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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.

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.

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.

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".

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

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in children and adolescents. Survivors of severe TBI are more prone to functional deficits, resulting in poorer school performance, poor health-related quality of life (HRQoL), and increased risk of mental health problems. Critical gaps in knowledge of pathophysiological differences between children and adults concerning TBI outcomes, the paucity of pediatric trials and prognostic models and the uncertain extrapolation of adult data to pediatrics pose significant challenges and demand global efforts. Here, we explore the clinical and research unmet needs focusing on severe pediatric TBI to identify best practices in pathways of care and optimize both inpatient and outpatient management of children following TBI.

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

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

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.

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

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.

Adenovirus infection is common in childhood and is generally associated with self-limited disease. Cidofovir, a viral DNA polymerase inhibitor, is used to treat adenovirus infection in select populations but is not often recommended for immunocompetent patients because of limited antiviral activity and nephrotoxicity. Here, we report a case of fulminant adenovirus infection associated with lymphopenia and multiple organ failure requiring extracorporeal membrane oxygenation support in a previously healthy child. After 1 week of supportive therapy, the patient had persistent organ failure and continued to have adenoviremia of >560 000 copies per mL. Weekly doses of cidofovir with concurrent probenecid for renal protection was initiated. Adenovirus blood load declined after the first cidofovir dose, becoming undetectable after 3 doses. The patient was successfully decannulated from extracorporeal membrane oxygenation, extubated, and eventually discharged at his functional baseline without need for ongoing respiratory support. Lymphopenia improved after viremia resolved, and a subsequent immunologic workup revealed no evidence of primary immunodeficiency. The viral isolate was genotyped as adenovirus type 7. This case reveals the successful use of cidofovir for management of severe adenovirus infection in a previously healthy child. To date, there are no universally accepted recommendations for the use of cidofovir in this population. Further study is warranted to determine the potential role of cidofovir in treating severe adenovirus infections in immunocompetent children.

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.

Despite decades of basic and clinical research, treatments to improve outcomes after traumatic brain injury (TBI) are limited. However, based on the recent recognition of the prevalence of mild TBI, and its potential link to neurodegenerative disease, many new and exciting secondary injury mechanisms have been identified and several new therapies are being evaluated targeting both classic and novel paradigms. This includes a robust increase in both preclinical and clinical investigations. Using a mechanism-based approach the authors define the targets and emerging therapies for TBI. They address putative new therapies for TBI across both the spectrum of injury severity and the continuum of care, from the field to rehabilitation. They discuss TBI therapy using 11 categories, namely, (1) excitotoxicity and neuronal death, (2) brain edema, (3) mitochondria and oxidative stress, (4) axonal injury, (5) inflammation, (6) ischemia and cerebral blood flow dysregulation, (7) cognitive enhancement, (8) augmentation of endogenous neuroprotection, (9) cellular therapies, (10) combination therapy, and (11) TBI resuscitation. The current golden age of TBI research represents a special opportunity for the development of breakthroughs in the field.

The “silent epidemic” of traumatic brain injury (TBI) has been placed in the spotlight following investigations and popular press coverage of athletes and returning soldiers with single and repetitive injuries; however, treatments to improve the outcome for patients with TBI across the spectrum from mild to severe TBI are lacking. Neuroinflammation may cause acute secondary injury after TBI, and it has been linked to chronic neurodegenerative diseases. Despite these findings, anti-inflammatory agents have failed to improve outcomes in clinical trials. We therefore propose in this review a new framework for future exploration of targeted immunomodulation after TBI that incorporates factors such as the time from injury, mechanism of injury, and secondary insults in considering potential treatment options. Structured around the dynamics of the immune response to TBI – from initial triggers to chronic neuroinflammation – the ability of soluble and cellular inflammatory mediators to promote repair and regeneration versus secondary injury and neurodegeneration is highlighted, with knowledge from human studies explicitly defined throughout this review. Recent advances in neuroimmunology and TBI-responsive neuroinflammation are incorporated, including inflammasomes, mechanisms of microglial polarization, and glymphatic clearance. In addition, we identify throughout this review where these findings may offer novel therapeutic targets for translational and clinical research, incorporate evidence from other brain injury models, and identify outstanding questions in the field.

Acute encephalitis remains one of the contemporary challenges of critical care medicine. The diagnosis is difficult and sometimes unconfirmed, and encephalitis remains without clear evidence-based therapies or even therapeutic goals for the prevention of high neurologic sequelae. This article provides a framework for pediatric intensivists to guide the diagnosis and management of patients with suspected encephalitis. It provides an in-depth review of the most common causes of encephalitis in children. The article promotes early recognition, appropriate testing and empiric treatment, and management of the expected complications of acute encephalitis.

Hemophagocytic lymphohistiocytosis is a syndrome of pathologic immune activation that shares similar clinical and laboratory phenotypes with severe sepsis. Recent studies led to better recognition of hemophagocytic lymphohistiocytosis by clinicians, but no consensus exists on the criteria for high-risk patients.We retrospectively reviewed the medical records of patients diagnosed with hemophagocytic lymphohistiocytosis to analyze the risk factors associated with poor outcome.Pediatric intensive care and hematology units of three tertiary hospitals in Turkey.Fifty-two children with hemophagocytic lymphohistiocytosis.None.There were a total of 52 children meeting the diagnostic criteria of Histiocytic Society. Of them, 28 (54%) had a primary hemophagocytic lymphohistiocytosis. Mutation studies were performed in 18 of 28 patients (65%). Fourteen of them had PRF1, STX11, STXBP2, and UNC13D mutations, and four had Rab27a and LYST mutations. The remaining 24 patients (46%) were defined as having secondary hemophagocytic lymphohistiocytosis. Twenty-one of them had infection-associated hemophagocytic lymphohistiocytosis, and three had lysinuric protein intolerance. The mortality rate was significantly higher in primary hemophagocytic lymphohistiocytosis (64%) than in secondary hemophagocytic lymphohistiocytosis (16%) (p0.05). There were no significant differences for survival rate between hemophagocytic lymphohistiocytosis 94 (44%) and hemophagocytic lymphohistiocytosis 2004 (64%) protocols (p0.05). Age below 2 years, hyperferritinemia, thrombocytopenia, high disseminated intravascular coagulation score at diagnosis, and no clinical response at 2 weeks of treatment were independent prognostic factors for poor prognosis.Our data suggest that disseminated intravascular coagulation score greater than or equal to 5 can be used in the definition of high-risk patients. Early recognition of poor risk factors has important prognostic and therapeutic implications.

Handoff miscommunications are a leading cause of medical errors. Studies comprehensively assessing handoff improvement programs are lacking.To determine whether introduction of a multifaceted handoff program was associated with reduced rates of medical errors and preventable adverse events, fewer omissions of key data in written handoffs, improved verbal handoffs, and changes in resident-physician workflow.Prospective intervention study of 1255 patient admissions (642 before and 613 after the intervention) involving 84 resident physicians (42 before and 42 after the intervention) from July-September 2009 and November 2009-January 2010 on 2 inpatient units at Boston Children's Hospital.Resident handoff bundle, consisting of standardized communication and handoff training, a verbal mnemonic, and a new team handoff structure. On one unit, a computerized handoff tool linked to the electronic medical record was introduced.The primary outcomes were the rates of medical errors and preventable adverse events measured by daily systematic surveillance. The secondary outcomes were omissions in the printed handoff document and resident time-motion activity.Medical errors decreased from 33.8 per 100 admissions (95% CI, 27.3-40.3) to 18.3 per 100 admissions (95% CI, 14.7-21.9; P .001), and preventable adverse events decreased from 3.3 per 100 admissions (95% CI, 1.7-4.8) to 1.5 (95% CI, 0.51-2.4) per 100 admissions (P = .04) following the intervention. There were fewer omissions of key handoff elements on printed handoff documents, especially on the unit that received the computerized handoff tool (significant reductions of omissions in 11 of 14 categories with computerized tool; significant reductions in 2 of 14 categories without computerized tool). Physicians spent a greater percentage of time in a 24-hour period at the patient bedside after the intervention (8.3%; 95% CI 7.1%-9.8%) vs 10.6% (95% CI, 9.2%-12.2%; P = .03). The average duration of verbal handoffs per patient did not change. Verbal handoffs were more likely to occur in a quiet location (33.3%; 95% CI, 14.5%-52.2% vs 67.9%; 95% CI, 50.6%-85.2%; P = .03) and private location (50.0%; 95% CI, 30%-70% vs 85.7%; 95% CI, 72.8%-98.7%; P = .007) after the intervention.Implementation of a handoff bundle was associated with a significant reduction in medical errors and preventable adverse events among hospitalized children. Improvements in verbal and written handoff processes occurred, and resident workflow did not change adversely.

In pediatric medicine, few conditions can compare with the high morbidity and mortality attributable to out-of-hospital cardiac arrest (OHCA). Pioneering work in cardiopulmonary resuscitation (CPR) procedures by Dr. Peter Safar and training of emergency medical services (EMS) personnel by Dr. Nancy Caroline were early contributions towards improving outcomes for these patients1,2. Subsequently, development of evidenced-based basic and pediatric advanced life support guidelines, growth of EMS systems, better post-resuscitation care, and introduction of long-term rehabilitation programs for children with brain injury have led to improved outcomes in some cardiac arrest patients3. In addition, research using animal and cell culture models have broadened our understanding of the pathophysiologic mechanisms underlying brain injury and multi-organ dysfunction syndrome after cardiac arrest. Ultimately, however, the most important gauge of our collective progress is to evaluate temporal morbidity and mortality trends, to assess if the sum of these efforts is having the desired impact and inform us of opportunities to do better.