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Introduction: Continuous neurologic assessment in the pediatric intensive care unit is challenging. Current electroencephalography (EEG) guidelines support monitoring status epilepticus, vasospasm detection, and cardiac arrest prognostication, but the scope of brain dysfunction in critically ill patients is larger. We explore quantitative EEG in pediatric intensive care unit patients with neurologic emergencies to identify quantitative EEG changes preceding clinical detection. Methods: From 2017 to 2020, we identified pediatric intensive care unit patients at a single quaternary children's hospital with EEG recording near or during acute neurologic deterioration. Quantitative EEG analysis was performed using Persyst P14 (Persyst Development Corporation). Included features were fast Fourier transform, asymmetry, and rhythmicity spectrograms, “from-baseline” patient-specific versions of the above features, and quantitative suppression ratio. Timing of quantitative EEG changes was determined by expert review and prespecified quantitative EEG alert thresholds. Clinical detection of neurologic deterioration was defined pre hoc and determined through electronic medical record documentation of examination change or intervention. Results: Ten patients were identified, age 23 months to 27 years, and 50% were female. Of 10 patients, 6 died, 1 had new morbidity, and 3 had good recovery; the most common cause of death was cerebral edema and herniation. The fastest changes were on “from-baseline” fast Fourier transform spectrograms, whereas persistent changes on asymmetry spectrograms and suppression ratio were most associated with morbidity and mortality. Median time from first quantitative EEG change to clinical detection was 332 minutes (interquartile range: 201-456 minutes). Conclusion: Quantitative EEG is potentially useful in earlier detection of neurologic deterioration in critically ill pediatric intensive care unit patients. Further work is required to quantify the predictive value, measure improvement in outcome, and automate the process.

Purpose of review Acute central and peripheral nervous system injury may occur in association with coronavirus disease 2019 (COVID-19) caused by infection with the severe acute respiratory syndrome coronavirus 2 virus. This review will assist readers to recognize neurologic manifestations associated with COVID-19 including common and life-threatening symptoms and diagnostic testing. We will also review current recommendations for treatment of neurologic injury associated with COVID-19 infection in children. Recent findings Data from systematic reviews and prospectively collected cohorts of children with COVID-19 are beginning to characterize the breadth of neurologic manifestations associated with COVID-19 in the acute infectious and postinfectious periods. Among hospitalized children in particular, neurologic symptoms are common. Life threatening conditions including encephalitis, myelitis, stroke, and demyelinating syndromes have been reported. Within the pediatric population, age, and preexisting neurologic conditions appear to be important factors in determining likely phenotypes. Treatment at this time is based on careful neuromonitoring, supportive care, and neuromodulatory therapies as indicated. Summary Neurologic symptoms are common in children with COVID-19 and may be life threatening. The pathophysiology, therapeutic options, and long-term outcomes from COVID-19 associated neurologic injury are currently being investigated.

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.

Pediatric encephalitis has significant morbidity and mortality, yet 50% of cases are unexplained. Host genetics plays a role in encephalitis' development; however, the contributing variants are poorly understood. One child with anti-NMDA receptor encephalitis and ten with unexplained encephalitis underwent whole genome sequencing to identify rare candidate variants in genes known to cause monogenic immunologic and neurologic disorders, and polymorphisms associated with increased disease risk. Using the professional Human Genetic Mutation Database (Qiagen), we divided the candidate variants into three categories: monogenic deleterious or potentially deleterious variants (1) in a disease-consistent inheritance pattern; (2) in carrier states; and (3) disease-related polymorphisms. Six patients (55%) had a deleterious or potentially deleterious variant in a disease-consistent inheritance pattern, five (45%) were heterozygous carriers for an autosomal recessive condition, and six (55%) carried a disease-related polymorphism. Finally, seven (64%) had more than one variant, suggesting possible polygenetic risk. Among variants identified were those implicated in atypical hemolytic uremic syndrome, common variable immunodeficiency, hemophagocytic lymphohistiocytosis, and systemic lupus erythematosus. This preliminary study shows genetic variation related to inborn errors of immunity in acute pediatric encephalitis. Future research is needed to determine if these variants play a functional role in the development of unexplained encephalitis.

Progression of hemorrhagic injury (PHI) in children with traumatic brain injury portends poor outcomes. The association between thromboelastography (TEG), functional coagulation assays, and PHI is not well characterized in children.This was a retrospective cohort study of children presenting with PHI at a pediatric level I academic trauma center from 2015 to 2020. Inclusion criteria were as follows: age less than 18 years, intracranial hemorrhage on admission head computed tomography scan, and admission rapid TEG assay and conventional coagulation tests. PHI was defined by the following radiographic criteria: any expansion of or new intracranial hemorrhage on subsequent head computed tomography scan. Rapid TEG values included Activated Clotting Time (ACT), alpha angle, maximum amplitude, and lysis at 30 min. Wilcoxon rank-sum test was used to assess baseline differences between groups with PHI and without PHI, including laboratory assays. Univariate analysis was performed to examine the association between variables of interest and PHI. Patients were dichotomized on the basis of this cut point to generate a "low ACT" group and a "high ACT" group. These variables were included in a multivariable logistic regression model to determine independent association with traumatic brain injury progression.In total, 219 patients met criteria for analysis. In this cohort, the median (interquartile range [IQR]) age = 6 (2-12) years, median (IQR) Injury Severity Score = 21 (11-27), 68% were boys, and 69% sustained blunt injury. The rate of PHI was 25% (54). Median (IQR) time to PHI was 1 (0-4) days. Children with PHI had a higher Injury Severity Score (p 0.001), lower Glasgow Coma Scale (p 0.001), greater incidence of shock (p = 0.04), and lower admission hemoglobin (p = 0.02) compared with those without PHI. Children with PHI had a higher International Normalized Ratio (INR) and longer TEG-ACT; other TEG values (alpha angle, maximum amplitude, and lysis at 30 min) were not associated with PHI. In the logistic regression model accounting for other covariates associated with PHI, elevated ACT remained an independent predictor of progression (odds ratio = 2.25, 95% confidence interval 1.09-4.66; p = 0.03; area under the receiver operating characteristic curve = 0.76). After adjusting for confounders, INR fell out of the model and was not an independent predictor of progression (odds ratio = 1.32, 95% confidence interval 0.60-2.93; p = 0.49).Although INR was elevated in children with PHI and has been associated with poor clinical outcomes, only admission TEG-ACT was independently associated with PHI. Further study is warranted to determine whether TEG-ACT reflects an actionable therapeutic target.

Targeted temperature management (TTM) is an important treatment modality in pediatric neurocritical care. There are different types of devices available to deliver this therapy, but limited pediatric data exist. This quality improvement study evaluates the use of a surface cooling device that uses gel-adhesive pads for TTM in critically ill pediatric patients. An institutional TTM protocol to use the gel-adhesive pad system was developed with three different temperature goals: normothermia (goal temperature 37°C), mild hypothermia (goal temperature 35°C with rewarming duration of 12 hours to normothermia), and moderate hypothermia (goal temperature 33°C with rewarming duration of 24 hours to normothermia). Protocol and device implementation required several different educational sessions for all members of the critical care team. An exploratory analysis was performed for 19 patients with complete clinical and device temperature data. The most common protocol used was normothermia (73.6%). By protocol, time to goal temperature was 58 minutes (22.0–112.8) for normothermia, 46.5 minutes (44.3–48.8) for mild hypothermia, and 93 minutes (46.5–406.5) for moderate hypothermia. Patients remained within ±0.5°C temperature goal 99% (96.0–99.3) of the time in the normothermia protocol, 99.5% (99–100) in mild hypothermia, and 93% (80–100) for the moderate hypothermia protocol. Shivering was the most common adverse event (35%). Our results show that use of the gel-adhesive pad system for pediatric TTM is feasible, efficacious with regard to achieving both a short time to target temperature and maintaining temperature goal, and, in this limited sample, was free from major adverse events. We also defined several technical aspects of device use in pediatric patients that should be considered in future trial design and/or clinical use. Further studies are needed to determine if this device is superior to other cooling devices for temperature management in the pediatric population.

Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population.

New neuroprotective therapies for severe traumatic brain injury (TBI) have not translated from pre-clinical to clinical success. Numerous explanations have been suggested in both the pre-clinical and clinical arenas. Coverage of TBI in the lay press has reinvigorated interest, creating a golden age of TBI research with innovative strategies to circumvent roadblocks. We discuss the need for more robust therapies. We present concepts for traditional and novel approaches to defining therapeutic targets. We review lessons learned from the ongoing work of the pre-clinical drug and biomarker screening consortium Operation Brain Trauma Therapy and suggest ways to further enhance pre-clinical consortia. Biomarkers have emerged that empower choice and assessment of target engagement by candidate therapies. Drug combinations may be needed, and it may require moving beyond conventional drug therapies. Precision medicine may also link the right therapy to the right patient, including new approaches to TBI classification beyond the Glasgow Coma Scale or anatomical phenotyping-incorporating new genetic and physiologic approaches. Therapeutic breakthroughs may also come from alternative approaches in clinical investigation (comparative effectiveness, adaptive trial design, use of the electronic medical record, and big data). The full continuum of care must also be represented in translational studies, given the important clinical role of pre-hospital events, extracerebral insults in the intensive care unit, and rehabilitation. TBI research from concussion to coma can cross-pollinate and further advancement of new therapies. Misconceptions can stifle/misdirect TBI research and deserve special attention. Finally, we synthesize an approach to deliver therapeutic breakthroughs in this golden age of TBI research.

Background and Aims Intracranial compliance refers to the relationship between a change in intracranial volume and the resultant change in intracranial pressure (ICP). Measurement of compliance is useful in managing cardiovascular and respiratory failure; however, there are no contemporary means to assess intracranial compliance. Knowledge of intracranial compliance could complement ICP and cerebral perfusion pressure (CPP) monitoring in patients with severe traumatic brain injury (TBI) and may enable a proactive approach to ICP management. In this proof-of-concept study, we aimed to capitalize on the physiologic principles of intracranial compliance and vascular reactivity to CO2, and standard-of-care neurocritical care monitoring, to develop a method to assess dynamic intracranial compliance. Methods Continuous ICP and end-tidal CO2 (ETCO2) data from children with severe TBI were collected after obtaining informed consent in this Institutional Review Board-approved study. An intracranial pressure-PCO2 Compliance Index (PCI) was derived by calculating the moment-to-moment correlation between change in ICP and change in ETCO2. As such, “good” compliance may be reflected by a lack of correlation between time-synched changes in ICP in response to changes in ETCO2, and “poor” compliance may be reflected by a positive correlation between changes in ICP in response to changes in ETCO2. Results A total of 978 h of ICP and ETCO2 data were collected and analyzed from eight patients with severe TBI. Demographic and clinical characteristics included patient age 7.1 ± 5.8 years (mean ± SD); 6/8 male; initial Glasgow Coma Scale score 3 [3–7] (median [IQR]); 6/8 had decompressive surgery; 7.1 ± 1.4 ICP monitor days; ICU length of stay (LOS) 16.1 ± 6.8 days; hospital LOS 25.9 ± 8.4 days; and survival 100%. The mean PCI for all patients throughout the monitoring period was 0.18 ± 0.04, where mean ICP was 13.7 ± 2.1 mmHg. In this cohort, PCI was observed to be consistently above 0.18 by 12 h after monitor placement. Percent time spent with PCI thresholds > 0.1, 0.2, and 0.3 were 62% [24], 38% [14], and 23% [15], respectively. The percentage of time spent with an ICP threshold > 20 mmHg was 5.1% [14.6]. Conclusions Indirect assessment of dynamic intracranial compliance in TBI patients using standard-of-care monitoring appears feasible and suggests a prolonged period of derangement out to 5 days post-injury. Further study is ongoing to determine if the PCI—a new physiologic index, complements utility of ICP and/or CPP in guiding management of patients with severe TBI. Electronic supplementary material The online version of this article (10.1007/s12028-020-01004-3) contains supplementary material, which is available to authorized users.

CONTEXT Acute neurologic dysfunction is common in critically ill children and contributes to outcomes and end of life decision-making. OBJECTIVE To develop consensus criteria for neurologic dysfunction in critically ill children by evaluating the evidence supporting such criteria and their association with outcomes. DATA SOURCES Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020, by using a combination of medical subject heading terms and text words to define concepts of neurologic dysfunction, pediatric critical illness, and outcomes of interest. STUDY SELECTION Studies were included if the researchers evaluated critically ill children with neurologic injury, evaluated the performance characteristics of assessment and scoring tools to screen for neurologic dysfunction, and assessed outcomes related to mortality, functional status, organ-specific outcomes, or other patient-centered outcomes. Studies with an adult population or premature infants (≤36 weeks' gestational age), animal studies, reviews or commentaries, case series with sample size ≤10, and studies not published in English with an inability to determine eligibility criteria were excluded. DATA EXTRACTION Data were abstracted from each study meeting inclusion criteria into a standard data extraction form by task force members. DATA SYNTHESIS The systematic review supported the following criteria for neurologic dysfunction as any 1 of the following: (1) Glasgow Coma Scale score ≤8; (2) Glasgow Coma Scale motor score ≤4; (3) Cornell Assessment of Pediatric Delirium score ≥9; or (4) electroencephalography revealing attenuation, suppression, or electrographic seizures. CONCLUSIONS We present consensus criteria for neurologic dysfunction in critically ill children.

We hypothesized that serum biomarkers of inflammation including chemokine, cytokine, pituitary hormones, and growth factors following cardiac arrest in children would independently associate with 6-month neurologic outcome.In this prospective observational single center study of children with in-hospital and out-of-hospital cardiac arrest surviving to intensive care unit admission, serum was obtained twice per 24 h period between 0 h and 96 h and once at approximately 196 h post-cardiac arrest. Inflammatory mediators, hormones, and growth factors were analyzed by Luminex Multiplex Bead Immunoassay. We recorded demographics, resuscitation characteristics, and Pediatric Cerebral Performance Category (PCPC) at 6 months. We analyzed the association and area under the curve (AUC) of biomarker levels with favorable (PCPC 1-3) or unfavorable (PCPC 4-6, or 1 increase from baseline) outcome.Forty-two children (50% female; median age of 2.5 [IQR: 0.4-10.2]) were enrolled and 18 (42%) died prior to 6-month follow up. Receiver operator curves for initial levels of ciliary neurotrophic factor (CNTF, AUC 0.84, 95% CI 0.73-0.96, p 0.001) and interleukin (IL-17, AUC 0.84, 95% CI 0.73-0.97, p 0.001) best classified favorable versus unfavorable 6-month outcome. In multivariable analysis, initial levels of CNTF and IL-17 remained associated with 6-month PCPC. Peak levels of interferon-γ-inducible protein 10 (IP-10), CNTF, and hepatocyte growth factor (HGF) were also independently associated with outcome.Increased serum concentrations of CNTF and IL-17 associated with unfavorable 6-month neurologic outcome of children surviving cardiac arrest. Further investigation of the prognostic utility and roles of CNTF and IL-17 in the pathophysiology of post-cardiac arrest syndrome are warranted. This project is registered with clinicaltrials.gov (NCT00797680) as "Duration of Hypothermia for Neuroprotection after Pediatric Cardiac Arrest: A Randomized, Controlled Trial".

Background The glymphatic system is a proposed pathway for clearance of proteins and macromolecules from brain, and disrupted glymphatic flux is implicated in neurological disease. We capitalized on colorimetric, fluorescent, and protein-binding properties of Evans blue to evaluate glymphatic flux. New method Twenty-five μL of 1% Evans blue-labeled albumin (EBA) in artificial cerebrospinal fluid (aCSF) was injected into the intracisternal space of anesthetized postnatal day 17 rats. Serum was collected at various time points after injection (n = 37) and EBA was measured spectrophotometrically. In separate rats (n = 3), a cranial window was placed over the parietal cortex and EBA transit was evaluated using in vivo multiphoton microscopy. Separate rats (n = 6) were processed for immunohistochemistry to examine localization of EBA. In some rats, intracranial pressure (ICP) was increased via intracisternal injection of aCSF. Results EBA was detected in serum as early as 30 min, was maximal at 4 h, and was undetectable at 72 h after intracisternal injection. Using intra-vital microscopy and immunohistochemistry EBA could be tracked from CSF to perivascular locations. Consistent with removal via glymphatic flux, increasing ICP to 40 mmHg accelerated transit of EBA from CSF to blood. Comparison with existing methods Transit of EBA from CSF to serum could be quantified spectrophotometrically without radioactive labeling. Glymphatic flux could also be qualitatively evaluated using EBA fluorescence. Conclusion We present a novel technique for simultaneous quantitative and qualitative evaluation of glymphatic flux in rats.

OBJECTIVE: Hemophagocytic lymphohistiocytosis (HLH) poses significant challenges due to limited tools to guide clinical decisions in a population at high risk of death. We sought to assess whether disseminated intravascular coagulation (DIC) and hepatobiliary dysfunction (HBD), significant comorbidities seen in critical care settings, would identify HLH patients with increased risk of mortality. DESIGN: Retrospective chart review. SETTING: Single-center pediatric intensive care unit PATIENTS: All patients admitted to a tertiary care children’s hospital diagnosed with HLH from 2005 – 2012 INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Forty-three patients were diagnosed with HLH with median age of 61 months. The 5-year overall survival was 51% (22/43). Univariate analyses revealed ferritin levels > 10,000 (ng/mL), international normalized ratio >1.5, or platelet counts < 100,000/mcL at initiation of dexamethasone were individually associated with mortality. Development of DIC, HBD or both increased the likelihood of death in HLH patients (relative risk; 95% confidence interval) (6; 1.4 – 34; p

The need for improved cerebral resuscitation was born out of progress – advancements in resuscitation, intensive care, and rehabilitation have decreased mortality associated with brain injury in infants and children, but increased the number living with disability. Indeed morbidity, and mortality for that matter, remains unacceptably high. To date, cerebral resuscitation after global ischemic injury due to cardiac arrest and traumatic brain injury (TBI) remains largely supportive, although many promising therapies are being explored at the bench and some at the bedside. This challenge to move innovative monitoring and therapies to the bedside to assist patients in attaining improved outcomes and quality of life has remained elusive. In the interim, optimizing patient care management in the prehospital setting, emergency department, pediatric intensive care unit (PICU), and rehabilitation facilities is our greatest opportunity for improving outcome in these pediatric patients.

Type I interferon response to systemic infections after head trauma or stroke impairs angiogenesis in injured tissues and may contribute to secondary neurological injury.

Objectives To evaluate the effect of a tracheal intubation safety bundle on adverse tracheal intubation-associated events across 15 PICUs. Design Multicenter time-series study. Setting PICUs in the United States. Patients All patients received tracheal intubations in ICUs. Interventions We implemented a tracheal intubation safety bundle as a quality-improvement intervention that includes: 1) quarterly site benchmark performance report and 2) airway safety checklists (preprocedure risk factor, approach, and role planning, preprocedure bedside "time-out," and immediate postprocedure debriefing). We define each quality-improvement phase as baseline (-24 to -12 mo before checklist implementation), benchmark performance reporting only (-12 to 0 mo before checklist implementation), implementation (checklist implementation start to time achieving > 80% bundle adherence), early bundle adherence (0-12 mo), and sustained (late) bundle adherence (12-24 mo). Bundle adherence was defined a priori as greater than 80% of checklist use for tracheal intubations for 3 consecutive months. Measurements and main results The primary outcome was the adverse tracheal intubation-associated event, and secondary outcomes included severe tracheal intubation-associated events, multiple tracheal intubation attempts, and hypoxemia less than 80%.From January 2013 to December 2015, out of 19 participating PICUs, 15 ICUs (79%) achieved bundle adherence. Among the 15 ICUs, the adverse tracheal intubation-associated event rates were baseline phase: 217/1,241 (17.5%), benchmark reporting only phase: 257/1,750 (14.7%), early 0-12 month complete bundle compliance phase: 247/1,591 (15.5%), and late 12-24 month complete bundle compliance phase: 137/1,002 (13.7%). After adjusting for patient characteristics and clustering by site, the adverse tracheal intubation-associated event rate significantly decreased compared with baseline: benchmark: odds ratio, 0.83 (0.72-0.97; p = 0.016); early bundle: odds ratio, 0.80 (0.63-1.02; p = 0.074); and late bundle odds ratio, 0.63 (0.47-0.83; p = 0.001). Conclusions Effective implementation of a quality-improvement bundle was associated with a decrease in the adverse tracheal intubation-associated event that was sustained for 24 months.

Signaling between intestinal microbiota and the brain influences neurologic outcome in multiple forms of brain injury. The impact of gut microbiota following traumatic brain injury (TBI) has not been well established. Our objective was to compare TBI outcomes in specific pathogen-free mice with or without depletion of intestinal bacteria. Adult male C57BL6/J SPF mice (n=6/group) were randomized to standard drinking water or ampicillin (1g/L), metronidazole (1g/L), neomycin (1g/L), and vancomycin (0.5g/L) (AMNV) containing drinking water 14 days prior to controlled cortical impact (CCI) model of TBI. 16S rRNA gene sequencing of fecal pellets was performed and alpha and beta diversity determined. Hippocampal neuronal density and microglial activation was assessed 72 hours post-injury by immunohistochemistry. In addition, mice (n=8–12/group) were randomized to AMNV or no treatment initiated immediately after CCI and memory acquisition (fear conditioning) and lesion volume assessed. Mice receiving AMNV had significantly reduced alpha diversity (p

Cricoid pressure is often used to prevent regurgitation during induction and mask ventilation prior to high-risk tracheal intubation in critically ill children. Clinical data in children showing benefit are limited. Our objective was to evaluate the association between cricoid pressure use and the occurrence of regurgitation during tracheal intubation for critically ill children in PICU.A retrospective cohort study of a multicenter pediatric airway quality improvement registry.Thirty-five PICUs within general and children's hospitals (29 in the United States, three in Canada, one in Japan, one in Singapore, and one in New Zealand).Children (18 yr) with initial tracheal intubation using direct laryngoscopy in PICUs between July 2010 and December 2015.None.Multivariable logistic regression analysis was used to evaluate the association between cricoid pressure use and the occurrence of regurgitation while adjusting for underlying differences in patient and clinical care factors. Of 7,825 events, cricoid pressure was used in 1,819 (23%). Regurgitation was reported in 106 of 7,825 (1.4%) and clinical aspiration in 51 of 7,825 (0.7%). Regurgitation was reported in 35 of 1,819 (1.9%) with cricoid pressure, and 71 of 6,006 (1.2%) without cricoid pressure (unadjusted odds ratio, 1.64; 95% CI, 1.09-2.47; p = 0.018). On multivariable analysis, cricoid pressure was not associated with the occurrence of regurgitation after adjusting for patient, practice, and known regurgitation risk factors (adjusted odds ratio, 1.57; 95% CI, 0.99-2.47; p = 0.054). A sensitivity analysis in propensity score-matched cohorts showed cricoid pressure was associated with a higher regurgitation rate (adjusted odds ratio, 1.01; 95% CI, 1.00-1.02; p = 0.036).Cricoid pressure during induction and mask ventilation before tracheal intubation in the current ICU practice was not associated with a lower regurgitation rate after adjusting for previously reported confounders. Further studies are needed to determine whether cricoid pressure for specific indication with proper maneuver would be effective in reducing regurgitation events.

As of July 2013, pediatric resident trainee guidelines in the United States no longer require proficiency in nonneonatal tracheal intubation. We hypothesized that laryngoscopy by pediatric residents has decreased over time, with a more pronounced decrease after this guideline change.Prospective cohort study.Twenty-five PICUs at various children's hospitals across the United States.Tracheal intubations performed in PICUs from July 2010 to June 2016 in the multicenter tracheal intubation database (National Emergency Airway Registry for Children).None.Prospective cohort study in which all primary tracheal intubations occurring in the United States from July 2010 to June 2016 in the multicenter tracheal intubation database (National Emergency Airway Registry for Children) were analyzed. Participating PICU leaders were also asked to describe their local airway management training for residents. Resident participation trends over time, stratified by presence of a Pediatric Critical Care Medicine fellowship and airway training curriculum for residents, were described. A total of 9,203 tracheal intubations from 25 PICUs were reported. Pediatric residents participated in 16% of tracheal intubations as first laryngoscopists: 14% in PICUs with a Pediatric Critical Care Medicine fellowship and 34% in PICUs without one (p0.001). Resident participation decreased significantly over time (3.4% per year; p0.001). The decrease was significant in ICUs with a Pediatric Critical Care Medicine fellowship (p0.001) but not in ICUs without one (p = 0.73). After adjusting for site-level clustering, patient characteristics, and Pediatric Critical Care Medicine fellowship presence, the Accreditation Council for Graduate Medical Education guideline change was not associated with lower participation by residents (odds ratio, 0.86; 95% CI, 0.59-1.24; p = 0.43). The downward trend of resident participation was similar regardless of the presence of an airway curriculum for residents.Laryngoscopy by pediatric residents has substantially decreased over time. This downward trend was not associated with the 2013 Accreditation Council for Graduate Medical Education change in residency requirements.

OBJECTIVES Evaluate differences in tracheal intubation-associated events and process variances (i.e., multiple intubation attempts and oxygen desaturation) between pediatric cardiac ICUs and noncardiac PICUs in children with underlying cardiac disease. DESIGN Retrospective cohort study using a multicenter tracheal intubation quality improvement database (National Emergency Airway Registry for Children). SETTING Thirty-six PICUs (five cardiac ICUs, 31 noncardiac ICUs) from July 2012 to March 2016. PATIENTS Children with medical or surgical cardiac disease who underwent intubation in an ICU. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Our primary outcome was the rate of any adverse tracheal intubation-associated event. Secondary outcomes were severe tracheal intubation-associated events, multiple tracheal intubation attempt rates, and oxygen desaturation. There were 1,502 tracheal intubations in children with underlying cardiac disease (751 in cardiac ICUs, 751 in noncardiac ICUs) reported. Cardiac ICUs and noncardiac ICUs had similar proportions of patients with surgical cardiac disease. Patients undergoing intubation in cardiac ICUs were younger (median age, 1 mo [interquartile range, 0-6 mo]) compared with noncardiac ICUs (median 3 mo [interquartile range, 1-11 mo]; p < 0.001). Tracheal intubation-associated event rates were not different between cardiac ICUs and noncardiac ICUs (16% vs 19%; adjusted odds ratio, 0.74; 95% CI, 0.54-1.02; p = 0.069). However, in a sensitivity analysis comparing cardiac ICUs with mixed ICUs (i.e., ICUs caring for children with either general pediatric or cardiac diseases), cardiac ICUs had decreased odds of adverse events (adjusted odds ratio, 0.71; 95% CI, 0.52-0.97; p = 0.033). Rates of severe tracheal intubation-associated events and multiple attempts were similar. Desaturations occurred more often during intubation in cardiac ICUs (adjusted odds ratio, 1.61; 95% CI, 1.04-1.15; p = 0.002). CONCLUSIONS In children with underlying cardiac disease, rates of adverse tracheal intubation-associated events were not lower in cardiac ICUs as compared to noncardiac ICUs, even after adjusting for differences in patient characteristics and care models.

Waveform capnography use has been incorporated into guidelines for the confirmation of tracheal intubation. We aim to describe the trend in waveform capnography use in emergency departments and PICUs and assess the association between waveform capnography use and adverse tracheal intubation-associated events.A multicenter retrospective cohort study.Thirty-four hospitals (34 ICUs and nine emergency departments) in the National Emergency Airway Registry for Children quality improvement initiative.Primary tracheal intubation in children younger than 18 years.None.Patient, provider, and practice data for tracheal intubation procedure including a type of end-tidal carbon dioxide measurement, as well as the procedural safety outcomes, were prospectively collected. The use of waveform capnography versus colorimetry was evaluated in association with esophageal intubation with delayed recognition, cardiac arrest, and oxygen desaturation less than 80%. During January 2011 and December 2015, 9,639 tracheal intubations were reported. Waveform capnography use increased over time (39% in 2010 to 53% in 2015; p0.001), whereas colorimetry use decreased (0.001). There was significant variability in waveform capnography use across institutions (median 49%; interquartile range, 25-85%; p0.001). Capnography was used more often in emergency departments as compared with ICUs (66% vs. 49%; p0.001). The rate of esophageal intubation with delayed recognition was similar with waveform capnography versus colorimetry (0.39% vs. 0.46%; p = 0.62). The rate of cardiac arrest was also similar (p = 0.49). Oxygen desaturation occurred less frequently when capnography was used (17% vs. 19%; p = 0.03); however, this was not significant after adjusting for patient and provider characteristics.Significant variations existed in capnography use across institutions, with the use increasing over time in both emergency departments and ICUs. The use of capnography during intubation was not associated with esophageal intubation with delayed recognition or the occurrence of cardiac arrest.

In response to cell injury, the danger signal high mobility group box-1 (HMGB) is released, activating macrophages by binding pattern recognition receptors. We investigated the role of the anti-inflammatory drug minocycline in attenuating HMGB1 translocation, microglial activation, and neuronal injury in a rat model of pediatric traumatic brain injury (TBI). Post-natal day 17 Sprague-Dawley rats underwent moderate-severe controlled cortical impact (CCI). Animals were randomized to treatment with minocycline (90 mg/kg, intraperitoneally) or vehicle (saline) at 10 min and 20 h after injury. Shams received anesthesia and craniotomy. We analyzed HMGB1 translocation (protein fractionation and Western blotting), microglial activation (Iba-1 immunohistochemistry), neuronal death (Fluoro-Jade-B [FJB] immunofluorescence), and neuronal cell counts (unbiased stereology). Behavioral assessments included motor and Morris-water maze testing. Nuclear to cytosolic translocation of HMGB1 in the injured brain was attenuated in minocycline versus vehicle-treated rats at 24 h (p

Oxygen desaturation during tracheal intubation is known to be associated with adverse ICU outcomes in critically ill children. We aimed to determine the occurrence and severity of desaturation during tracheal intubations and the association with adverse hemodynamic tracheal intubation-associated events.Retrospective cohort study as a part of the National Emergency Airway Registry for Children Network's quality improvement project from January 2012 to December 2014.International PICUs.Critically ill children younger than 18 years undergoing primary tracheal intubations in the ICUs.tracheal intubation processes of care and outcomes were prospectively collected using standardized operational definitions. We defined moderate desaturation as oxygen saturation less than 80% and severe desaturation as oxygen saturation less than 70% during tracheal intubation procedures in children with initial oxygen saturation greater than 90% after preoxygenation. Adverse hemodynamic tracheal intubation-associated event was defined as cardiac arrests, hypo or hypertension requiring intervention, and dysrhythmia.A total of 5,498 primary tracheal intubations from 31 ICUs were reported. Moderate desaturation was observed in 19.3% associated with adverse hemodynamic tracheal intubation-associated events (9.8% among children with moderate desaturation vs 4.4% without desaturation; p0.001). Severe desaturation was observed in 12.9% of tracheal intubations, also significantly associated with hemodynamic tracheal intubation-associated events. After adjusting for patient, provider, and practice factors, the occurrence of moderate desaturation was independently associated with hemodynamic tracheal intubation-associated events: adjusted odds ratio 1.83 (95% CI, 1.34-2.51; p0.001). The occurrence of severe desaturation was also independently associated with hemodynamic tracheal intubation-associated events: adjusted odds ratio 2.16 (95% CI, 1.54-3.04; p0.001). Number of tracheal intubation attempts was also significantly associated with the frequency of moderate and severe desaturations (p0.001).In this large tracheal intubation quality improvement database, we found moderate and severe desaturation are reported among 19% and 13% of all tracheal intubation encounters. Moderate and severe desaturations were independently associated with the occurrence of adverse hemodynamic events. Future quality improvement interventions may focus to reduce desaturation events.

Adjunctive therapies have been proposed for use in at least 5 inflammation pathobiology phenotypes in pediatric sepsis-induced multiple organ failure (MOF). Here, we provide host-pathogen interaction prototypes to facilitate understanding of the rationale for personalized therapy in these phenotypes. Meningococcemic sepsis and Shiga-like toxin-associated atypical Hemolytic Uremic Syndrome sepsis result in thrombocytopenia and MOF due to endothelial dysfunction and formation of small vessel thromboses that can respond to plasma exchange and C5a monoclonal antibody therapy. H1N1 Influenza A sepsis is associated with immune paralysis that can result in opportunistic secondary infection with invasive methicillin resistant Staphylococcus aureus (MRSA) and MOF that can respond to Granulocyte Macrophage Colony Stimulating Factor therapy. Hyperleukocytosis-associated MOF is associated with critical Bordetella Pertussis pulmonary hypertension and cardiovascular collapse which can respond to leukoreduction therapy. Epstein Barr Virus lymphoproliferative disease-associated sequential MOF has high levels of soluble-Fas Ligand that cause liver failure, and can respond to anti-CD20 monoclonal antibody therapy. Viral hemorrhagic fevers such as Ebola or Dengue can lead to macrophage activation syndrome characterized by hyperferritinemia, hepatobiliary dysfunction and disseminated intravascular coagulation (DIC)-related MOF that can theoretically respond to anti-inflammatory therapies. We discuss the literature on adjunctive anti-inflammatory and immune modulation therapies that, in addition to traditional organ support and infection source control, might be part of a personalized precision medicine approach to reverse of each of these inflammatory pathobiology phenotypes.

Objective:Video (indirect) laryngoscopy is used as a primary tracheal intubation device for difficult airways in emergency departments and in adult ICUs. The use and outcomes of video laryngoscopy compared with direct laryngoscopy has not been quantified in PICUs or cardiac ICUs.Design:Retrospective

Inflammasome-mediated neuroinflammation may cause secondary injury following traumatic brain injury (TBI) in children. The pattern recognition receptors NACHT domain-, Leucine-rich repeat-, and PYD-containing Protein 1 (NLRP1) and NLRP3 are essential components of their respective inflammasome complexes. We sought to investigate whether NLRP1 and/or NLRP3 abundance is altered in children with severe TBI.Cerebrospinal fluid (CSF) from children (n = 34) with severe TBI (Glasgow coma scale score [GCS] ≤8) who had externalized ventricular drains (EVD) placed for routine care was evaluated for NLRP1 and NLRP3 at 0-24, 25-48, 49-72, and72 h post-TBI and was compared to infection-free controls that underwent lumbar puncture to rule out CNS infection (n = 8). Patient age, sex, initial GCS, mechanism of injury, treatment with therapeutic hypothermia, and 6-month Glasgow outcome score were collected.CSF NLRP1 was undetectable in controls and detected in 2 TBI patients at only24 h post-TBI. CSF NLRP3 levels were increased in TBI patients compared with controls at all time points, p 0.001. TBI patients ≤4 years of age had higher peak NLRP3 levels versus patients4 (15.50 [3.65-25.71] vs. 3.04 [1.52-8.87] ng/mL, respectively; p = 0.048). Controlling for initial GCS in multivariate analysis, peak NLRP36.63 ng/mL was independently associated with poor outcome at 6 months.In the first report of NLRP1 and NLRP3 in childhood neurotrauma, we found that CSF NLRP3 is elevated in children with severe TBI and independently associated with younger age and poor outcome. Future studies correlating NLRP3 with other markers of inflammation and response to therapy are warranted.

To evaluate the relationship between detection of DNA viruses, ferritin, and outcomes in children with severe sepsis.We enrolled 75 pediatric patients with severe sepsis admitted to a tertiary care children's hospital. Plasma ferritin was measured within 48 hours of diagnosis and subsequently twice weekly. Herpes simplex type 1, human herpesvirus 6, Epstein-Barr virus, cytomegalovirus, and adenovirus DNAemia were assessed by polymerase chain reaction.The incidence of DNAemia was increased significantly in patients with ferritin ≥1000 ng/mL (78% vs 28%; P .05). Patients with ferritin ≥1000 ng/mL were more likely to have multiple DNA viruses detected in plasma (39% vs 4%; P .001). The number of viruses detected in plasma directly correlated with the degree of hyperferritinemia and development of combined hepatobiliary and hematologic dysfunction after we controlled for bacterial and fungal coinfections (P .05) as well as increased mortality after we controlled for severity of illness and cancer diagnosis (OR 2.6, 95% CI 1.1-6.3, P.05).Viral DNAemia was associated with hyperferritinemia and adverse outcome in pediatric severe sepsis. Prospective studies are needed to determine whether hyperferritinemia may be used to identify patients at risk of occult DNAemia.

Acute flaccid myelitis is a debilitating illness characterized by acute onset of limb weakness, with one or more spinal segments displaying magnetic resonance imaging–confirmed gray matter lesions. Since the first outbreak in 2014, tracking by the Centers for Disease Control and Prevention has demonstrated biennial epidemics in the United States, with a current outbreak occurring in 2018. The cases of 3 children with acute flaccid myelitis who were initially thought to have common nonneurologic diagnoses are presented. Emergency physicians need to be vigilant to recognize the subtleties of acute flaccid myelitis because the illness progression is rapid and therapy is nuanced.

Primary neurological conditions and secondary neurological insults occurring in the hospital result in high mortality and morbidity in children. Critical differences in development demand that neurocritical care for children be optimally based on pediatric evidence and experience. Further, the approach to neurocritical care practices should to be tailored to a child’s neurological condition, developmental stage, and clinical presentation. These insights and increasing patient and clinician demand have led to the growth of the field of pediatric neurocritical care to improve outcomes based on best evidence and practices using a multidisciplinary care delivery model.