsin OR Lithium OR Dilithium OR Lithane OR Lithobid OR Lithonate OR “CP-15,467 61” OR “CP15,46761” OR Micalith OR “NSC 16895” OR NSC16895 OR Priadel OR “Quilinorm Retard” OR Quilinormretard OR Eskalith OR Lithotabs OR Lorazepam OR Ativan OR Temesta OR “Orfidal Wyeth” OR Donix OR Duralozam OR Durazolam OR Idalprem OR Laubeel OR “Lorazep von CT” OR “Novo Lorazem” OR NovoLorazem OR “Nu Loraz” OR NuLoraz OR Sedicepan OR Sinestron OR Somagerol OR Tolid OR “WY 4036” OR WY4036 OR ApoLorazepam OR Loxapine OR Cloxazepine OR Oxilapine OR Loxitane OR Loxipine OR Loxapinsuccinate OR “CL 71,563” OR “CL71,563” OR Lurasidone OR “SM 13496” OR SM13496 OR “SM-13,496” OR “SM13,496” OR Latuda OR Methylphenidate OR Metadate OR Equasym OR Methylin OR Concerta OR Phenidylate OR Ritalin OR Ritaline OR Tsentedrin OR Centedrin OR Daytrana OR Mianserin OR Tolvon OR Lerivon OR Org GB 94 OR Midazolam OR Dormicum OR Versed OR “Ro 21 3981” OR “Ro 213981” OR Milnacipran OR Midalcipran OR Levomilnacipran OR Savella OR “F 2207” OR Ixel OR Mirtazapine OR “6 Azamianserin” OR Esmirtazapine OR Remeron OR Remergil OR Zispin OR Norset OR Rexer OR “Org 50081” OR “ OR G 3770” OR Moclobemide OR Moclobamide OR Arima OR Aurorix OR Manerix OR Moclamine OR Aurorex OR Deprenorm OR Feraken OR Moclobemid OR Moclobeta OR Moclodura OR Moclonorm OR Rimoc OR “Ro 11 1163” OR Modafinil OR Benzhydrylsulfinylacetamide OR “CRL 40476” OR Vigil OR Provigil OR Sparlon OR Alertec OR Modiodal OR Molindone OR Moban OR Nefazodone OR Rulivan OR Serzone OR Dutonin OR Nefadar OR Menfazona OR Nitrazepam OR Nitrodiazepam OR “Dormo Puren” OR Eatan OR Imadorm OR Imeson OR Mogadon OR Nitrazadon OR Nitrazep OR Novanox OR Radedorm OR Remnos OR Serenade OR Somnite OR Alodorm OR Dormalon OR Nortriptyline OR Desmethylamitriptylin OR Desitriptyline OR Aventyl OR Paxtibi OR Allegron OR Norfenazin OR Pamelor OR Nortrilen OR Olanzapine OR Zolafren OR “LY 170052” OR Zyprexa OR “LY 170053” OR Oxazepam OR Serax OR Tazepam OR Adumbran OR Oxcarbazepine OR Timox OR Trileptal OR “GP 47680” OR Paliperidone OR “9 OH Risperidone” OR “9 Hydroxy Risperidone” OR “9 Hydroxyrisperidone” OR Invega OR “R 76477” OR R76477 OR Paroxetine OR “BRL 29060” OR BRL29060 OR “FG 7051” OR FG7051 OR Seroxat OR Paxil OR Aropax OR Periciazine OR Propericiazine OR Pericyazine OR Neuleptil OR Neuleptyl OR Aolept OR Phenelzine OR “Beta Phenylethylhydrazine” OR “2 Phenethylhydrazine” OR Fenelzin OR Phenethylhydrazine OR Nardelzine OR Nardil OR Phenobarbital OR Phenobarbitone OR “Phenylethylbarbituric Acid” OR Phenemal OR Phenylbarbital OR Hysteps OR Luminal OR Gardenal OR Pindolol OR Prindolol OR Visken OR “LB 46” OR LB46 OR Prazepam OR Lysanxia OR Reapam OR Centrax OR Demetrin OR Pregabalin OR “3 Isobutyl GABA” OR Lyrica OR “CI 1008” OR CI1008 OR Prochlorperazine OR Compazine OR Promazine OR Sparine OR Sinophenin OR Protactyl OR Promethazine OR Prometazin OR Proazamine OR Rumergan OR Diprazin OR Phenergan OR Phenargan OR Phensedyl OR Pipolfen OR Pipolphen OR Promet OR Prothazin OR Pyrethia OR Remsed OR Atosil OR Diphergan OR Propranolol OR Propanolol OR Inderal OR Avlocardyl OR “AY 20694” OR AY20694 OR Rexigen OR Dexpropranolol OR Dociton OR Obsidan OR Obzidan OR Anaprilin OR Anapriline OR Betadren OR Protriptyline OR Vivactil OR Quetiapine OR “ICI 204,636” OR “ICI 204636” OR ICI204636 OR Seroquel OR Reboxetine OR Vestra OR Remoxipride OR “FLA 731” OR FLA731 OR Risperidone OR Risperdal OR Risperidal OR “R 64,766” OR “R64,766” OR “R 64766” OR R64766 OR Selegiline OR Selegyline OR “L Deprenyl” OR “E 250” OR E250 OR Eldepryl OR Emsam OR Zelapar OR Deprenil OR Deprenalin OR Yumex OR Jumex OR Humex OR Deprenyl OR Sertindole OR Serlect OR “Lu 23 174” OR Serdolect OR Sertraline OR Zoloft OR Altruline OR Lustral OR Aremis OR Besitran OR Sealdin OR Gladem OR Sulpiride OR Sulperide OR Arminol OR Deponerton OR Meresa OR Desisulpid OR Digton OR Dogmatil OR Dolmatil OR Eglonyl OR Ekilid OR Guastil OR Lebopride OR Neogama OR Pontiride OR Psicocen OR Sulp OR Sulpitil OR Sulpivert OR Sulpor OR Synedil OR Tepavil OR Aiglonyl OR Temazepam OR Hydroxydiazepam OR Methyloxazepam OR Signopam OR Tenox OR “WY 3917” OR WY3917 OR Dasuen OR Euhypnos OR Levanxol OR “Norkotral Tema” OR Normison OR Nocturne OR Temtabs OR Normitab OR Nortem OR Planum OR “Pronervon T” OR Remestan OR Restoril OR “Ro 5 5345” OR Ro55345 OR “SaH 47 603” OR “SaH 47603” OR Temaze OR “Temazep von CT” OR Thioridazine OR ApoThioridazine OR Meleril OR Melleril OR Melleryl OR Mellaril OR Melleretten OR Melzine OR Thiozine OR Sonapax OR Thioridazineneurazpharm OR Aldazine OR Rideril OR Thiothixene OR Tiotixene OR Navane OR Topiramate OR USL255 OR “McN 4853” OR Topamax OR Epitomax OR Tranylcypromine OR “Trans 2 Phenylcyclopropylamine” OR Jatrosom OR Transamine OR Parnate OR Trazodone OR Tradozone OR “AF 1161” OR AF1161 OR Deprax OR Desyrel OR Molipaxin OR Trittico OR Thombran OR “Trazodon Hexal” OR “Trazodon Neuraxpharm” OR Trazon OR Triazolam OR “U 33,030” OR “U33,030” OR Halcion OR Trilam OR “Apo Triazo” OR Trifluoperazine OR Trifluoroperazine OR Trifluperazine OR Eskazine OR Flupazine OR Terfluzine OR Triftazin OR Stelazine OR Trimipramine OR Trimeprimine OR Herphonal OR Trimineurin OR NovoTripramine OR Rhotrimine OR Stangyl OR Surmontil OR Trimidura OR Trimineurin OR Trimipramin OR “Apo Trimip” OR ApoTrimip OR Eldoral OR Venlafaxine OR “Wy 45030” OR Wy45030 OR “Wy 45,030” OR “Wy45,030” OR Effexor OR Trevilor OR Vandral OR Efexor OR Dobupal OR Vigabatrin OR “Gamma Vinyl GABA” OR “Gamma Vinyl Gamma Aminobutyric Acid” OR Sabril OR Sabrilex OR Vortioxetine OR Brintellix OR “Lu AA21004” OR LuAA21004 OR Zaleplon OR “SKP 1041” OR Sonata OR Zelepion OR Starnoc OR “CL 284,846” OR “CL284,846” OR “CL 284846” OR “L 846” OR Ziprasidone OR Ziprazidone OR “CP 88,059” OR “CP 88059” OR Zolpidem OR Amsic OR Bikalm OR Dalparan OR “SL 80.0750” OR “SL 800750 23 N” OR Stilnoct OR Stilnox OR Zodormdura OR Zoldem OR Zolirin OR “Zolpi Lich” OR Zolpinox OR Zolpimist OR Ambien OR Zopiclone OR Zop OR Zopicalma OR Zopiclodura OR Zopiclon OR Zopitan OR Zorclone OR Imovane OR Ximovan OR Zimovane OR Limovan OR Optidorm OR Rhovane OR “RP 27 267” OR Siaten OR Somnosan OR Zileze OR Zimoclone OR “Zopi Puren” OR Zopicalm OR Zotepine OR Zoleptil OR Nipolept OR Zuclopenthixol OR Zuclopentixol OR Clopixol OR Zuclopenthixole OR Acuphase).ti,ab.
- (1 AND 2) NOT (Animals NOT (Humans NOT Animals)).sh.
- Limit 3 to English
Appendix II: Data extraction form
Basic study identifying information
Additional notes/questions for “basic study identifying information”
Study methodology – overall
Additional notes/questions for “study methodology – overall”
Study methodology – traumatic brain injury
Additional notes/questions for “study methodology – traumatic brain injury”
Study methodology – post traumatic amnesia
Additional notes/questions for “study methodology – post traumatic amnesia”
Study methodology – neurobehavioral symptoms in post traumatic amnesia
Additional notes/questions for “study methodology – neurobehavioral symptoms in post traumatic amnesia”
Study methodology – “pharmacotherapy intervention/exposure”
Additional notes/questions for “study methodology – pharmacotherapy intervention/exposure”
Study methodology – comparator conditions
Additional notes/questions for “study methodology – comparator conditions”
Study methodology – co-interventions
Additional notes/questions for “study methodology – co-interventions”
Study methodology – outcomes
Additional notes/questions for “study methodology – outcomes
Study methodology – treatment harms and adverse events
Additional notes/questions for “study methodology – treatment harms and adverse events”
Study sample and findings
Study sample and findings – participant demographics
Additional notes/questions for “study sample and findings – participant demographics”
Study sample and findings – participant baseline characteristics
Additional notes/questions for “study sample and findings – participant baseline characteristics”
Study sample and findings – recruitment and study completion rates
Additional notes/questions for “study sample and findings – study completion rates”
Study sample and findings – compliance rates
Additional notes/questions for “study sample and findings – compliance rates”
Study sample and findings – extent of missing data
Additional notes/questions for “study sample and findings – extent of missing data”
Study sample and findings – main results
Additional notes/questions for “study sample and findings – main results”
Study sample and findings – treatment harms and adverse events
Additional notes/questions for “study sample and findings – treatment harms and adverse events”
Study sample and findings – direct and indirect healthcare costs
Additional notes/questions for “direct & indirect healthcare costs”
Any overall comments or conclusions
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