Patterns of Multiple Organ Dysfunction and Renal Recovery in Critically Ill Children and Young Adults Receiving Continuous Renal Replacement Therapy.

OBJECTIVES: Acute kidney injury requiring dialysis (AKI-D) commonly occurs in the setting of multiple organ dysfunction syndrome (MODS). Continuous renal replacement therapy (CRRT) is the modality of choice for AKI-D. Mid-term outcomes of pediatric AKI-D supported with CRRT are unknown. We aimed to describe the pattern and impact of organ dysfunction on renal outcomes in critically ill children and young adults with AKI-D. DESIGN: Retrospective cohort. SETTING: Two large quarternary care pediatric hospitals. PATIENTS: Patients 26 y old or younger who received CRRT from 2014 to 2020, excluding patients with chronic kidney disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Organ dysfunction was assessed using the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) score. MODS was defined as greater than or equal to two organ dysfunctions. The primary outcome was major adverse kidney events at 30 days (MAKE30) (decrease in estimated glomerular filtration rate greater than or equal to 25% from baseline, need for renal replacement therapy, and death). Three hundred seventy-three patients, 50% female, with a median age of 84 mo (interquartile range [IQR] 16-172) were analyzed. PELOD-2 increased from 6 (IQR 3-9) to 9 (IQR 7-12) between ICU admission and CRRT initiation. Ninety-seven percent of patients developed MODS at CRRT start and 266 patients (71%) had MAKE30. Acute kidney injury (adjusted odds ratio [aOR] 3.55 [IQR 2.13-5.90]), neurologic (aOR 2.07 [IQR 1.15-3.74]), hematologic/oncologic dysfunction (aOR 2.27 [IQR 1.32-3.91]) at CRRT start, and progressive MODS (aOR 1.11 [IQR 1.03-1.19]) were independently associated with MAKE30. CONCLUSIONS: Ninety percent of critically ill children and young adults with AKI-D develop MODS by the start of CRRT. Lack of renal recovery is associated with specific extrarenal organ dysfunction and progressive multiple organ dysfunction. Currently available extrarenal organ support strategies, such as therapeutic plasma exchange lung-protective ventilation, and other modifiable risk factors, should be incorporated into clinical trial design when investigating renal recovery.

N-Acetylcysteine and Probenecid Adjuvant Therapy for Traumatic Brain Injury.

N-Acetylcysteine (NAC) has shown promise as a putative neurotherapeutic for traumatic brain injury (TBI). Yet, many such promising compounds have limited ability to cross the blood-brain barrier (BBB), achieve therapeutic concentrations in brain, demonstrate target engagement, among other things, that have hampered successful translation. A pharmacologic strategy for overcoming poor BBB permeability and/or efflux out of the brain of organic acid-based, small molecule therapeutics such as NAC is co-administration with a targeted or nonselective membrane transporter inhibitor. Probenecid is a classic ATP-binding cassette and solute carrier inhibitor that blocks transport of organic acids, including NAC. Accordingly, combination therapy using probenecid as an adjuvant with NAC represents a logical neurotherapeutic strategy for treatment of TBI (and other CNS diseases). We have completed a proof-of-concept pilot study using this drug combination in children with severe TBI-the Pro-NAC Trial (ClinicalTrials.gov NCT01322009). In this review, we will discuss the background and rationale for combination therapy with probenecid and NAC in TBI, providing justification for further clinical investigation.

Anticoagulation practices associated with bleeding and thrombosis in pediatric extracorporeal membrane oxygenation; a multi-center secondary analysis.

To determine associations between anticoagulation practices and bleeding and thrombosis during pediatric extracorporeal membrane oxygenation (ECMO), we performed a secondary analysis of prospectively collected data which included 481 children (<19 years), between January 2012 and September 2014. The primary outcome was bleeding or thrombotic events. Bleeding events included a blood product transfusion >80 ml/kg on any day, pulmonary hemorrhage, or intracranial bleeding, Thrombotic events included pulmonary emboli, intracranial clot, limb ischemia, cardiac clot, and arterial cannula or entire circuit change. Bleeding occurred in 42% of patients. Five percent of subjects thrombosed, of which 89% also bled. Daily bleeding odds were independently associated with day prior activated clotting time (ACT) (OR 1.03, 95% CI= 1.00, 1.05, p=0.047) and fibrinogen levels (OR 0.90, 95% CI 0.84, 0.96, p <0.001). Thrombosis odds decreased with increased day prior heparin dose (OR 0.88, 95% CI 0.81, 0.97, p=0.006). Lower ACT values and increased fibrinogen levels may be considered to decrease the odds of bleeding. Use of this single measure, however, may not be sufficient alone to guide optimal anticoagulation practice during ECMO.

Calcium use during paediatric in-hospital cardiac arrest is associated with worse outcomes.

AIM: To evaluate associations between calcium administration and outcomes among children with in-hospital cardiac arrest and among specific subgroups in which calcium use is hypothesized to provide clinical benefit. METHODS: This is a secondary analysis of observational data collected prospectively as part of the ICU-RESUScitation project. Children 37 weeks post-conceptual age to 18 years who received chest compressions in one of 18 intensive care units from October 2016-March 2021 were eligible. Data included child and event characteristics, pre-arrest laboratory values, pre- and intra-arrest haemodynamics, and outcomes. Outcomes included sustained return of spontaneous circulation (ROSC), survival to hospital discharge, and survival to hospital discharge with favourable neurologic outcome. A propensity score weighted cohort was used to evaluate associations between calcium use and outcomes. Subgroups included neonates, and children with hyperkalaemia, sepsis, renal insufficiency, cardiac surgery with cardiopulmonary bypass, and calcium-avid cardiac diagnoses. RESULTS: Of 1,100 in-hospital cardiac arrests, median age was 0.63 years (IQR 0.19, 3.81); 450 (41%) received calcium. Among the weighted cohort, calcium use was not associated with sustained ROSC (aOR, 0.87; CI95 0.61-1.24; p = 0.445), but was associated with lower rates of both survival to hospital discharge (aOR, 0.68; CI95 0.52-0.89; p = 0.005) and survival with favourable neurologic outcome at hospital discharge (aOR, 0.75; CI95 0.57-0.98; p = 0.038). Among subgroups, calcium use was associated with lower rates of survival to hospital discharge in children with sepsis and renal insufficiency. CONCLUSIONS: Calcium use was common during paediatric in-hospital cardiac arrest and associated with worse outcomes at hospital discharge.

Temporal and Spatial Changes in the Microbiome Following Pediatric Severe Traumatic Brain Injury.

OBJECTIVES: 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 time point and confounded by preexisting 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 Analysis of Composition of Microbiomes. SETTING: Five quaternary-care PICUs. PATIENTS: Patients less than 18 years with severe TBI requiring placement of an intracranial pressure monitor. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three hundred twenty-seven samples were analyzed from 23 children with severe TBI and 35 controls. The community composition of initial oral (F = 3.2756, R2 = 0.0535, p = 0.012) and rectal (F = 3.0702, R2 = 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 < 0.05). In exploratory analyses, antibiotic exposure, presence of an endotracheal tube, and occurrence of an infection were associated with greater differences of the rectal and oral microbiomes between TBI patients and healthy controls, whereas enteral nutrition was associated with smaller differences (p < 0.05). CONCLUSIONS: The microbiome of children with severe TBI is characterized by early depletion of commensal bacteria, loss of site specificity, and an enrichment of potential pathogens. Additional studies are needed to determine the impact of these changes on clinical outcomes.

Hepatic Encephalopathy in Children With Acute Liver Failure: Utility of Serum Neuromarkers.

BACKGROUND: Pediatric acute liver failure (PALF) is a public heath burden, often requiring prolonged hospitalization and liver transplantation. Hepatic encephalopathy (HE) is a complication of PALF with limited diagnostic tools to predict outcomes. Serum neurological markers (neuron-specific enolase, S100ß, and myelin basic protein) can be elevated in traumatic or ischemic brain injury. We hypothesized that these neuromarkers would be associated with the development of HE in PALF. METHODS: PALF study participants enrolled between May 2012 and December 2014 by 12 participating centers were the subjects of this analysis. Daily HE assessments were determined by study investigators. Neurological and inflammatory markers were measured using enzyme-linked immunosorbent assay and MILLIPLEX techniques, respectively. To model encephalopathy, these markers were log2 transformed and individually examined for association with HE using a generalized linear mixed model with a logit link and random intercept. RESULTS: Eighty-two children had neurological and inflammatory marker levels and HE assessments recorded, with the majority having assessments for 3 days during their illness. An indeterminate diagnosis (29%) was most common and the median age was 2.9 years. Significant associations were observed for HE with S100ß (odds ratio 1.16, 95% confidence interval [1.03-1.29], P = 0.04) and IL-6 (odds ratio 1.24 [1.11-1.38], P = 0.006). CONCLUSIONS: Serum S100ß and IL-6 are associated with HE in children with PALF. Measuring these markers may assist in assessing neurological injury in PALF, impacting clinical decisions.

Speciation and accumulation of Zn in sweetcorn kernels for genetic and agronomic biofortification programs.

MAIN CONCLUSION: In sweetcorn (Zea mays L.), embryo Zn is accumulated mainly as Zn-phytate, whereas endosperm Zn is complexed with a N- or S-containing ligand. Understanding the speciation of Zn in crop plants helps improve the effectiveness of biofortification efforts. Kernels of four sweetcorn (Zea mays L.) varieties were analysed for Zn concentration and content. We also assessed the speciation of the Zn in the embryo, endosperm, and pericarp in situ using synchrotron-based X-ray absorption spectroscopy. The majority of the Zn was in the endosperm and pericarp (72%), with the embryo contributing 28%. Approximately 79% of the Zn in the embryo accumulated as Zn-phytate, whereas in the endosperm most of the Zn was complexed with a N- or S-containing ligand, possibly as Zn-histidine and Zn-cysteine. This suggests that whilst the Zn in the endosperm and pericarp is likely to be bioavailable for humans, the Zn in the embryo is of low bioavailability. This study highlights the importance of targeting the endosperm of sweetcorn kernels as the tissue for increasing bioavailable Zn concentration.

Management of Pediatric Severe Traumatic Brain Injury: 2019 Consensus and Guidelines-Based Algorithm for First and Second Tier Therapies.

OBJECTIVES: To produce a treatment algorithm for the ICU management of infants, children, and adolescents with severe traumatic brain injury. DATA SOURCES: Studies included in the 2019 Guidelines for the Management of Pediatric Severe Traumatic Brain Injury (Glasgow Coma Scale score ≤ 8), consensus when evidence was insufficient to formulate a fully evidence-based approach, and selected protocols from included studies. DATA SYNTHESIS: Baseline care germane to all pediatric patients with severe traumatic brain injury along with two tiers of therapy were formulated. An approach to emergent management of the crisis scenario of cerebral herniation was also included. The first tier of therapy focuses on three therapeutic targets, namely preventing and/or treating intracranial hypertension, optimizing cerebral perfusion pressure, and optimizing partial pressure of brain tissue oxygen (when monitored). The second tier of therapy focuses on decompressive craniectomy surgery, barbiturate infusion, late application of hypothermia, induced hyperventilation, and hyperosmolar therapies. CONCLUSIONS: This article provides an algorithm of clinical practice for the bedside practitioner based on the available evidence, treatment protocols described in the articles included in the 2019 guidelines, and consensus that reflects a logical approach to mitigate intracranial hypertension, optimize cerebral perfusion, and improve outcomes in the setting of pediatric severe traumatic brain injury.

Acute Neurologic Injury in Children Admitted to the Cardiac Intensive Care Unit.

BACKGROUND: Children with acquired and congenital heart disease both have low mortality but an increased risk of neurologic morbidity that is multifactorial. Our hypothesis was that acute neurologic injuries contribute to mortality in such children and are an important cause of death. METHODS: All admissions to the pediatric cardiac intensive care unit (CICU) from January 2011 through January 2015 were retrospectively reviewed. Patients were assessed for any acute neurologic events (ANEs) during admission, as defined by radiologic findings or seizures documented on an electroencephalogram. RESULTS: Of the 1,573 children admitted to the CICU, the incidence of ANEs was 8.6%. Mortality of the ANE group was 16.3% compared with 1.5% for those who did not have an ANE. The odds ratio for death with ANEs was 8.55 (95% confidence interval, 4.56 to 16.03). Patients with ANEs had a longer hospital length of stay than those without ANEs (41.4 ± 4 vs 14.2 ± 0.6 days; p < 0.001). Need for extracorporeal membrane oxygenation, previous cardiac arrest, and prematurity were independently associated with the presence of an ANE. CONCLUSIONS: Neurologic injuries are common in pediatric CICUs and are associated with an increase in mortality and hospital length of stay. Children admitted to the CICU are likely to benefit from improved surveillance and neuroprotective strategies to prevent neurologic death.

Exploratory Application of Neuropharmacometabolomics in Severe Childhood Traumatic Brain Injury.

OBJECTIVES: To employ metabolomics-based pathway and network analyses to evaluate the cerebrospinal fluid metabolome after severe traumatic brain injury in children and the capacity of combination therapy with probenecid and N-acetylcysteine to impact glutathione-related and other pathways and networks, relative to placebo treatment. DESIGN: Analysis of cerebrospinal fluid obtained from children enrolled in an Institutional Review Board-approved, randomized, placebo-controlled trial of a combination of probenecid and N-acetylcysteine after severe traumatic brain injury (Trial Registration NCT01322009). SETTING: Thirty-six-bed PICU in a university-affiliated children's hospital. PATIENTS AND SUBJECTS: Twelve children 2-18 years old after severe traumatic brain injury and five age-matched control subjects. INTERVENTION: Probenecid (25 mg/kg) and N-acetylcysteine (140 mg/kg) or placebo administered via naso/orogastric tube. MEASUREMENTS AND MAIN RESULTS: The cerebrospinal fluid metabolome was analyzed in samples from traumatic brain injury patients 24 hours after the first dose of drugs or placebo and control subjects. Feature detection, retention time, alignment, annotation, and principal component analysis and statistical analysis were conducted using XCMS-online. The software "mummichog" was used for pathway and network analyses. A two-component principal component analysis revealed clustering of each of the groups, with distinct metabolomics signatures. Several novel pathways with plausible mechanistic involvement in traumatic brain injury were identified. A combination of metabolomics and pathway/network analyses showed that seven glutathione-centered pathways and two networks were enriched in the cerebrospinal fluid of traumatic brain injury patients treated with probenecid and N-acetylcysteine versus placebo-treated patients. Several additional pathways/networks consisting of components that are known substrates of probenecid-inhibitable transporters were also identified, providing additional mechanistic validation. CONCLUSIONS: This proof-of-concept neuropharmacometabolomics assessment reveals alterations in known and previously unidentified metabolic pathways and supports therapeutic target engagement of the combination of probenecid and N-acetylcysteine treatment after severe traumatic brain injury in children.

Phase I randomized clinical trial of N-acetylcysteine in combination with an adjuvant probenecid for treatment of severe traumatic brain injury in children.

BACKGROUND: There are no therapies shown to improve outcome after severe traumatic brain injury (TBI) in humans, a leading cause of morbidity and mortality. We sought to verify brain exposure of the systemically administered antioxidant N-acetylcysteine (NAC) and the synergistic adjuvant probenecid, and identify adverse effects of this drug combination after severe TBI in children. METHODS: IRB-approved, randomized, double-blind, placebo controlled Phase I study in children 2 to 18 years-of-age admitted to a Pediatric Intensive Care Unit after severe TBI (Glasgow Coma Scale [GCS] score ≤8) requiring an externalized ventricular drain for measurement of intracranial pressure (ICP). Patients were recruited from November 2011-August 2013. Fourteen patients (n = 7/group) were randomly assigned after obtaining informed consent to receive probenecid (25 mg/kg load, then 10 mg/kg/dose q6h×11 doses) and NAC (140 mg/kg load, then 70 mg/kg/dose q4h×17 doses), or placebos via naso/orogastric tube. Serum and CSF samples were drawn pre-bolus and 1-96 h after randomization and drug concentrations were measured via UPLC-MS/MS. Glasgow Outcome Scale (GOS) score was assessed at 3 months. RESULTS: There were no adverse events attributable to drug treatment. One patient in the placebo group was withdrawn due to adverse effects. In the treatment group, NAC concentrations ranged from 16,977.3±2,212.3 to 16,786.1±3,285.3 in serum and from 269.3±113.0 to 467.9±262.7 ng/mL in CSF, at 24 to 72 h post-bolus, respectively; and probenecid concentrations ranged from 75.4.3±10.0 to 52.9±25.8 in serum and 5.4±1.0 to 4.6±2.1 µg/mL in CSF, at 24 to 72 h post-bolus, respectively (mean±SEM). Temperature, mean arterial pressure, ICP, use of ICP-directed therapies, surveillance serum brain injury biomarkers, and GOS at 3 months were not different between groups. CONCLUSIONS: Treatment resulted in detectable concentrations of NAC and probenecid in CSF and was not associated with undesirable effects after TBI in children. TRIAL REGISTRATION: ClinicalTrials.gov NCT01322009.

Serum Neuronal Biomarkers in Neonates With Congenital Heart Disease Undergoing Cardiac Surgery.

BACKGROUND: Newborns with congenital heart disease have associated brain damage that affects short-and long-term neurodevelopment. Several neuronal biomarkers exist that could predict brain damage. We investigated the pattern of neuron-specific enolase (NSE) and s100B levels after cardiopulmonary bypass surgery in neonates with congenital heart disease. METHODS: We completed a prospective observational study of neonates with congenital heart disease who were undergoing cardiopulmonary bypass surgery. NSE and s100B levels were measured from serum samples obtained preoperatively, immediately postoperatively, and once daily on postoperative days one to seven. Cranial ultrasounds were obtained preoperatively and postoperatively and findings were scored using an internally developed scoring system. RESULTS: Eighteen neonates were included. Immediate postoperative and peak levels of both NSE (58.0 [21.6] and 68.1 [55.7] µg/L) and s100B (0.14 [0.3] and 0.14 [0.3] µg/L) were significantly increased when compared with preoperative levels (34.0 [21.6] µg/L; P < 0.01 and 0.08 [0.1] µg/L; P < 0.02). By postoperative day seven, NSE and s100B levels were lower than preoperative levels: NSE (18 [5.7]; P = 0.09) and s100B (0.03 [0.05]; P < 0.01). Postoperative s100B levels were negatively correlated with age at surgery and positively correlated with circulatory arrest time. Although there was no significant correlation between either NSE or s100B levels and intensive care unit length of stay, hospital length of stay, and pediatric cerebral performance category score, there was a negative correlation between postoperative levels of NSE and ventriculomegaly. CONCLUSIONS: NSE and s100B levels increase after bypass surgery and return below preoperative baseline levels by postoperative day seven. The levels of s100B were positively correlated with circulatory arrest time and negatively correlated with age at time of surgery. This finding may be supportive of pre-existing prenatal brain injury that could be enhanced by longer surgical times but also of some brain protection effect associated with longer wait until surgery.

Morbidity and mortality prediction in pediatric heart surgery: Physiological profiles and surgical complexity.

OBJECTIVES: Outcome prediction for pediatric heart surgery has focused on mortality but mortality has been significantly reduced over the past 2 decades. Clinical care practices now emphasize reducing morbidity. Physiology-based profiles assessed by the Pediatric Risk of Mortality (PRISM) score are associated with new significant functional morbidity detected at hospital discharge. Our aims were to assess the relationship between new functional morbidity and surgical risk categories (Risk Adjustment for Congenital Heart Surgery [RACHS] and Society for Thoracic Surgery Congenital Heart Surgery Database Mortality Risk [STAT]), measure the performance of 3-level (intact survival, survival with new functional morbidity, or death) and 2-level (survival or death) PRISM prediction algorithms, and assess whether including RACHS or STAT complexity categories improves the PRISM predictive performance. METHODS: Patients (newborn to age 18 years) were randomly selected from 7 sites (December 2011-April 2013). Morbidity (using the Functional Status Scale) and mortality were assessed at hospital discharge. The most recently published PRISM algorithms were tested for goodness of fit, and discrimination with and without the RACHS and STAT complexity categories. RESULTS: The mortality rate in the 1550 patients was 3.2%. Significant new functional morbidity rate occurred in 4.8%, increasing from 1.8% to 13.9%, 1.7%, and 12.9% from the lowest to the highest RACHS and STAT categories, respectively. The 3-level and 2-level PRISM models had satisfactory goodness of fit and substantial discriminative ability. Inclusion of RACHS and STAT complexity categories did not improve model performance. CONCLUSIONS: Both mortality and new, functional morbidity are important outcomes associated with surgical complexity and can be predicted using PRISM algorithms. Adding surgical complexity to the physiologic profiles does not improve predictor performance.

Cerebrospinal Fluid Markers of Macrophage and Lymphocyte Activation After Traumatic Brain Injury in Children.

OBJECTIVES: The magnitude and role of the cellular immune response following pediatric traumatic brain injury remains unknown. We tested the hypothesis that macrophage/microglia and T-cell activation occurs following pediatric traumatic brain injury by measuring cerebrospinal fluid levels of soluble cluster of differentiation 163 and ferritin and soluble interleukin-2 receptor α, respectively, and determined whether these biomarkers were associated with relevant clinical variables and outcome. DESIGN: Retrospective analysis of samples from an established, single-center cerebrospinal fluid bank. SETTING: PICU in a tertiary children's hospital. PATIENTS: Sixty-six pediatric patients after severe traumatic brain injury (Glasgow Coma Scale score < 8) who were 1 month to 16 years old and 17 control patients who were 1 month to 14 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Cerebrospinal fluid levels of soluble cluster of differentiation 163, ferritin, and soluble interleukin-2 receptor α were determined by enzyme-linked immunosorbent assay at two time points (t1 = 17 ± 10 hr; t2 = 72 ± 15 hr) for each traumatic brain injury patient. Cerebrospinal fluid levels of soluble cluster of differentiation 163, ferritin, and soluble interleukin-2 receptor α after traumatic brain injury were compared with controls and analyzed for associations with age, patient sex, initial Glasgow Coma Scale score, diagnosis of abusive head trauma, the presence of hemorrhage on CT scan, and Glasgow Outcome Scale score. Cerebrospinal fluid level of soluble cluster of differentiation 163 was increased in traumatic brain injury patients at t2 versus t1 and controls (median, 95.4 ng/mL [interquartile range, 21.8-134.0 ng/mL] vs 31.0 ng/mL [5.7-77.7 ng/mL] and 27.8 ng/mL [19.1-43.1 ng/mL], respectively; p < 0.05). Cerebrospinal fluid level of ferritin was increased in traumatic brain injury patients at t2 and t1 versus controls (8.3 ng/mL [<7.5-19.8 ng/mL] and 8.9 ng/mL [<7.5-26.7 ng/mL] vs <7.5 ng/mL below lower limit of detection, respectively; p < 0.05). Cerebrospinal fluid levels of soluble interleukin-2 receptor α in traumatic brain injury patients at t2 and t1 were not different versus controls. Multivariate regression revealed associations between high ferritin and age 4 years or younger, lower Glasgow Coma Scale score, abusive head trauma, and unfavorable Glasgow Outcome Scale score. CONCLUSIONS: Children with traumatic brain injury demonstrate evidence for macrophage activation after traumatic brain injury, and in terms of cerebrospinal fluid ferritin, this appears more prominent with young age, initial injury severity, abusive head trauma, and unfavorable outcome. Further study is needed to determine whether biomarkers of macrophage activation may be used to discriminate between aberrant and adaptive immune responses and whether inflammation represents a therapeutic target after traumatic brain injury.

Acute care clinical indicators associated with discharge outcomes in children with severe traumatic brain injury.

OBJECTIVE: The effect of the 2003 severe pediatric traumatic brain injury (TBI) guidelines on outcomes has not been examined. We aimed to develop a set of acute care guideline-influenced clinical indicators of adherence and tested the relationship between these indicators during the first 72 hours after hospital admission and discharge outcomes. DESIGN: Retrospective multicenter cohort study. SETTING: Five regional pediatric trauma centers affiliated with academic medical centers. PATIENTS: Children under 18 years with severe traumatic brain injury (admission Glasgow Coma Scale score ≤ 8, International Classification of Diseases, 9th Edition, diagnosis codes of 800.0-801.9, 803.0-804.9, 850.0-854.1, 959.01, 950.1-950.3, 995.55, maximum head abbreviated Injury Severity Score ≥ 3) who received tracheal intubation for at least 48 hours in the ICU between 2007 and 2011 were examined. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total percent adherence to the clinical indicators across all treatment locations (prehospital, emergency department, operating room, and ICU) during the first 72 hours after admission to study center were determined. Main outcomes were discharge survival and Glasgow Outcome Scale score. Total adherence rate across all locations and all centers ranged from 68% to 78%. Clinical indicators of adherence were associated with survival (adjusted hazard ratios, 0.94; 95% CI, 0.91-0.96). Three indicators were associated with survival: absence of prehospital hypoxia (adjusted hazard ratios, 0.20; 95% CI, 0.08-0.46), early ICU start of nutrition (adjusted hazard ratios, 0.06; 95% CI, 0.01-0.26), and ICU PaCO2 more than 30 mm Hg in the absence of radiographic or clinical signs of cerebral herniation (adjusted hazard ratios, 0.22; 95% CI, 0.06-0.8). Clinical indicators of adherence were associated with favorable Glasgow Outcome Scale among survivors (adjusted hazard ratios, 0.99; 95% CI, 0.98-0.99). Three indicators were associated with favorable discharge Glasgow Outcome Scale: all operating room cerebral perfusion pressure more than 40 mm Hg (adjusted relative risk, 0.61; 95% CI, 0.58-0.64), all ICU cerebral perfusion pressure more than 40 mm Hg (adjusted relative risk, 0.73; 95% CI, 0.63-0.84), and no surgery (any type; adjusted relative risk, 0.68; 95% CI, 0.53- 0.86). CONCLUSIONS: Acute care clinical indicators of adherence to the Pediatric Guidelines were associated with significantly higher discharge survival and improved discharge Glasgow Outcome Scale. Some indicators were protective, regardless of treatment location, suggesting the need for an interdisciplinary approach to the care of children with severe traumatic brain injury.

Cerebral regional oxygen saturation and serum neuromarkers for the prediction of adverse neurologic outcome in pediatric cardiac surgery.

BACKGROUND: The aim of this study is to determine the utility of non-invasive bedside neuromonitoring, including cerebral regional oxygen saturation (rSO2) measured by near-infrared spectroscopy and serum biomarkers, in identifying children at risk from adverse neurological outcome after heart surgery. METHODS: Prospective observational study including 39 consecutive children undergoing heart surgery with cardiopulmonary bypass (CPB) and normal neurologic exam prior to surgery. Cerebral rSO2 was measured at baseline (prior to surgery) and then continuously during surgery and for the first 16 h post-operatively. Neuromarkers [neuron-specific enolase (NSE), S100ß, glial fibrillary acidic protein (GFAP), and brain-derived neurotrophic factor (BDNF)] were measured in serum at baseline, immediately after CPB and at 16 h post-operatively. Adverse neurological outcome was defined as an abnormal pediatric cerebral performance category (PCPC) scale score at 12 months after surgery. RESULTS: Sixteen children (41 %) had an abnormal PCPC scale score at the 12-month evaluation after surgery. In children with unfavorable neurological outcomes, mean cerebral rSO2 values were lower and the area-under-the-curve below a threshold of 40 and 20% below baseline were also increased. No significant differences were found in serum neuromarkers between groups at the time points that were assessed. CONCLUSIONS: Bedside determination of cerebral rSO2 may have some utility in identifying children at risk for adverse neurological outcome after heart surgery in children. Additional studies that are sufficiently powered to control for the many covariates in this patient population will be required to fully interrogate this important question. The role of serum neuromarkers in the immediate post-operative period do not appear to be helpful in this question, though more thorough interrogation of delayed periods may ultimately demonstrate some utility in answering this question.

The potential for bio-mediators and biomarkers in pediatric traumatic brain injury and neurocritical care.

The use of biomarkers of brain injury in pediatric neurocritical care has been explored for at least 15 years. Two general lines of research on biomarkers in pediatric brain injury have been pursued: (1) studies of "bio-mediators" in cerebrospinal fluid (CSF) of children after traumatic brain injury (TBI) to explore the components of the secondary injury cascades in an attempt to identify potential therapeutic targets and (2) studies of the release of structural proteins into the CSF, serum, or urine in order to diagnose, monitor, and/or prognosticate in patients with TBI or other pediatric neurocritical care conditions. Unique age-related differences in brain biology, disease processes, and clinical applications mandate the development and testing of brain injury bio-mediators and biomarkers specifically in pediatric neurocritical care applications. Finally, although much of the early work on biomarkers of brain injury in pediatrics has focused on TBI, new applications are emerging across a wide range of conditions specifically for pediatric neurocritical care including abusive head trauma, cardiopulmonary arrest, septic shock, extracorporeal membrane oxygenation, hydrocephalus, and cardiac surgery. The potential scope of the utility of biomarkers in pediatric neurocritical care is thus also discussed.

Hedgehog-responsive mesenchymal clusters direct patterning and emergence of intestinal villi.

In the adult intestine, an organized array of finger-like projections, called villi, provide an enormous epithelial surface area for absorptive function. Villi first emerge at embryonic day (E) 14.5 from a previously flat luminal surface. Here, we analyze the cell biology of villus formation and examine the role of paracrine epithelial Hedgehog (Hh) signals in this process. We find that, before villus emergence, tight clusters of Hh-responsive mesenchymal cells form just beneath the epithelium. Cluster formation is dynamic; clusters first form dorsally and anteriorly and spread circumferentially and posteriorly. Statistical analysis of cluster distribution reveals a patterned array; with time, new clusters form in spaces between existing clusters, promoting approximately four rounds of villus emergence by E18.5. Cells within mesenchymal clusters express Patched1 and Gli1, as well as Pdgfrα, a receptor previously shown to participate in villus development. BrdU-labeling experiments show that clusters form by migration and aggregation of Hh-responsive cells. Inhibition of Hh signaling prevents cluster formation and villus development, but does not prevent emergence of villi in areas where clusters have already formed. Conversely, increasing Hh signaling increases the size of villus clusters and results in exceptionally wide villi. We conclude that Hh signals dictate the initial aspects of the formation of each villus by controlling mesenchymal cluster aggregation and regulating cluster size.

Dysautonomia after pediatric brain injury.

AIM: Dysautonomia after brain injury is a diagnosis based on fever, tachypnea, hypertension, tachycardia, diaphoresis, and/or dystonia. It occurs in 8 to 33% of adults with brain injury and is associated with poor outcome. We hypothesized that children with brain injury with dysautonomia have worse outcomes and prolonged rehabilitation, and sought to determine the prevalence of dysautonomia in children and to characterize its clinical features. METHOD: We developed a database of children (n = 249, 154 males, 95 females; mean [SD] age 11 years 10 months [5 y 7 mo]) with traumatic brain injury, cardiac arrest, stroke, infection of the central nervous system, or brain neoplasm admitted for rehabilitation to The Children's Institute of Pittsburgh between 2002 and 2009. Dysautonomia diagnosis, injury type, clinical signs, length of stay, and Functional Independence Measure for Children (WeeFIM) testing were extracted from medical records, and analysed for differences between groups with and without dysautonomia. RESULTS: Dysautonomia occurred in 13% of children with brain injury (95% confidence interval 9.3-18.0%), occurring in 10% after traumatic brain injury and 31% after cardiac arrest. The combination of hypertension, diaphoresis, and dystonia best predicted a diagnosis of dysautonomia (area under the curve = 0.92). Children with dysautonomia had longer stays, worse WeeFIM scores, and improved less on the score's motor component (all p ≤ 0.001). INTERPRETATION: Dysautonomia is common in children with brain injury and is associated with prolonged rehabilitation. Prospective study and standardized diagnostic approaches are needed to maximize outcomes.