Publications by authors named "James S Hutchison"

40 Publications

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

Clin Neurophysiol 2021 Jul 31;132(7):1505-1514. Epub 2021 Mar 31.

Division of Neurology, The Hospital for Sick Children and Department of Paediatrics, University of Toronto, Toronto, Canada. Electronic address:

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.
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July 2021

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

BMJ Open 2021 04 20;11(4):e044480. Epub 2021 Apr 20.

Division of Infectious Diseases, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

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.
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April 2021

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

J Neurotrauma 2021 May 13. Epub 2021 May 13.

Neuroscience and Mental Health Research Program, Hospital for Sick Children, Toronto, Ontario, Canada.

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.
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May 2021

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

Pediatrics 2020 04 26;145(4). Epub 2020 Mar 26.

Department of Pediatrics, Alberta Children's Hospital Research Institute and.

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.
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April 2020

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

Front Neurol 2020 4;11:43. Epub 2020 Feb 4.

Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.

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 ( = 16) along with a healthy control group ( = 15). The second sample consisted of patients with mTBI prospectively recruited from a Level 1 trauma center who had either good recovery (GOSE = 8; = 32) or poor recovery (GOSE < 8; = 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 ( = 4.308, < 0.001) and to mTBI patients with good recovery in Sample 2 ( = 3.169, < 0.001). As would be expected, participants with poor outcome in Sample 2 had a higher burden of typical rather than atypical symptoms [ = 4.750, < 0.001, = 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.
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February 2020

Seizure Identification by Critical Care Providers Using Quantitative Electroencephalography.

Crit Care Med 2018 12;46(12):e1105-e1111

Program in Neurosciences & Mental Health, The Hospital for Sick Children Research Institute, Toronto, ON, Canada.

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.
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December 2018

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

J Neurotrauma 2018 08;35(16):1858-1863

9 CHU de Québec - Université Laval Research Center , Population Health and Optimal Health Practices Research Unit (Trauma - Emergency - Critical Care Medicine), Québec City, Québec, 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.
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August 2018

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

Scand J Pain 2018 04;18(2):151-164

Neuroscience Therapeutic Area, Janssen Research and Development, LLC, NJ, USA, Tel.: 609-730-6779.

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.
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April 2018

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

JAMA 2018 03;319(10):1002-1012

Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.

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: Identifier: NCT01260831.
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March 2018

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

J Int Neuropsychol Soc 2018 03 4;24(3):224-236. Epub 2017 Oct 4.

1Murdoch Childrens Research Institute,Melbourne,Australia.

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).
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March 2018

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

J Head Trauma Rehabil 2018 May/Jun;33(3):200-209

Murdoch Children's Research Institute, Melbourne, Victoria, Australia (Drs Crichton, Anderson, and Babl, Mr Oakley, and Mss Greenham and Delzoppo); Victorian Peadiatric Rehabilitation Service, Monash Children's, Melbourne, Victoria, Australia (Dr Crichton); Department of Psychology (Dr Anderson) and School of Psychological Sciences (Dr Crichton and Ms Greenham), University of Melbourne, Melbourne, Victoria, Australia; Department of Peadiatrics, University of Melbourne, Melbourne, Victoria, Australia (Dr Babl and Mr Oakley); Royal Children's Hospital (RCH), Melbourne, Victoria, Australia (Mr Oakley, Dr Babl, and Ms Delzoppo); Department of Psychology, University of Montreal, Montreal, Quebec, Canada (Dr Beauchamp); Research Center, Ste-Justine Hospital (HSJ), Montreal, Quebec, Canada (Dr Beauchamp) Neuroscience and Mental Health Research Program (Drs Hutchison and Guerguerian), The Hospital for Sick Children (HSK), Toronto, Ontario, Canada (Drs Hutchison, Guerguerian, and Boutis); and University of Toronto, Toronto, Ontario, Canada (Drs Hutchison and Boutis).

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.
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August 2019

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

Resuscitation 2015 Sep 19;94:1-7. Epub 2015 Jun 19.

Department of Critical Care and Neuroscience and Mental Health Research Program, The Hospital for Sick Children, Toronto, ON, Canada; Interdepartmental Division of Critical Care Medicine, Faculty of Medicine and Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada. Electronic address:

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.
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September 2015

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

Trials 2015 Jun 2;16:245. Epub 2015 Jun 2.

Hospital for Sick Children, Toronto, ON, Canada.

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 date: 14 December 2010.
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June 2015

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

Shock 2015 Nov;44(5):402-9

*Children's Hospital of Eastern Ontario, University of Ottawa †McMaster Children's Hospital, McMaster University ‡Ottawa Hospital Research Institute, University of Ottawa §Cincinnati Children's Hospital Medical Center, University of Cincinnati.

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.
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November 2015

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

Pediatr Crit Care Med 2014 Jul;15(6):e270-9

1Department of Pediatrics, Critical Care, Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada. 2Department of Clinical Epidemiology and Biostatistics, McMaster University & Biostatistics Unit, St Joseph's Healthcare, Hamilton, ON, Canada. 3Department of Pediatrics and Critical Care, Children's Hospital, London Health Sciences Centre, London, ON, Canada. 4Department of Pediatrics and Critical Care, The Hospital for Sick Children, Toronto, ON, Canada. 5Department of Pediatrics and Critical Care, Stollery Children's Hospital, University of Alberta, Edmonton, AB, Canada. 6Department of Pediatrics, CHU Ste-Justine, Montreal, QC, Canada. 7Department of Pediatrics, Epidemiology and Biostatistics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada. 8Child Health Evaluative Sciences, Hospital for Sick Children & Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. 9Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.

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.
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July 2014

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

Brain 2014 May 4;137(Pt 5):1429-38. Epub 2014 Mar 4.

1 Division of Neurology, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, M5G 1X8, Canada.

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.
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May 2014

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

Pediatr Crit Care Med 2013 Oct;14(8):811-8

1Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA. 2Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA. 3Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA. 4Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ. 5Department of Critical Care Medicine, University of Toronto, Toronto, CA. 6Department of Neurology, Harvard Medical School, Boston, MA. 7Department of Anesthesia, Harvard Medical School, Boston, MA. 8Division of Critical Care, Boston Children's Hospital, Boston, MA. 9Department of Anesthesia, University of Washington, Seattle, WA. 10Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA. 11Department of Epidemiology and Biostatistics, University of Pittsburgh, Pittsburgh, PA.

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.
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October 2013

Cooling of children with severe traumatic brain injury.

Lancet Neurol 2013 Jun 8;12(6):527-9. Epub 2013 May 8.

Hospital for Sick Children, Hospital for Sick Children Research Institute, and University of Toronto, Toronto, ON, Canada.

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June 2013

Predictors of nonconvulsive seizures among critically ill children.

Epilepsia 2011 Nov 17;52(11):1973-8. Epub 2011 Oct 17.

Division of Neurology, The Hospital for Sick Children, and University of Toronto, Toronto, Ontario, Canada.

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.
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November 2011

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

Crit Care 2011 Aug 3;15(4):R184. Epub 2011 Aug 3.

Department of Critical Care Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.

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.
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August 2011

Impact of hypotension and low cerebral perfusion pressure on outcomes in children treated with hypothermia therapy following severe traumatic brain injury: a post hoc analysis of the Hypothermia Pediatric Head Injury Trial.

Dev Neurosci 2010 21;32(5-6):406-12. Epub 2011 Jan 21.

Department of Critical Care, Hospital for Sick Children, Toronto, Ont., Canada.

Hypotension and low cerebral perfusion pressure are known to be associated with unfavorable outcome in children and adults with traumatic brain injury. Using the database from a previously published, randomized controlled trial of 24 h of hypothermia therapy in children with severe traumatic brain injury, we compared the number of patients with hypotension or low cerebral perfusion pressure between the hypothermia therapy and normothermia groups. We also determined the association between these physiologic insults and unfavorable outcome using regression analysis. There were more patients with episodes of hypotension or low cerebral perfusion pressure in the hypothermia therapy group than in the normothermia group. These physiologic insults were associated with unfavorable outcome in both intervention groups. Hypotension and low cerebral perfusion pressure should be anticipated and prevented in future trials of hypothermia therapy in patients with traumatic brain injury.
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May 2011

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

Pediatr Crit Care Med 2011 May;12(3):319-24

Division of Critical Care Medicine, Department of Pediatrics, University of Western Ontario, London, ON, Canada.

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.
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May 2011

Cardiac arrhythmias associated with severe traumatic brain injury and hypothermia therapy.

Pediatr Crit Care Med 2010 May;11(3):408-14

Department of Pediatrics, Division of Pediatric Intensive Care Medicine, Centre Mère-Enfant du CHUQ, Université Laval, Québec, Canada.

Objective: Severe head trauma and/or severe hypothermia (< or =32 degrees C) can cause cardiac arrhythmias. Effect of moderate hypothermia (32-33 degrees C) on cardiac arrhythmias in children after severe traumatic brain injury is not well characterized. The objective is to determine the effect of moderate and short-term (24 hrs) hypothermia therapy on the incidence and severity of cardiac arrhythmias in children with severe traumatic brain injury compared with normothermic control subject using a 24-hr Holter recording.

Design: Prospective ancillary study of a multicenter randomized, controlled clinical trial.

Setting: A Canadian university-affiliated pediatric intensive care unit in a level III trauma center. PATIENTS Patients <18 yrs with severe traumatic brain injury.

Interventions: Holter recording during moderate hypothermia (HYPO group; esophageal temperature 32-33 degrees C) or normothermia (NORMO group; 36.5-37.5 degrees C) induced for 24 hrs started within 8 hrs after a severe traumatic brain injury.

Measurements And Main Results: Sixteen patients who had a median age of 12.7 yrs (range, 7.2-17.0 yrs) were enrolled. The time from the injury to the start of the cooling process was 7.3 hrs (range, 6.6-7.8 hrs). The temperature when Holter recording began was 32.9 degrees C (range, 31.6-34.4 degrees C) in the HYPO group. Overall, 44% of all patients (seven of 16 patients) had arrhythmias (two of nine in the NORMO group and five of seven in the HYPO group, p = .13). The most frequent arrhythmias were isolated premature atrial contractions. Hypothermic patients had lower heart rates than normothermic patients (p = .01), but none had a severe bradycardia. In the NORMO group, one patient had accelerated junctional rhythm associated with hypotension. In the HYPO group, one patient had nonsustained monomorphic ventricular tachycardia.

Conclusions: Arrhythmias are frequent in severe pediatric traumatic brain injury. Further studies are needed to characterize the epidemiology and clinical impact of arrhythmias associated with severe pediatric head trauma and moderate hypothermia.
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May 2010

Association between length of storage of transfused red blood cells and multiple organ dysfunction syndrome in pediatric intensive care patients.

Transfusion 2010 Sep;50(9):1902-13

Pediatric Critical Care and the Hematology-Oncology Division, Sainte-Justine Hospital and Université de Montréal, Montréal, Québec, Canada.

Background: The objective was to determine if there is an association between red blood cell (RBC) storage time and development of new or progressive multiple organ dysfunction syndrome (MODS) in critically ill children.

Study Design And Methods: This was an analytic cohort analysis of patients enrolled in a randomized controlled trial, TRIPICU (Transfusion Requirements in Pediatric Intensive Care Units; ISRCTN37246456), in which stable critically ill children were randomly assigned to a restrictive or liberal strategy. Transfused patients were analyzed using three different sliding time cutoffs (7, 14, and 21 days). Storage time for multiply transfused patients was defined according to the oldest unit transfused.

Results: A total of 455 patients were retained (liberal, 310; restrictive, 145). Multivariate logistic regression was performed to determine independent associations. In the restrictive group, a maximum RBC storage time of more than 21 days was independently associated with new or progressive MODS (adjusted odds ratio [OR], 3.29; 95% confidence interval [CI], 1.21-9.04). The same association was found in the liberal group for a storage time of more than 14 days (adjusted OR, 2.50; 95% CI, 1.12-5.58). When the two groups were combined in a meta-analysis, a storage time of more than 14 days was independently associated with increased MODS (adjusted OR, 2.23; 95% CI, 1.20-4.15) and more than 21 days was associated with increased Pediatric Logistic Organ Dysfunction (PELOD) scores (adjusted mean difference, 4.26; 95% CI, 1.99-6.53) and higher mortality (9.2% vs. 3.8%).

Conclusion: Stable critically ill children who receive RBC units with storage times longer than 2 to 3 weeks may be at greater risk of developing new or progressive MODS.
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September 2010

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

Am J Respir Crit Care Med 2010 Jul 18;182(2):246-51. Epub 2010 Mar 18.

Pediatric Intensive Care Unit, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, K1S 3H2 Canada.

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.
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July 2010

Study of hypothermia therapy after pediatric cardiac arrest.

Pediatr Crit Care Med 2010 Mar;11(2):315-6; author reply 316-7

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March 2010

Clinical management and functional neuromonitoring in traumatic brain injury in children.

Curr Opin Pediatr 2009 Dec;21(6):737-44

Department of Critical Care Medicine, Neurosciences and Mental Health Research Program, Hospital for Sick Children, Toronto, Ontario, Canada.

Purpose Of Review: Traumatic brain injury is the main cause of childhood disability and death. In this review, we highlight recent original findings and emerging themes from published literature on children with serious traumatic brain injury.

Recent Findings: We focus this review on lessons learned from our recent randomized clinical trial of hypothermia therapy in severe traumatic brain injury in children and on bedside neuromonitoring. We propose that integrating the measurement of biomarkers into clinical care as surrogate endpoints and as potential prognostic markers would allow us to evaluate earlier the effect of injury and clinical care in children after traumatic brain injury. Several methods are now more readily available to monitor cerebral physiology in children. These methods include indices evaluating the integrity of cerebral autoregulation, such as the pressure reactivity index derived from values obtained from intracranial pressure measurements, flow velocity measurements from transcranial Doppler ultrasonography or from cerebral oximetry. Other methods allow the evaluation of coma with the nonlinear analysis of electroencephalography or the evaluation of cerebral metabolism and cell death pathways with biomarkers from serum, cerebral spinal fluid, and cerebral microdialysis.

Summary: We suggest expanding clinical functional neuromonitoring to help clinicians understand the burden of exposure to physiological variables and response to therapies during intensive care in order to enhance the management of critically ill children with traumatic brain injury.
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December 2009

Vasopressin in pediatric vasodilatory shock: a multicenter randomized controlled trial.

Am J Respir Crit Care Med 2009 Oct 16;180(7):632-9. Epub 2009 Jul 16.

Department of Pediatrics and Critical Care McMaster Children's Hospital, 1200 Main Street West, Room 3A78, Hamilton, ON, L8N 3Z5 Canada.

Rationale: Vasopressin has been proposed as a potent vasoactive agent in the treatment of vasodilatory shock in adults and children. The objective of this trial was to evaluate the efficacy and safety of vasopressin as an adjunctive agent in pediatric vasodilatory shock.

Methods: In this multicenter, double-blind trial, children with vasodilatory shock were randomized to receive low-dose vasopressin (0.0005-0.002 U/kg/min) or placebo in addition to open-label vasoactive agents. Vasoactive infusions were titrated to clinical endpoints of adequate perfusion. The primary outcome was time to vasoactive-free hemodynamic stability. Secondary outcomes included mortality, organ-failure-free days, length of critical care unit stay, and adverse events.

Measurements And Main Results: Sixty-five of 69 children (94%) who were randomized received the study drug (33 vasopressin, 32 placebo) and were included in the analysis. There was no significant difference in the primary outcome between the vasopressin and placebo groups (49.7 vs. 47.1 hours; P = 0.85). There were 10 deaths (30%) in the vasopressin group and five (15.6%) in the placebo group (relative risk, 1.94; 95% confidence interval, 0.75-5.05; P = 0.24). There were no significant differences with respect to organ failure-free days (22 vs. 25.5 days; P = 0.11), ventilator-free days (16.5 23 days; P = 0.15), length of stay (8 vs. 8.5 days; P = 0.93), or adverse event rate ratios (12.0%; 95% confidence interval, -2.6 to 26.7; P = 0.15).

Conclusions: Low-dose vasopressin did not demonstrate any beneficial effects in this pediatric trial. Although not statistically significant, there was a concerning trend toward increased mortality. Clinical trial registered with (ISRCTN11597444).
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October 2009

Hypothermia therapy after pediatric cardiac arrest.

Circulation 2009 Mar 9;119(11):1492-500. Epub 2009 Mar 9.

Department of Anaesthesia, Division of Pediatric Intensive Care, Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, ON, Canada.

Background: Hypothermia therapy improves mortality and functional outcome after cardiac arrest and birth asphyxia in adults and newborns. The effect of hypothermia therapy in infants and children with cardiac arrest is unknown.

Methods And Results: A 2-year, retrospective, 5-center study was conducted, and 222 patients with cardiac arrest were identified. Seventy-nine (35.6%) of these patients met eligibility criteria for the study (age >40 weeks postconception and <18 years, cardiac arrest >3 minutes in duration, survival for > or = 12 hours after return of circulation, and no birth asphyxia). Twenty-nine (36.7%) of these 79 patients received hypothermia therapy and were cooled to 33.7+/-1.3 degrees C for 20.8+/-11.9 hours. Hypothermia therapy was associated with higher mortality (P=0.009), greater duration of cardiac arrest (P=0.005), more resuscitative interventions (P<0.001), higher postresuscitation lactate levels (P<0.001), and use of extracorporeal membrane oxygenation (P<0.001). When adjustment was made for duration of cardiac arrest, use of extracorporeal membrane oxygenation, and propensity scores by use of a logistic regression model, no statistically significant differences in mortality were found (P=0.502) between patients treated with hypothermia therapy and those treated with normothermia. Also, no differences in hypothermia-related adverse events were found between groups.

Conclusions: Hypothermia therapy was used in resuscitation scenarios that are associated with greater risk of poor outcome. In an adjusted analysis, the effectiveness of hypothermia therapy was neither supported nor refuted. A randomized controlled trial is needed to rigorously evaluate the benefits and harms of hypothermia therapy after pediatric cardiac arrest.
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March 2009

Fluctuations in cortical synchronization in pediatric traumatic brain injury.

J Neurotrauma 2008 Jun;25(6):615-27

Critical Care Medicine Program, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada.

Traumatic brain injury (TBI) is the leading cause of death and acquired disability in the pediatric population worldwide. We hypothesized that electroencephalography (EEG) synchrony and its temporal variability, analyzed during the acute phase following TBI, would be altered from that of normal children and as such would offer insights into TBI pathophysiology. Seventeen pediatric patients with mild to severe head injury admitted to a pediatric critical care unit were recruited along with 10 age- and gender-matched controls. Patients had two electroencephalographs performed 3 days apart. Outcome was measured at 1 year post-TBI utilizing the Pediatric Cerebral Performance Category score (PCPC). Maximal synchrony between EEG channels correlated to areas of primary injury as seen on computed tomography (CT) scan. The temporal variability of phase synchronization among EEG electrodes increased as patients recovered and emerged from coma (p < 0.001). This temporal variability correlated with outcome (Pearson coefficient of 0.74) better than the worst Glasgow Coma Scale score, length of coma, or extent of injury on CT scan. This represents a novel approach in the evaluation of TBI in children.
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June 2008