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.

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.

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).

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.

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).

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.

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.

Seizure burden is independently associated with short term outcome in critically ill children.

Seizures are common among critically ill children, but their relationship to outcome remains unclear. We sought to quantify the relationship between electrographic seizure burden and short-term neurological outcome, while controlling for diagnosis and illness severity. Furthermore, we sought to determine whether there is a seizure burden threshold above which there is an increased probability of neurological decline. We prospectively evaluated all infants and children admitted to our paediatric and cardiac intensive care units who underwent clinically ordered continuous video-electroencephalography monitoring over a 3-year period. Seizure burden was quantified by calculating the maximum percentage of any hour that was occupied by electrographic seizures. Outcome measures included neurological decline, defined as a worsening Paediatric Cerebral Performance Category score between hospital admission and discharge, and in-hospital mortality. Two hundred and fifty-nine subjects were evaluated (51% male) with a median age of 2.2 years (interquartile range: 0.3 days-9.7 years). The median duration of continuous video-electroencephalography monitoring was 37 h (interquartile range: 21-56 h). Seizures occurred in 93 subjects (36%, 95% confidence interval = 30-42%), with 23 (9%, 95% confidence interval = 5-12%) experiencing status epilepticus. Neurological decline was observed in 174 subjects (67%), who had a mean maximum seizure burden of 15.7% per hour, compared to 1.8% per hour for those without neurological decline (P < 0.0001). Above a maximum seizure burden threshold of 20% per hour (12 min), both the probability and magnitude of neurological decline rose sharply (P < 0.0001) across all diagnostic categories. On multivariable analysis adjusting for diagnosis and illness severity, the odds of neurological decline increased by 1.13 (95% confidence interval = 1.05-1.21, P = 0.0016) for every 1% increase in maximum hourly seizure burden. Seizure burden was not associated with mortality (odds ratio: 1.003, 95% confidence interval: 0.99-1.02, P = 0.613). We conclude that in this cohort of critically ill children, increasing seizure burden was independently associated with a greater probability and magnitude of neurological decline. Our observation that a seizure burden of more than 12 min in a given hour was strongly associated with neurological decline suggests that early antiepileptic drug management is warranted in this population, and identifies this seizure burden threshold as a potential therapeutic target. These findings support the hypothesis that electrographic seizures independently contribute to brain injury and worsen outcome. Our results motivate and inform the design of future studies to determine whether more aggressive seizure treatment can improve outcome.

Acute rehabilitation practices in critically ill children: a multicenter study.

OBJECTIVE: To evaluate acute rehabilitation practices in pediatric critical care units across Canada. DESIGN: Retrospective cohort study. SETTING: Six Canadian, tertiary care pediatric critical care units. PATIENTS/SUBJECTS: Six hundred children aged under 17 years admitted to pediatric critical care unit during a winter and summer month of 2011 with a greater than 24-hour length of stay. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome of interest was the nature and timing of pediatric critical care unit rehabilitation practices.Rehabilitation was classified according to mobility and nonmobility interventions. Predictors of mobilization and the time to mobilization were evaluated through regression and time-dependent survival analyses, respectively. The most common form of rehabilitation provided in pediatric critical care unit was physical therapy (45.5% patients) followed by occupational therapy (4.5%) and speech and language therapy (1.5%). Interventions were primarily nonmobility in nature (69.7% of sessions), most frequently in the form of chest physiotherapy (42.7% of sessions). The median time to mobilization was 2 days (interquartile range, 1-6) as compared with 1 day for nonmobility interventions (interquartile range, 1-3). Only 57 patients (9.5%) received early mobilization. Regression analyses revealed that increasing age, admission during winter, neuromuscular blockade, and sedative infusions were associated with an increased likelihood of receiving mobility therapy. Increasing age was a predictor of early mobilization, while neuromuscular blockade was associated with delayed mobilization. No significant differences in adverse events were found between nonmobility and mobility interventions. CONCLUSIONS: Only half of the children receive rehabilitation while in the pediatric critical care unit, and when it occurs, therapy is primarily focused on respiratory function. Mobilization appears to be reserved for at-risk children who were muscle relaxed and sedated; however, its implementation in these patients is delayed. Future pediatric-specific research is essential to identify patients at risk and to understand treatment priorities and rehabilitation strategies to improve functional recovery in critically ill children.

Differences in medical therapy goals for children with severe traumatic brain injury-an international study.

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

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.

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.

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.

Hypothermia therapy after traumatic brain injury in children.

BACKGROUND: Hypothermia therapy improves survival and the neurologic outcome in animal models of traumatic brain injury. However, the effect of hypothermia therapy on the neurologic outcome and mortality among children who have severe traumatic brain injury is unknown. METHODS: In a multicenter, international trial, we randomly assigned children with severe traumatic brain injury to either hypothermia therapy (32.5 degrees C for 24 hours) initiated within 8 hours after injury or to normothermia (37.0 degrees C). The primary outcome was the proportion of children who had an unfavorable outcome (i.e., severe disability, persistent vegetative state, or death), as assessed on the basis of the Pediatric Cerebral Performance Category score at 6 months. RESULTS: A total of 225 children were randomly assigned to the hypothermia group or the normothermia group; the mean temperatures achieved in the two groups were 33.1+/-1.2 degrees C and 36.9+/-0.5 degrees C, respectively. At 6 months, 31% of the patients in the hypothermia group, as compared with 22% of the patients in the normothermia group, had an unfavorable outcome (relative risk, 1.41; 95% confidence interval [CI], 0.89 to 2.22; P=0.14). There were 23 deaths (21%) in the hypothermia group and 14 deaths (12%) in the normothermia group (relative risk, 1.40; 95% CI, 0.90 to 2.27; P=0.06). There was more hypotension (P=0.047) and more vasoactive agents were administered (P<0.001) in the hypothermia group during the rewarming period than in the normothermia group. Lengths of stay in the intensive care unit and in the hospital and other adverse events were similar in the two groups. CONCLUSIONS: In children with severe traumatic brain injury, hypothermia therapy that is initiated within 8 hours after injury and continued for 24 hours does not improve the neurologic outcome and may increase mortality. (Current Controlled Trials number, ISRCTN77393684 [controlled-trials.com].).

Predictors of nonconvulsive seizures among critically ill children.

PURPOSE: Continuous electroencephalography (EEG) monitoring is a valuable tool for the detection of seizures among critically ill children, in particular when these seizures occur without clinical signs: termed nonconvulsive seizures. Continuous EEG monitoring is a limited resource in many centers. We sought to identify which critically ill children most frequently experience nonconvulsive seizures, and thus may particularly benefit from continuous EEG monitoring. METHODS: Single-center review was undertaken of consecutive diagnostic continuous EEG (cEEG) recordings performed in our pediatric and neonatal intensive care units (ICUs). We examined the indications for monitoring, the clinical characteristics of monitored patients, the occurrence and timing of seizures, and clinical and EEG characteristics associated with nonconvulsive seizures. KEY FINDINGS: One hundred twenty-one patients underwent diagnostic continuous EEG monitoring, for a mean duration of 26 h. Seizures were detected in 32% of these patients, of which 90% experienced some nonconvulsive seizures, and 72% experienced exclusively nonconvulsive seizures. Patients with nonconvulsive seizures had significantly greater odds of having acute epilepsy, acute structural brain injury, prior in-hospital convulsive seizures, and the presence of interictal epileptiform abnormalities on EEG. SIGNIFICANCE: Seizures are common among critically ill children undergoing diagnostic cEEG monitoring. The great majority of these seizures are nonconvulsive, requiring EEG for their detection. Predictors of nonconvulsive seizures include acute epilepsy, acute structural brain injury, prior in-hospital convulsive seizures, and interictal epileptiform abnormalities on EEG. These findings can help inform future allocation of limited cEEG monitoring resources to those patients at greatest risk for nonconvulsive seizures.

Multicentre validation of the bedside paediatric early warning system score: a severity of illness score to detect evolving critical illness in hospitalised children.

INTRODUCTION: The timely provision of critical care to hospitalised patients at risk for cardiopulmonary arrest is contingent upon identification and referral by frontline providers. Current approaches require improvement. In a single-centre study, we developed the Bedside Paediatric Early Warning System (Bedside PEWS) score to identify patients at risk. The objective of this study was to validate the Bedside PEWS score in a large patient population at multiple hospitals. METHODS: We performed an international, multicentre, case-control study of children admitted to hospital inpatient units with no limitations on care. Case patients had experienced a clinical deterioration event involving either an immediate call to a resuscitation team or urgent admission to a paediatric intensive care unit. Control patients had no events. The scores ranged from 0 to 26 and were assessed in the 24 hours prior to the clinical deterioration event. Score performance was assessed using the area under the receiver operating characteristic (AUCROC) curve by comparison with the retrospective rating of nurses and the temporal progression of scores in case patients. RESULTS: A total of 2,074 patients were evaluated at 4 participating hospitals. The median (interquartile range) maximum Bedside PEWS scores for the 12 hours ending 1 hour before the clinical deterioration event were 8 (5 to 12) in case patients and 2 (1 to 4) in control patients (P < 0.0001). The AUCROC curve (95% confidence interval) was 0.87 (0.85 to 0.89). In case patients, mean scores were 5.3 at 20 to 24 hours and 8.4 at 0 to 4 hours before the event (P < 0.0001). The AUCROC curve (95% CI) of the retrospective nurse ratings was 0.83 (0.81 to 0.86). This was significantly lower than that of the Bedside PEWS score (P < 0.0001). CONCLUSIONS: The Bedside PEWS score identified children at risk for cardiopulmonary arrest. Scores were elevated and continued to increase in the 24 hours before the clinical deterioration event. Prospective clinical evaluation is needed to determine whether this score will improve the quality of care and patient outcomes.

Severe traumatic brain injury in children elevates glial fibrillary acidic protein in cerebrospinal fluid and serum.

OBJECTIVES: 1) To determine the levels of glial fibrillary acidic protein (GFAP) in both cerebrospinal fluid and serum; 2) to determine whether serum GFAP levels correlate with functional outcome; and 3) to determine whether therapeutic hypothermia, as compared with normothermia, alters serum GFAP levels in children with severe traumatic brain injury (TBI). DESIGN: Laboratory-based analyses; postrandomized, controlled trial. SETTING: Four Canadian pediatric intensive care units and a university-affiliated laboratory. PATIENTS: Twenty-seven children, aged 2-17 yrs, with severe TBI (Glasgow Coma Scale score of ≤ 8). INTERVENTIONS: Hypothermia therapy (32.5°C) for 24 hrs with cooling started within 8 hrs of injury and rewarming at a rate of 0.5°C every 2 hrs or normothermia (37.0°C). MEASUREMENTS AND MAIN RESULTS: GFAP was measured in cerebrospinal fluid and serum, using enzyme-linked immunosorbent assay. Levels of GFAP were maximal on day 1 post-TBI, with cerebrospinal fluid GFAP (15.5 ± 6.1 ng/mL) 25-fold higher than serum GFAP (0.6 ± 0.2 ng/mL). Cerebrospinal fluid GFAP normalized by day 7, whereas serum GFAP decreased gradually to reach a steady state by day 10. Serum GFAP measured on day 1 correlated with Pediatric Cerebral Performance Category scores determined at 6 months post-TBI (ρ = 0.527; p = .008) but failed to correlate with the injury scoring on admission, physiologic variables, or indices of injury measured on computerized tomography imaging. The areas under the receiver operating characteristic curves for pediatric intensive care unit day 1 serum GFAP in determining good outcome were 0.80 (pediatric cerebral performance category, 1-2; normal-mild disability) and 0.91 (pediatric cerebral performance category, 1-3; normal-moderate disability). For a serum GFAP cutoff level of 0.6 ng/mL, sensitivity and specificity were 88% to 90% and 43% to 71%, respectively. Serum GFAP levels were similar among children randomized to either therapeutic hypothermia or normothermia. CONCLUSIONS: GFAP was markedly elevated in cerebrospinal fluid and serum in children after severe TBI and serum GFAP measured on pediatric intensive care unit day 1 correlated with functional outcome at 6 months. Hypothermia therapy did not alter serum GFAP levels compared with normothermia after severe TBI in children. Serum GFAP concentration, together with other biomarkers, may have prognostic value after TBI in children.

A prospective multicenter study of adrenal function in critically ill children.

RATIONALE: Adrenal insufficiency is a clinical condition associated with fluid- and catecholamine-resistant hypotension. OBJECTIVES: The objectives of this study were to determine the prevalence of adrenal insufficiency, risk factors and potential mechanisms for its development, and its association with clinically important outcomes in critically ill children. METHODS: A prospective, cohort study was conducted from 2005 to 2008 in seven tertiary-care, pediatric intensive care units in Canada on patients up to 17 years of age with existing vascular access. Adrenocorticotropic hormone stimulation tests (1 microg) were performed and adrenocorticotropic hormone levels measured in all participants. MEASUREMENTS AND MAIN RESULTS: A total of 381 patients had adrenal testing on admission. The prevalence of adrenal insufficiency was 30.2% (95% confidence interval, 25.9-35.1). Patients with adrenal insufficiency had higher baseline cortisol levels (28.6 microg/dl vs. 16.7 microg/dl, P < 0.001) and were significantly older (11.5 yr vs. 2.3 yr, P < 0.001) than those without adrenal insufficiency. Adrenal insufficiency was associated with an increased need for catecholamines (P < 0.001) and more fluid boluses (P = 0.026). The sensitivity and specificity of the low-dose adrenocorticotropic hormone stimulation test were 100% and 84%, respectively. CONCLUSIONS: Adrenal insufficiency occurs in many disease conditions in critically ill children and is associated with an increased use of catecholamines and fluid boluses. It is likely multifactorial in etiology and is associated with high baseline cortisol levels. Further research is necessary to determine which of these critically ill children are truly cortisol deficient before any treatment recommendations can be made.

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.

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.