Chest CT Imaging Provides More Information Than Chest Radiography Alone in Determining Extent of Physiologic Impairment in Pulmonary Sarcoidosis.

BACKGROUND: Sarcoidosis staging primarily has relied on the Scadding chest radiographic system, although chest CT imaging is finding increased clinical use. RESEARCH QUESTION: Whether standardized chest CT scan assessment provides additional understanding of lung function beyond Scadding stage and demographics is unknown and the focus of this study. STUDY DESIGN AND METHODS: We used the National Heart, Lung, and Blood Institute study Genomics Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis cases of sarcoidosis (n = 351) with Scadding stage and chest CT scans obtained in a standardized manner. One chest radiologist scored all CT scans with a visual scoring system, with a subset read by another chest radiologist. We compared demographic features, Scadding stage, and CT scan findings and the correlation between these measures. Associations between spirometry results and Dlco, CT scan findings, and Scadding stage were determined using regression analysis (n = 318). Agreement between readers was evaluated using Cohen's κ value. RESULTS: CT scan features were inconsistent with Scadding stage in approximately 40% of cases. Most CT scan features assessed on visual scoring were associated negatively with lung function. Associations persisted for FEV1 and Dlco when adjusting for Scadding stage, although some CT scan feature associations with FVC became insignificant. Scadding stage was associated primarily with FEV1, and inclusion of CT scan features reduced significance in association between Scadding stage and lung function. Multivariable regression modeling to identify radiologic measures explaining lung function included Scadding stage for FEV1 and FEV1 to FVC ratio (P < .05) and marginally for Dlco (P < .15). Combinations of CT scan measures accounted for Scadding stage for FVC. Correlations among Scadding stage and CT scan features were noted. Agreement between readers was poor to moderate for presence or absence of CT scan features and poor for degree and location of abnormality. INTERPRETATION: CT scan features explained additional variability in lung function beyond Scadding stage, with some CT scan features obviating the associations between lung function and Scadding stage. Whether CT scan features, phenotypes, or endotypes could be useful for managing patients with sarcoidosis needs more study.

Early Cold Stored Platelet Transfusion Following Severe Injury: A Randomized Clinical Trial.

OBJECTIVE: To determine the feasibility, efficacy, and safety of early cold stored platelet transfusion compared with standard care resuscitation in patients with hemorrhagic shock. BACKGROUND: Data demonstrating the safety and efficacy of early cold stored platelet transfusion are lacking following severe injury. METHODS: A phase 2, multicenter, randomized, open label, clinical trial was performed at 5 US trauma centers. Injured patients at risk of large volume blood transfusion and the need for hemorrhage control procedures were enrolled and randomized. The intervention was the early transfusion of a single apheresis cold stored platelet unit, stored for up to 14 days versus standard care resuscitation. The primary outcome was feasibility and the principal clinical outcome for efficacy and safety was 24-hour mortality. RESULTS: Mortality at 24 hours was 5.9% in patients who were randomized to early cold stored platelet transfusion compared with 10.2% in the standard care arm (difference, -4.3%; 95% CI, -12.8% to 3.5%; P =0.26). No significant differences were found for any of the prespecified ancillary outcomes. Rates of arterial and/or venous thromboembolism and adverse events did not differ across treatment groups. CONCLUSIONS AND RELEVANCE: In severely injured patients, early cold stored platelet transfusion is feasible, safe and did not result in a significant lower rate of 24-hour mortality. Early cold stored platelet transfusion did not result in a higher incidence of arterial and/or venous thrombotic complications or adverse events. The storage age of the cold stored platelet product was not associated with significant outcome differences. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04667468.

Effects of inpatient rehabilitation after acute care on motor, neuropsychological and behavioral outcomes in children with severe traumatic brain injury.

PURPOSE: An observational study of children with severe traumatic brain injury (TBI) (Approaches and Decisions in Acute Pediatric TBI [ADAPT] Trial) demonstrated the benefits of inpatient rehabilitation on functional outcomes for those with more severely impaired consciousness when medically stable. We conducted a secondary analysis to assess whether using an inpatient rehabilitation or skilled nursing facility after acute hospitalization was associated with better motor, neuropsychological, and behavioral outcomes compared to receiving only non-inpatient rehabilitation among children with severe TBI. MATERIALS AND METHODS: We included 180 children who used an inpatient rehabilitation or skilled nursing facility and 74 children who only received non-inpatient rehabilitation from the ADAPT trial. At 12 months post-injury, children underwent tests of motor skills, intellectual functioning, verbal learning, memory, processing speed, and cognitive flexibility. Parents/guardians rated children's executive function and behaviors. We performed inverse probability weighting to adjust for potential confounders. RESULTS: No significant differences were found in any motor, neuropsychological, or behavioral measures between children receiving inpatient rehabilitation and children receiving only non-inpatient rehabilitation. CONCLUSIONS: Analyses of comprehensive outcomes did not show differences between children receiving inpatient rehabilitation and children receiving only non-inpatient rehabilitation, suggesting a need for more research on specific components of the rehabilitation process.

Our study showed no differences in motor, neuropsychological, or behavioral outcomes at 12 months after severe traumatic brain injury (TBI) between children using an inpatient rehabilitation or skilled nursing facility and children receiving only non-inpatient rehabilitation after acute hospitalization.Children surviving severe TBI should be evaluated for the need of inpatient and outpatient rehabilitation therapies at discharge from an acute care hospital.Children with rehabilitation requirements after severe TBI should be followed up periodically to ensure the continuity of care and reduce the gaps to the needed rehabilitation therapies.

Symptoms and Impaired Quality of Life After COVID-19 Hospitalization: Effect of Therapeutic Heparin in Non-ICU Patients in the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 Acute Trial: Effect on 3-Month Symptoms and Quality of Life.

BACKGROUND: Therapeutic-dose heparin decreased days requiring organ support in noncritically ill patients hospitalized for COVID-19, but its impact on persistent symptoms or quality of life (QOL) is unclear. RESEARCH QUESTION: In the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE (ACTIV-4a) trial, was randomization of patients hospitalized for COVID-19 illness to therapeutic-dose vs prophylactic heparin associated with fewer symptoms and better QOL at 90 days? STUDY DESIGN AND METHODS: This was an open-label randomized controlled trial at 34 hospitals in the United States and Spain. A total of 727 noncritically ill patients hospitalized for COVID-19 from September 2020 to June 2021 were randomized to therapeutic-dose vs prophylactic heparin. Only patients with 90-day data on symptoms and QOL were analyzed. We ascertained symptoms and QOL by the EQ-5D-5L at 90-day follow-up in a preplanned analysis for the ACTIV-4a trial. Individual domains assessed by the EQ-5D-5L included mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Univariate and multivariate analyses were performed. RESULTS: Among 571 patients, 288 (50.4%) reported at least one symptom. Among 410 patients, 148 (36.1%) reported moderate to severe impairment in one or more domains of the EQ-5D-5L. The presence of 90-day symptoms was associated with moderate-severe impairment in the EQ-5D-5L domains of mobility (adjusted OR [aOR], 2.37; 95% CI, 1.22-4.59), usual activities (aOR, 3.66; 95% CI, 1.75-7.65), pain (aOR, 2.43; 95% CI, 1.43-4.12), and anxiety (aOR, 4.32; 95% CI, 2.06-9.02), compared with patients reporting no symptoms There were no differences in symptoms or in the overall EQ-5D-5L index score between treatment groups. Therapeutic-dose heparin was associated with less moderate-severe impairment in all physical functioning domains (mobility, self-care, usual activities) but was independently significant only in the self-care domain (aOR, 0.32; 95% CI, 0.11-0.96). INTERPRETATION: In a randomized controlled trial of hospitalized noncritically ill patients with COVID-19, therapeutic-dose heparin was associated with less severe impairment in the self-care domain of EQ-5D-5L. However, this type of impairment was uncommon, affecting 23 individuals. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04505774; URL: www. CLINICALTRIALS: gov.

Prehospital Time Following Traumatic Injury Is Independently Associated With the Need for In-Hospital Blood and Early Mortality for Specific Injury Types.

OBJECTIVE: Treating traumatic hemorrhage is time sensitive. Prehospital care and transport modes (eg, helicopter and ground) may influence in-hospital events. We hypothesized that prehospital time (on-scene time [OST] and total prehospital time [TPT]) and transport mode are associated with same-day transfusion and mortality. Furthermore, we sought to identify regions of anatomic injury that modify the relationship between prehospital time and outcomes in strata corresponding to transport types. METHODS: We obtained prehospital, in-hospital, and trauma registry data from an 8-center cohort of adult nonburn trauma patients from 2017 to 2022 directly transported from the scene to the hospital and having an Injury Severity Score (ISS) > 9 for the Task Order 1 project of the Linking Investigators in Trauma and Emergency Services research network. We excluded patients missing prehospital times, patients < 18 years of age, patients from interfacility transfers, and recipients of prehospital blood. Our same-day outcomes were in-hospital transfusions within 4 hours and 24-hour mortality. Each outcome was adjusted using multivariable logistic regression for covariates of prehospital phases (OST and TPT), mode of transport (helicopter and ground), age, sex, ISS, Glasgow Coma Scale motor subscale score < 6, and field hypotension (systolic blood pressure < 90 mm Hg). We evaluated the association of prehospital time on outcomes for scene missions by transport mode across severe injury patterns defined by Abbreviated Injury Scale > 2 body regions. RESULTS: Of 78,198 subjects, 34,504 were eligible for the study with a mean age of 47.6 ± 20.3 years, ISS of 18 ± 11, OST of 15.9 ± 9.5 minutes, and TPT of 48.7 ± 20.3 minutes. Adjusted for injury severity and demographic factors, transport type significantly modified the relationship between prehospital time and outcomes. The association of OST and TPT with the odds of 4-hour transfusion was absent for the ground emergency medical services (GEMS) cohort and present for the helicopter emergency medical services (HEMS) ambulance cohort, whereas these times were associated with decreased 24-hour mortality for both transport types. When stratifying by injury to most anatomic regions, OST and TPT were associated with a decreased need for 4-hour transfusions in the GEMS cohort. However, OST was associated with increased early transfusion only among patients with severe injuries of the thorax, and this association persisted after adjusting additionally for injury type (odds ratio [OR] = 1.03; 95% confidence interval [CI], 1.00-1.05; P = .02). The presence of polytrauma supported an association between prehospital time and decreased 24-hour mortality for the GEMS cohort (OST: OR = 0.97; 95% CI, 0.95-0.99; P < .01; TPT: OR = 0.99; 95% CI, 0.98-0.99; P = .02), whereas no injuries showed significant association of helicopter prehospital time on mortality after adjustment. CONCLUSION: We determined that transport type affects the relationship between prehospital time and hospital outcomes (4-hour transfusion: positive relationship for HEMS and negative for GEMS, 24-hour mortality: negative for both transport types). Furthermore, we identified regions of anatomic injury that modify the relationship between prehospital time and outcomes in strata corresponding to transport types. Of these regions, most notable were severe isolated injuries to the thorax that supported a positive relationship between HEMS OST and 4-hour transfusions and polytrauma that showed a negative relationship between GEMS OST or TPT and 24-hour mortality after adjustment.

Lifestyle Intervention and Excess Weight in Chronic Obstructive Pulmonary Disease (COPD): INSIGHT COPD Randomized Clinical Trial.

Rationale: Being overweight or obese is common among patients with chronic obstructive pulmonary disease (COPD), but whether interventions targeted at weight loss improve functional impairments is unknown. Objectives: INSIGHT (Intervention Study in Overweight Patients with COPD) tested whether a pragmatic low-intensity lifestyle intervention would lead to better physical functional status among overweight or obese participants with COPD. Methods: The trial was a 12-month, multicenter, patient-level pragmatic clinical trial. Participants were recruited from April 2017 to August 2019 from 38 sites across the United States and randomized to receive usual care or usual care plus lifestyle intervention. The intervention was a self-directed video program delivering the Diabetes Prevention Program's Group Lifestyle Balance curriculum. Results: The primary outcome was 6-minute-walk test distance at 12 months. Priority secondary outcomes were postwalk modified Borg dyspnea at 12 months and weight at 12 months. Participants (N = 684; mean age, 67.0 ± 8.0 yr [standard deviation]; 41.2% female) on average were obese (body mass index, 33.0 ± 4.6 kg/m2) with moderate COPD (forced expiratory volume in 1 second % predicted, 58.1 ± 15.7%). At 12 months, participants randomized to the intervention arm walked farther (adjusted difference, 42.3 ft [95% confidence interval (CI), 7.9-76.7 ft]; P = 0.02), had less dyspnea at the end of the 6-minute-walk test (adjusted difference, -0.36 [95% CI, -0.63 to -0.09]; P = 0.008), and had greater weight loss (adjusted difference, -1.34 kg [95% CI, -2.33 to -0.34 kg]; P = 0.008) than control participants. The intervention did not improve the odds of achieving clinically meaningful thresholds of walk distance (98.4 ft) or dyspnea (1 unit) but did achieve meaningful thresholds of weight loss (3% and 5%). Conclusions: Among participants with COPD who were overweight or obese, a self-guided low-intensity video-based lifestyle intervention led to modest weight loss but did not lead to clinically important improvements in physical functional status and dyspnea. Clinical trial registered with www.clinicaltrials.gov (NCT02634268).

Whole Blood Resuscitation and Association with Survival in Injured Patients with an Elevated Probability of Mortality.

BACKGROUND: Low-titer group O whole blood (LTOWB) resuscitation is becoming common in both military and civilian settings and may represent the ideal resuscitation intervention. We sought to characterize the safety and efficacy of LTOWB resuscitation relative to blood component resuscitation. STUDY DESIGN: A prospective, multicenter, observational cohort study was performed using 7 trauma centers. Injured patients at risk of massive transfusion who required both blood transfusion and hemorrhage control procedures were enrolled. The primary outcome was 4-hour mortality. Secondary outcomes included 24-hour and 28-day mortality, achievement of hemostasis, death from exsanguination, and the incidence of unexpected survivors. RESULTS: A total of 1,051 patients in hemorrhagic shock met all enrollment criteria. The cohort was severely injured with >70% of patients requiring massive transfusion. After propensity adjustment, no significant 4-hour mortality difference across LTOWB and component patients was found (relative risk [RR] 0.90, 95% CI 0.59 to 1.39, p = 0.64). Similarly, no adjusted mortality differences were demonstrated at 24 hours or 28 days for the enrolled cohort. When patients with an elevated prehospital probability of mortality were analyzed, LTOWB resuscitation was independently associated with a 48% lower risk of 4-hour mortality (relative risk [RR] 0.52, 95% CI 0.32 to 0.87, p = 0.01) and a 30% lower risk of 28-day mortality (RR 0.70, 95% CI 0.51 to 0.96, p = 0.03). CONCLUSIONS: Early LTOWB resuscitation is safe but not independently associated with survival for the overall enrolled population. When patients were selected with an elevated probability of mortality based on prehospital injury characteristics, LTOWB was independently associated with a lower risk of mortality starting at 4 hours after arrival through 28 days after injury.

Blood component ratios in children with non-traumatic life-threatening bleeding.

BACKGROUND AND OBJECTIVES: In paediatric trauma patients, there are limited prospective data regarding blood components and mortality, with some literature suggesting decreased mortality with high ratios of plasma and platelets to red blood cells (RBCs) in massive transfusions; however, most paediatric massive transfusions occur for non-traumatic aetiologies and few studies assess blood product ratios in these children. This study's objective was to evaluate whether high blood product ratios or low deficits conferred a survival benefit in children with non-traumatic life-threatening bleeding. MATERIALS AND METHODS: This is a secondary analysis of the five-year, multicentre, prospective, observational massive transfusion epidemiology and outcomes in children study of children with life-threatening bleeding from US, Canadian and Italian medical centres. Primary interventions were plasma:RBC and platelets:RBC (high ratio ≥1:2 ml/kg) and plasma and platelet deficits. The primary outcome was mortality at 6 h, 24 h and 28 days. Multivariate logistic regression models were used to determine independent associations with mortality. RESULTS: A total of 222 children were included from 24 medical centres: 145 children (median [interquartile range] age 2.1 years [0.3-11.8]) with operative bleeding and 77 (8.0 years [1.2-14.7]) with medical bleeding. In adjusted analyses, neither blood product ratios nor deficits were associated with mortality at 6 h, 24 h or 28 days. CONCLUSION: This paper addresses a lack of prospective data in children regarding optimal empiric massive transfusion strategies in non-traumatic massive haemorrhage and in finding no decrease in mortality with high plasma or platelet to RBC ratios or lower deficits supports an exploratory analysis for mortality.

Proteomics of Coagulopathy Following Injury Reveals Limitations of Using Laboratory Assessment to Define Trauma-Induced Coagulopathy to Predict Massive Transfusion.

Objective: Trauma-induced coagulopathy (TIC) is provoked by multiple mechanisms and is perceived to be one driver of massive transfusions (MT). Single laboratory values using prothrombin time (INR) or thrombelastography (TEG) are used to clinically define this complex process. We used a proteomics approach to test whether current definitions of TIC (INR, TEG, or clinical judgement) are sufficient to capture the majority of protein changes associated with MT. Methods: Eight level-I trauma centers contributed blood samples from patients available early after injury. TIC was defined as INR >1.5 (INR-TIC), TEG maximum amplitude <50mm (TEG-TIC), or clinical judgement (Clin-TIC) by the trauma surgeon. MT was defined as > 10 units of red blood cells in 24 hours or > 4 units RBC/hour during the first 4 hr. SomaLogic proteomic analysis of 1,305 proteins was performed. Pathways associated with proteins dysregulated in patients with each TIC definition and MT were identified. Results: Patients (n=211) had a mean injury severity score of 24, with a MT and mortality rate of 22% and 12%, respectively. We identified 578 SOMAscan analytes dysregulated among MT patients, of which INR-TIC, TEG-TIC, and Clin-TIC patients showed dysregulation only in 25%, 3%, and 4% of these, respectively. TIC definitions jointly failed to show changes in 73% of the protein levels associated with MT, and failed to identify 26% of patients that received a massive transfusion. INR-TIC and TEG-TIC patients showed dysregulation of proteins significantly associated with complement activity. Proteins dysregulated in Clin-TIC or massive transfusion patients were not significantly associated with any pathway. Conclusion: These data indicate there are unexplored opportunities to identify patients at risk for massive bleeding. Only a small subset of proteins that are dysregulated in patients receiving MT are statistically significantly dysregulated among patients whose TIC is defined based solely on laboratory measurements or clinical assessment.

Effects of inpatient rehabilitation after acute care on functional and quality-of-life outcomes in children with severe traumatic brain injury.

OBJECTIVE: Few studies have assessed the effectiveness of the rehabilitation process in children surviving severe traumatic brain injury (TBI). We evaluated whether receiving inpatient rehabilitation after acute hospitalization was associated with better functional outcomes compared to receiving only non-inpatient rehabilitation in children with severe TBI and explored an effect modification for Glasgow Coma Scale (GCS) score at hospital discharge. METHODS: We included 254 children who received rehabilitation following severe TBI from a multinational observational study. The Pediatric Glasgow Outcome Scale - Extended (GOS-E Peds), parent/guardian-reported and child-reported Pediatric Quality of Life Inventory (PedsQL) at 12 months post-injury were assessed and described using summary statistics. Unadjusted and propensity score-weighted linear/ordinal logistic regression modeling were also performed. RESULTS: 180 children received inpatient rehabilitation and 74 children received only non-inpatient rehabilitation after acute hospitalization. Among children with a GCS<13 at discharge, those receiving inpatient rehabilitation had a more favorable GOS-E Peds score (OR = 0.12, p = 0.045). However, no such association was observed in children with a higher GCS. We found no differences in PedsQL scores between rehabilitation groups. CONCLUSIONS: Future studies are warranted to confirm the benefits of inpatient rehabilitation for children with more severely impaired consciousness when medically stable.

Bronchodilators in Tobacco-Exposed Persons with Symptoms and Preserved Lung Function.

BACKGROUND: Many persons with a history of smoking tobacco have clinically significant respiratory symptoms despite an absence of airflow obstruction as assessed by spirometry. They are often treated with medications for chronic obstructive pulmonary disease (COPD), but supporting evidence for this treatment is lacking. METHODS: We randomly assigned persons who had a tobacco-smoking history of at least 10 pack-years, respiratory symptoms as defined by a COPD Assessment Test score of at least 10 (scores range from 0 to 40, with higher scores indicating worse symptoms), and preserved lung function on spirometry (ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC] ≥0.70 and FVC ≥70% of the predicted value after bronchodilator use) to receive either indacaterol (27.5 µg) plus glycopyrrolate (15.6 µg) or placebo twice daily for 12 weeks. The primary outcome was at least a 4-point decrease (i.e., improvement) in the St. George's Respiratory Questionnaire (SGRQ) score (scores range from 0 to 100, with higher scores indicating worse health status) after 12 weeks without treatment failure (defined as an increase in lower respiratory symptoms treated with a long-acting inhaled bronchodilator, glucocorticoid, or antibiotic agent). RESULTS: A total of 535 participants underwent randomization. In the modified intention-to-treat population (471 participants), 128 of 227 participants (56.4%) in the treatment group and 144 of 244 (59.0%) in the placebo group had at least a 4-point decrease in the SGRQ score (difference, -2.6 percentage points; 95% confidence interval [CI], -11.6 to 6.3; adjusted odds ratio, 0.91; 95% CI, 0.60 to 1.37; P = 0.65). The mean change in the percent of predicted FEV1 was 2.48 percentage points (95% CI, 1.49 to 3.47) in the treatment group and -0.09 percentage points (95% CI, -1.06 to 0.89) in the placebo group, and the mean change in the inspiratory capacity was 0.12 liters (95% CI, 0.07 to 0.18) in the treatment group and 0.02 liters (95% CI, -0.03 to 0.08) in the placebo group. Four serious adverse events occurred in the treatment group, and 11 occurred in the placebo group; none were deemed potentially related to the treatment or placebo. CONCLUSIONS: Inhaled dual bronchodilator therapy did not decrease respiratory symptoms in symptomatic, tobacco-exposed persons with preserved lung function as assessed by spirometry. (Funded by the National Heart, Lung, and Blood Institute and others; RETHINC ClinicalTrials.gov number, NCT02867761.).

Comparative Effectiveness of Diversion of Cerebrospinal Fluid for Children With Severe Traumatic Brain Injury.

Importance: Diversion of cerebrospinal fluid (CSF) has been used for decades as a treatment for children with severe traumatic brain injury (TBI) and is recommended by evidenced-based guidelines. However, these recommendations are based on limited studies. Objective: To determine whether CSF diversion is associated with improved Glasgow Outcome Score-Extended for Pediatrics (GOS-EP) and decreased intracranial pressure (ICP) in children with severe TBI. Design, Setting, and Participants: This observational comparative effectiveness study was performed at 51 clinical centers that routinely care for children with severe TBI in 8 countries (US, United Kingdom, Spain, the Netherlands, Australia, New Zealand, South Africa, and India) from February 2014 to September 2017, with follow-up at 6 months after injury (final follow-up, October 22, 2021). Children with severe TBI were included if they had Glasgow Coma Scale (GCS) scores of 8 or lower, had intracranial pressure (ICP) monitor placed on-site, and were aged younger than 18 years. Children were excluded if they were pregnant or an ICP monitor was not placed at the study site. Consecutive children were screened and enrolled, data regarding treatments were collected, and at discharge, consent was obtained for outcomes testing. Propensity matching for pretreatment characteristics was performed to develop matched pairs for primary analysis. Data analyses were completed on April 18, 2022. Exposures: Clinical care followed local standards, including the use of CSF diversion (or not), with patients stratified at the time of ICP monitor placement (CSF group vs no CSF group). Main Outcomes and Measures: The primary outcome was GOS-EP at 6 months, while ICP was considered as a secondary outcome. CSF vs no CSF was treated as an intention-to-treat analysis, and a sensitivity analysis was performed for children who received delayed CSF diversion. Results: A total of 1000 children with TBI were enrolled, including 314 who received CSF diversion (mean [SD] age, 7.18 [5.45] years; 208 [66.2%] boys) and 686 who did not (mean [SD] age, 7.79 [5.33] years; 437 [63.7%] boys). The propensity-matched analysis included 98 pairs. In propensity score-matched analyses, there was no difference between groups in GOS-EP (median [IQR] difference, 0 [-3 to 1]; P = .08), but there was a decrease in overall ICP in the CSF group (mean [SD] difference, 3.97 [0.12] mm Hg; P < .001). Conclusions and Relevance: In this comparative effectiveness study, CSF diversion was not associated with improved outcome at 6 months after TBI, but a decrease in ICP was observed. Given the higher quality of evidence generated by this study, current evidence-based guidelines related to CSF diversion should be reconsidered.

Comparison of Intracranial Pressure Measurements Before and After Hypertonic Saline or Mannitol Treatment in Children With Severe Traumatic Brain Injury.

Importance: Hyperosmolar agents are cornerstone therapies for pediatric severe traumatic brain injury. Guideline recommendations for 3% hypertonic saline (HTS) are based on limited numbers of patients, and no study to date has supported a recommendation for mannitol. Objectives: To characterize current use of hyperosmolar agents in pediatric severe traumatic brain injury and assess whether HTS or mannitol is associated with greater decreases in intracranial pressure (ICP) and/or increases in cerebral perfusion pressure (CPP). Design, Setting, and Participants: In this comparative effectiveness research study, 1018 children were screened and 18 were excluded; 787 children received some form of hyperosmolar therapy during the ICP-directed phase of care, with 521 receiving a bolus. Three of these children were excluded because they had received only bolus administration of both HTS and mannitol in the same hour, leaving 518 children (at 44 clinical sites in 8 countries) for analysis. The study was conducted from February 1, 2014, to September 31, 2017, with follow-up for 1 week after injury. Final analysis was performed July 20, 2021. Interventions: Boluses of HTS and mannitol were administered. Main Outcomes and Measures: Data on ICP and CPP were collected before and after medication administration. Statistical methods included linear mixed models and corrections for potential confounding variables to compare the 2 treatments. Results: A total of 518 children (mean [SD] age, 7.6 [5.4] years; 336 [64.9%] male; 274 [52.9%] White) were included. Participants' mean (SD) Glasgow Coma Scale score was 5.2 (1.8). Bolus HTS was observed to decrease ICP and increase CPP (mean [SD] ICP, 1.03 [6.77] mm Hg; P < .001; mean [SD] CPP, 1.25 [12.47] mm Hg; P < .001), whereas mannitol was observed to increase CPP (mean [SD] CPP, 1.20 [11.43] mm Hg; P = .009). In the primary outcome, HTS was associated with a greater reduction in ICP compared with mannitol (unadjusted ß, -0.85; 95% CI, -1.53 to -0.19), but no association was seen after adjustments (adjusted ß, -0.53; 95% CI, -1.32 to 0.25; P = .18). No differences in CPP were observed. When ICP was greater than 20 mm Hg, greater than 25 mm Hg, or greater than 30 mm Hg, HTS outperformed mannitol for each threshold in observed ICP reduction (>20 mm Hg: unadjusted ß, -2.51; 95% CI, -3.86 to -1.15, P < .001; >25 mm Hg: unadjusted ß, -3.88; 95% CI, -5.69 to -2.06, P < .001; >30 mm Hg: unadjusted ß, -4.07; 95% CI, -6.35 to -1.79, P < .001), with results remaining significant for ICP greater than 25 mm Hg in adjusted analysis. Conclusions and Relevance: In this comparative effectiveness research study, bolus HTS was associated with lower ICP and higher CPP, whereas mannitol was associated only with higher CPP. After adjustment for confounders, both therapies showed no association with ICP and CPP. During ICP crises, HTS was associated with better performance than mannitol.

Transfusion Ratios and Deficits in Injured Children With Life-Threatening Bleeding.

OBJECTIVES: To assess the impact of plasma and platelet ratios and deficits in injured children with life-threatening bleeding. DESIGN: Secondary analysis of the MAssive Transfusion epidemiology and outcomes In Children study dataset, a prospective observational study of children with life-threatening bleeding events. SETTING: Twenty-four childrens hospitals in the United States, Canada, and Italy. PATIENTS: Injured children 0-17 years old who received greater than 40 mL/kg total blood products over 6 hours or were transfused under activation of massive transfusion protocol. INTERVENTION/EXPOSURE: Weight-adjusted blood product volumes received during the bleeding event were recorded. Plasma:RBC ratio (plasma/RBC weight-adjusted volume in mL/kg) and platelet:RBC ratio (platelet/RBC weight-adjusted volume in mL/kg) were analyzed. Plasma deficit was calculated as RBC mL/kg - plasma mL/kg; platelet deficit was calculated as RBC mL/kg - platelet mL/kg. MEASUREMENTS AND MAIN RESULTS: Of 191 patients analyzed, median (interquartile range) age was 10 years (5-15 yr), 61% were male, 61% blunt mechanism, and median (interquartile range) Injury Severity Score was 29 (24-38). After adjusting for Pediatric Risk of Mortality score, cardiac arrest, use of vasoactive medications, and blunt mechanism, a high plasma:RBC ratio (> 1:2) was associated with improved 6-hour survival compared with a low plasma:RBC ratio (odds ratio [95% CI] = 0.12 [0.03-0.52]; p = 0.004). Platelet:RBC ratio was not associated with survival. After adjusting for age, Pediatric Risk of Mortality score, cardiac arrest, and mechanism of injury, 6-hour and 24-hour mortality were increased in children with greater plasma deficits (10% and 20% increased odds of mortality for every 10 mL/kg plasma deficit at 6 hr [p = 0.04] and 24 hr [p = 0.01], respectively); 24-hour mortality was increased in children with greater platelet deficits (10% increased odds of 24-hr mortality for every 10 mL/kg platelet deficit [p = 0.02)]). CONCLUSIONS: In injured children, balanced resuscitation may improve early survival according to this hypothesis generating study. Multicenter clinical trials are needed to assess whether clinicians should target ratios and deficits as optimal pediatric hemostatic resuscitation practice.

Effect of vitamin D supplementation on total and allergen-specific IgE in children with asthma and low vitamin D levels.

BACKGROUND: Observational studies have yielded inconsistent findings for the relation between vitamin D level and total IgE or allergic sensitization. OBJECTIVE: To determine whether vitamin D supplementation reduces levels of total IgE and IgE to each of 2 common indoor allergens in children with asthma and low vitamin D levels. METHODS: Total IgE, IgE to Dermatophagoides pteronyssinus, and IgE to Blattella germanica were measured at the randomization and exit visits for 174 participants in the Vitamin D Kids Asthma Study, a multicenter, double-blind, randomized placebo-controlled trial of vitamin D3 supplementation (4000 IU/d) to prevent severe exacerbations in children with persistent asthma and vitamin D levels less than 30 ng/mL. Multivariable linear regression was used for the analysis of the effect of vitamin D supplementation on change in each IgE measure. RESULTS: Participants were followed for an average of 316 days. At the exit visit, more subjects in the vitamin D arm achieved a vitamin D level equal to or more than 30 ng/mL compared with those in the placebo arm (87% vs 30%; P < .001). In a multivariable analysis, vitamin D3 supplementation had no significant effect on change in total IgE, IgE to Dermatophagoides pteronyssinus, or IgE to Blattella germanica between the exit and randomization visits (eg, for log10 total IgE, ß = 0.007; 95% CI, -0.061 to 0.074; P = .85). CONCLUSIONS: Vitamin D supplementation, compared with placebo, has no significant effect on serum levels of total IgE, IgE to dust mite, or IgE to cockroach in children with asthma and low vitamin D levels.

Violence-related distress and lung function in two longitudinal studies of youth.

BACKGROUND: Exposure to violence has been associated with lower lung function in cross-sectional studies. METHODS: We examined whether increasing violence-related distress over time is associated with worse lung function and worse asthma control or quality of life in a secondary analysis of a 48-week randomised clinical trial in 98 youth with asthma (aged 9-16 years) treated with low-dose inhaled corticosteroids (Vitamin D Kids Asthma Study (VDKA)). We then replicated our findings for lung function in a prospective study of 232 Puerto Rican youth followed for an average of 5.4 years. Violence-related distress was assessed using the Checklist of Children's Distress Symptoms (CCDS) scale. Our outcomes of interest were percent predicted lung function measures and (in VDKA only) asthma control (assessed using the Asthma Control Test) and asthma-related quality of life (assessed using the Pediatric Asthma Quality of Life Questionnaire (PAQLQ)). RESULTS: In a multivariable analysis in VDKA, each 1-point increment in CCDS score was associated with decrements of 3.27% in forced expiratory volume in 1 s (FEV1) % pred (95% CI -6.44- -0.22%; p=0.04), 2.65% in forced vital capacity (FVC) % pred (95% CI -4.86- -0.45%; p=0.02) and 0.30 points in the overall PAQLQ score (95% CI -0.50- -0.10 points; p<0.01). Similar findings for FEV1 and FVC were obtained in the prospective study of Puerto Rican youth. CONCLUSIONS: Our findings suggest that violence-related distress may worsen lung function and quality of life in youth with asthma (even those treated with low-dose inhaled corticosteroids), and further support policies to reduce exposure to violence among children in the USA and Puerto Rico.

Use of Antifibrinolytics in Pediatric Life-Threatening Hemorrhage: A Prospective Observational Multicenter Study.

OBJECTIVES: To assess the impact of antifibrinolytics in children with life-threatening hemorrhage. DESIGN: Secondary analysis of the MAssive Transfusion epidemiology and outcomes In Children study dataset, a prospective observational study of children with life-threatening bleeding events. SETTING: Twenty-four children's hospitals in the United States, Canada, and Italy. PATIENTS: Children 0-17 years old who received greater than 40 mL/kg of total blood products over 6 hours or were transfused under activation of massive transfusion protocol. INTERVENTION/EXPOSURE: Children were compared according to receipt of antifibrinolytic medication (tranexamic acid or aminocaproic acid) during the bleeding event. MEASUREMENTS AND MAIN RESULTS: Patient characteristics, medications administered, and clinical outcomes were analyzed using Cox proportional hazard and Kaplan-Meier survival analysis. The primary outcome was 24-hour mortality. Of 449 patients analyzed, median age was 7 years (2-15 yr), and 55% were male. The etiology of bleeding was 46% traumatic, 34% operative, and 20% medical. Twelve percent received antifibrinolytic medication during the bleeding event (n = 54 unique subjects; n = 18 epsilon aminocaproic acid, n = 35 tranexamic acid, and n = 1 both). The antifibrinolytic group was comparable with the nonantifibrinolytic group on baseline demographic and physiologic parameters; the antifibrinolytic group had longer massive transfusion protocol duration, received greater volume blood products, and received factor VII more frequently. In the antifibrinolytic group, there was significantly less 6-hour mortality overall (6% vs 17%; p = 0.04) and less 6-hour mortality due to hemorrhage (4% vs 14%; p = 0.04). After adjusting for age, bleeding etiology, Pediatric Risk of Mortality score, and plasma deficit, the antifibrinolytic group had decreased mortality at 6- and 24-hour postbleed (adjusted odds ratio, 0.29 [95% CI, 0.09-0.93]; p = 0.04 and adjusted odds ratio, 0.45 [95% CI, 0.21-0.98]; p = 0.04, respectively). CONCLUSIONS: Administration of antifibrinolytic medications during the life-threatening event was independently associated with improved 6- and 24-hour survivals in bleeding children. Consideration should be given to use of antifibrinolytics in pediatric patients with life-threatening hemorrhage.

Survey to inform trial of low-titer group O whole-blood compared to conventional blood components for children with severe traumatic bleeding.

BACKGROUND: Low-titer group O whole-blood (LTOWB) is being used for children with life-threatening traumatic bleeding. A survey was conducted to determine current LTOWB utilization and interest in participation in a randomized control trial (RCT) of LTOWB versus standard blood component transfusion in this population. STUDY DESIGN AND METHODS: Transfusion medicine (TM) directors and pediatric trauma directors at 36 US children's hospitals were surveyed by e-mail in June 2020. Hospitals were selected by participation in the Massive Transfusion Epidemiology and Outcomes in Children Study or being among the largest 30 children's hospitals by bed capacity per the Becker Hospital Review. RESULTS: The response rate was 83.3% (30/36) from TM directors and 88.9% (32/36) from trauma directors. The median of massive transfusion protocol activations for traumatic bleeding was reported as 12 (IQR 5.8-20) per year by TM directors. LTOWB was used by 18.8% (6/32) of trauma directors. Survey responses indicate that 86.7% (26/30) of TM directors and 90.6% (29/32) of trauma directors either moderately or strongly agree that a LTOWB RCT is important to perform. About 83.3% (25/30) of TM directors and 93.8% (30/32) of trauma directors were willing to participate in the proposed trial. About 80% (24/30) of TM directors and 71.9% (23/32) of trauma directors would transfuse RhD+ LTOWB to male children, but fewer would transfuse Rh + LTOWB to females [20% (6/30) TM directors and 37.5% (12/32) of trauma directors]. CONCLUSIONS: A majority of respondents supported an RCT comparing LTOWB to component therapy in children with severe traumatic bleeding.