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Stewart T.C.,London Health Sciences Center | Gilliland J.,University of Western Ontario | Gilliland J.,Childrens Health Research Institute | Fraser D.D.,Childrens Health Research Institute | Fraser D.D.,Center for Critical Illness Research
Journal of Trauma and Acute Care Surgery | Year: 2014

BACKGROUND: The objective of this study was to describe the epidemiology of concussions presenting to the emergency department (ED). METHODS: A retrospective cohort of concussions for pediatric (age < 18 years) patients treated in the ED of a regional pediatric Level 1 trauma center from 2006 to 2011 was examined. Descriptive and geographic analyses were completed, with comparisons by age groups and residence (urban/rural). RESULTS: There were a total of 2,112 treated pediatric concussions. Two thirds of the concussions occurred in males (67%), with a median age of 13 years (interquartile range [IQR], 6). Nearly half of the pediatric concussions were sports related (48%); 36% of these concussions were from hockey. Significant differences were found in the distribution of the mechanism of injury across age groups (p < 0.001). Falls were most prevalent among young children, and sports concussions, for children 10 years and older. Two fifths of concussions occurred during winter months. Discharge disposition significantly differed by age (p < 0.001), with home discharge increasing with age up to 14 years. There were a total of 387 rural (19%) and 1,687 urban (81%) concussed patients, for a mean ED concussion visit rate of 2.2 per 1,000 and 3.5 per 1,000, respectively. Rural patients were older (14 [IQR, 6] vs. 13 [IQR, 6], p = 0.019] and sustained 2.5 times more concussions from a motor vehicle crash compared with urban youth patients (p < 0.001). CONCLUSION: Males in early adolescence are at highest risk for concussion, particularly from sport-related activities. Urban and rural children have differences in their etiology and severity of concussions. Concussions are predictable, and their prevention should be targeted based on epidemiologic and environmental data. Copyright © 2014 Lippincott Williams & Wilkins.


Alharfi I.M.,University of Western Ontario | Alharfi I.M.,Childrens Hospital | Stewart T.C.,University of Western Ontario | Stewart T.C.,London Health Sciences Center | And 7 more authors.
Pediatric Critical Care Medicine | Year: 2013

OBJECTIVES:: To determine the occurrence rate of central diabetes insipidus in pediatric patients with severe traumatic brain injury and to describe the clinical, injury, biochemical, imaging, and intervention variables associated with mortality. DESIGN:: Retrospective chart and imaging review. SETTING:: Children's Hospital, level 1 trauma center. PATIENTS:: Severely injured (Injury Severity Score ≥ 12) pediatric trauma patients (>1 month and <18 yr) with severe traumatic brain injury (presedation Glasgow Coma Scale ≤ 8 and head Maximum Abbreviated Injury Scale ≥ 4) that developed acute central diabetes insipidus between January 2000 and December 2011. MEASUREMENTS AND MAIN RESULTS:: Of 818 severely injured trauma patients, 180 had severe traumatic brain injury with an overall mortality rate of 27.2%. Thirty-two of the severe traumatic brain injury patients developed acute central diabetes insipidus that responded to desamino-8-D-arginine vasopressin and/or vasopressin infusion, providing an occurrence rate of 18%. At the time of central diabetes insipidus diagnosis, median urine output and serum sodium were 6.8 ml/kg/hr (interquartile range = 5-11) and 154 mmol/L (interquartile range = 149-159), respectively. The mortality rate of central diabetes insipidus patients was 87.5%, with 71.4% declared brain dead after central diabetes insipidus diagnosis. Early central diabetes insipidus onset, within the first 2 days of severe traumatic brain injury, was strongly associated with mortality (p < 0.001), as were a lower presedation Glasgow Coma Scale (p = 0.03), a lower motor Glasgow Coma Scale (p = 0.01), an occurrence of fixed pupils (p = 0.04), and a prolonged partial thromboplastin time (p = 0.04). Cerebral edema on the initial computed tomography, obtained in the first 24 hrs after injury, was the only imaging finding associated with death (p = 0.002). Survivors of central diabetes insipidus were more likely to have intracranial pressure monitoring (p = 0.03), have thiopental administered to induce coma (p = 0.04) and have received a decompressive craniectomy for elevated intracranial pressure (p = 0.04). CONCLUSIONS:: The incidence of central diabetes insipidus in pediatric patients with severe traumatic brain injury is 18%. Mortality was associated with early central diabetes insipidus onset and cerebral edema on head computed tomography. Central diabetes insipidus nonsurvivors were less likely to have received intracranial pressure monitoring, thiopental coma and decompressive craniectomy. © 2013 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.


Brisson A.R.,Translational Research Center | Brisson A.R.,Childrens Health Research Institute | Matsui D.,Childrens Health Research Institute | Matsui D.,University of Western Ontario | And 7 more authors.
Pediatrics | Year: 2012

Translational research is expanding and has become a focus of National Research funding agencies, touted as the primary avenue to improve health care practice. The use of human tissues for research on disease etiology is a pillar of translational research, particularly with innovations in research technologies to investigate the building blocks of disease. In pediatrics, translational research using human tissues has been hindered by the many practical and ethical considerations associated with tissue procurement from children and also by a limited population base for study, by the increasing complexities in conducting clinical research, and by a lack of dedicated child-health research funding. Given these obstacles, pediatric translational research can be enhanced by developing strategic and efficient biobanks that will provide scientists with quality tissue specimens to render accurate and reproducible research results. Indeed, tissue sampling and biobanking within pediatric academic settings has potential to impact child health by promoting bidirectional interaction between clinicians and scientists, helping to maximize research productivity, and providing a competitive edge for attracting and maintaining high-quality personnel. The authors of this review outline key issues and practical solutions to optimize pediatric tissue sampling and biobanking for translational research, activities that will ultimately reduce the burden of childhood disease. Copyright © 2012 by the American Academy of Pediatrics.


Alharfi I.M.,University of Western Ontario | Charyk Stewart T.,University of Western Ontario | Charyk Stewart T.,London Health Sciences Center | Al Helali I.,University of Western Ontario | And 5 more authors.
Journal of Neurotrauma | Year: 2014

Infections can increase medical costs and worsen patient outcomes. Our aims in pediatric severe traumatic brain injury (sTBI) patients were to determine the infection and fever rates, and to report on associated clinical, imaging, treatment, and outcome factors. We included 180 sTBI patients (presedation Glasgow Coma Scale ≤8 and Maximum Abbreviated Injury Scale ≥4) admitted to our pediatric intensive care unit. Overall, 17% of sTBI patients (n=30 of 180) developed 36 infections, consisting primarily of urinary tract infections (UTIs; n=13 of 36) and ventilator-associated pneumonias (n=11 of 36). Most infections were nosocomial, occurring >2 days after admission. Fever was found in 36% of sTBI patients during the first few hospital days, but fewer than 7% of patients had infections. Infections occurred more frequently in sTBI patients who were older, heavier, and with a higher injury severity score (ISS; p<0.05). Admission head computed tomography imaging abnormalities (subarachnoid hemorrhage, intraventricular hemorrhage, and diffuse axonal injury), placement of an intracranial pressure (ICP) monitor, and administration of ICP-lowering therapies (hypertonic saline, mannitol, and thiopental) were associated with infections (p<0.05). Those with infections had fewer ventilator-free days, greater hospital lengths of stays, and were less likely to be discharged home. Logistic regression demonstrated that infections were independently associated with use of hypertonic saline (odds ratio [OR], 4.46; p=0.001) and higher ISS (OR, 1.05; p=0.028). In summary, infections were prevalent in sTBI patients and were associated with greater head-imaging abnormalities and use of ICP-lowering therapies. Hypertonic saline administration was strongly associated with infection, but further analyses are required to determine the nature of this relationship. Fever was a poor indicator of infection after sTBI. © Mary Ann Liebert, Inc.


Foster J.R.,University of Western Ontario | Foster J.R.,Childrens Health Research Institute | Morrison G.,University of Western Ontario | Fraser D.D.,University of Western Ontario | And 3 more authors.
Stroke Research and Treatment | Year: 2011

Diabetic ketoacidosis (DKA) is a state of severe insulin deficiency, either absolute or relative, resulting in hyperglycemia and ketonemia. Although possibly underappreciated, up to 10 of cases of intracerebral complications associated with an episode of DKA, and/or its treatment, in children and youth are due to hemorrhage or ischemic brain infarction. Systemic inflammation is present in DKA, with resultant vascular endothelial perturbation that may result in coagulopathy and increased hemorrhagic risk. Thrombotic risk during DKA is elevated by abnormalities in coagulation factors, platelet activation, blood volume and flow, and vascular reactivity. DKA-associated cerebral edema may also predispose to ischemic injury and hemorrhage, though cases of stroke without concomitant cerebral edema have been identified. We review the current literature regarding the pathogenesis of stroke during an episode of DKA in children and youth. Copyright © 2011 Jennifer Ruth Foster et al.


Alharfi I.M.,University of Western Ontario | Stewart T.C.,University of Western Ontario | Stewart T.C.,London Health Sciences Center | Kelly S.H.,University of Western Ontario | And 5 more authors.
Journal of Neurotrauma | Year: 2013

Acquired hypernatremia in hospitalized patients is often associated with poorer outcomes. Our aim was to evaluate the relationship between acquired hypernatremia and outcome in children with severe traumatic brain injury (sTBI). We performed a retrospective cohort study of all severely injured trauma patients (Injury Severity Score ≥12) with sTBI (Glasgow Coma Scale [GCS] ≤8 and Maximum Abbreviated Injury Scale [MAIS] ≥4) admitted to a Pediatric Critical Care Unit ([PCCU]; 2000-2009). In a cohort of 165 patients, 76% had normonatremia (135-150 mmol/L), 18% had hypernatremia (151-160 mmol/L), and 6% had severe hypernatremia (>160 mmol/L). The groups were similar except for lower GCS (p=0.002) and increased incidence of fixed pupil(s) on admission in both hypernatremia groups (p<0.001). Mortality rate was four-fold and six-fold greater with hypernatremia and severe hypernatremia, respectively (p<0.001), and mortality rates were unchanged when patients with fixed pupils or those with central diabetes insipidus were excluded (p<0.001). Hypernatremic patients had fewer ventilator-free days (p<0.001). Survivors with hypernatremia had greater PCCU (p=0.001) and hospital (p=0.031) lengths of stays and were less frequently discharged home (p=0.008). Logistic regression analyses of patient characteristics and sTBI interventions demonstrated that hypernatremia was independently associated with the presence of fixed pupil(s) on admission (odds ratio [OR] 5.38; p=0.003); administration of thiopental (OR 8.64; p=0.014), and development of central diabetes insipidus (OR 5.66; p=0.005). Additional logistic regression analyses demonstrated a significant association between hypernatremia and mortality (OR 6.660; p=0.034). In summary, acquired hypernatremia appears to signal higher risk of mortality in pediatric sTBI and is associated with a higher discharge level of care in sTBI survivors. © 2013, Mary Ann Liebert, Inc. 2013.


Augustine C.,University of Western Ontario | Augustine C.,Childrens Health Research Institute | Augustine C.,Center for Critical Illness Research | Cepinskas G.,Center for Critical Illness Research | And 4 more authors.
Neuroscience | Year: 2014

Brain injury causes dysfunction of the blood-brain barrier (BBB). The BBB is comprised of perivascular astrocytes whose end-feet ensheath brain microvascular endothelial cells. We investigated trauma-induced morphological changes of human astrocytes (HA) and human cerebral microvascular endothelial cells (hCMEC/D3) in vitro, including the potential role of mitogen-activated protein kinase (MAPK) signal-transduction pathways. HA or hCMEC/D3 were grown on flexible culture membranes and subjected to single traumatic injury normalized to 20%, 30% or 55% membrane deformation. Cells were assayed for morphological changes (i.e. retraction) and MAPK phosphorylation and/or expression (c-Jun NH2-terminal kinase (JNK)1/2, extracellular signal-regulated kinase (ERK)1/2, and p38). HA retraction was rapidly elicited with a single traumatic injury (55% membrane deformation; p<0.01). Morphological recovery of HA was observed within 2h (p<0.05). Traumatic injuries increased phospho-JNK1/2 (p<0.05) in HA, indicating MAPK activation. Pre-treatment of HA with structurally distinct JNK inhibitors (25μM), either SP600125 or SU3327, reduced JNK phosphorylation (p<0.05) and trauma-induced HA retraction (P<0.05). In contrast to HA, traumatic injury failed to induce either morphological changes or MAPK activation in hCMEC/D3. In summary, traumatic injury induces JNK-mediated HA retraction in vitro, while sparing morphological changes in cerebral microvascular endothelial cells. Astrocyte retraction from microvascular endothelial cells in vivo may occur after brain trauma, resulting in cellular uncoupling and BBB dysfunction. JNK may represent a potential therapeutic target for traumatic brain injuries. © 2014 IBRO.


Stewart T.C.,University of Western Ontario | Stewart T.C.,London Health Sciences Center | Alharfi I.M.,King Fahad Medical City | Fraser D.D.,University of Western Ontario | And 3 more authors.
Journal of Trauma and Acute Care Surgery | Year: 2013

BACKGROUND: The study objective was to describe the epidemiology of serious concomitant injuries and their effects on outcome in pediatric severe traumatic brain injury (sTBI). METHODS: A retrospective cohort of all severely injured (Injury Severity Score [ISS] ≥ 12) pediatric patients (G18 years) admitted to our pediatric intensive care unit, between 2000 and 2011, after experiencing an sTBI (Glasgow Coma Scale [GCS] score ≤ 8 and head Abbreviated Injury Scale [AIS] ≥ 4) were included. Two groups were compared based on the presence of serious concomitant injuries (maximum AIS score ≥ 3). Multivariate logistic regression was undertaken to determine variable associations with mortality. RESULTS: Of the 180 patients with sTBI, 113 (63%) sustained serious concomitant injuries. Chest was the most commonly injured extracranial body region (84%), with lung being the most often injured. Patients with serious concomitant injuries had increased age, weight, and injury severity (p < 0.001) and were more likely injured in a motor vehicle collision (91% vs. 48%, p < 0.001). Those with serious concomitant injuries had worse sTBI, based on lower presedation GCS (p = 0.031), higher frequency of fixed pupils (p = 0.006), and increased imaging abnormalities (SAH and DAI, p ≤ 0.01). Non-neurosurgical operations and blood transfusions were more frequent in the serious concomitant injury group (p < 0.01). The differences in mortality for the two groups failed to reach statistical significant (p = 0.053), but patients with serious concomitant injuries had higher rates of infection and acute central diabetes insipidus, fewer ventilator-free days, and greater length of stays (p < 0.05). Multivariate analyses revealed fixed pupillary response (odd ratio [OR], 63.58; p < 0.001), presedation motor GCS (OR, 0.23; p = 0.001), blood transfusion (OR, 5.80; p = 0.008), and hypotension (OR, 4.82; p = 0.025) were associated with mortality, but serious concomitant injuries was not (p = 0.283). CONCLUSION: Head injury is the most important prognostic factor in mortality for sTBI pediatric patients, but the presence of serious concomitant injuries does contribute to greater morbidity, including longer stays, more infections, fewer ventilator-free days, and a higher level of care required on discharge from hospital. Copyright © 2013 by Lippincott Williams & Wilkins.


PubMed | University of Western Ontario, Center for Critical Illness Research and Childrens Health Research Institute
Type: Journal Article | Journal: Pediatric research | Year: 2016

Diabetic ketoacidosis (DKA) in children is associated with cerebrovascular-related complications. We recently reported that DKA facilitates leukocyte adherence to the brain microvascular endothelium. Adhered leukocytes can release enzymes that instigate vascular dysfunction. Our aims were to measure plasma levels of leukocyte-derived matrix metalloproteinases (MMPs) from DKA patients and to correlate plasma MMP concentrations with DKA severity.Plasma was obtained from children with type 1 diabetes, either in DKA (n = 16) or insulin controlled (CON; n = 16). Antibody microarray and gelatin zymography were used to quantify plasma MMPs and their endogenous tissue inhibitors (TIMPs). MMP concentrations were correlated with DKA severity (blood pH). Quantitative PCR of leukocyte mRNA was used to help determine the origin of plasma MMPs.DKA was associated with altered plasma levels of MMP-2 (P < 0.001), MMP-8 (P < 0.001), MMP-9 (P < 0.05), and TIMP-4 (P < 0.001), as compared with CON. Elevated MMP-8 and MMP-9 were both positively correlated with DKA severity (P < 0.05). DKA was associated with increased leukocyte mRNA for MMP-8, MMP-9, and TIMP-4 (P < 0.005).MMPs are dynamically regulated during DKA. Plasma MMP-8 and MMP-9 concentrations correlate with DKA severity and are known to degrade brain microvascular endothelial cell tight junctions. Thus, leukocyte-derived MMPs might contribute to DKA-associated cerebrovascular complications.


Patterson E.K.,Center for Critical Illness Research | Fraser D.D.,Center for Critical Illness Research | Fraser D.D.,Lawson Health Research Institute | Fraser D.D.,University of Western Ontario | And 4 more authors.
Free Radical Biology and Medicine | Year: 2014

Polymorphonuclear leukocyte (PMN)-derived myeloperoxidase (MPO) contributes to the pathophysiology of numerous systemic inflammatory disorders through: (1) direct peroxidation of targets and (2) production of strong oxidizing compounds, e.g., hypohalous acids, particularly hypochlorous acid, which furthers oxidant damage and contributes to the propagation of inflammation and tissue injury/dysfunction. Carbon monoxide-releasing molecules (CORMs) offer potent anti-inflammatory effects; however, the mechanism(s) of action is not fully understood. This study assessed the potential of MPO activity inhibition by a water-soluble CORM, CORM-3. To this end, we used in vitro assays to study CORM-3-dependent modulation of MPO activity with respect to: (1) the inhibition of MPO's catalytic activity generally and (2) the specific inhibition of MPO's peroxidation and halogenation (i.e., production of hypochlorous acid) reactions. Further, we employed primary human umbilical vein endothelial cells (HUVECs) to investigate MPO-dependent cellular activation and dysfunction by measuring intracellular oxidant stress (DHR-123 oxidation) and HUVEC permeability (flux of Texas red-dextran), respectively. The results indicate that CORM-3 significantly inhibits MPO activity as well as MPO's peroxidation and hypohalous acid cycles specifically (p<0.05 vs uninhibited MPO). In addition, CORM-3 significantly decreases PMN homogenate- or rhMPO-induced intracellular DHR-123 oxidation in HUVECs and rhMPO-induced HUVEC monolayer permeability (p<0.05 vs untreated). In all assays the inactivated CORM-3 was significantly less effective than CORM-3 (p<0.05). Taken together our findings indicate that CORM-3 is a novel MPO inhibitor and mitigates inflammatory damage at least in part through a mechanism involving the inhibition of neutrophilic MPO activity. © 2014 Elsevier Inc.

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