Association of delayed adequate antimicrobial treatment and organ dysfunction in pediatric bloodstream infections.

BACKGROUND: Bloodstream infections (BSIs) are associated with significant mortality and morbidity, including multiple organ dysfunction. We explored if delayed adequate antimicrobial treatment for children with BSIs is associated with change in organ dysfunction as measured by PELOD-2 scores. METHODS: We conducted a multicenter, retrospective cohort study of critically ill children <18 years old with BSIs. The primary outcome was change in PELOD-2 score between days 1 (index blood culture) and 5. The exposure variable was delayed administration of adequate antimicrobial therapy by ≥3 h from blood culture collection. We compared PELOD-2 score changes between those who received early and delayed treatment. RESULTS: Among 202 children, the median (interquartile range) time to adequate antimicrobial therapy was 7 (0.8-20.1) hours; 124 (61%) received delayed antimicrobial therapy. Patients who received early and delayed treatment had similar baseline characteristics. There was no significant difference in PELOD-2 score changes from days 1 and 5 between groups (PELOD-2 score difference -0.07, 95% CI -0.92 to 0.79, p = 0.88). CONCLUSIONS: We did not find an association between delayed adequate antimicrobial therapy and PELOD-2 score changes between days 1 and 5 from detection of BSI. PELOD-2 score was not sensitive for clinical effects of delayed antimicrobial treatment. IMPACT: In critically ill children with bloodstream infections, there was no significant change in organ dysfunction as measured by PELOD-2 scores between patients who received adequate antimicrobial therapy within 3 h of their initial positive blood culture and those who started after 3 h. Higher PELOD-2 scores on day 1 were associated with larger differences in PELOD-2 scores between days 1 and 5 from index positive blood cultures. Further study is required to determine if PELOD-2 or alternative measures of organ dysfunction could be used as primary outcome measures in trials of antimicrobial interventions in pediatric critical care research.

Criterion validity of the brief test of adult cognition by telephone (BTACT) for mild traumatic brain injury.

OBJECTIVES: There is a growing demand for remote assessment options for measuring cognition after mild traumatic brain injury (mTBI). The current study evaluated the criterion validity of the Brief Test of Adult Cognition by Telephone (BTACT) in distinguishing between adults with mTBI and trauma controls (TC) who sustained injuries not involving the head or neck. METHODS: The BTACT was administered to the mTBI (n = 46) and TC (n = 35) groups at 1-2 weeks post-injury. Participants also completed the Rivermead Post Concussion Symptoms Questionnaire. RESULTS: The BTACT global composite score did not significantly differ between the groups (t(79) = -1.04, p = 0.30); the effect size was small (d = 0.23). In receiver operating characteristic curve analyses, the BTACT demonstrated poor accuracy in differentiating between the groups (AUC = 0.567, SE = 0.065, 95% CI [0.44, 0.69]). The BTACT's ability to discriminate between mTBI and TCs did not improve after excluding mTBI participants (n = 15) who denied ongoing cognitive symptoms (AUC = 0.567, SE = 0.072, 95% CI [0.43, 0.71]). CONCLUSIONS: The BTACT may lack sensitivity to subacute cognitive impairment attributable to mTBI (i.e., not explained by bodily pain, post-traumatic stress, and other nonspecific effects of injury).

Antibiotic treatment duration for bloodstream infections in critically ill children-A survey of pediatric infectious diseases and critical care clinicians for clinical equipoise.

OBJECTIVE: To describe antibiotic treatment durations that pediatric infectious diseases (ID) and critical care clinicians usually recommend for bloodstream infections in critically ill children. DESIGN: Anonymous, online practice survey using five common pediatric-based case scenarios of bloodstream infections. SETTING: Pediatric intensive care units in Canada, Australia and New Zealand. PARTICIPANTS: Pediatric intensivists, nurse practitioners, ID physicians and pharmacists. MAIN OUTCOME MEASURES: Recommended treatment durations for common infectious syndromes associated with bloodstream infections and willingness to enrol patients into a trial to study treatment duration. RESULTS: Among 136 survey respondents, most recommended at least 10 days antibiotics for bloodstream infections associated with: pneumonia (65%), skin/soft tissue (74%), urinary tract (64%) and intra-abdominal infections (drained: 90%; undrained: 99%). For central vascular catheter-associated infections without catheter removal, over 90% clinicians recommended at least 10 days antibiotics, except for infections caused by coagulase negative staphylococci (79%). Recommendations for at least 10 days antibiotics were less common with catheter removal. In multivariable linear regression analyses, lack of source control was significantly associated with longer treatment durations (+5.2 days [95% CI: 4.4-6.1 days] for intra-abdominal infections and +4.1 days [95% CI: 3.8-4.4 days] for central vascular catheter-associated infections). Most clinicians (73-95%, depending on the source of bloodstream infection) would be willing to enrol patients into a trial of shorter versus longer antibiotic treatment duration. CONCLUSIONS: The majority of clinicians currently recommend at least 10 days of antibiotics for most scenarios of bloodstream infections in critically ill children. There is practice heterogeneity in self-reported treatment duration recommendations among clinicians. Treatment durations were similar across different infectious syndromes. Under appropriate clinical conditions, most clinicians would be willing to enrol patients into a trial of shorter versus longer treatment for common syndromes associated with bloodstream infections.

Noninferiority Margin Size and Acceptance of Trial Results: Contingent Valuation Survey of Clinician Preferences for Noninferior Mortality.

OBJECTIVES: We used modified contingent valuation methodology to determine how noninferiority margin sizes influence clinicians' willingness to accept clinical trial results that compare mortality in critically ill children. METHODS: We surveyed pediatric infectious diseases and critical care clinicians in Canada, Australia, and New Zealand and randomized respondents to review 1 of 9 mock abstracts describing a noninferiority trial of bacteremic critically ill children assigned to 7 or 14 d of antibiotics. Each scenario showed higher mortality in the 7-d group but met noninferiority criterion. We explored how noninferiority margins and baseline mortality rates influenced respondent acceptance of results. RESULTS: There were 106 survey respondents: 65 (61%) critical care clinicians, 28 (26%) infectious diseases physicians, and 13 (12%) pharmacists. When noninferiority margins were 5% and 10%, 73% (24/33) and 79% (27/33) respondents would accept shorter treatment, compared with 44% (17/39) when the margin was 20% (P = 0.003). Logistic regression adjusted for baseline mortality showed 5% and 10% noninferiority margins were more likely to be associated with acceptance of shorter treatment compared with 20% margins (odds ratio [OR] 3.5, 95% confidence interval [CI]: 1.3-9.6, P = 0.013; OR 5.1, 95% CI: 1.8-14.6, P = 0.002). Baseline mortality was not a significant predictor of acceptance of shorter treatment. CONCLUSIONS: Clinicians are more likely to accept shorter treatment when noninferiority margins are ≤10%. However, nearly half of respondents who reviewed abstracts with 20% margins were still willing to accept shorter treatment. This is a novel application of contingent valuation methodology to elicit acceptance of research results among end users of the medical literature. HIGHLIGHTS: Clinicians are more likely to accept shorter treatment durations based on noninferior mortality results when the noninferiority margin is 5% or 10% than if the margin is 20%.However, nearly half of clinicians would still accept shorter-duration treatment as noninferior with margins of 20%.Baseline mortality does not independently predict acceptance of shorter-duration treatment.Contingent valuation is a novel approach to elicit the acceptance of research design parameters from the perspective of endusers of the medical literature.

Antimicrobial treatment duration for uncomplicated bloodstream infections in critically ill children: a multicentre observational study.

BACKGROUND: Bloodstream infections (BSIs) cause significant morbidity and mortality in critically ill children but treatment duration is understudied. We describe the durations of antimicrobial treatment that critically ill children receive and explore factors associated with treatment duration. METHODS: We conducted a retrospective observational cohort study in six pediatric intensive care units (PICUs) across Canada. Associations between treatment duration and patient-, infection- and pathogen-related characteristics were explored using multivariable regression analyses. RESULTS: Among 187 critically ill children with BSIs, the median duration of antimicrobial treatment was 15 (IQR 11-25) days. Median treatment durations were longer than two weeks for all subjects with known sources of infection: catheter-related 16 (IQR 11-24), respiratory 15 (IQR 11-26), intra-abdominal 20 (IQR 14-26), skin/soft tissue 17 (IQR 15-33), urinary 17 (IQR 15-35), central nervous system 33 (IQR 15-46) and other sources 29.5 (IQR 15-55) days. When sources of infection were unclear, the median duration was 13 (IQR 10-16) days. Treatment durations varied widely within and across PICUs. In multivariable linear regression, longer treatment durations were associated with severity of illness (+ 0.4 days longer [95% confidence interval (CI), 0.1 to 0.7, p = 0.007] per unit increase in PRISM-IV) and central nervous system infection (+ 17 days [95% CI, 6.7 to 27.4], p = 0.001). Age and pathogen type were not associated with treatment duration. CONCLUSIONS: Most critically ill children with BSIs received at least two weeks of antimicrobial treatment. Further study is needed to determine whether shorter duration therapy would be effective for selected critically ill children.

Death and Dying in Hospitalized Pediatric Patients: A Prospective Multicenter, Multinational Study.

Background: For hospitalized children admitted outside of a critical care unit, the location, mode of death, "do-not-resuscitate" order (DNR) use, and involvement of palliative care teams have not been described across high-income countries. Objective: To describe location of death, patient and terminal care plan characteristics of pediatric inpatient deaths inside and outside the pediatric intensive care unit (PICU). Design: Secondary analysis of inpatient deaths in the Evaluating Processes of Care and Outcomes of Children in Hospital (EPOCH) randomized controlled trial. Setting/Subjects: Twenty-one centers from Canada, Belgium, the United Kingdom, Ireland, Italy, the Netherlands, and New Zealand. Measurement: Descriptive statistics were used to compare patient and terminal care plan characteristics. A multivariable generalized estimating equation examined if palliative care consult during hospital admission was associated with location of death. Results: A total of 365 of 144,539 patients enrolled in EPOCH died; 219 (60%) died in PICU and 143 (40%) died on another inpatient unit. Compared with other inpatient wards, patients who died in PICU were less likely to be expected to die, have a DNR or palliative care consult. Hospital palliative care consultation was more common in older children and independently associated with a lower adjusted odds (95% confidence interval) of dying in PICU [0.59 (0.52-0.68)]. Conclusion: Most pediatric inpatient deaths occur in PICU where patients were less likely to have a DNR or palliative care consult. Palliative care consultation could be better integrated into end-of-life care for younger children and those dying in PICU.

Alterations in coordinated EEG activity precede the development of seizures in comatose children.

OBJECTIVE: We aimed to test the hypothesis that computational features of the first several minutes of EEG recording can be used to estimate the risk for development of acute seizures in comatose critically-ill children. METHODS: In a prospective cohort of 118 comatose children, we computed features of the first five minutes of artifact-free EEG recording (spectral power, inter-regional synchronization and cross-frequency coupling) and tested if these features could help identify the 25 children who went on to develop acute symptomatic seizures during the subsequent 48 hours of cEEG monitoring. RESULTS: Children who developed acute seizures demonstrated higher average spectral power, particularly in the theta frequency range, and distinct patterns of inter-regional connectivity, characterized by greater connectivity at delta and theta frequencies, but weaker connectivity at beta and low gamma frequencies. Subgroup analyses among the 97 children with the same baseline EEG background pattern (generalized slowing) yielded qualitatively and quantitatively similar results. CONCLUSIONS: These computational features could be applied to baseline EEG recordings to identify critically-ill children at high risk for acute symptomatic seizures. SIGNIFICANCE: If confirmed in independent prospective cohorts, these features would merit incorporation into a decision support system in order to optimize diagnostic and therapeutic management of seizures among comatose children.

Testing for non-inferior mortality: a systematic review of non-inferiority margin sizes and trial characteristics.

OBJECTIVE: To describe the size and variability of non-inferiority margins used in non-inferiority trials of medications with primary outcomes involving mortality, and to examine the association between trial characteristics and non-inferiority margin size. DESIGN: Systematic review. DATA SOURCES: Medline, Medline In Process, Medline Epub Ahead of Print and Embase Classic+Embase databases from January 1989 to December 2019. ELIGIBILITY CRITERIA: Prospective non-inferiority randomised controlled trials comparing pharmacological therapies, with primary analyses for non-inferiority and primary outcomes involving mortality alone or as part of a composite outcome. Trials had to prespecify non-inferiority margins as absolute risk differences or relative to risks of outcome and provide a baseline risk of primary outcome in the control intervention. RESULTS: 3992 records were screened, 195 articles were selected for full text review and 111 articles were included for analyses. 82% of trials were conducted in thrombosis, infectious diseases or oncology. Mortality was the sole primary outcome in 23 (21%) trials, and part of a composite primary outcome in 88 (79%) trials. The overall median non-inferiority margin was an absolute risk difference of 9% (IQR 4.2%-10%). When non-inferiority margins were expressed relative to the baseline risk of primary outcome in control groups, the median relative non-inferiority margin was 1.5 (IQR 1.3-1.7). In multivariable regression analyses examining the association between trial characteristics (medical specialty, inclusion of paediatric patients, mortality as a sole or part of a composite primary outcome, presence of industry funding) and non-inferiority margin size, only medical specialty was significantly associated with non-inferiority margin size. CONCLUSION: Absolute and relative non-inferiority margins used in published trials comparing medications are large, allowing conclusions of non-inferiority in the context of large differences in mortality. Accepting the potential for large increases in outcomes involving mortality while declaring non-inferiority is a challenging methodological issue in the conduct of non-inferiority trials.

Magnetic Resonance Imaging Findings Are Associated with Long-Term Global Neurological Function or Death after Traumatic Brain Injury in Critically Ill Children.

The identification of children with traumatic brain injury (TBI) who are at risk of death or poor global neurological functional outcome remains a challenge. Magnetic resonance imaging (MRI) can detect several brain pathologies that are a result of TBI; however, the types and locations of pathology that are the most predictive remain to be determined. Forty-two critically ill children with TBI were recruited prospectively from pediatric intensive care units at five Canadian children's hospitals. Pathologies detected on subacute phase MRIs included cerebral hematoma, herniation, cerebral laceration, cerebral edema, midline shift, and the presence and location of cerebral contusion or diffuse axonal injury (DAI) in 28 regions of interest were assessed. Global functional outcome or death more than 12 months post-injury was assessed using the Pediatric Cerebral Performance Category score. Linear modeling was employed to evaluate the utility of an MRI composite score for predicting long-term global neurological function or death after injury, and nonlinear Random Forest modeling was used to identify which MRI features have the most predictive utility. A linear predictive model of favorable versus unfavorable long-term outcomes was significantly improved when an MRI composite score was added to clinical variables. Nonlinear Random Forest modeling identified five MRI variables as stable predictors of poor outcomes: presence of herniation, DAI in the parietal lobe, DAI in the subcortical white matter, DAI in the posterior corpus callosum, and cerebral contusion in the anterior temporal lobe. Clinical MRI has prognostic value to identify children with TBI at risk of long-term unfavorable outcomes.

Efficacy of Melatonin in Children With Postconcussive Symptoms: A Randomized Clinical Trial.

BACKGROUND: Approximately 25% of children with concussion have persistent postconcussive symptoms (PPCS) with resultant significant impacts on quality of life. Melatonin has significant neuroprotective properties, and promising preclinical data suggest its potential to improve outcomes after traumatic brain injury. We hypothesized that treatment with melatonin would result in a greater decrease in PPCS symptoms when compared with a placebo. METHODS: We conducted a randomized, double-blind trial of 3 or 10 mg of melatonin compared with a placebo (NCT01874847). We included youth (ages 8-18 years) with PPCS at 4 to 6 weeks after mild traumatic brain injury. Those with significant medical or psychiatric histories or a previous concussion within the last 3 months were excluded. The primary outcome was change in the total youth self-reported Post-Concussion Symptom Inventory score measured after 28 days of treatment. Secondary outcomes included change in health-related quality of life, cognition, and sleep. RESULTS: Ninety-nine children (mean age: 13.8 years; SD = 2.6 years; 58% girls) were randomly assigned. Symptoms improved over time with a median Post-Concussion Symptom Inventory change score of -21 (95% confidence interval [CI]: -16 to -27). There was no significant effect of melatonin when compared with a placebo in the intention-to-treat analysis (3 mg melatonin, -2 [95% CI: -13 to 6]; 10 mg melatonin, 4 [95% CI: -7 to 14]). No significant group differences in secondary outcomes were observed. Side effects were mild and similar to the placebo. CONCLUSIONS: Children with PPCS had significant impairment in their quality of life. Seventy-eight percent demonstrated significant recovery between 1 and 3 months postinjury. This clinical trial does not support the use of melatonin for the treatment of pediatric PPCS.

Atypical Somatic Symptoms in Adults With Prolonged Recovery From Mild Traumatic Brain Injury.

Somatization may contribute to persistent symptoms after mild traumatic brain injury (mTBI). In two independently-recruited study samples, we characterized the extent to which symptoms atypical of mTBI but typical for patients suffering from somatization (e.g., gastrointestinal upset, musculoskeletal, and cardiorespiratory complaints) were present in adult patients with prolonged recovery following mTBI. The first sample was cross-sectional and consisted of mTBI patients recruited from the community who reported ongoing symptoms attributable to a previous mTBI (n = 16) along with a healthy control group (n = 15). The second sample consisted of patients with mTBI prospectively recruited from a Level 1 trauma center who had either good recovery (GOSE = 8; n = 32) or poor recovery (GOSE < 8; n = 29). In all participants, we evaluated atypical somatic symptoms using the Patient Health Questionnaire-15 and typical post-concussion symptoms with the Rivermead Post-Concussion Symptom Questionnaire. Participants with poor recovery from mTBI had significantly higher "atypical" somatic symptoms as compared to the healthy control group in Sample 1 (b = 4.308, p < 0.001) and to mTBI patients with good recovery in Sample 2 (b = 3.169, p < 0.001). As would be expected, participants with poor outcome in Sample 2 had a higher burden of typical rather than atypical symptoms [t (28) = 4.750, p < 0.001, d = 0.88]. However, participants with poor recovery still reported atypical somatic symptoms that were significantly higher (1.4 standard deviations, on average) than those with good recovery. Our results suggest that although "typical" post-concussion symptoms predominate after mTBI, a broad range of somatic symptoms also frequently accompanies mTBI, and that somatization may represent an important, modifiable factor in mTBI recovery.

Seizure Identification by Critical Care Providers Using Quantitative Electroencephalography.

OBJECTIVES: To compare the performance of critical care providers with that of electroencephalography experts in identifying seizures using quantitative electroencephalography display tools. DESIGN: Diagnostic accuracy comparison among healthcare provider groups. SETTING: Multispecialty quaternary children's hospital in Canada. SUBJECTS: ICU fellows, ICU nurses, neurophysiologists, and electroencephalography technologists. INTERVENTION: Two-hour standardized one-on-one training, followed by a supervised individual review of 27 continuous electroencephalography recordings with the task of identifying individual seizures on eight-channel amplitude-integrated electroencephalography and color density spectral array displays. MEASUREMENTS AND MAIN RESULTS: Each participant reviewed 27 continuous electroencephalograms comprising 487 hours of recording containing a total of 553 seizures. Performance for seizure identification was compared among groups using a nested model analysis with adjustment for interparticipant variability within groups and collinearity among recordings. Using amplitude-integrated electroencephalography, sensitivity for seizure identification was comparable among ICU fellows (83.8%), ICU nurses (73.1%), and neurophysiologists (81.5%) but lower among electroencephalographic technologists (66.7%) (p = 0.003). Using color density spectral array, sensitivity was comparable among ICU fellows (82.4%), ICU nurses (88.2%), neurophysiologists (83.3%), and electroencephalographic technologists (73.3%) (p = 0.09). Daily false-positive rates were also comparable among ICU fellows (2.8 for amplitude-integrated electroencephalography, 7.7 for color density spectral array), ICU nurses (4.2, 7.1), neurophysiologists (1.2, 1.5), and electroencephalographic technologists (0, 0) (p = 0.41 for amplitude-integrated electroencephalography; p = 0.13 for color density spectral array). However, performance varied greatly across individual electroencephalogram recordings. Professional background generally played a greater role in determining performance than individual skill or electroencephalogram recording characteristics. CONCLUSIONS: Following standardized training, critical care providers and electroencephalography experts displayed similar performance for identifying individual seizures using both amplitude-integrated electroencephalography and color density spectral array displays. Although these quantitative electroencephalographic trends show promise as a tool for bedside seizure screening by critical care providers, these findings require confirmation in a real-world ICU environment and in daily clinical use.

The Canadian Traumatic Brain Injury Research Consortium: Epitomizing Collaborative Research in Canada.

Traumatic brain injury (TBI) is the leading cause of death in the first half of life and a chronic disability for Canadians of all ages. Despite the recognized importance of TBI, there is no integrated national strategy for research and best practices in Canada. We therefore created the Canadian TBI Research Consortium (CTRC) to build an ideal model of collaboration between Canadian TBI researchers. Our objectives were to: (1) Create a collaborative Canadian research network, (2) improve patient survival, functional outcome, and health through sustainable and scalable evidence-based practice implementation, (3) strengthen the healthcare system for patients with TBI, (4) provide international leadership and collaboration in TBI research, (5) build stronger links with patients and their representatives to help set the research agenda, and to participate in analysis of its impacts, and (6) support current researchers and prepare the next generation of leaders in TBI research. Building on the highly successful 30-year history of the Canadian Critical Care Trials Group, we developed a highly collaborative research group that integrates the multi-disciplinary network of TBI researchers in Canada. The CTRC conducts multi-center clinically relevant practice changing research. Our research is developed around investigator-led project-based research using a programmatic approach and multiple methodologies. Through strong and sustainable career development and mentorship programs, we train and develop the next generation of TBI researchers. Our group is composed of more than 100 Canadian researchers from coast to coast, most of them funded by the Canadian Institutes of Health Research and other granting agencies. In conclusion, the CTRC prioritizes investigator-led TBI research and broadens the research agenda by integrating researchers from different disciplines in the field of TBI research to optimize delivery of care and improve the health of Canadians with TBI. Our goals are being accomplished across the whole continuum of care by conducting clinically relevant and practice-changing research.

A multiple-dose double-blind randomized study to evaluate the safety, pharmacokinetics, pharmacodynamics and analgesic efficacy of the TRPV1 antagonist JNJ-39439335 (mavatrep).

BACKGROUND AND AIMS: This double-blind (DB), randomized, placebo-controlled, sequential-group, multiple-ascending dose, phase 1 study evaluated safety, pharmacokinetics and pharmacodynamics of JNJ-39439335 in healthy men (part 1), and in participants with knee osteoarthritis (part 2). METHODS: Both parts 1 and 2 consisted of screening (upto 21 days), 21-day DB treatment phase [eight participants/group: JNJ-39439335 (part 1: 2-50 mg; part 2: 10-50 mg): n=6; placebo: n=2] and follow-up (total study duration ~10 weeks). RESULTS: Plasma concentrations and systemic exposure of JNJ-39439335 increased in slightly higher than dose-proportional fashion (steady-state reached by day 14). Renal excretion of JNJ-39439335 was negligible. Marked dose-related increases in pharmacodynamic heat pain assessments were observed in JNJ-39439335-treated participants, which persisted throughout the treatment with no signs of tolerance with repeated dosing. No effect on pharmacodynamic cold pain or mechanical pain assessments were seen. Effects on pharmacodynamic capsaicin-induced flare assessments in JNJ-39439335-treated participants versus placebo were consistent with effects observed with single-dose, and did not demonstrate tolerance with multiple dosing. In participants with knee osteoarthritis, significant improvements versus placebo were observed in a stair-climbing-induced pain model. All JNJ-39439335-treated participants reported ≥1 treatment-emergent adverse events (TEAE); most common (≥50% incidence) TEAEs in part 1 were feeling hot (79%), thermohypoesthesia (71%), paresthesia (58%) and feeling cold (50%), and in part 2, were minor thermal burns (50%). CONCLUSIONS: JNJ-39439335 (doses 2-50 mg) was well-tolerated, and associated with acceptable multiple-dose pharmacokinetic profile. JNJ-39439335 demonstrated sustained pharmacodynamic effects (heat pain perception, heat pain latency, capsaicin-induced flare), and an efficacy signal in participants with osteoarthritis pain. IMPLICATIONS: Given the efficacy signal observed and the unique safety profile, larger phase 2 studies are needed to better understand the potential of JNJ-39439335 in the treatment of chronic pain. Analgesic efficacy of lower doses administered over a longer period of time and improved patient counseling techniques to reduce the minor thermal burns can be explored to minimize the adverse events.

Effect of a Pediatric Early Warning System on All-Cause Mortality in Hospitalized Pediatric Patients: The EPOCH Randomized Clinical Trial.

Importance: There is limited evidence that the use of severity of illness scores in pediatric patients can facilitate timely admission to the intensive care unit or improve patient outcomes. Objective: To determine the effect of the Bedside Paediatric Early Warning System (BedsidePEWS) on all-cause hospital mortality and late admission to the intensive care unit (ICU), cardiac arrest, and ICU resource use. Design, Setting, and Participants: A multicenter cluster randomized trial of 21 hospitals located in 7 countries (Belgium, Canada, England, Ireland, Italy, New Zealand, and the Netherlands) that provided inpatient pediatric care for infants (gestational age ≥37 weeks) to teenagers (aged ≤18 years). Participating hospitals had continuous physician staffing and subspecialized pediatric services. Patient enrollment began on February 28, 2011, and ended on June 21, 2015. Follow-up ended on July 19, 2015. Interventions: The BedsidePEWS intervention (10 hospitals) was compared with usual care (no severity of illness score; 11 hospitals). Main Outcomes and Measures: The primary outcome was all-cause hospital mortality. The secondary outcome was a significant clinical deterioration event, which was defined as a composite outcome reflecting late ICU admission. Regression analyses accounted for hospital-level clustering and baseline rates. Results: Among 144 539 patient discharges at 21 randomized hospitals, there were 559 443 patient-days and 144 539 patients (100%) completed the trial. All-cause hospital mortality was 1.93 per 1000 patient discharges at hospitals with BedsidePEWS and 1.56 per 1000 patient discharges at hospitals with usual care (adjusted between-group rate difference, 0.01 [95% CI, -0.80 to 0.81 per 1000 patient discharges]; adjusted odds ratio, 1.01 [95% CI, 0.61 to 1.69]; P = .96). Significant clinical deterioration events occurred during 0.50 per 1000 patient-days at hospitals with BedsidePEWS vs 0.84 per 1000 patient-days at hospitals with usual care (adjusted between-group rate difference, -0.34 [95% CI, -0.73 to 0.05 per 1000 patient-days]; adjusted rate ratio, 0.77 [95% CI, 0.61 to 0.97]; P = .03). Conclusions and Relevance: Implementation of the Bedside Paediatric Early Warning System compared with usual care did not significantly decrease all-cause mortality among hospitalized pediatric patients. These findings do not support the use of this system to reduce mortality. Trial Registration: clinicaltrials.gov Identifier: NCT01260831.

Fatigue Following Traumatic Brain Injury in Children and Adolescents: A Longitudinal Follow-Up 6 to 12 Months After Injury.

BACKGROUND: Longitudinal fatigue data in children suffering from traumatic brain injury (TBI) are lacking. OBJECTIVES: To examine the effects of time postinjury (6-12 months) and injury severity on fatigue after childhood TBI. Secondarily, we compared fatigue 12 months postinjury against published control data. SETTING: Three tertiary children's hospitals across Australia (n = 1) and Canada (n = 2). PARTICIPANTS: Parents (n = 109) of children (mean [M] = 9.9 years at injury; range, 1.0-16.9 years) admitted to one of 3 participating hospitals with mild (n = 69) or moderate/severe (n = 37) TBI. DESIGN: Longitudinal prospective study. MEASURES: Primary: Pediatric Quality of Life Multidimensional Fatigue Scale (total, general, sleep/rest, and cognitive), rated by parents 6 and 12 months postinjury. Secondary: Pediatric Injury Functional Outcome Scale (fatigue and sleep items, rated on recruitment and 6 and 12 months postinjury). Demographic and children data were collected at recruitment. RESULTS: Mixed-models analysis demonstrated nonsignificant effects of time (6 vs 12 months postinjury) on multidimensional fatigue scores. Cognitive fatigue worsened over time. Moderate/severe TBI was associated with worse fatigue 12 months postinjury (general, P = .03; cognitive, P = .02). Across all severities, fatigue 12 months postinjury was significantly worse compared with control data (total fatigue, P < .001; all domains, all Ps < .025). CONCLUSION: Fatigue remains significant at 12 months since injury, particularly for those with moderate/severe TBI.

Predicting Fatigue 12 Months after Child Traumatic Brain Injury: Child Factors and Postinjury Symptoms.

OBJECTIVES: Fatigue is a common and persisting symptom after childhood brain injury. This study examined whether child characteristics and symptomatology preinjury or 6 months postinjury (pain, sleep, and mood, inattention) predicted fatigue at 12months postinjury. METHODS: Parents of 79 children (0-18 years) rated fatigue at 12 months after injury on a multidimensional scale (general, sleep/rest, and cognitive). Demographic and clinical data were collected at injury. Parents rated child sleep, pain, physical/motor function, mood, and inattention at injury (preinjury description), and 6 months postinjury. Children were divided into two traumatic brain injury severity groups: mild TBI (n=57) and moderate/severe TBI (n=27). Hierarchical regression models were used to examine (i) preinjury factors and (ii) symptoms 6 months postinjury predictive of fatigue (general, sleep/rest, and cognitive) at 12 months postinjury. RESULTS: Sleep/rest fatigue was predicted by preinjury fatigue (7% of variance) and psychological symptoms preinjury (10% of variance). General fatigue was predicted by physical/motor symptoms (27%), sleep (10%) and mood symptoms (9%) 6 months postinjury. Sleep/rest fatigue was predicted by physical/motor symptoms (10%), sleep symptoms (13%) and mood symptoms (9%) 6 months postinjury. Cognitive fatigue was predicted by physical/motor symptoms (17%) 6 months postinjury. CONCLUSIONS: Preinjury fatigue and psychological functioning identified those at greatest risk of fatigue 12 months post-TBI. Predictors of specific fatigue domains at 12 months differed across each of the domains, although consistently included physical/motor function as well as sleep and mood symptoms postinjury. (JINS, 2018, 24, 224-236).

Evaluating processes of care and outcomes of children in hospital (EPOCH): study protocol for a randomized controlled trial.

BACKGROUND: The prevention of near and actual cardiopulmonary arrest in hospitalized children is a patient safety imperative. Prevention is contingent upon the timely identification, referral and treatment of children who are deteriorating clinically. We designed and validated a documentation-based system of care to permit identification and referral as well as facilitate provision of timely treatment. We called it the Bedside Paediatric Early Warning System (BedsidePEWS). Here we describe the rationale for the design, intervention and outcomes of the study entitled Evaluating Processes and Outcomes of Children in Hospital (EPOCH). METHODS/DESIGN: EPOCH is a cluster-randomized trial of the BedsidePEWS. The unit of randomization is the participating hospital. Eligible hospitals have a Pediatric Intensive Care Unit (PICU), are anticipated to have organizational stability throughout the study, are not using a severity of illness score in hospital wards and are willing to be randomized. Patients are >37 weeks gestational age and <18 years and are hospitalized in inpatient ward areas during all or part of their hospital admission. Randomization is to either BedsidePEWS or control (no severity of illness score) in a 1:1 ratio within two strata (<200, ≥ 200 hospital beds). All-cause hospital mortality is the selected primary outcome. It is objective, independent of do-not-resuscitate status and can be reliably measured. The secondary outcomes include (1) clinical outcomes: clinical deterioration, severity of illness at and during ICU admission, and potentially preventable cardiac arrest; (2) processes of care outcomes: immediate calls for assistance, hospital and ICU readmission, and perceptions of healthcare professionals; and (3) resource utilization: ICU days and use of ICU therapies. DISCUSSION: Following funding by the Canadian Institutes of Health Research and local ethical approvals, site enrollment started in 2010 and was closed in February 2014. Patient enrollment is anticipated to be complete in July 2015. The results of EPOCH will strengthen the scientific basis for local, regional, provincial and national decision-making and for the recommendations of national and international bodies. If negative, the costs of hospital-wide implementation can be avoided. If positive, EPOCH will have provided a scientific justification for the major system-level changes required for implementation. TRIAL REGISTRATION: NCT01260831 ClinicalTrials.gov date: 14 December 2010.

Time on the scene and interventions are associated with improved survival in pediatric out-of-hospital cardiac arrest.

BACKGROUND: Survival is less than 10% for pediatric patients following out-of-hospital cardiac arrest. It is not known if more time on the scene of the cardiac arrest and advanced life support interventions by emergency services personnel are associated with improved survival. AIM: This study was performed to determine which times on the scene and which prehospital interventions were associated with improved survival. METHODS: We studied patients aged 3 days to 19 years old with out-of-hospital cardiac arrest, using the Resuscitation Outcomes Consortium cardiac arrest database from 11 North American regions, from 2005 to 2012. We evaluated survival to hospital discharge according to on-scene times (<10, 10 to 35 and >35 min). RESULTS: Data were available for 2244 patients (1017 infants, 594 children and 633 adolescents). Infants had the lowest rate of survival (3.7%) compared to children (9.8%) and adolescents (16.3%). Survival improved over the 7 year study period especially among adolescents. Survival was highest in the 10 to 35 min on-scene time group (10.2%) compared to the >35 min. group (6.9%) and the <10 min. group (5.3%, p=0.01). Intravenous or intra-osseous access attempts and fluid administration were associated with improved survival, whereas advanced airway attempts were not associated with survival and resuscitation drugs were associated with worse survival. CONCLUSIONS: In this observational study, a scene time of 10 to 35 min was associated with the highest survival, especially among adolescents. Access for fluid resuscitation was associated with increased survival but advanced airway and resuscitation drugs were not.

A Cohort Study of Pediatric Shock: Frequency of Corticosteriod Use and Association with Clinical Outcomes.

INTRODUCTION: Pediatric shock is associated with significant morbidity and limited evidence suggests treatment with corticosteroids. The objective of this study was to describe practice patterns and outcomes associated with corticosteroid use in children with shock. METHODS: We conducted a retrospective, cohort study in four pediatric intensive care units (PICU) in Canada. Patients aged newborn to 17 years admitted to PICU with shock between January 2010 and June 2011 were eligible. RESULTS: 364 patients were included. The frequency of hydrocortisone administration was 22.3% overall (95% CI: 18.0, 26.5) and 59.4% in patients who received at least 60 cc/kg of fluid and were on two or more vasoactive agents. Patients administered hydrocortisone had higher PRISM scores (19, IQR 11-24 versus 9, IQR 5-16; P < 0.0001), higher inotrope scores (15, IQR 10-25 versus 7.5, IQR 3.3-10.6, P < 0.0001) and were more likely to have received 60 cc/kg of fluid resuscitation (59.3% versus 33.6%, OR 2.88, 95% CI: 2.09, 3.96). In an adjusted analysis, patients who received hydrocortisone spent more time on vasoactive infusions (64 versus 34  hours, hazard ratio 0.72, 95% CI: 0.62, 0.84) and had a higher incidence of positive cultures between day 4 and day 28 post admission (24.7% versus 14.5%, OR 1.79, 95% CI: 1.58, 2.04). CONCLUSION: Hydrocortisone administration was associated with longer time on vasopressors and increased incidence of positive cultures even after correcting for illness severity. Caution should be exercised in administering hydrocortisone for shock until there is clear evidence for benefit in this patient population.