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OBJECTIVE: The microbiome may be affected by trauma and critical illness. Many studies of the microbiome in critical illness are restricted to a single body site or timepoint and confounded by pre-existing conditions. We report temporal and spatial alterations in the microbiome of previously healthy children with severe traumatic brain injury (TBI). DESIGN: We collected oral, rectal, and skin swabs within 72 hours of admission and then twice weekly until ICU discharge. Samples were analyzed by 16S rRNA gene amplicon sequencing. Children undergoing elective outpatient surgery served as controls. Alpha and beta diversity comparisons were performed with Phyloseq and differentially abundant taxa were predicted using ANCOM. SETTING: Five quaternary care pediatric intensive care units PATIENTS: Patients < 18 years with severe TBI requiring placement of an intracranial pressure (ICP) monitor INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: 327 samples were analyzed from 23 children with severe TBI and 35 controls. The community composition of initial oral (F=3.2756, R(2)=0.0535, p=0.012) and rectal (F=3.0702, R(2)=0.0649, p=0.007) samples differed between TBI and control patients. Rectal samples were depleted of commensal bacteria from Ruminococcaceae, Bacteroidaceae, and Lachnospiraceae families and enriched in Staphylococcaceae after TBI (p

OBJECTIVES To define the clinical characteristics of hospitalized children with moderate traumatic brain injury and identify factors associated with deterioration to severe traumatic brain injury. DESIGN Retrospective cohort study. SETTING Tertiary Children's Hospital with Level 1 Trauma Center designation. PATIENTS Inpatient children less than 18 years old with an International Classification of Diseases code for traumatic brain injury and an admission Glasgow Coma Scale score of 9-13. MEASUREMENTS AND RESULTS We queried the National Trauma Data Bank for our institutional data and identified 177 patients with moderate traumatic brain injury from 2010 to 2017. These patients were then linked to the electronic health record to obtain baseline and injury characteristics, laboratory data, serial Glasgow Coma Scale scores, CT findings, and neurocritical care interventions. Clinical deterioration was defined as greater than or equal to 2 recorded values of Glasgow Coma Scale scores less than or equal to 8 during the first 48 hours of hospitalization. Thirty-seven patients experienced deterioration. Children who deteriorated were more likely to require intubation (73% vs 26%), have generalized edema, subdural hematoma, or contusion on CT scan (30% vs 8%, 57% vs 37%, 35% vs 16%, respectively), receive hypertonic saline (38% vs 7%), undergo intracranial pressure monitoring (24% vs 0%), were more likely to be transferred to inpatient rehabilitation following hospital discharge (32% vs 5%), and incur greater costs of care ($25,568 vs $10,724) (all p < 0.01). There was no mortality in this cohort. Multivariable regression demonstrated that a higher Injury Severity Score, a higher initial international normalized ratio, and a lower admission Glasgow Coma Scale score were associated with deterioration to severe traumatic brain injury in the first 48 hours (p < 0.05 for all). CONCLUSIONS A substantial subset of children (21%) presenting with moderate traumatic brain injury at a Level 1 pediatric trauma center experienced deterioration in the first 48 hours, requiring additional resource utilization associated with increased cost of care. Deterioration was independently associated with an increased international normalized ratio higher Injury Severity Score, and a lower admission Glasgow Coma Scale score.

s: Few feasibility, safety, and efficacy data exist regarding ICU-based rehabilitative services for children. We hypothesized that early protocolized assessment and therapy would be feasible and safe versus usual care in pediatric neurocritical care patients.Randomized controlled trial.Three tertiary care PICUs in the United States.Fifty-eight children between the ages of 3-17 years with new traumatic or nontraumatic brain insult and expected ICU admission greater than 48 hours.Early protocolized (consultation of physical therapy, occupational therapy, and speech and language therapy within 72 hr ICU admission, n = 26) or usual care (consultation per treating team, n = 32).Primary outcomes were consultation timing, treatment type, and frequency of deferrals and safety events. Secondary outcomes included patient and family functional and quality of life outcomes at 6 months. Comparing early protocolized (n = 26) and usual care groups (n = 32), physical therapy was consulted during the hospital admission in 26 of 26 versus 28 of 32 subjects (p = 0.062) on day 2.4 ± 0.8 versus 7.7 ± 4.8 (p = 0.001); occupational therapy in 26 of 26 versus 23 of 32 (p = 0.003), on day 2.3 ± 0.6 versus 6.9 ± 4.8 (p = 0.001); and speech and language therapy in 26 of 26 versus 17 of 32 (p = 0.011) on day 2.3 ± 0.7 versus 13.0 ± 10.8 (p = 0.026). More children in the early protocolized group had consults and treatments occur in the ICU versus ward for all three services (all p0.001). Eleven sessions were discontinued early: nine during physical therapy and two during occupational therapy, none impacting patient outcome. There were no group differences in functional or quality of life outcomes.A protocol for early personalized rehabilitation by physical therapy, occupational therapy, and speech and language therapy in pediatric neurocritical care patients could be safely implemented and led to more ICU-based treatment sessions, accelerating the temporal profile and changing composition of interventions versus usual care, but not altering the total dose of rehabilitation.

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 ResearchIn this Supplement to Pediatric Critical Care Medicine, we are pleased to present the Third Edition o

OBJECTIVES: The evidence to guide therapy in pediatric traumatic brain injury is lacking, including insight into the intracranial pressure/cerebral perfusion pressure thresholds in abusive head trauma. We examined intracranial pressure/cerebral perfusion pressure thresholds and indices of intracranial pressure and cerebral perfusion pressure burden in relationship with outcome in severe traumatic brain injury and in accidental and abusive head trauma cohorts. DESIGN: A prospective observational study. SETTING: PICU in a tertiary children's hospital. PATIENTS: Children less than18 years old admitted to a PICU with severe traumatic brain injury and who had intracranial pressure monitoring. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A pediatric traumatic brain injury database was interrogated with 85 patients (18 abusive head trauma) enrolled. Hourly intracranial pressure and cerebral perfusion pressure (in mm Hg) were collated and compared with various thresholds. C-statistics for intracranial pressure and cerebral perfusion pressure data in the entire population were determined. Intracranial hypertension and cerebral hypoperfusion indices were formulated based on the number of hours with intracranial pressure more than 20 mm Hg and cerebral perfusion pressure less than 50 mm Hg, respectively. A secondary analysis was performed on accidental and abusive head trauma cohorts. All of these were compared with dichotomized 6-month Glasgow Outcome Scale scores. The models with the number of hours with intracranial pressure more than 20 mm Hg (C = 0.641; 95% CI, 0.523-0.762) and cerebral perfusion pressure less than 45 mm Hg (C = 0.702; 95% CI, 0.586-0.805) had the best fits to discriminate outcome. Two factors were independently associated with a poor outcome, the number of hours with intracranial pressure more than 20 mm Hg and abusive head trauma (odds ratio = 5.101; 95% CI, 1.571-16.563). As the number of hours with intracranial pressure more than 20 mm Hg increases by 1, the odds of a poor outcome increased by 4.6% (odds ratio = 1.046; 95% CI, 1.012-1.082). Thresholds did not differ between accidental versus abusive head trauma. The intracranial hypertension and cerebral hypoperfusion indices were both associated with outcomes. CONCLUSIONS: The duration of hours of intracranial pressure more than 20 mm Hg and cerebral perfusion pressure less than 45 mm Hg best discriminated poor outcome. As the number of hours with intracranial pressure more than 20 mm Hg increases by 1, the odds of a poor outcome increased by 4.6%. Although abusive head trauma was strongly associated with unfavorable outcome, intracranial pressure/cerebral perfusion pressure thresholds did not differ between accidental and abusive head trauma. Language: en

OBJECTIVES: To describe acute cerebral hemodynamic effects of medications commonly used to treat intracranial hypertension in children with traumatic brain injury. Currently, data supporting the efficacy of these medications are insufficient. DESIGN: In this prospective observational study, intracranial hypertension (intracranial pressure ≥ 20 mm Hg for > 5 min) was treated by clinical protocol. Administration times of medications for intracranial hypertension (fentanyl, 3% hypertonic saline, mannitol, and pentobarbital) were prospectively recorded and synchronized with an automated database that collected intracranial pressure and cerebral perfusion pressure every 5 seconds. Intracranial pressure crises confounded by external stimulation or mechanical ventilator adjustments were excluded. Mean intracranial pressure and cerebral perfusion pressure from epochs following drug administration were compared with baseline values using Kruskal-Wallis analysis of variance and Dunn test. Frailty modeling was used to analyze the time to intracranial pressure crisis resolution. Mixed-effect models compared intracranial pressure and cerebral perfusion pressure 5 minutes after the medication versus baseline and rates of treatment failure. SETTING: A tertiary care children's hospital. PATIENTS: Children with severe traumatic brain injury (Glasgow Coma Scale score ≤ 8). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed 196 doses of fentanyl, hypertonic saline, mannitol, and pentobarbital administered to 16 children (median: 12 doses per patient). Overall, intracranial pressure significantly decreased following the administration of fentanyl, hypertonic saline, and pentobarbital. After controlling for administration of multiple medications, intracranial pressure was decreased following hypertonic saline and pentobarbital administration; cerebral perfusion pressure was decreased following fentanyl and was increased following hypertonic saline administration. After adjusting for significant covariates (including age, Glasgow Coma Scale score, and intracranial pressure), hypertonic saline was associated with a two-fold faster resolution of intracranial hypertension than either fentanyl or pentobarbital. Fentanyl was significantly associated with the most frequent treatment failure. CONCLUSIONS: Intracranial pressure decreased after multiple drug administrations, but hypertonic saline may warrant consideration as the first-line drug for treating intracranial hypertension, as it was associated with the most favorable cerebral hemodynamics and fastest resolution of intracranial hypertension. Language: en

Traumatic brain injury is the most common cause of death and disability in children with nearly 500,000 children suffering from TBI each year (1). Unfortunately, specific therapies are lacking with existing treatment primarily being supportive. Given that the tools to reverse primary tissue injury after TBI are currently lacking, significant effort is being placed on identifying means of manipulating secondary injury pathways that follow TBI and contribute to ongoing cellular dysfunction and death. Inflammation is one such secondary process that may represent a therapeutic target following TBI. Inflammation following experimental TBI has been well documented and is mediated by both CNS immune cells as well as those of the peripheral immune system following disruption of the blood-brain barrier (BBB)(2). There are also reports identifying cellular inflammation after TBI in adult patients (3, 4). There are caveats in regard to manipulating neuroinflammation; however, as it has been shown to have both beneficial and detrimental roles following TBI. These divergent roles likely depend on timing (5, 6), severity (7), and type of injury (8), as well as on age (9), genetics (10), and other factors. As such, strategies will be required that harness the beneficial effects such as repair, trophic factor release, and debridement, while minimizing undesirable effects such as edema and supraphysiologic inflammation. (11). Identifying markers of an aberrant or supraphysiologic inflammatory state would thus be useful in attempting to strategically manipulate the neuroinflammatory response after TBI. An extreme example of an aberrant inflammatory state is hemophagocytic lymphohistiocytosis (HLH), a condition of immune dysregulation resulting in hyper-inflammation due to uncontrolled macrophage and T-cell activation. A case definition of HLH requires diagnostic criteria identifying macrophage and T-cell activation, including measurement of ferritin and soluble interleukin-2 receptor α (sIL-2Rα), respectively (12). More recently soluble cluster of differentiation 163 (sCD163) has also been suggested to be a marker of macrophage activation (13). Neurological involvement is common in HLH, occurring in 30–50% of cases at presentation (12), and includes neuroinflammation, necrosis, white matter abnormalities, and hemorrhage (14). Coincidentally, Rooms et al. (15) reported a series of three children with brain injuries suspected to be caused by abusive head trauma (AHT) that met diagnostic laboratory criteria for HLH raising concerns that AHT may lead to systemic activation of the immune system, or that systemic macrophage or resident microglial activation could cause intracranial findings that could be misconstrued as findings of child abuse (15). While the pathophysiology of CNS involvement in HLH is not completely understood, it likely is in part due to local uncontrolled macrophage and T-cell activation. These studies raise the question of whether excessive CNS immune activation could be triggered by an inciting event such as trauma, and whether this could be identified by similar markers of macrophage/microglial and T-cell activation. Accordingly, the purpose of this study was to investigate the presence of markers of macrophage/microglial and T-cell activation in pediatric TBI, as characterized by elevations in cerebrospinal fluid (CSF) sCD163, ferritin, and sIL-2Rα. While previous studies have looked at various markers of inflammation following pediatric TBI (16–21), this is the first study looking specifically for the presence of markers of macrophage and T-cell activation. These findings may represent a means for identification of patients likely to respond to strategies targeting cellular inflammation, and/or a means for therapeutic drug monitoring for future clinical trials targeting inflammation after TBI.

To describe the differences in goals for their usual practice for various medical therapies from a number of international centers for children with severe traumatic brain injury.A survey of the goals from representatives of the international centers.Thirty-two pediatric traumatic brain injury centers in the United States, United Kingdom, France, and Spain.None.None.A survey instrument was developed that required free-form responses from the centers regarding their usual practice goals for topics of intracranial hypertension therapies, hypoxia/ischemia prevention and detection, and metabolic support. Cerebrospinal fluid diversion strategies varied both across centers and within centers, with roughly equal proportion of centers adopting a strategy of continuous cerebrospinal fluid diversion and a strategy of no cerebrospinal fluid diversion. Use of mannitol and hypertonic saline for hyperosmolar therapies was widespread among centers (90.1% and 96.9%, respectively). Of centers using hypertonic saline, 3% saline preparations were the most common but many other concentrations were in common use. Routine hyperventilation was not reported as a standard goal and 31.3% of centers currently use PbO(2) monitoring for cerebral hypoxia. The time to start nutritional support and glucose administration varied widely, with nutritional support beginning before 96 hours and glucose administration being started earlier in most centers.There were marked differences in medical goals for children with severe traumatic brain injury across our international consortium, and these differences seemed to be greatest in areas with the weakest evidence in the literature. Future studies that determine the superiority of the various medical therapies outlined within our survey would be a significant advance for the pediatric neurotrauma field and may lead to new standards of care and improved study designs for clinical trials.