Steven Shein

Risk Factors for Mortality in Children with Abusive Head Trauma

OBJECTIVE We sought to identify risk factors for mortality in a large clinical cohort of children with abusive head trauma. STUDY DESIGN Bivariate analysis and multivariable logistic regression models identified demographic, physical examination, and radiologic findings associated with in-hospital mortality of children with abusive head trauma at 4 pediatric centers. An initial Glasgow Coma Scale (GCS) ≤ 8 defined severe abusive head trauma. Data are shown as OR (95% CI). RESULTS Analysis included 386 children with abusive head trauma. Multivariable analysis showed children with initial GCS either 3 or 4-5 had increased mortality vs children with GCS 12-15 (OR = 57.8; 95% CI, 12.1-277.6 and OR = 15.6; 95% CI, 2.6-95.1, respectively, P < .001). Additionally, retinal hemorrhage (RH), intraparenchymal hemorrhage, and cerebral edema were independently associated with mortality. In the subgroup with severe abusive head trauma and RH (n = 117), cerebral edema and initial GCS of 3 or 4-5 were independently associated with mortality. Chronic subdural hematoma was independently associated with survival. CONCLUSIONS Low initial GCS score, RH, intraparenchymal hemorrhage, and cerebral edema are independently associated with mortality in abusive head trauma. Knowledge of these risk factors may enable researchers and clinicians to improve the care of these vulnerable children.

Hemorrhagic Shock Shifts the Serum Cytokine Profile from Pro- to Anti-Inflammatory after Experimental Traumatic Brain Injury in Mice

Secondary insults, such as hemorrhagic shock (HS), worsen outcome from traumatic brain injury (TBI). Both TBI and HS modulate levels of inflammatory mediators. We evaluated the addition of HS on the inflammatory response to TBI. Adult male C57BL6J mice were randomized into five groups (n=4 [naïve] or 8/group): naïve; sham; TBI (through mild-to-moderate controlled cortical impact [CCI] at 5 m/sec, 1-mm depth), HS; and CCI+HS. All non-naïve mice underwent identical monitoring and anesthesia. HS and CCI+HS underwent a 35-min period of pressure-controlled hemorrhage (target mean arterial pressure, 25-27 mm Hg) and a 90-min resuscitation with lactated Ringers injection and autologous blood transfusion. Mice were sacrificed at 2 or 24 h after injury. Levels of 13 cytokines, six chemokines, and three growth factors were measured in serum and in five brain tissue regions. Serum levels of several proinflammatory mediators (eotaxin, interferon-inducible protein 10 [IP-10], keratinocyte chemoattractant [KC], monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein 1alpha [MIP-1α], interleukin [IL]-5, IL-6, tumor necrosis factor alpha, and granulocyte colony-stimulating factor [G-CSF]) were increased after CCI alone. Serum levels of fewer proinflammatory mediators (IL-5, IL-6, regulated upon activation, normal T-cell expressed, and secreted, and G-CSF) were increased after CCI+HS. Serum level of anti-inflammatory IL-10 was significantly increased after CCI+HS versus CCI alone. Brain tissue levels of eotaxin, IP-10, KC, MCP-1, MIP-1α, IL-6, and G-CSF were increased after both CCI and CCI+HS. There were no significant differences between levels after CCI alone and CCI+HS in any mediator. Addition of HS to experimental TBI led to a shift toward an anti-inflammatory serum profile--specifically, a marked increase in IL-10 levels. The brain cytokine and chemokine profile after TBI was minimally affected by the addition of HS.

Polynitroxylated-Pegylated Hemoglobin Attenuates Fluid Requirements and Brain Edema in Combined Traumatic Brain Injury Plus Hemorrhagic Shock in Mice

Polynitroxylated-pegylated hemoglobin (PNPH), a bovine hemoglobin decorated with nitroxide and polyethylene glycol moieties, showed neuroprotection vs. lactated Ringer’s (LR) in experimental traumatic brain injury plus hemorrhagic shock (TBI + HS). Hypothesis: Resuscitation with PNPH will reduce intracranial pressure (ICP) and brain edema and improve cerebral perfusion pressure (CPP) vs. LR in experimental TBI + HS. C57/BL6 mice (n = 20) underwent controlled cortical impact followed by severe HS to mean arterial pressure (MAP) of 25 to 27 mm Hg for 35 minutes. Mice (n = 10/group) were then resuscitated with a 20 mL/kg bolus of 4% PNPH or LR followed by 10 mL/kg boluses targeting MAP > 70 mm Hg for 90 minutes. Shed blood was then reinfused. Intracranial pressure was monitored. Mice were killed and %brain water (%BW) was measured (wet/dry weight). Mice resuscitated with PNPH vs. LR required less fluid (26.0 ± 0.0 vs. 167.0 ± 10.7 mL/kg, P < 0.001) and had a higher MAP (79.4 ± 0.40 vs. 59.7 ± 0.83 mm Hg, P < 0.001). The PNPH-treated mice required only 20 mL/kg while LR-resuscitated mice required multiple boluses. The PNPH-treated mice had a lower peak ICP (14.5 ± 0.97 vs. 19.7 ± 1.12 mm Hg, P = 0.002), higher CPP during resuscitation (69.2 ± 0.46 vs. 45.5 ± 0.68 mm Hg, P < 0.001), and lower %BW vs. LR (80.3 ± 0.12 vs. 80.9 ± 0.12%, P = 0.003). After TBI + HS, resuscitation with PNPH lowers fluid requirements, improves ICP and CPP, and reduces brain edema vs. LR, supporting its development.

Effectiveness of pharmacological therapies for intracranial hypertension in children with severe traumatic brain injury-results from an automated data collection system time-synched to drug administration

Objectives: To describe acute cerebral hemodynamic effects of medications commonly used to treat intracranial hypertension in children with traumatic brain injury. Currently, data supporting the efficacy of these medications are insufficient. Design: In this prospective observational study, intracranial hypertension (intracranial pressure ≥ 20 mm Hg for > 5 min) was treated by clinical protocol. Administration times of medications for intracranial hypertension (fentanyl, 3% hypertonic saline, mannitol, and pentobarbital) were prospectively recorded and synchronized with an automated database that collected intracranial pressure and cerebral perfusion pressure every 5 seconds. Intracranial pressure crises confounded by external stimulation or mechanical ventilator adjustments were excluded. Mean intracranial pressure and cerebral perfusion pressure from epochs following drug administration were compared with baseline values using Kruskal-Wallis analysis of variance and Dunn test. Frailty modeling was used to analyze the time to intracranial pressure crisis resolution. Mixed-effect models compared intracranial pressure and cerebral perfusion pressure 5 minutes after the medication versus baseline and rates of treatment failure. Setting: A tertiary care children’s hospital. Patients: Children with severe traumatic brain injury (Glasgow Coma Scale score ⩽ 8). Interventions: None. Measurements and Main Results: We analyzed 196 doses of fentanyl, hypertonic saline, mannitol, and pentobarbital administered to 16 children (median: 12 doses per patient). Overall, intracranial pressure significantly decreased following the administration of fentanyl, hypertonic saline, and pentobarbital. After controlling for administration of multiple medications, intracranial pressure was decreased following hypertonic saline and pentobarbital administration; cerebral perfusion pressure was decreased following fentanyl and was increased following hypertonic saline administration. After adjusting for significant covariates (including age, Glasgow Coma Scale score, and intracranial pressure), hypertonic saline was associated with a two-fold faster resolution of intracranial hypertension than either fentanyl or pentobarbital. Fentanyl was significantly associated with the most frequent treatment failure. Conclusions: Intracranial pressure decreased after multiple drug administrations, but hypertonic saline may warrant consideration as the first-line drug for treating intracranial hypertension, as it was associated with the most favorable cerebral hemodynamics and fastest resolution of intracranial hypertension.

Intracranial Hypertension and Cerebral Hypoperfusion in Children With Severe Traumatic Brain Injury: Thresholds and Burden in Accidental and Abusive Insults.

Objectives: The evidence to guide therapy in pediatric traumatic brain injury is lacking, including insight into the intracranial pressure/cerebral perfusion pressure thresholds in abusive head trauma. We examined intracranial pressure/cerebral perfusion pressure thresholds and indices of intracranial pressure and cerebral perfusion pressure burden in relationship with outcome in severe traumatic brain injury and in accidental and abusive head trauma cohorts. Design: A prospective observational study. Setting: PICU in a tertiary children’s hospital. Patients: Children less than18 years old admitted to a PICU with severe traumatic brain injury and who had intracranial pressure monitoring. Interventions: None. Measurements and Main Results: A pediatric traumatic brain injury database was interrogated with 85 patients (18 abusive head trauma) enrolled. Hourly intracranial pressure and cerebral perfusion pressure (in mm Hg) were collated and compared with various thresholds. C-statistics for intracranial pressure and cerebral perfusion pressure data in the entire population were determined. Intracranial hypertension and cerebral hypoperfusion indices were formulated based on the number of hours with intracranial pressure more than 20 mm Hg and cerebral perfusion pressure less than 50 mm Hg, respectively. A secondary analysis was performed on accidental and abusive head trauma cohorts. All of these were compared with dichotomized 6-month Glasgow Outcome Scale scores. The models with the number of hours with intracranial pressure more than 20 mm Hg (C = 0.641; 95% CI, 0.523–0.762) and cerebral perfusion pressure less than 45 mm Hg (C = 0.702; 95% CI, 0.586–0.805) had the best fits to discriminate outcome. Two factors were independently associated with a poor outcome, the number of hours with intracranial pressure more than 20 mm Hg and abusive head trauma (odds ratio = 5.101; 95% CI, 1.571–16.563). As the number of hours with intracranial pressure more than 20 mm Hg increases by 1, the odds of a poor outcome increased by 4.6% (odds ratio = 1.046; 95% CI, 1.012–1.082). Thresholds did not differ between accidental versus abusive head trauma. The intracranial hypertension and cerebral hypoperfusion indices were both associated with outcomes. Conclusions: The duration of hours of intracranial pressure more than 20 mm Hg and cerebral perfusion pressure less than 45 mm Hg best discriminated poor outcome. As the number of hours with intracranial pressure more than 20 mm Hg increases by 1, the odds of a poor outcome increased by 4.6%. Although abusive head trauma was strongly associated with unfavorable outcome, intracranial pressure/cerebral perfusion pressure thresholds did not differ between accidental and abusive head trauma.

Blood eosinophilia is associated with unfavorable hospitalization outcomes in children with bronchiolitis.

Bronchiolitis, the most common indication for hospitalization of young children, is associated with subsequent asthma. Blood eosinophilia is associated with increased severity of asthma, but it is unclear if eosinophilia is associated with severity of illness in bronchiolitis. We hypothesized that blood eosinophilia is associated with unfavorable short‐term outcomes of bronchiolitis hospitalizations.

The Dose Makes the Poison: Comparing Epinephrine With Dopamine in Pediatric Septic Shock.

e308 www.ccmjournal.org May 2016 • Volume 44 • Number 5 company-sponsored lectures on high-frequency oscillatory ventilation); Vapotherm (received honoraria for the development of educational materials and company-sponsored lectures on high-flow nasal cannula therapy); and Elsevier (receives royalties for the role of associate editor in a pediatric critical care textbook). The remaining authors have disclosed that they do not have any potential conflicts of interest.

Intracranial monitoring and continuous data collection.

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Adjunctive Pharmacotherapies in Children With Asthma Exacerbations Requiring Continuous Albuterol Therapy: Findings From The Ohio Pediatric Asthma Repository

OBJECTIVES To identify associations between use of ipratropium and/or intravenous magnesium and outcomes of children hospitalized with acute asthma exacerbations and treated with continuous albuterol. METHODS Secondary analysis of data from children prospectively enrolled in the multicenter Ohio Pediatric Asthma Repository restricted to only children who were treated with continuous albuterol in their initial inpatient location. Children were treated with adjunctive therapies per the clinical team. RESULTS Among 242 children who received continuous albuterol, 94 (39%) received ipratropium only, 13 (5%) received magnesium alone, 42 (17%) received both, and 93 (38%) received neither. The median duration of continuous albuterol was 7.0 (interquartile range [IQR]: 2.8-12.0) hours. Ipratropium use was associated with a shorter duration of continuous albuterol (4.9 [IQR: 2.0-10.0] hours) compared with dual therapy (11.0 [IQR: 5.6-28.6] hours; P = .001), but magnesium use was not (7.5 [IQR: 2.5-16.0] hours; P = .542). In Cox proportional models (adjusted for hospital, demographics, treatment location, and respiratory failure), magnesium was associated with longer durations of continuous albuterol (hazard ratio, 0.54 [95% confidence interval: 0.37-0.77]; P < .001) and hospitalization (hazard ratio, 0.41 [95% confidence interval: 0.28-0.60]; P < .001), but ipratropium was not. CONCLUSIONS Ipratropium and magnesium were both often used in children with severe asthma hospitalizations that required continuous albuterol therapy. Magnesium use was associated with unfavorable outcomes, possibly reflecting preferential treatment to patients with more severe cases and differing practices between centers. Given the high prevalence of asthma, wide variations in practice, and the potential to improve outcomes and costs, prospective trials of these adjunctive therapies are needed.

Neurologic and Functional Morbidity in Critically Ill Children with Bronchiolitis

Objectives: Neurologic and functional morbidity occurs in ~30% of PICU survivors, and young children may be at particular risk. Bronchiolitis is a common indication for PICU admission among children less than 2 years old. Two single-center studies suggest that greater than 10–25% of critical bronchiolitis survivors have neurologic and functional morbidity but those estimates are 20 years old. We aimed to estimate the burden of neurologic and functional morbidity among more recent bronchiolitis patients using two large, multicenter databases. Design: Analysis of the Pediatric Health Information System and the Virtual Pediatric databases. Setting: Forty-eight U.S. children’s hospitals (Pediatric Health Information System) and 40 international (mostly United States) children’s hospitals (Virtual Pediatric Systems). Patients: Previously healthy PICU patients less than 2 years old admitted with bronchiolitis between 2009 and 2015 who survived and did not require extracorporeal membrane oxygenation or cardiopulmonary resuscitation. Interventions: None. Neurologic and functional morbidity was defined as a Pediatric Overall Performance Category greater than 1 at PICU discharge (Virtual Pediatric Systems subjects), or a subsequent hospital encounter involving developmental delay, feeding tubes, MRI of the brain, neurologist evaluation, or rehabilitation services (Pediatric Health Information System subjects). Measurements and Main Results: Among 3,751 Virtual Pediatric Systems subjects and 9,516 Pediatric Health Information System subjects, ~20% of patients received mechanical ventilation. Evidence of neurologic and functional morbidity was present at PICU discharge in 707 Virtual Pediatric Systems subjects (18.6%) and more chronically in 1,104 Pediatric Health Information System subjects (11.6%). In both cohorts, neurologic and functional morbidity was more common in subjects receiving mechanical ventilation (27.5% vs 16.5% in Virtual Pediatric Systems; 14.5% vs 11.1% in Pediatric Health Information System; both p < 0.001). In multivariate models also including demographics, use of mechanical ventilation was the only variable that was associated with increased neurologic and functional morbidity in both cohorts. Conclusions: In two large, multicenter databases, neurologic and functional morbidity was common among previously healthy children admitted to the PICU with bronchiolitis. Prospective studies are needed to measure neurologic and functional outcomes using more precise metrics. Identification of modifiable risk factors may subsequently lead to improved outcomes from this common PICU condition.