Development, implementation and validation of resource-stratified guidelines in low-income and middle-income countries: a scoping review protocol.

INTRODUCTION: Nearly every field of medicine has some form of clinical practice guidelines. However, only within the past 5-10 years has the medical community acknowledged the need for well-developed guidelines tailored to the local healthcare needs and the resources available. In most low-income and middle-income countries (LMICs), healthcare workers depend on guidelines developed in high-income countries (HICs), yet many interventions validated in a HIC are ineffective when implemented in an LMIC. The variation in infrastructure, medical personnel, technology and environmental conditions exhibited in LMICs relative to HICs necessitates a careful appraisal of the evidence base used in clinical guideline recommendations. This review aims to map the use of resource-stratified guidelines across all fields of medicine. The review seeks to answer three questions for the identified guidelines: (1) what was the method of development, (2) have they been implemented and, if so, (3) have they been validated. METHODS: The search strategy will aim to locate studies from inception to November 2021. An initial limited search of PubMed and Scopus was undertaken to identify articles on the topic. The text words contained in the titles and abstracts of relevant articles, and the index terms used to describe the articles were used to develop a full search strategy for PubMed and Scopus. This scoping review will be conducted in accordance with the Joanna Briggs Institute (JBI) methodology for scoping reviews. Data to be extracted from each study will include population characteristics of both developers and intended implementation population, medical specialty, validation status, method of guideline development, whether the study is consensus or evidence-based in addition to a summary of recommendations for practice. ETHICS AND DISSEMINATION: Ethical approval is not required for this review. The plan for dissemination is to publish review findings in a peer-reviewed journal.

System dynamics modeling for traumatic brain injury: Mini-review of applications.

Traumatic brain injury (TBI) is a highly complex phenomenon involving a cascade of disruptions across biomechanical, neurochemical, neurological, cognitive, emotional, and social systems. Researchers and clinicians urgently need a rigorous conceptualization of brain injury that encompasses nonlinear and mutually causal relations among the factors involved, as well as sources of individual variation in recovery trajectories. System dynamics, an approach from systems science, has been used for decades in fields such as management and ecology to model nonlinear feedback dynamics in complex systems. In this mini-review, we summarize some recent uses of this approach to better understand acute injury mechanisms, recovery dynamics, and care delivery for TBI. We conclude that diagram-based approaches like causal-loop diagramming have the potential to support the development of a shared paradigm of TBI that incorporates social support aspects of recovery. When developed using adequate data from large-scale studies, simulation modeling presents opportunities for improving individualized treatment and care delivery.

Protocol for a Multicenter, Prospective, Observational Pilot Study on the Implementation of Resource-Stratified Algorithms for the Treatment of Severe Traumatic Brain Injury Across Four Treatment Phases: Prehospital, Emergency Department, Neurosurgery, and Intensive Care Unit.

BACKGROUND: Severe traumatic brain injury (sTBI) is a public health issue with great disparity among low- and middle-income countries where the implementation of evidence-based guidelines is challenging because resources are often unavailable. A consensus process including experts in the prehospital, emergency department, neurosurgery, and intensive care unit took place in Colombia to develop a set of stratified protocols called BOOTStraP, targeting resource-poor environments, but it has not been systematically implemented and tested. OBJECTIVE: To identify the facilitators of, and barriers to, collecting data about patients with sTBI and to implement a stratified protocol across the treatment phases of prehospital, emergency department, neurosurgery, and intensive care unit in low-resource settings. We also aim to identify a possible association between adherence to these protocols and outcomes for these patients. METHODS: A prospective, observational, before and after, pilot study will be performed in three phases as follows: before implementation, implementation, and after implementation. The BOOTStraP protocols will be implemented in three Colombian centers. EXPECTED OUTCOMES: We expect to find numerous barriers during the implementation phase. We also expect moderate adherence to the protocols. However, we expect to find an increase in the survival rate to hospital discharge and an improvement in neurological outcomes at discharge. DISCUSSION: This pilot study will serve as a first step to identify variables that are critical to successful implementation, to be considered for the design of a future large-scale international study to measure the effectiveness of resource-based protocols and to improve outcomes from sTBI.

Prehospital Airway Management: A Systematic Review.

Objective: To assess comparative benefits and harms across three airway management approaches (bag valve mask [BVM], supraglottic airway [SGA], and endotracheal intubation [ETI]) used by prehospital emergency medical services (EMS) to treat patients with trauma, cardiac arrest, or medical emergencies, and how they differ based on techniques and devices, EMS personnel and patient characteristics. Data sources: We searched electronic citation databases (Ovid® MEDLINE®, CINAHL®, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus®) from 1990 to September 2020. Review methods: We followed Agency for Healthcare Research and Quality Effective Health Care Program Methods guidance. Outcomes included mortality, neurological function, return of spontaneous circulation (ROSC), and successful advanced airway insertion. Meta-analyses using profile-likelihood random effects models were conducted, with analyses stratified by study design, emergency type, and age. Results: We included 99 studies involving 630,397 patients. We found few differences in primary outcomes across airway management approaches. For survival, there was no difference for BVM versus ETI or SGA in adult and pediatric patients with cardiac arrest or trauma. For neurological function, there was no difference for BVM versus ETI and SGA versus ETI in pediatric patients with cardiac arrest. There was no difference in BVM versus ETI in adults with cardiac arrest, but improved neurological function with BVM or ETI versus SGA. There was no difference in ROSC for patients with cardiac arrest for BVM versus ETI or SGA in adults and pediatrics, or SGA versus ETI in pediatrics. There was higher frequency of ROSC in adults with SGA versus ETI. For successful advanced airway insertion, there was higher first-pass success with SGA versus ETI for all patients except adult medical patients (no difference), and no difference in overall success using SGA versus ETI in adults. Conclusions: The currently available evidence does not indicate benefits of more invasive airway approaches based on survival, neurological function, ROSC, or successful airway insertion. Strength of evidence was low or moderate; most included studies were observational. This supports the need for high-quality randomized controlled trials to advance clinical practice and EMS education and policy, and improve patient-centered outcomes.

Recommendations of the Colombian Consensus Committee for the Management of Traumatic Brain Injury in Prehospital, Emergency Department, Surgery, and Intensive Care (Beyond One Option for Treatment of Traumatic Brain Injury: A Stratified Protocol [BOOTStraP]).

Background Traumatic brain injury (TBI) is a global public health problem. In Colombia, it is estimated that 70% of deaths from violence and 90% of deaths from road traffic accidents are TBI related. In the year 2014, the Ministry of Health of Colombia funded the development of a clinical practice guideline (CPG) for the diagnosis and treatment of adult patients with severe TBI. A critical barrier to the widespread implementation was identified-that is, the lack of a specific protocol that spans various levels of resources and complexity across the four treatment phases. The objective of this article is to present the process and recommendations for the management of patients with TBI in various resource environments, across the treatment phases of prehospital care, emergency department (ED), surgery, and intensive care unit. Methods Using the Delphi methodology, a consensus of 20 experts in emergency medicine, neurosurgery, prehospital care, and intensive care nationwide developed recommendations based on 13 questions for the management of patients with TBI in Colombia. Discussion It is estimated that 80% of the global population live in developing economies where access to resources required for optimum treatment is limited. There is limitation for applications of CPGs recommendations in areas where there is low availability or absence of resources for integral care. Development of mixed methods consensus, including evidence review and expertise points of good clinical practices can fill gaps in application of CPGs. BOOTStraP (Beyond One Option for Treatment of Traumatic Brain Injury: A Stratified Protocol) is intended to be a practical handbook for care providers to use to treat TBI patients with whatever resources are available. Results Stratification of recommendations for interventions according to the availability of the resources on different stages of integral care is a proposed method for filling gaps in actual evidence, to organize a better strategy for interventions in different real-life scenarios. We develop 10 algorithms of management for building TBI protocols based on expert consensus to articulate treatment options in prehospital care, EDs, neurological surgery, and intensive care, independent of the level of availability of resources for care.

The Role of Decompressive Craniectomy in the Context of Severe Traumatic Brain Injury: Summary of Results and Analysis of the Confidence Level of Conclusions From Systematic Reviews and Meta-Analyses.

Introduction: Traumatic brain injury (TBI) is a global epidemic. The incidence of TBI in low and middle-income countries (LMICs) is three times greater than in high-income countries (HICs). Decompressive craniectomy (DC) is a surgical procedure to reduce intracranial pressure (ICP) and prevent secondary injury. Multiple comparative studies, and several randomized controlled trials (RCTs) have been conducted to investigate the influence of DC for patients with severe TBI on outcomes such as mortality, ICP, neurological outcomes, and intensive care unit (ICU) and hospital length of stay. The results of these studies are inconsistent. Systematic reviews and meta-analyses have been conducted in an effort to aggregate the data from the individual studies, and perhaps derive reliable conclusions. The purpose of this project was to conduct a review of the reviews about the effectiveness of DC to improve outcomes. Methods: We conducted a systematic search of the literature to identify reviews and meta-analyses that met our pre-determined criteria. We used the AMSTAR 2 instrument to assess the quality of each of the included reviews, and determine the level of confidence. Results: Of 973 citations from the original search, five publications were included in our review. Four of them included meta-analyses. For mortality, three reviews found a positive effect of DC compared to medical management and two found no significant difference between groups. The four reviews that measured neurological outcome found no benefit of DC. The two reviews that assessed ICP both found DC to be beneficial in reducing ICP. DC demonstrated a significant reduction in ICU length of stay in the one study that measured it, and a significant reduction in hospital length of stay in the two studies that measured it. According to the AMSTAR 2 criteria, the five reviews ranged in levels of confidence from low to critically low. Conclusion: Systematic reviews and meta-analyses are important approaches for aggregating information from multiple studies. Clinicians rely of these methods for concise interpretation of scientific literature. Standards for quality of systematic reviews and meta-analyses have been established to support the quality of the reviews being produced. In the case of DC, more attention must be paid to quality standards, in the generation of both individual studies and reviews.

Management of Pediatric Severe Traumatic Brain Injury: 2019 Consensus and Guidelines-Based Algorithm for First and Second Tier Therapies.

OBJECTIVES: To produce a treatment algorithm for the ICU management of infants, children, and adolescents with severe traumatic brain injury. DATA SOURCES: Studies included in the 2019 Guidelines for the Management of Pediatric Severe Traumatic Brain Injury (Glasgow Coma Scale score ≤ 8), consensus when evidence was insufficient to formulate a fully evidence-based approach, and selected protocols from included studies. DATA SYNTHESIS: Baseline care germane to all pediatric patients with severe traumatic brain injury along with two tiers of therapy were formulated. An approach to emergent management of the crisis scenario of cerebral herniation was also included. The first tier of therapy focuses on three therapeutic targets, namely preventing and/or treating intracranial hypertension, optimizing cerebral perfusion pressure, and optimizing partial pressure of brain tissue oxygen (when monitored). The second tier of therapy focuses on decompressive craniectomy surgery, barbiturate infusion, late application of hypothermia, induced hyperventilation, and hyperosmolar therapies. CONCLUSIONS: This article provides an algorithm of clinical practice for the bedside practitioner based on the available evidence, treatment protocols described in the articles included in the 2019 guidelines, and consensus that reflects a logical approach to mitigate intracranial hypertension, optimize cerebral perfusion, and improve outcomes in the setting of pediatric severe traumatic brain injury.

Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition: Update of the Brain Trauma Foundation Guidelines, Executive Summary.

OBJECTIVES: The purpose of this work is to identify and synthesize research produced since the second edition of these Guidelines was published and incorporate new results into revised evidence-based recommendations for the treatment of severe traumatic brain injury in pediatric patients. METHODS AND MAIN RESULTS: This document provides an overview of our process, lists the new research added, and includes the revised recommendations. Recommendations are only provided when there is supporting evidence. This update includes 22 recommendations, nine are new or revised from previous editions. New recommendations on neuroimaging, hyperosmolar therapy, analgesics and sedatives, seizure prophylaxis, temperature control/hypothermia, and nutrition are provided. None are level I, three are level II, and 19 are level III. The Clinical Investigators responsible for these Guidelines also created a companion algorithm that supplements the recommendations with expert consensus where evidence is not available and organizes possible interventions into first and second tier utilization. The purpose of publishing the algorithm as a separate document is to provide guidance for clinicians while maintaining a clear distinction between what is evidence based and what is consensus based. This approach allows, and is intended to encourage, continued creativity in treatment and research where evidence is lacking. Additionally, it allows for the use of the evidence-based recommendations as the foundation for other pathways, protocols, or algorithms specific to different organizations or environments. The complete guideline document and supplemental appendices are available electronically from this journal. These documents contain summaries and evaluations of all the studies considered, including those from prior editions, and more detailed information on our methodology. CONCLUSIONS: New level II and level III evidence-based recommendations and an algorithm provide additional guidance for the development of local protocols to treat pediatric patients with severe traumatic brain injury. Our intention is to identify and institute a sustainable process to update these Guidelines as new evidence becomes available.

Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition: Update of the Brain Trauma Foundation Guidelines, Executive Summary.

The purpose of this work is to identify and synthesize research produced since the second edition of these Guidelines was published and incorporate new results into revised evidence-based recommendations for the treatment of severe traumatic brain injury in pediatric patients. This document provides an overview of our process, lists the new research added, and includes the revised recommendations. Recommendations are only provided when there is supporting evidence. This update includes 22 recommendations, 9 are new or revised from previous editions. New recommendations on neuroimaging, hyperosmolar therapy, analgesics and sedatives, seizure prophylaxis, temperature control/hypothermia, and nutrition are provided. None are level I, 3 are level II, and 19 are level III. The Clinical Investigators responsible for these Guidelines also created a companion algorithm that supplements the recommendations with expert consensus where evidence is not available and organizes possible interventions into first and second tier utilization. The complete guideline document and supplemental appendices are available electronically (https://doi.org/10.1097/PCC.0000000000001735). The online documents contain summaries and evaluations of all the studies considered, including those from prior editions, and more detailed information on our methodology. New level II and level III evidence-based recommendations and an algorithm provide additional guidance for the development of local protocols to treat pediatric patients with severe traumatic brain injury. Our intention is to identify and institute a sustainable process to update these Guidelines as new evidence becomes available.

Geographical Disparity and Traumatic Brain Injury in America: Rural Areas Suffer Poorer Outcomes.

INTRODUCTION: Significant heterogeneity exists in traumatic brain injury (TBI) outcomes. In the United States, TBI remains a primary driver of injury-related mortality and morbidity. Prior work has suggested that disparity exists in rural areas; our objective was to evaluate potential differences in TBI mortality across urban and rural areas on a national scale. METHODS: Age-adjusted TBI fatality rates were obtained at the county level across the U.S. from 2008 to 2014. To evaluate geography, urban influence codes (UIC) were also obtained at the county level. UIC codes range from 1 (most urban) to 12 (most rural). Metropolitan counties are defined as those with an UIC ≤2, while nonmetropolitan counties are defined as an UIC ≥3. County-level fatality rates and UIC classification were geospatially mapped. Linear regression was used to evaluate the change in TBI fatality rate at each category of UIC. The median TBI fatality rate was also compared between metropolitan and nonmetropolitan counties. RESULTS: Geospatial analysis demonstrated higher fatality rates distributed among nonmetropolitan counties across the United States. The TBI fatality rate was 13.00 deaths per 100,000 persons higher in the most rural UIC category compared to the most urban UIC category (95% confidence interval 12.15, 13.86; P < 0.001). The median TBI rate for nonmetropolitan counties was significantly higher than metropolitan counties (22.32 vs. 18.22 deaths per 100,000 persons, P < 0.001). CONCLUSIONS: TBI fatality rates are higher in rural areas of the United States. Additional studies to evaluate the mechanisms and solutions to this disparity are warranted and may have implications for lower-and middle-income countries.

Predictive Utility of the Total Glasgow Coma Scale Versus the Motor Component of the Glasgow Coma Scale for Identification of Patients With Serious Traumatic Injuries.

STUDY OBJECTIVE: The motor component of the Glasgow Coma Scale (mGCS) has been proposed as an easier-to-use alternative to the total GCS (tGCS) for field assessment of trauma patients by emergency medical services. We perform a systematic review and meta-analysis to compare the predictive utility of the tGCS versus the mGCS or Simplified Motor Scale in field triage of trauma for identifying patients with adverse outcomes (inhospital mortality or severe brain injury) or who underwent procedures (neurosurgical intervention or emergency intubation) indicating need for high-level trauma care. METHODS: Ovid MEDLINE, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Health and Psychosocial Instruments, and the Cochrane databases were searched through June 2016 for English-language cohort studies. We included studies that compared the area under the receiver operating characteristic curve (AUROC) of the tGCS versus the mGCS or Simplified Motor Scale assessed in the field or shortly after arrival in the emergency department for predicting the outcomes described above. Meta-analyses were performed with a random-effects model, and subgroup and sensitivity analyses were conducted. RESULTS: We included 18 head-to-head studies of predictive utility (n=1,703,388). For inhospital mortality, the tGCS was associated with slightly greater discrimination than the mGCS (pooled mean difference in [AUROC] 0.015; 95% confidence interval [CI] 0.009 to 0.022; I2=85%; 12 studies) or the Simplified Motor Scale (pooled mean difference in AUROC 0.030; 95% CI 0.024 to 0.036; I2=0%; 5 studies). The tGCS was also associated with greater discrimination than the mGCS or Simplified Motor Scale for nonmortality outcomes (differences in AUROC from 0.03 to 0.05). Findings were robust in subgroup and sensitivity analyses. CONCLUSION: The tGCS is associated with slightly greater discrimination than the mGCS or Simplified Motor Scale for identifying severe trauma. The small differences in discrimination are likely to be clinically unimportant and could be offset by factors such as convenience and ease of use.

Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition.

The scope and purpose of this work is 2-fold: to synthesize the available evidence and to translate it into recommendations. This document provides recommendations only when there is evidence to support them. As such, they do not constitute a complete protocol for clinical use. Our intention is that these recommendations be used by others to develop treatment protocols, which necessarily need to incorporate consensus and clinical judgment in areas where current evidence is lacking or insufficient. We think it is important to have evidence-based recommendations to clarify what aspects of practice currently can and cannot be supported by evidence, to encourage use of evidence-based treatments that exist, and to encourage creativity in treatment and research in areas where evidence does not exist. The communities of neurosurgery and neuro-intensive care have been early pioneers and supporters of evidence-based medicine and plan to continue in this endeavor. The complete guideline document, which summarizes and evaluates the literature for each topic, and supplemental appendices (A-I) are available online at https://www.braintrauma.org/coma/guidelines.

Postdischarge Care of Pediatric Traumatic Brain Injury in Argentina: A Multicenter Randomized Controlled Trial.

OBJECTIVE: To develop, in partnership with families of children with traumatic brain injury, a postdischarge intervention that is effective, simple, and sustainable. DESIGN: Randomized Controlled Trial. SETTING: Seven Level 1 Pediatric Trauma Centers in Argentina. PATIENTS: Persons less than 19 years of age admitted to one of the study hospitals with a diagnosis of severe, moderate, or complicated mild traumatic brain injury and were discharged alive. INTERVENTIONS: Patients were randomly assigned to either the intervention or standard care group. A specially trained Community Resource Coordinator was assigned to each family in the intervention group. We hypothesized that children with severe, moderate, and complicated mild traumatic brain injury who received the intervention would have significantly better functional outcomes at 6 months post discharge than those who received standard care. We further hypothesized that there would be a direct correlation between patient outcome and measures of family function. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was a composite measured at 6 months post injury. There were 308 patients included in the study (61% men). Forty-four percent sustained a complicated mild traumatic brain injury, 18% moderate, and 38% severe. Sixty-five percent of the patients were 8 years old or younger, and over 70% were transported to the hospital without ambulance assistance. There was no significant difference between groups on the primary outcome measure. There was a statistically significant correlation between the primary outcome measure and the scores on the Family Impact Module of the Pediatric Quality of Life Inventory (ρ = 0.57; p < 0.0001). Children with better outcomes lived with families reporting better function at 6 months post injury. CONCLUSIONS: Although no significant effect of the intervention was demonstrated, this study represents the first conducted in Latin America that documents the complete course of treatment for pediatric patients with traumatic brain injury spanning hospital transport through hospital care and into the postdischarge setting.

Results of early cranial decompression as an initial approach for damage control therapy in severe traumatic brain injury in a hospital with limited resources.

INTRODUCTION: Severe traumatic brain injury (sTBI) is a disease that generates significant mortality and disability in Latin America, and specifically in Colombia. The purpose of this study was to evaluate the 12-month clinical outcome in patients with sTBI managed with an early cranial decompression (ECD) as the main procedure for damage control (DC) therapy, performed in a University Hospital in Colombia over a 4-year period. MATERIALS AND METHODS: A database of 106 patients who received the ECD procedure, and were managed according to the strategy for DC in neurotrauma, was analyzed. Variables were evaluated, and the patient outcome was determined according to the Glasgow Outcome Score (GOS) at 12 months postinjury. This was used to generate a dichotomous variable with "favorable" (GOS of 4 or 5) or "unfavorable" (GOS of 1-3) outcomes; analysis of variance was performed with the Chi-square, Wilcoxon-Mann-Whitney and Fisher tests. RESULTS: An overall survival rate of 74.6% was observed for the procedure, At 12 months postsurgery, a favorable clinical outcome (GOS 4-5) was found in 70 patients (66.1%), Unfavorable outcomes in patients were associated with the following factors: Closed trauma, an Injury Severity Score >16, obliterated basal cisterns, subdural hematoma as the main injury seen on the admission computed tomography, and nonreactive pupils observed in the emergency department. CONCLUSION: Twelve months outcome of patients with sTBI managed with ECD in a neuromonitoring limited resource University Hospital in Colombia shows an important survival rate with favorable clinical outcome measure with GOS.

Damage control of civilian penetrating brain injuries in environments of low neuro-monitoring resources.

INTRODUCTION: Gunshot wounds to the head are more common in military settings. Recently, a damage control (DC) approach for the management of these lesions has been used in combat areas. The aim of this study was to evaluate the results of civilian patients with penetrating gunshot wounds to the head, managed with a strategy of early cranial decompression (ECD) as a DC procedure in a university hospital with few resources for intensive care unit (ICU) neuro-monitoring in Colombia. MATERIALS AND METHODS: Fifty-four patients were operated according to the DC strategy (<12 h after injury), over a 4-year period. Variables were analysed and results were evaluated according to the Glasgow Outcome Scale (GOS) at 12 months post injury; a dichotomous variable was established as 'favourable' (GOS 4-5) or 'unfavourable' (GOS 1-3). A univariate analysis was performed using a χ(2) test. RESULTS: Forty (74.1%) of the patients survived and 36 (90%) of them had favourable GOS. Factors associated with adverse outcomes were: Injury Severity Score (ISS) greater than 25, bi-hemispheric involvement, intra-cerebral haematoma on the first CT, closed basal cisterns and non-reactive pupils in the emergency room. CONCLUSION: DC for neurotrauma with ECD is an option to improve survival and favourable neurological outcomes 12 months after injury in patients with penetrating traumatic brain injury treated in a university hospital with few resources for ICU neuro-monitoring.

Global neurotrauma research challenges and opportunities.

Traumatic injury to the brain or spinal cord is one of the most serious public health problems worldwide. The devastating impact of 'trauma', a term used to define the global burden of disease related to all injuries, is the leading cause of loss of human potential across the globe, especially in low- and middle-income countries. Enormous challenges must be met to significantly advance neurotrauma research around the world, specifically in underserved and austere environments. Neurotrauma research at the global level needs to be contextualized: different regions have their own needs and obstacles. Interventions that are not considered a priority in some regions could be a priority for others. The introduction of inexpensive and innovative interventions, including mobile technologies and e-health applications, focused on policy management improvement are essential and should be applicable to the needs of the local environment. The simple transfer of a clinical question from resource-rich environments to those of low- and middle-income countries that lack sophisticated interventions may not be the best strategy to address these countries' needs. Emphasis on promoting the design of true 'ecological' studies that include the evaluation of human factors in relation to the process of care, analytical descriptions of health systems, and how leadership is best applied in medical communities and society as a whole will become crucial.

Concussion guidelines step 1: systematic review of prevalent indicators.

BACKGROUND: Currently, there is no evidence-based definition for concussion that is being uniformly applied in clinical and research settings. OBJECTIVE: To conduct a systematic review of the highest-quality literature about concussion and to assemble evidence about the prevalence and associations of key indicators of concussion. The goal was to establish an evidence-based foundation from which to derive, in future work, a definition, diagnostic criteria, and prognostic indicators for concussion. METHODS: Key questions were developed, and an electronic literature search from 1980 to 2012 was conducted to acquire evidence about the prevalence of and associations among signs, symptoms, and neurologic and cognitive deficits in samples of individuals exposed to potential concussive events. Included studies were assessed for potential for bias and confound and rated as high, medium, or low potential for bias and confound. Those rated as high were excluded from the analysis. Studies were further triaged on the basis of whether the definition of a case of concussion was exclusive or inclusive; only those with wide, inclusive case definitions were used in the analysis. Finally, only studies reporting data collected at fixed time points were used. For a study to be included in the conclusions, it was required that the presence of any particular sign, symptom, or deficit be reported in at least 2 independent samples. RESULTS: From 5437 abstracts, 1362 full-text publications were reviewed, of which 231 studies were included in the final library. Twenty-six met all criteria required to be used in the analysis, and of those, 11 independent samples from 8 publications directly contributed data to conclusions. Prevalent and consistent indicators of concussion are (1) observed and documented disorientation or confusion immediately after the event, (2) impaired balance within 1 day after injury, (3) slower reaction time within 2 days after injury, and/or (4) impaired verbal learning and memory within 2 days after injury. CONCLUSION: The results of this systematic review identify the consistent and prevalent indicators of concussion and their associations, derived from the strongest evidence in the published literature. The product is an evidence-based foundation from which to develop diagnostic criteria and prognostic indicators.