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

Abstract

Severe Traumatic Brain Injury in Infants, Children, and Adolescents in 2019: Some Overdue Progress, Many Remaining Questions, and Exciting Ongoing Work in the Field of Traumatic Brain Injury Research In this Supplement to Pediatric Critical Care Medicine, we are pleased to present the Third Edition of the Guidelines for the Management of Pediatric Severe Traumatic Brain Injury (TBI). This body of work updates the Second Edition of the guidelines that was published in 2012 (1). It represents a substantial effort by a multidisciplinary group of individuals assembled to reflect the team approach to the treatment of these complex, critically ill patients that is essential to optimizing critical care and improving outcomes. This work also represents the strong and always-evolving partnership between investigators from the medical and research communities, forged in Chicago in 2000, from which the first pediatric TBI guidelines were developed. The mutual trust and respect we share have been the foundation of our commitment to bringing evidence-based care to children with TBI. Updating these guidelines was particularly exciting to the individuals who have participated in the previous two editions because several new studies have been published which begin to address a number of major gaps in the pediatric TBI literature—gaps that were specifically identified as targets for future research in earlier editions. For example, we are now able to include reports on the effects of commonly used sedatives and analgesics on intracranial pressure (ICP). Similarly, initial head-to-head comparisons of the influence of agents in routine “real world” use such as hypertonic saline (HTS), fentanyl, and others now inform these guidelines (2,3). A total of 48 new studies were included in this Third Edition. Although some progress has been made and should be celebrated, overall the level of evidence informing these guidelines remains low. High-quality randomized studies that could support level I recommendations remain absent; the available evidence produced only three level II recommendations, whereas most recommendations are level III, supported by low-quality evidence. Based in part on a number of requests from the readership to individual clinical investigators, we have included a companion article in the regular pages of Pediatric Critical Care Medicine that presents a “Critical Pathway” algorithm of care for both first-tier and second-tier (refractory intracranial hypertension) approaches. The algorithm reflects both the evidence-based recommendations from these guidelines and consensus-based expert opinion, vetted by the clinical investigators, where evidence was not available. An algorithm was provided in the First but not Second Editions of the guidelines, and we believe that given the new reports available, along with the existing gaps in evidence, a combination of evidence-based and consensus-based recommendations provides additional and much-needed guidance for clinicians at the bedside. The algorithm also addresses a number of issues that are important but were not previously covered in the guidelines, given the lack of research and the focus on evidence-based recommendations. This includes addressing issues such as a stepwise approach to elevated ICP, differences in tempo of therapy in different types of patients, scenarios with a rapidly escalating need for ICP-directed therapy in the setting of impending herniation, integration of multiple monitoring targets, and other complex issues such as minimal versus optimal therapeutic targets and approaches to weaning therapies. We hope that the readership finds the algorithm document helpful, recognizing that it represents a challenging albeit important step. Designing and developing this pediatric TBI evidence-based guidelines document required an expert administrative management team, and to that end, we are extremely grateful to the staff of the Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, for their vital contribution to this work. We are also grateful to the Brain Trauma Foundation and the Department of Defense for supporting the development and publication of these guidelines documents. We are grateful to the endorsing societies for recognizing the importance of this work and for the considerable work of the clinical investigators in constructing the final document. We are also pleased to have collaborated with the Congress of Neurological Surgeons and the journal Neurosurgery that is copublishing the Executive Summary document of these guidelines for its readership. We are also grateful to Hector Wong for serving as Guest Editor, along with the external reviewers of this final document. Finally, we thank each of the clinical investigators and coauthors on this project. We believe that the considerable uncompensated time and effort devoted to this important project will help to educate clinicians worldwide and enhance the outcomes of children with severe TBI. Clinical investigators provided Conflict of Interest Disclosures at the beginning of the process, which were re-reviewed at the time of publication. No clinical investigator made inclusion decisions or provided assessments on publications for which they were an author. Looking forward, it is important to recognize that these guidelines were written as the Approaches and Decisions in Acute Pediatric TBI Trial (ADAPT) (4–6), one of the most important in the field of pediatric TBI, was coming to a close. The ADAPT completed enrollment of 1,000 cases of severe pediatric TBI and is one example of the recent heightened general interest in TBI as a disease. This new interest in the importance of TBI has emerged in part from the recognition of the high prevalence of TBI across the injury severity spectrum, particularly concussion, and from the need for new classification systems and new trial design for TBI in both children and adults (7,8). In addition, the emerging links between TBI and a number of neurodegenerative diseases have broadened the interest in TBI, have led to additional support of TBI research, and have produced an unprecedented level of research in TBI and a quest for new therapies (9–11). We expect that the results of ADAPT, along with those of other ongoing and recently completed research in the field, will help provide new insight and clarity into the acute medical management (MM) of infants, children, and adolescents with severe TBI, and mandate further refinement of the recommendations in these documents. We know that we speak for the entire team of clinical investigators in welcoming the opportunity to incorporate additional high-level evidence into future updates of these guidelines. METHODS The methods for developing these guidelines were organized in two phases: a systematic review, assessment, and synthesis of the literature; and use of that product as the foundation for evidence-based recommendations. These guidelines are the product of the two-phased, evidence-based process. Based on almost 2 decades of collaboration, the team of clinical investigators and methodologists (Appendix A, Supplemental Digital Content 1, https://links.lww.com/PCC/A774) is grounded in and adheres to the fundamental principles of evidence-based medicine to derive recommendations, and is committed to maintaining the distinction between evidence and consensus. It is important that this distinction is clear to promote transparency and inspire innovative future research that will expand the evidence base for TBI care. Because these guidelines only provide recommendations based on available evidence, most often they do not provide direction for all phases of clinical care. Ideally, clinically useful protocols begin with evidence-based guidelines, and then use clinical experience and consensus to fill the gaps where evidence is insufficient. The goal is to use the evidence and the evidence-based recommendations as the backbone to which expertise and consensus can be added to produce protocols appropriate to specific clinical environments (Fig. 1, “Future Research section”). In a process independent from developing this Third Edition of the guidelines, the team engaged in a consensus process and produced the algorithm for treatment of severe TBI in pediatric patients.Figure 1.: Dynamic process for guidelines, protocols, and future research. The diagram shows the flow of information from available evidence to a guideline. The guideline leads to gaps that identify future research and consensus-based clinical protocols that fill gaps, both of which lead to a generation of new research.The following “Methods section” describes the process we used to produce the systematic review and evidence-based recommendations. The methods used to develop the algorithm are described in that document (12). Phase I: Systematic Evidence Review and Synthesis Scope of the Systematic Review Criteria for Including Publications Appendix B (Supplemental Digital Content 1, https://links.lww.com/PCC/A774) lists the criteria for including studies for review using the categories of population, interventions, comparators, outcomes, timing, settings, study designs, and publication types. The criteria for population are as follows: Age 18 years old or younger TBI Glasgow Coma Scale (GCS) score less than 9 Included Topics. The team chose to carry forward topics from the Second Edition of these guidelines. No new topics were added. The topics are organized in three categories that are specific to severe TBI in children: monitoring, thresholds, and treatments. Monitoring 1. ICP 2. Advanced neuromonitoring 3. Neuroimaging Thresholds 4. ICP 5. Cerebral perfusion pressure (CPP) Treatments 6. Hyperosmolar therapy 7. Analgesics, sedatives, and neuromuscular blockade (NMB) 8. Cerebrospinal fluid (CSF) drainage 9. Seizure prophylaxis 10. Ventilation therapies 11. Temperature control 12. Barbiturates 13. Decompressive craniectomy 14. Nutrition 15. Corticosteroids Major Changes for This Edition. Major changes for this edition are summarized here, and details are provided in Appendix C (Supplemental Digital Content 1, https://links.lww.com/PCC/A774). The clinical investigators and methods team identified three primary endpoints considered important health outcomes for pediatric patients with TBI: To improve overall outcomes (mortality, morbidity, function) To control ICP To prevent posttraumatic seizures (PTSs) Two new meta-analyses were added to the evidence base for temperature control. The title of “Hyperventilation” was changed to “Ventilation Therapies.” Recommendations are provided as level I, II, or III. In some cases, publications from the second edition were not included in this 3rd Edition. Our rationale for excluding previously included studies was based on identification of current material that superseded our earlier work (See Appendix E, Supplemental Digital Content 1, https://links.lww.com/PCC/A774). Similarly, we removed or changed recommendations from the 2nd Edition when the current literature provided new and/or more accurate information (see Appendix A, Supplemental Digital Content 1, https://links.lww.com/PCC/A774). Study Selection and Compilation of Evidence Literature Search Strategies. The research librarian who worked on the Second Edition reviewed and updated the search strategies for that edition and executed the searches for this Third Edition. Ovid/MEDLINE was searched from 2010 to May of 2015, and an update was performed to include articles published and indexed through June of 2017. Publications recommended by peers that were not captured in the search were reviewed, and those meeting inclusion criteria were included in the final library. The search strategy is in Appendix D (Supplemental Digital Content 1, https://links.lww.com/PCC/A774). Abstract and Full-Text Review. Abstracts for publications captured in the search were reviewed independently by two members of the methods team. Articles were retained for full-text review if at least one person considered them relevant based on the abstract. Two methods team members read each full-text article and determined whether it met the inclusion criteria (Appendix B, Supplemental Digital Content 1, https://links.lww.com/PCC/A774). The included and excluded full-text articles for each topic were also reviewed by one or more clinical investigators who took the lead on each topic, and full-text articles were available for review by all authors. The key criteria for inclusion were as follows: the study population was pediatric patients (age, ≤ 18 yr old) with severe TBI (defined as GCS score of 3–8) and the study assessed an included outcome. Publications with samples that included adults, moderate or mild severities, or pathologies other than TBI (indirect evidence) were considered when direct evidence was limited or not available. Discrepancies between reviewers were resolved via consensus or by a third reviewer. A list of studies excluded after full-text review is in Appendix E (Supplemental Digital Content 1, https://links.lww.com/PCC/A774). Use of Indirect Evidence and Intermediate Outcomes Direct evidence comes from studies that compare important health outcomes (e.g., mortality, morbidity, function) between two or more intervention groups or between an intervention group and a control group that represent the population of interest, in this case pediatric patients with severe TBI. When direct evidence was limited or not available, indirect evidence was used to support a recommendation. Indirect evidence has been defined in previous work by this methods team (1,13,14) and other evidence-based methods groups (15,16). In this edition, we included two types of indirect evidence. 1. Evidence That Improvement in an Intermediate Outcome Is Associated With Important Health Outcomes In some cases, there is a lack of direct evidence that utilization of a specific treatment option results in improved patient outcomes such as mortality or morbidity, but there is evidence about changes in an intermediate outcome, which is then associated with improved mortality or morbidity. The most notable intermediate outcome for the treatment of TBI is management of ICP. Multiple studies (cited in the ICP Monitoring topic of this guideline) consistently demonstrate that patients whose ICP is successfully maintained at or under a maximum threshold have reduced mortality and improved function. As a consequence, the clinical investigators elected to identify “Control of ICP” as an important intermediate outcome, and use the available indirect evidence to support the recommendations about monitoring ICP and for treatments designed to lower ICP. Intermediate outcomes and indirect evidence of this nature were used in three topics for this edition of the guidelines: ICP Monitoring, Ventilation Therapies, and Temperature Control. In each of these topics, an intermediate outcome was used as the endpoint because, although direct evidence was lacking that intervening improves mortality or function, indirect evidence was available associating management of the intermediate outcome with improved mortality or function. For ICP monitoring, the intermediate outcome was managed ICP; indirect evidence that patients with managed ICP had better outcomes was used to support the recommendation. For ventilation therapies, the intermediate outcomes were prevention of severe hypocarbia (SH). There were no pediatric studies that directly related hyperventilation to poor outcomes. However, there was evidence of an association between SH and mortality; thus, studies that demonstrated this association were used as indirect evidence. For temperature control, the intermediate outcomes were mean and peak CSF myelin basic protein concentrations and phenytoin levels. 2. Evidence From Samples With Mixed Ages, Severities, or Pathologies In some cases, when direct evidence was lacking, we considered studies that included patients with mixed severities (mild, moderate, and severe TBI), mixed ages, or mixed pathologies (traumatic and non-TBI) using the following criteria: How relevant to (or different from) our target population is the population in the indirect study? To what extent does the relevant physiology of the population in the indirect study approximate the relevant physiology of the population of interest? To what extent are differences in physiology expected to influence the outcome? In what direction would these differences influence the observed effect? In this edition, indirect evidence from studies with mixed severities, ages, or pathologies was included in the topics about analgesics, sedatives, and NMB; CSF drainage; and seizure prophylaxis. When indirect evidence was included, it is noted in the table describing the quality of the body of evidence. Quality Assessment of Individual Studies All included studies were assessed for potential for bias, which is an approach to assessing the internal validity or quality of an individual study. This assessment is a core component of systematic review methods. It is an approach to considering and rating studies in terms of how the study design and conduct addressed issues such as selection bias, confounding, and attrition. The criteria used for this edition are described in Appendix F (Supplemental Digital Content 1, https://links.lww.com/PCC/A774). Two reviewers independently evaluated each study using the criteria appropriate for the study design (i.e., randomized controlled trials [RCTs], observational studies, studies of thresholds) and rated the study as class 1, 2, or 3 evidence based on the combination of study design and conduct. Class 1 is the highest class and is limited to good-quality RCTs. Class 2 includes moderate-quality RCTs and good-quality cohort or case-control studies. Class 3 is the lowest class and is given to low-quality RCTs, moderate- to low-quality cohort or case-control studies, and treatment series and other noncomparative designs. Differences in ratings were reconciled via consensus or the inclusion of a third reviewer as needed. Data Abstraction Data were abstracted from studies by a member of the methods team and checked for accuracy by a second member. Information was recorded about the study population, design, and results. Key elements of each included study are presented in the Summary of Evidence tables for each topic. Complete abstraction tables are available upon request. Synthesis The final phase of the evidence review is the synthesis of individual studies into information that the clinical investigators and the methods team use to develop recommendations. This synthesis is described for each topic in the section titled “Evaluation of the Evidence,” following the Recommendations and preceding the Evidence Summary. Identification of Subtopics and Synthesis For each monitoring, thresholds, or treatment topic, the clinical investigators identified important subtopics or clinical questions. The studies in each topic were reviewed to determine if quantitative synthesis—meta-analysis—was feasible. This involved determining if the patient populations, specifics of the intervention, and the outcomes were similar enough across several studies that the study results could be combined. The result of this assessment is included in the Quality of the Body of Evidence table for each subtopic. For this edition, we did not identify any topics for which quantitative synthesis was appropriate according to current standards. For this reason, the evidence was synthesized qualitatively. Quality of the Body of Evidence Assessing the quality of the body of evidence involves four domains: the aggregate quality of the included individual studies, the consistency of the results across studies, whether the evidence provided is direct or indirect, and the precision of the estimates of the outcomes. The criteria and ratings are outlined below, and more detailed definitions are given in Appendix G (Supplemental Digital Content 1, https://links.lww.com/PCC/A774). In addition, the number of studies and number of included subjects are considered. Based on these, an overall assessment is made as to whether the quality of the body of evidence is high, moderate, low, or insufficient. The assessment of the body of evidence for each subtopic is included in a summary table in each section following the recommendations. Criteria Quality of Individual Studies: This identifies the quality of the individual studies. It details how many studies are class 1, class 2, and class 3. Consistency: Consistency is the extent to which the results and conclusions are similar across studies. It is rated high (all are similar), moderate (most are similar), or low (no one conclusion is more frequent). It is not applicable when the body of evidence consists of a single study. Directness: We define directness as whether the study population is the same as the population of interest and whether the outcomes are clinical rather than intermediate outcomes. Evidence is labeled as direct, indirect, or mixed. Precision: Precision is the degree of certainty surrounding the effect estimate for a given outcome. Precision is rated high, moderate, or low. How this is determined depends on the type of analysis used in a specific study but may include consideration of the width of CIs, other indicators of variance, or the magnitude of p values used to determine statistical significance. Ratings. These criteria are then considered when assigning a rating to the body of evidence. The ratings are defined as follows: High: High confidence that the evidence reflects the true effect. Further research is very unlikely to change the confidence in the estimate of effect. Moderate: Moderate confidence that the evidence reflects the true effect. Further research may change the confidence in the estimate of effect and may change the estimate. Low: Low confidence that the evidence reflects the true effect. Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate. Insufficient: Evidence is unavailable or does not permit a conclusion. A determination of quality of the body of evidence requires a judgment about the relative importance of the criteria, and these may vary across topics and subtopics. The following general examples are provided to illustrate the variations that are possible but are not intended as exhaustive decision rules. If two or more class 1 studies demonstrate contradictory findings for a particular topic, the overall quality of the body of evidence may be assessed as low because there is uncertainty about the effect. Similarly, class 1 or 2 studies that provide indirect evidence may only constitute low-quality evidence overall. In some cases, the body of evidence may be a single study, but the rating may vary. A single study may constitute a high-quality body of evidence if it is a large, multisite, class 1 RCT; a moderate-quality body of evidence if it is a single-site, class 2 study with a sizable sample and moderate precision; or insufficient evidence if the sample is small and the precision of the estimate of effect is low. Applicability Applicability is the extent to which research findings are useful for informing recommendations for a broader population (usually the population that is the target of the recommendations). What is important to consider when assessing applicability will vary depending on the topic, and the assessment is context specific. Consequently, there is currently no generally accepted universal rating system for applicability. Common considerations focus on the characteristics of the patient population (e.g., to which patients are the results applicable?) and the settings for care delivery (e.g., where could a similar result be expected?). Even if the patient population meets the inclusion criteria established for the review, there may be specific characteristics that affect applicability. The characteristics of the setting in which a study was conducted may also be important to consider. For example, a study conducted in a Veterans Administration (VA) Medical Center may or may not be applicable to other settings, depending on how similar the Veterans are to the population of interest or how similar the context of the VA is to the care setting of interest. Additional characteristics to be considered may include the geographic location (e.g., country, state, urban, or rural) and the type of hospital (e.g., level of trauma center). The geographic area and type of hospital are considered because it is possible that the patients, practice patterns, and available services are different across environments. In this edition, we consider the applicability of individual studies in the “Quality of the Body of Evidence and Applicability section” immediately following the recommendations. Phase II: Development of Recommendations Inclusion of Recommendations Class 1, 2, or 3 studies constitute the evidence on which the recommendations are based. Under our current methods, identification of evidence is necessary but not sufficient for the development of recommendations. No recommendations were made without a basis in evidence. Once evidence was identified, whether it could be used to inform recommendations was based on the quality of the body of evidence and consideration of applicability. Given this, there were cases in which evidence was identified, but the quality was low and applicability concerns restricted our ability to translate the evidence into recommendations. Even if a recommendation was not made, the evidence was included for future consideration because in the future, new studies may be added, resulting in changes in the assessment of the quality of the body of evidence. Level of Recommendation Recommendations in this edition are designated as level I, level II, or level III. The level of recommendation is determined by the assessment of the quality of the body of evidence, rather than the class of the included studies. The levels were primarily based on the quality of the body of evidence as follows: Level I recommendations were based on a high-quality body of evidence. Level II recommendations were based on a moderate-quality body of evidence. Level III recommendations were based on a low-quality body of evidence. Applicability could result in a level III recommendation (e.g., a “moderate-quality body of evidence” with significant applicability concerns). In this edition, applicability alone was not used to downgrade a recommendation. However, given the lack of standards and developed methods in this area, we cited applicability issues that were identified and discussed by the clinical investigators. “Insufficient” was used in cases where there were no studies identified or because the body of evidence had major quality limitations. If the evidence was insufficient, no recommendations were made. Recommendation Review and Revision Preliminary Topic Reviews. After completion of the literature review, identification of new studies, quality assessment, and data abstraction, the methods team sent drafts for each topic to two clinical investigators. The clinical investigators read the included studies and the draft recommendations, provided input, and suggested additional studies for consideration. Methods team members incorporated the input, acquired and reviewed new studies, and provided the clinical investigators with new publications and a revised summary of the evidence for each topic. Clinical Investigator Review Meeting. In a day-long meeting in 2016, each topic was presented and discussed by the group. Based on these discussions, the methods team revised the draft guidelines. Review of Complete Draft. The complete draft of all topics and the other sections of the guidelines (e.g., Methods; Appendices, Supplemental Digital Content 1, https://links.lww.com/PCC/A774) was sent to all clinical investigators for review and comment. Phone conferences and e-mail exchanges occurred through April 2018 to answer questions, discuss the draft, and finalize the document. Peer Review. After revisions were made based on input from the clinical investigators, the complete, revised Third Edition and an Executive Summary were sent to the journal Pediatric Critical Care Medicine for peer review. A comprehensive peer review was also conducted by members of the American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Guidelines Review Committee, in collaboration with the clinical investigators and methods team, to facilitate publication in the journal Neurosurgery. MONITORING ICP Monitoring Recommendations Strength of Recommendations: Weak Levels I and II There was insufficient evidence to support a level I or II recommendation for this topic. Level III To Improve Overall Outcomes. III.1. Use of ICP monitoring is suggested. Changes From Prior Edition. There are no content changes from the Second Edition to the recommendations. Three new class 3 retrospective observational studies were added to the evidence base for this topic (17–19). Introduction Secondary injury to the brain after severe TBI is a result of a pathophysiologic cascade of events that reduces perfusion of surviving neural tissue, oxygen and metabolite delivery, and clearance of metabolic waste and toxins. Brain swelling resulting from vasogenic and or cytotoxic edema, occurring within the closed compartment of the skull, leads to intracranial hypertension, cerebral herniation syndromes, further focal ischemic injury, and brainstem compression. Sustained elevation of ICP thus represents a key pathophysiologic variable in the occurrence of secondary brain injury phase following TBI (20–22). Since the late 1970s, significant improvements in both survival and functional outcome after severe TBI have been achieved using intens