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Effectiveness of non-pharmacological interventions for managing agitation during post-traumatic amnesia following traumatic brain injury: a systematic review protocol

Carrier, Sarah L.1,2; Hicks, Amelia J.1,2; Ponsford, Jennie L.1,2,3; McKay, Adam1,2,3

Author Information
doi: 10.11124/JBIES-20-00216
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Traumatic brain injury (TBI) is one of the leading causes of death and disability, with approximately 10 million people worldwide sustaining a TBI annually.1 Traumatic brain injury is defined as an alteration in brain function, or other evidence of brain pathology, as a result of external force.2 It is often associated with debilitating neurological and neurobehavioral sequelae, which can negatively impact patient recovery and long-term functional outcomes.1,3 Many neurobehavioral symptoms emerge in the early stages of recovery, known as “post-traumatic amnesia” (PTA), which is characterized by disorientation to person, place and time, and anterograde amnesia.4 Duration of PTA has shown to be an indicator of TBI severity, and consequently a predictor of long-term functional outcomes.5,6

Agitation is one of the most prevalent and significant sequelae observed during PTA, seen in approximately half of TBI patients.7,8 Agitated behaviors during this period include inattention, disinhibition, motor and verbal perseveration, impulsivity, emotional lability, restlessness, confusion, and aggression.7,9 Although the causes of agitation are poorly understood, agitated behaviors are associated with underlying cognitive deficits in orientation, memory, and attention, which can impact an individual's ability to process and contextualize internal and external stimuli, resulting in inappropriate responses that manifest as agitation.10-13 Agitation during PTA is associated with increased length of hospital stay, reduced engagement in rehabilitation, and poorer cognitive and motor functioning.7,9,14 Agitated behaviors also pose a risk to staff and patient safety.15

There is a clear lack of evidence regarding effective intervention for managing agitation during PTA.14,16,17 Pharmacological agents are frequently used, particularly carbamazepine, trazodone, tricyclic antidepressants, amantadine, beta-blockers, benzodiazepines, narcotics, and neuroleptics.10,11,18 However, there are few guidelines in place to inform best practice and a lack of strong evidence on the effects of pharmacological interventions in treating any neurobehavioral symptoms in PTA, including agitation.19,20 Pharmacological agents may even paradoxically increase agitation, due to effects on cognition, thus further hindering recovery efforts.21

The aim of non-pharmacological interventions is to reduce the occurrence of agitated behaviors, primarily through environmental and behavioral approaches, in order to reduce length of hospital stay, improve functional outcomes, and reduce the health care burden. Research suggests that maintaining a quiet and calm environment may assist in minimizing patient agitation during PTA.17,21,22 Furthermore, agitated patients may benefit from room modifications, such as lowering beds, and using padding and safety rails.22 Several studies describe the use of orientation cues (eg, clocks and calendars), familiarizing cues (eg, photographs), and consistent staffing to calm and reassure patients, and consequently reduce agitation.21-23 Providing adequate sleep opportunities and rest breaks may also reduce agitation for patients with PTA, who typically require more sleep, as they fatigue more quickly.16,22

Behavioral interventions involving operant conditioning principles may also aid in reducing agitation.24 Education and training for staff may also be critical for managing agitation, and educating family may ensure they engage with the patient in a way that promotes recovery, rather than further contributing to agitation.21,22 Integrative therapies, such as music therapy, may also be useful for reducing agitation.25

There is a paucity of research investigating the effects of non-pharmacological interventions for managing agitation during PTA. An understanding of best management practices is largely derived from clinical experience and recommendations, guidelines derived from expert consensus, and interventions in other clinical populations who experience agitation.

A preliminary search of PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews, JBI Database of Systematic Reviews and Implementation Reports, PROSPERO, and Epistemonikos was conducted and no current or in-progress systematic reviews on the topic were identified.

The objective of this review is to evaluate the effectiveness of non-pharmacological interventions for managing agitation during PTA in adults with a TBI.

Review question

What is the effectiveness of non-pharmacological interventions for managing agitation during PTA in adults (aged 16 years and older) who have sustained a TBI?

Inclusion criteria


This review will consider studies that include participants aged 16 years and older, of any gender, who exhibit agitated behaviors during PTA after sustaining a TBI (irrespective of severity or mechanism). Studies where 80% of the sample are 16 years and older will be considered. Traumatic brain injury must be confirmed according to established criterion, including brain imaging findings, Glasgow Coma Scale (GCS) score, and PTA status; self- or informant-reported TBI will not be included. Studies with acquired brain injury populations will be included if TBI results are reported separately or at least 80% of the sample has sustained a TBI. Studies will be accepted if patients are in PTA at study commencement (ie, baseline). Post-traumatic amnesia status will be determined based on reference to terms such as PTA, post-traumatic confusional state, delirium, disorientation, confusion, and amnesia; tools such as the Rancho Los Amigos Scales (RLAS), Confusion Assessment Protocol (CAP), Westmead PTA Scale (WPTAS), Galveston Orientation and Amnesia Test (GOAT), Orientation-Log (O-Log); and time post-injury and setting. Retrospective and prospective measurements of PTA will be accepted. Studies with patients in and out of PTA at baseline will be included if more than 50% of the sample is in PTA or if data can be disaggregated. Studies will be included if the intervention targets agitation broadly or behaviors reflective of agitation. Participants will not be excluded based on diagnostic or assessment criteria for agitation. Medical and nursing notes or logbooks will be accepted if results are presented quantitatively; qualitative descriptions of behavior change will not be sufficient. Studies will be included where agitation was not the presenting symptom but was measured as an outcome variable; such studies will be analyzed separately. Participants must be patients in acute care or inpatient settings.


This review will consider studies that evaluate non-pharmacological interventions for managing agitation, with no restriction on type, duration, frequency, timing of delivery, or combination of interventions used (including pharmacology). Non-pharmacological interventions include environmental modifications, behavioral strategies, sleep hygiene approaches, restraints, or any other non-pharmacological intervention intended to reduce agitation. Studies reporting on mixed interventions will be included if data for the non-pharmacological intervention are reported separately.


This review will consider studies that compare the intervention to all types of comparators, including placebo conditions, supportive, or standard care, baseline phase, and other non-pharmacological and pharmacological interventions.


This review will consider studies that include the following outcomes:

  • Change in agitation severity during PTA (including inattention, restlessness, frustration, disinhibition, motor and verbal perseveration, impulsivity, emotional lability, confusion, and aggression) measured as acute episodes, change in severity on continuous measures or a dichotomous diagnosis. Validated measurement tools include the Agitated Behavior Scale (ABS), RLAS, Overt Aggression Scale (OAS) and CAP. Change in agitation severity may also be measured by change in restraints, pharmacology, and amount of direct supervision/observation required.
  • Harms resulting from non-pharmacological intervention; adverse events, and medications needed to manage such, will be documented qualitatively. Examples of harms include increased agitated behavior, reduced energy, and increased fatigue.

Secondary outcomes of interest include:

  • Changes in arousal/alertness and cognitive functioning (measured by tools such as the RLAS), sleep-wake cycles (measured by tools such as the Pittsburgh Sleep Quality Index), mood (measured by tools such as the Hospital Anxiety and Depression Scale), and fatigue (measured by tools such as the Fatigue Severity Scale).
  • Length of stay (measured in days).
  • Duration of PTA using retrospective and prospective measurement tools (if participants are cleared of PTA by study conclusion).
  • Functional outcomes measured on scales such as the Functional Independence Measure.
  • Family and staff burden, using validated measures such as the Family Assessment Device and the Maslach Burnout Inventory.

Types of studies

This review will consider both experimental and quasi-experimental study designs including randomized controlled trials, non-randomized controlled trials, before-and-after studies and interrupted time-series studies. This review will also consider analytical observational studies including prospective and retrospective cohort studies and case-control studies, and case series and single-arm studies for inclusion. Case reports will be included but analyzed and reported separately.

This review will not consider case series with only post-test outcomes, qualitative research, protocols, methodological papers, descriptive cross-sectional studies, mechanism-based reasoning studies, comparative studies without concurrent controls, cluster clinical trials where the unit of analysis is the cluster, epidemiological studies of incidence and prevalence, and studies of treatment preferences.

Studies published in English will be included; relevant non-English titles will be translated via the Cochrane Task Exchange network and included where possible. Studies will be included irrespective of publication year.


The proposed systematic review will be conducted in accordance with JBI guidance for systematic reviews of effectiveness26 and reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines.27 This review has been registered in PROSPERO (CRD42020186802).

Search strategy

The search strategy will aim to locate published and unpublished studies. An initial limited search of CENTRAL and PubMed was undertaken to identify articles on the topic; text words contained in titles and abstracts of relevant articles and search strategies of relevant systematic reviews were used to develop a search strategy for PubMed, which will then be adapted for each information source. A full search strategy for MEDLINE is provided in Appendix I. The reference lists of all studies selected for critical appraisal will be screened for additional studies.

The search strategy will be developed by an information specialist, using keywords (linked with Boolean operators) and controlled vocabulary. The search strategy will be peer-reviewed against the Peer Review of Electronic Search Strategies (PRESS) checklist. If the review takes longer than 12 months from the date of the literature searches, the searches will be re-run immediately prior to final analyses to identify recent studies that meet inclusion criteria.

Information sources

The databases to be searched include MEDLINE (Ovid SP), PubMed excluding MEDLINE, CINAHL, Excerpta Medica Database (Embase) excluding MEDLINE Ovid SP, PsycINFO, and Cochrane CENTRAL. The clinical trial registries, International Clinical Trials Registry Platform Search Portal, and will be searched using the term “traumatic brain injury.” Experts in the field and key authors will be contacted to identify additional studies.

Study selection

Following the search, all identified citations will be collated and uploaded into EndNote V9.2 (Clarivate Analytics, PA, USA) and duplicates removed. Titles and abstracts will be screened by two independent reviewers for assessment against the inclusion criteria for review. Potentially relevant studies will be retrieved in full and citation details imported into the JBI System for the Unified Management, Assessment and Review of Information (JBI SUMARI; JBI, Adelaide, Australia). The full text of selected citations will be assessed in detail against the inclusion criteria by two independent reviewers. Reasons for exclusion of full text studies that do not meet the inclusion criteria will be recorded and reported in the systematic review. Any disagreements that arise between the reviewers at each stage of the study selection process will be resolved through discussion, or with a third reviewer. The results of the search will be reported in full in the final systematic review and presented in a PRISMA flow diagram.27

Assessment of methodological quality

Eligible studies will be critically appraised by two independent reviewers at the study level for methodological quality in the review using standardized critical appraisal instruments from JBI for randomized controlled trials, quasi-experimental studies, analytical cross-sectional studies, cohort studies, case control studies, case series, and case reports.26 Authors of papers will be contacted to request missing or additional data for clarification, where required. Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer. The results of critical appraisal will be reported in narrative form and tables. All studies, regardless of the results of their methodological quality, will undergo data extraction and synthesis (where possible). Reviewers will not be blinded to the journal titles, study authors, or their institutions.

Data extraction

Data will be extracted from studies included in the review by two independent reviewers using a customized data extraction tool based on the standardized tool from JBI SUMARI (see Appendix II). The tool will be piloted and refined early in the data extraction phase. The data extracted will include specific details about the population (including details regarding TBI, PTA, and agitation), study methods, interventions (non-pharmacological), comparator conditions, participant demographics and characteristics at baseline, outcomes of significance to the review objective (primary and secondary outcomes and treatment harms and adverse events), statistical analyses used, recruitment and study completion rates, and extent of missing data. Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer. Authors of papers will be contacted to request missing or additional data, where required.

Data synthesis

Studies will, where possible, be pooled with statistical meta-analysis using JBI SUMARI. If there are sufficient studies for each type of non-pharmacological intervention (ie, environmental, behavioral, sleep-based, and restraint use), separate pooled analyses will be performed. Heterogeneity of studies will also be determined qualitatively by comparing participant characteristics, non-pharmacological interventions and frequency of use, accompanying therapies, and clinical settings. Heterogeneity in methodology will be determined qualitatively by comparing study designs, outcome measures, risk of bias, and control groups used. Effect sizes will be expressed as odds ratios (for dichotomous data) or weighted (or standardized) final post-intervention mean differences (for continuous data) and 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard χ2 and I2 tests. Statistical analyses will be performed using a random effects model.28 Subgroup analyses will be conducted based on gender, age, TBI severity, non-pharmacological intervention, and adverse effects, where sufficient data is available. Sensitivity analyses will be conducted to determine whether the results of the meta-analysis are robust to changes in criteria used during the review process; these analyses are not pre-specified as further issues may be identified. If sensitivity analysis indicates that the overall findings are affected by decisions made during the review process, further information will be sought from authors of relevant studies. Where statistical pooling is not possible, findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.

A funnel plot will be generated using STATA (Stata Corp LLC, Texas, USA) to assess publication bias if there are 10 or more studies included in a meta-analysis. Statistical tests for funnel plot asymmetry (Egger test, Begg test, Harbord test) will be performed where appropriate.

Assessing certainty in the findings

The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for grading the certainty of evidence will be followed and a Summary of Findings (SoF) will be created using GRADEpro GDT 2015 (McMaster University, ON, Canada).29 The SoF will present absolute risks for the treatment and control, estimates of relative risk, and a ranking of evidence quality based on risk of bias, directness, heterogeneity, precision, and risk of publication bias of the review results. If sufficient data is available, outcomes reported in the SoF will include change in agitation severity (including change in restraints, pharmacology, and direct supervision/observation required) and harms resulting from intervention (including adverse events and medications needed to manage such).


Farhad Shokraneh, information specialist, for input in the design of search strategies.

This review will partially fulfil degree requirements in the Doctor of Clinical Neuropsychology program for SC.

Appendix I: Search strategy

Ovid MEDLINE(R) ALL 1946

Search conducted on May 13, 2020, with 2033 records retrieved at this time point.


Appendix II: Data extraction instrument



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agitation; inpatient care; non-pharmacological intervention; post-traumatic amnesia; traumatic brain injury

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