Severe Traumatic Brain Injury

Inflicted Childhood Neurotrauma: New Insight into The Detection, Pathobiology, Prevention, and Treatment of Our Youngest Patients with Traumatic Brain Injury

Kochanek, Patrick M. MD, MCCM; Herrmann, Jeremy R. MD; Bleck, Thomas P. MD, MCCM, FNCS Author Information

Chapter 8. Hyperosmolar therapy

I. RECOMMENDATIONS Strength of Recommendations: Weak. Quality of Evidence: Low, from poor-quality class III studies. A. Level I There are insufficient data to support a level I recommendation for this topic. B. Level II There are insufficient data to support a level II recommendation for this topic. C. Level III* Etomidate may be considered to control severe intracranial hypertension; however, the risks resulting from adrenal suppression must be considered. Thiopental may be considered to control intracranial hypertension. *In the absence of outcome data, the specific indications, choice and dosing of analgesics, sedatives, and neuromuscular-blocking agents used in the management of infants and children with severe traumatic brain injury (TBI) should be left to the treating physician. *As stated by the Food and Drug Administration, continuous infusion of propofol for either sedation or the management of refractory intracranial hypertension in infants and children with severe TBI is not recommended. II. EVIDENCE TABLE (see Table 1)Table 1: Evidence tableIII. OVERVIEW Analgesics, sedatives, and neuromuscular-blocking agents are commonly used in the management severe pediatric TBI. Use of these agents can be divided into two major categories: 1) for emergency intubation; and 2) for management including control of elevated intracranial pressure (ICP) in the intensive care unit (ICU). This chapter evaluates these agents during ICU treatment. Analgesics and sedatives are believed to favorably treat a number of important pathophysiological derangements in severe TBI. They can facilitate necessary general aspects of patient care such as the ability to maintain the airway, vascular catheters, and other monitors. They can also facilitate patient transport for diagnostic procedures and mechanical ventilatory support. Other proposed benefits of sedatives after severe TBI include anticonvulsant and antiemetic actions, the prevention of shivering, and attenuating the long-term psychological trauma of pain and stress. Analgesics and sedatives also are believed to be useful by mitigating aspects of secondary damage. Pain and stress markedly increase cerebral metabolic demands and can pathologically increase cerebral blood volume and raise ICP. Studies in experimental models showed that a two- to threefold increase in cerebral metabolic rate for oxygen accompanies painful stimuli (1, 2). Noxious stimuli such as suctioning can also increase ICP (3–6). Painful and noxious stimuli and stress can also contribute to increases in sympathetic tone with hypertension and bleeding from operative sites (7). However, analgesic or sedative-induced reductions in arterial blood pressure can lead to cerebral ischemia as well as vasodilation and can exacerbate increases in cerebral blood volume and ICP. In the absence of advanced neuromonitoring, care must be taken to avoid this complication. The ideal sedative for patients with severe TBI has been described as one that is rapid in onset and offset, easily titrated to effect, has well-defined metabolism (preferably independent of end-organ function), neither accumulates nor has active metabolites, exhibits anticonvulsant actions, has no adverse cardiovascular or immune actions, and lacks drug–drug interactions while preserving the neurologic examination (8). Neuromuscular-blocking agents have been suggested to reduce ICP by a variety of mechanisms including a reduction in airway and intrathoracic pressure with facilitation of cerebral venous outflow and by prevention of shivering, posturing, or breathing against the ventilator (9). Reduction in metabolic demands by elimination of skeletal muscle contraction has also been suggested to represent a benefit. Risks of neuromuscular blockade include the potential devastating effect of hypoxemia secondary to inadvertent extubation, risks of masking seizures, increased incidence of nosocomial pneumonia (shown in adults with severe TBI) (9), cardiovascular side effects, immobilization stress (if neuromuscular blockade is used without adequate sedation/analgesia), and increased ICU length of stay (9, 10). Myopathy is most commonly seen with the combined use of nondepolarizing agents and corticosteroids. Incidence of this complication varies between 1% and over 30% of cases (5, 11, 12). Monitoring of the depth of neuromuscular blockade can shorten duration of its use in the ICU (13). IV. PROCESS For this update, MEDLINE was searched from 1996 through 2010 (Appendix B for search strategy), and results were supplemented with literature recommended by peers or identified from reference lists. Of 46 potentially relevant studies, two were included as evidence for this topic. V. SCIENTIFIC FOUNDATION The recommendations on the use of analgesics, sedatives, and neuromuscular-blocking agents in this chapter are for patients with a secure airway who are receiving mechanical ventilatory support yielding the desired arterial blood gas values and who have stable systemic hemodynamics and intravascular volume status. Two class III studies of the use of analgesics or sedatives met inclusion criteria for this topic and provide evidence to support the recommendations: one study about etomidate and one about thiopental. These studies only addressed ICP as the outcome (14, 15). No study addressed the most commonly used analgesics and sedatives (narcotics and benzodiazepines). Etomidate A study by Bramwell et al (14) carried out a prospective unblinded class III study of the effect of a single dose of etomidate (0.3 mg/kg, intravenously) on ICP >20 mm Hg in eight children with severe TBI. Etomidate reduced ICP vs. baseline in each 5-min interval during the 30-min study period. The patients in this study had severe intracranial hypertension and etomidate reduced ICP from 32.8 ± 6.6 mm Hg to 21.2 ± 5.2 mm Hg. An increase in cerebral perfusion pressure was also seen that was significant for the initial 25 mins after etomidate administration. Every patient in the study exhibited a reduction in ICP with treatment. No data were presented on cortisol levels in these patients. However, in the discussion section of the manuscript, the authors indicated that at 6 hrs after etomidate administration, adrenocorticotropic hormone stimulation tests were performed on each patient; four of the eight showed adrenal suppression. It is unclear if this degree of adrenal suppression is different from that normally observed in pediatric TBI (16). No patient showed clinical signs of adrenal insufficiency such as electrolyte disturbances or blood pressure lability, and no patient received steroid therapy. The availability of other sedatives and analgesics that do not suppress adrenal function, small sample size and single-dose administration in the study discussed previously, and limited safety profile in pediatric TBI limit the ability to endorse the general use of etomidate as a sedative other than as an option for single-dose administration in the setting of raised ICP. Barbiturates Barbiturates can be given as a sedative at doses lower than those required to induce or maintain barbiturate coma. No report specifically addressed their use in that capacity in pediatric TBI. One report did, however, address the effects of barbiturate administration outside of the setting of refractory raised ICP. A study by de Bray et al (15) was a prospective study of the effect of a single dose of thiopental (5 mg/kg, intravenously) on middle cerebral artery flow velocity in ten children with severe TBI and compared the findings with those seen with thiopental administration in ten children under general anesthesia for orthopedic procedures. In this small study, effects on ICP were assessed in only six of the ten children with severe TBI. In those six, thiopental reduced ICP by 48%. Flow velocity was reduced by approximately 15% to 21% in the pediatric patients with TBI. Baseline ICP was 16.5 mm Hg. Cerebral perfusion pressure was not significantly changed. At the class III level, this study supports the ability of thiopental, administered as a single dose, to reduce ICP, even when only moderately increased. The effects on flow velocity are also consistent with the reduction in cerebral blood volume that would be expected to mediate the reduction in ICP produced by thiopental. No study was identified, however, that specifically addressed barbiturate use as a sedative on any other outcome parameter. VI. INFORMATION FROM OTHER SOURCES A. Indications From the Adult Guidelines In the most recent adult guidelines, a chapter on “Anesthetics, Analgesics, and Sedatives” identified a class II study to recommend continuous infusion of propofol as the agent of choice. Only case reports or mixed adult and pediatric case series have been published supporting propofol use in pediatric TBI (17, 18). However, a number of reports (in cases not restricted to TBI) suggest that continuous infusion of propofol is associated with an unexplained increase in mortality risk in critically ill children. A syndrome of lethal metabolic acidosis (“propofol syndrome”) can occur (19–24). In light of these risks, and with alternative therapies available, continuous infusion of propofol for either sedation or management of refractory intracranial hypertension in severe pediatric TBI is not recommended. The Center for Drug Evaluation and Research Web site of the Food and Drug Administration (25) states, “Propofol is not indicated for pediatric ICU sedation as safety has not been established.” Based on the Food and Drug Administration recommendations against the continuous infusion of propofol for sedation in pediatric critical care medicine, the recommendation from the adult guidelines cannot be translated to pediatric TBI management and represents an important discontinuity between pediatric and adult TBI management. Neuromuscular-blocking agents were not addressed in the “Anesthetics, Analgesics, and Sedatives” chapter of the most recent adult guidelines. In the 2000 adult guidelines (26), the initial management section cited a study that examined 514 entries in the Traumatic Coma Data Bank and reported no beneficial effects of neuromuscular blockade and an increased incidence of nosocomial pneumonia and prolonged ICU stay associated with prophylactic neuromuscular blockade (9). It was suggested that use of neuromuscular-blocking agents be reserved for specific indications (intracranial hypertension, transport). B. Information Not Included as Evidence Ketamine exhibits neuroprotective effects in experimental models of TBI; however, concerns over its vasodilatory effects and their impact on ICP have long limited its consideration as a sedative in TBI. Recently, a study by Bar-Joseph et al (27) was carried out, which was a prospective study in 30 children with raised ICP, 24 with nonpenetrating TBI. A single dose of ketamine (1–1.5 mg/kg, intravenously) was evaluated for its ability to either 1) prevent further increases in ICP during a stressful procedure (i.e., suctioning); or 2) treat refractory intracranial hypertension. Ketamine reduced ICP in both settings. These patients had severe intracranial hypertension with an overall mean ICP of 25.8 mm Hg. The study did not meet inclusion criteria for these guidelines for two reasons. First, it fell just below the cutoff of 85% of TBI cases, and second, Glasgow Coma Scale score was not provided–although it is likely that the children had severe TBI given the ICP data. Regarding the use of etomidate in critical care, including severe TBI and multiple trauma victims (28–31), there are general concerns over adrenal suppression. As stated earlier, the availability of other sedatives and analgesics that do not suppress adrenal function, along with the small sample size and single-dose administration in the single study in the evidence table (Table 1) and limited safety profile in pediatric TBI, limit the ability to endorse the general use of etomidate as a sedative other than as an option for single-dose administration in the setting of raised ICP. VII. SUMMARY Two studies were identified that met inclusion criteria, rendering reserved class III recommendations that 1) etomidate may be considered to decrease intracranial hypertension, although the risks resulting from adrenal suppression must be considered; and 2) thiopental, given as a single dose, may be considered to control intracranial hypertension. Despite the common use of analgesics and sedatives in TBI management, there have been few studies of these drugs focused on pediatric patients with severe TBI, and studies meeting inclusion criteria for the most commonly used agents were lacking. Similarly, no studies were identified meeting inclusion criteria that addressed the use of neuromuscular blockade in pediatric patients with severe TBI. Until experimental comparisons among these agents are carried out, the choice and dosing of analgesics, sedatives, and neuromuscular-blocking agents used should be left to the treating physician. Based on recommendations of the Food and Drug Administration, continuous infusion of propofol is not recommended in the treatment of pediatric TBI. VIII. KEY ISSUES FOR FUTURE INVESTIGATION Studies are needed comparing the various sedatives and analgesics in pediatric patients with severe TBI, examining sedative and analgesic efficacy, effects on ICP, other surrogate markers, and functional outcome. Studies are needed to assess the toxicities, including hypotension, adrenal suppression, effects on long-term cognitive outcomes, and other adverse effects. Studies are needed on dosing, duration, and interaction effects with other concurrent therapies. Optimal sedation after severe TBI may differ between infants and older children and requires investigation. Specifically, given concerns over the effects of various anesthetics and sedatives on neuronal death in the developing brain (32, 33), studies of various analgesic and sedative regimens in infants with TBI are needed, including infants who are victims of abusive head trauma. The specific role of neuromuscular-blocking agents in infants and children with severe TBI needs to be defined.

Introduction

There is no consensus on the optimal timing and specific brain MRI sequences in the evaluation and management of severe pediatric traumatic brain injury (TBI), and information on current practices is lacking. The authors performed a survey of MRI practices among sites participating in a multicenter study of severe pediatric TBI to provide information for designing future clinical trials using MRI to assess brain injury after severe pediatric TBI. Information on current imaging practices and resources was collected from 27 institutions participating in the Approaches and Decisions after Pediatric TBI Trial. Multiple-choice questions addressed the percentage of patients with TBI who have MRI studies, timing of MRI, MRI sequences used to investigate TBI, as well as the magnetic field strength of MR scanners used at the participating institutions and use of standardized MRI protocols for imaging after severe pediatric TBI. Overall, the reported use of MRI in pediatric patients with severe TBI at participating sites was high, with 40% of sites indicating that they obtain MRI studies in > 95% of this patient population. Differences were observed in the frequency of MRI use between US and international sites, with the US sites obtaining MRI in a higher proportion of their pediatric patients with severe TBI (94% of US vs 44% of international sites reported MRI in at least 70% of patients with severe TBI). The reported timing and composition of MRI studies was highly variable across sites. Sixty percent of sites reported typically obtaining an MRI study within the first 7 days postinjury, with the remainder of responses distributed throughout the first 30-day postinjury period. Responses indicated that MRI sequences sensitive for diffuse axonal injury and ischemia are frequently obtained in patients with TBI, whereas perfusion imaging and spectroscopy techniques are less common. Results from this survey suggest that despite the lack of consensus or guidelines, MRI is commonly obtained during the acute clinical setting after severe pediatric TBI. The variation in MRI practices highlights the need for additional studies to determine the utility, optimal timing, and composition of clinical MRI studies after TBI. The information in this survey describes current clinical MRI practices in children with severe TBI and identifies important challenges and objectives that should be considered when designing future studies.

Chapter 7. Neuroimaging

Adequate nutrition support is considered important to recovery after pediatric traumatic brain injury. The 2003 Pediatric Guidelines recommend initiation of nutrition within 72 hrs after traumatic brain injury. We examined our local experience with nutritional support in severe pediatric traumatic brain injury patients (cases) and non-traumatic brain injury patients (controls). A retrospective review of pediatric patients with severe traumatic brain injury over an 11-yr period (1997-2009) and without traumatic brain injury over a 3-yr period (2007-2009). Level I pediatric trauma center pediatric intensive care unit. Patients with severe pediatric traumatic brain injury (age <15 yrs, Glasgow Coma Scale score of <9) and admitted to the pediatric intensive care unit for >7 days and patients without traumatic brain injury (age <15 yrs, head Abbreviated Injury Scale score of 0) and admitted to pediatric intensive care unit. None. Data from 101 severe traumatic brain injury and 92 non-traumatic brain injury patients were analyzed. Traumatic brain injury patients: All received enteral nutrition while 13 (12%) also received parenteral nutrition. Nutrition was started 53 ± 20 hrs (range 12-162) after pediatric intensive care unit admission. Fifty patients (52%) received nutrition within the first 48 hrs, and 83 (82%) received nutrition support within the first 72 hrs. Caloric and protein intakes were 47% and 40% of the goals on pediatric intensive care unit day 7 and 76% and 70% of the goals on pediatric intensive care unit day 14. Caloric and protein goals were met in 26% ± 16% and 18% ± 19% of pediatric intensive care unit stay, respectively. Patients whose intake met nutritional goals on pediatric intensive care unit day 7 had earlier initiation of nutrition support at admission than patients who never met the goals (calorie goal met vs. unmet by day 7, 44 ± 23 hrs vs. 67 ± 31 hrs; p < .001; protein goal met vs. unmet by day 7, 43 ± 17 hrs vs. 65 ± 29 hrs; p = .001). Patients gained 0.6% ± 11% weight by pediatric intensive care unit day 7 and lost 7% ± 11% weight by pediatric intensive care unit day 14. Non-traumatic brain injury patients: The time to start of nutrition for the non-traumatic brain injury group was earlier only for patients with isolated orthopedic injuries (24 ± 6 hrs; p = .02). The average caloric and protein intakes were less for the traumatic brain injury (n = 20) group (caloric 52% ± 16% of goal and protein 42% ± 18% of goal) than for the non-traumatic brain injury (n = 23) group (65% ± 11% of goal and protein 51% ± 20% of goal; both p < .01) for pediatric intensive care unit days 0-7. For pediatric intensive care unit days 8-14, there was no difference in average caloric (82% ± 22% vs. 79% ± 18% of goal) or protein (77% ± 6% vs. 79% ± 7% of goal) between the traumatic brain injury (n = 12) and non-traumatic brain injury (n = 10) groups. Addition of a nutritionist was associated with earlier time to nutrition start (p = .02). Nutritional support was initiated in most patients within 72 hrs of pediatric intensive care unit admission. Although daily caloric and protein goals were not achieved in the first 2 wks of pediatric intensive care unit stay and nutritional deficiencies were common, earlier start of nutritional support was associated with involvement of a nutritionist and with meeting both caloric and protein goals by pediatric intensive care unit day 7.

Purpose: Participation in home, school and community activities is considered as the ultimate aim of rehabilitation. The aims of this study were to examine participation seven years post-severe childhood traumatic brain injury and factors associated with participation.Materials and methods: Participants were enrolled in the Traumatisme Grave de l’Enfant (Severe Childhood Injury) cohort study following severe accidental childhood traumatic brain injury. Participation seven years post-injury, was examined using parent- and self-report forms of the Child and Adolescent Scale of Participation among 37 patients [62% males, mean age 15.4 years (SD = 4.4), mean length of coma 6.68 days (SD = 4.96)] and 33 matched controls.Results: Parent reports indicated significantly lower participation among patients compared to controls, but the self-reports did not. In the traumatic brain injury group, parent-reported participation was variable, with 22% of the patients clearly showing greater restrictions than controls. Participation restrictions were significantly associated with injury severity, poor functional outcome one-year post-injury, executive and behavioral difficulties and higher fatigue levels seven years post-injury, but not with pre-injury nor family factors.Conclusions: Several years after severe childhood traumatic brain injury, participation appears to depend more on injury-related factors than on environmental factors. In self-reports assessments of participation, it could be difficult for children and adolescents to distinguish capacity from performance.Implications for rehabilitationParticipation outcomes were highly variable in a sample of patients who sustained severe childhood traumatic brain injury.Participation should be assessed systematically following severe traumatic brain injury, both initially but also in the long-term, ideally using a combination of self- and proxy-report measures.Among patients with severe injuries, the influence of initial brain injury severity markers on participation seems much stronger than that of social/family environment factors.Children’s and adolescents’ self-reported participation assessed with the Child and Adolescent Scale of Participation may be difficult to interpret.

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: is the extent to which the results and are similar across studies. It is rated high are moderate are or one is more It is not when the body of evidence of a study. We as whether the study population is the as the population of interest and whether the outcomes are clinical than intermediate outcomes. Evidence is as indirect, or is the of the for a given outcome. is rated high, moderate, or low. How this is determined on the of used in a specific study but include of the of other of or the of used to determine These criteria are then considered when a rating to the body of evidence. The ratings are defined as follows: that the evidence reflects the research is to the in the of that the evidence reflects the research the in the of and the that the evidence reflects the research is to the in the of and is to the Evidence is or does not a A of quality of the body of evidence a about the importance of the and these across topics and The following general are provided to the that are but are not as two or more class 1 studies demonstrate for a topic, the overall quality of the body of evidence be assessed as because there is about the Similarly, class 1 or 2 studies that provide indirect evidence only low-quality evidence In some cases, the body of evidence be a but the rating A study a body of evidence if it is a class 1 a moderate-quality body of evidence if it is a class 2 study with a and moderate or evidence if the is and the precision of the of is low. is the extent to which research are useful for informing recommendations for a population the population that is the target of the is important to when assessing will on the topic, and the assessment is there is no rating for focus on the of the patient population (e.g., to which patients are the results and the for care (e.g., where could a similar result be if the patient population the inclusion criteria for the review, there be specific that The of the setting in which a study was also be important to For example, a study in a or not be to other settings, on how similar the are to the population of interest or how similar the of the is to the care setting of to be considered include the (e.g., or and the of (e.g., level of The and of are considered because it is that the patients, and available are different across In this edition, we the of individual studies in the of the Body of Evidence and section" following the recommendations. Phase of Recommendations of Recommendations Class 1, 2, or 3 studies the evidence on which the recommendations are our current identification of evidence is but not for the development of recommendations. No recommendations were made a in evidence. evidence was whether it could be used to inform recommendations was based on the quality of the body of evidence and of there were cases in which evidence was but the quality was and our to the evidence into recommendations. if a was not the evidence was included for future because in the new studies be in changes in the assessment of the quality of the body of evidence. of Recommendations in this edition are as level I, level II, or level III. The level of is determined by the assessment of the quality of the body of evidence, than the class of the included studies. The were based on the quality of the body of evidence as follows: I recommendations were based on a body of evidence. II recommendations were based on a moderate-quality body of evidence. recommendations were based on a low-quality body of evidence. could result in a level (e.g., a body of with In this edition, was not used to a recommendation. However, given the lack of and methods in this we issues that were identified and by the clinical was used in cases where there were no studies identified or because the body of evidence had major quality the evidence was no recommendations were Review and of the literature review, identification of new studies, quality assessment, and the methods team for each topic to two clinical The clinical investigators read the included studies and the recommendations, provided and additional studies for team members the and reviewed new studies, and provided the clinical investigators with new publications and a summary of the evidence for each topic. Clinical Review In a meeting in each topic was presented and by the Based on these the methods team the guidelines. Review of Complete The of all topics and the other of the guidelines (e.g., Supplemental Digital Content 1, https://links.lww.com/PCC/A774) was to all clinical investigators for review and and through to the and the document. Review. were made based on from the clinical investigators, the Third Edition and an Executive Summary were to the journal Pediatric Critical Care Medicine for A review was also by members of the of Neurological of Neurological Surgeons Guidelines Review in with the clinical investigators and methods team, to publication in the journal ICP Monitoring Recommendations of I and II There was evidence to support a level I or II for this topic. To Use of ICP monitoring is Changes From Edition. There are no changes from the Second Edition to the recommendations. new class 3 observational studies were added to the evidence base for this topic injury to the after severe TBI is a result of a of that perfusion of and and of and Brain from and or the of the leads to intracranial further and of ICP represents a key in the of injury phase following TBI the in both and outcome after severe TBI have been using

Chapter 16. Glucose and nutrition

XV. Steroids

Nerve growth factor expression correlates with severity and outcome of traumatic brain injury in children

Background : The objective of this study was to describe the functional level during the first year after moderate and severe traumatic brain injury (TBI), and to evaluate the predictive impact of pre-injury and injury-related factors. Methods : A cohort of 65 patients with moderate (N = 21) or severe (N = 44) TBI were examined with FIM (Functional Independence Measure) at admission and discharge from the rehabilitation clinic (on average two months after injury) and at 12 months, and with GOSE (Glasgow Outcome Scale Extended) at 12 months after injury. Possible predictors were analyzed in a regression model using FIM total score at 12 months as outcome. Results : All mean FIM scores improved significantly from injury to discharge from sub-acute rehabilitation. In the later period from discharge to 12 months after injury, the mean FIM motor score improved in severe TBI but not in moderate TBI patients. The mean FIM cognitive scores did not improve in any of the groups. At 12 months, 95% with moderate TBI had a FIM score from 109 - 126 (functionally independent) compared to 74% with severe TBI. Functional global outcome as assessed by GOSE was “good recovery” in 52% with moderate TBI versus 33% in severe TBI, “moderate disability” in 33% with moderate TBI versus 31% in severe TBI, and “severe disability” in 14% with moderate TBI versus 36% in severe TBI. Predictors such as PTA duration (B = -0.209), GCS admission rehabilitation (B = 5.058) and LOS rehabilitation (B = 0.458) explained 47% of the FIM variance 12 months post injury. Conclusions : The greatest improvement after moderate and severe TBI was in the sub-acute phase during the stay in a specialized rehabilitation unit. Residual disability was reported in 47% of moderate TBI patients as measured by GOSE at 12 months post injury indicating the importance of post-acute rehabilitation for these patients. Longer stays at the rehabilitation unit, a short PTA period and a high GCS score at admission to rehabilitation were positive predictors of functional level (FIM) at 12 months follow-up demonstrating that these factors are common predictors of early and late TBI phases. doi:10.4021/jnr20w

Background : The objective of this study was to describe the functional level during the first year after moderate and severe traumatic brain injury (TBI), and to evaluate the predictive impact of pre-injury and injury-related factors. Methods : A cohort of 65 patients with moderate (N = 21) or severe (N = 44) TBI were examined with FIM (Functional Independence Measure) at admission and discharge from the rehabilitation clinic (on average two months after injury) and at 12 months, and with GOSE (Glasgow Outcome Scale Extended) at 12 months after injury. Possible predictors were analyzed in a regression model using FIM total score at 12 months as outcome. Results : All mean FIM scores improved significantly from injury to discharge from sub-acute rehabilitation. In the later period from discharge to 12 months after injury, the mean FIM motor score improved in severe TBI but not in moderate TBI patients. The mean FIM cognitive scores did not improve in any of the groups. At 12 months, 95% with moderate TBI had a FIM score from 109 - 126 (functionally independent) compared to 74% with severe TBI. Functional global outcome as assessed by GOSE was “good recovery” in 52% with moderate TBI versus 33% in severe TBI, “moderate disability” in 33% with moderate TBI versus 31% in severe TBI, and “severe disability” in 14% with moderate TBI versus 36% in severe TBI. Predictors such as PTA duration (B = -0.209), GCS admission rehabilitation (B = 5.058) and LOS rehabilitation (B = 0.458) explained 47% of the FIM variance 12 months post injury. Conclusions : The greatest improvement after moderate and severe TBI was in the sub-acute phase during the stay in a specialized rehabilitation unit. Residual disability was reported in 47% of moderate TBI patients as measured by GOSE at 12 months post injury indicating the importance of post-acute rehabilitation for these patients. Longer stays at the rehabilitation unit, a short PTA period and a high GCS score at admission to rehabilitation were positive predictors of functional level (FIM) at 12 months follow-up demonstrating that these factors are common predictors of early and late TBI phases. J Neurol Res. 2011;1(2):48-58 doi: https://doi.org/10.4021/jnr20w