The effects of prehospital TXA on mortality and neurologic outcomes in patients with traumatic intracranial hemorrhage: a subgroup analysis from the prehospital TXA for TBI trial.

BACKGROUND: In the Prehospital Tranexamic Acid (TXA) for TBI Trial, TXA administered within two hours of injury in the out-of-hospital setting did not reduce mortality in all patients with moderate/severe traumatic brain injury (TBI). We examined the association between TXA dosing arms, neurologic outcome, and mortality in patients with intracranial hemorrhage (ICH) on computed tomography (CT). METHODS: This was a secondary analysis of the Prehospital Tranexamic Acid for TBI Trial (ClinicalTrials.gov [NCT01990768]) that randomized adults with moderate/severe TBI (Glasgow Coma Scale<13) and systolic blood pressure > =90 mmHg within two hours of injury to a 2-gram out-of-hospital TXA bolus followed by an in-hospital saline infusion, a 1-gram out-of-hospital TXA bolus/1-gram in-hospital TXA infusion, or an out-of-hospital saline bolus/in-hospital saline infusion (placebo). This analysis included the subgroup with ICH on initial CT. Primary outcomes included 28-day mortality, 6-month Glasgow Outcome Scale-Extended (GOSE) < = 4, and 6-month Disability Rating Scale (DRS). Outcomes were modeled using linear regression with robust standard errors. RESULTS: The primary trial included 966 patients. Among 541 participants with ICH, 28-day mortality was lower in the 2-gram TXA bolus group (17%) compared to the other two groups (1-gram bolus/1-gram infusion 26%, placebo 27%). The estimated adjusted difference between the 2-gram bolus and placebo groups was -8·5 percentage points (95% CI, -15.9 to -1.0) and between the 2-gram bolus and 1-gram bolus/1-gram infusion groups was -10.2 percentage points (95% CI, -17.6 to -2.9). DRS at 6 months was lower in the 2-gram TXA bolus group than the 1-gram bolus/1-gram infusion (estimated difference -2.1 [95% CI, -4.2 to -0.02]) and placebo groups (-2.2 [95% CI, -4.3, -0.2]). Six-month GOSE did not differ among groups. CONCLUSIONS: A 2-gram out-of-hospital TXA bolus in patients with moderate/severe TBI and ICH resulted in lower 28-day mortality and lower 6-month DRS than placebo and standard TXA dosing. LEVEL OF EVIDENCE: Therapeutic/Care Management, Level II.

Spectrum and frequency of critical procedures performed at a Level I adult and pediatric trauma center.

OBJECTIVES: The primary objective of this study was to provide physician-level data about the frequency of critical procedures at a combined adult and pediatric Level I trauma center, high-acuity, high-volume academic ED. The inspiration for this study question came from a previous study by Mittiga et al. (2013) describing pediatric critical procedure data at a similar high-acuity, high-volume, pediatric-only academic ED. Our secondary objective is to compare our pediatric level procedural spectrum and frequency with those published by Mittiga et al. (2013). METHODS: This prospective observational study occurred over eleven consecutive months at an urban, Level I combined adult/pediatric trauma center with 96,000 annual visits (8500 pediatric). We recorded only procedures performed in the resuscitation bays. All data analysis is descriptive. RESULTS: Over eleven months, data on 3891 resuscitations were collected (3686 adults and 205 children); 38 faculty physicians supervised 1838 total critical procedures, 64 on children. The mean number of critical procedures per physician per month was 4.42 (0.15 on children). Additionally, ultrasound for intravenous access, extended focused assessment with sonography for trauma (e-FAST), or cardiac ultrasound were performed in 3862 resuscitations (178 pediatric). CONCLUSIONS: Emergency medicine faculty physicians at a combined Level I adult and pediatric trauma center performed and/or supervised 4.4 total (0.15 pediatric) critical procedures per month per faculty which is nearly 6 times more critical procedures monthly than faculty at a similar volume pediatric-only trauma center. However, fewer critical procedures were performed on children at the combined facility.

Effect of Out-of-Hospital Tranexamic Acid vs Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury.

Importance: Traumatic brain injury (TBI) is the leading cause of death and disability due to trauma. Early administration of tranexamic acid may benefit patients with TBI. Objective: To determine whether tranexamic acid treatment initiated in the out-of-hospital setting within 2 hours of injury improves neurologic outcome in patients with moderate or severe TBI. Design, Setting, and Participants: Multicenter, double-blinded, randomized clinical trial at 20 trauma centers and 39 emergency medical services agencies in the US and Canada from May 2015 to November 2017. Eligible participants (N = 1280) included out-of-hospital patients with TBI aged 15 years or older with Glasgow Coma Scale score of 12 or less and systolic blood pressure of 90 mm Hg or higher. Interventions: Three interventions were evaluated, with treatment initiated within 2 hours of TBI: out-of-hospital tranexamic acid (1 g) bolus and in-hospital tranexamic acid (1 g) 8-hour infusion (bolus maintenance group; n = 312), out-of-hospital tranexamic acid (2 g) bolus and in-hospital placebo 8-hour infusion (bolus only group; n = 345), and out-of-hospital placebo bolus and in-hospital placebo 8-hour infusion (placebo group; n = 309). Main Outcomes and Measures: The primary outcome was favorable neurologic function at 6 months (Glasgow Outcome Scale-Extended score >4 [moderate disability or good recovery]) in the combined tranexamic acid group vs the placebo group. Asymmetric significance thresholds were set at 0.1 for benefit and 0.025 for harm. There were 18 secondary end points, of which 5 are reported in this article: 28-day mortality, 6-month Disability Rating Scale score (range, 0 [no disability] to 30 [death]), progression of intracranial hemorrhage, incidence of seizures, and incidence of thromboembolic events. Results: Among 1063 participants, a study drug was not administered to 96 randomized participants and 1 participant was excluded, resulting in 966 participants in the analysis population (mean age, 42 years; 255 [74%] male participants; mean Glasgow Coma Scale score, 8). Of these participants, 819 (84.8%) were available for primary outcome analysis at 6-month follow-up. The primary outcome occurred in 65% of patients in the tranexamic acid groups vs 62% in the placebo group (difference, 3.5%; [90% 1-sided confidence limit for benefit, -0.9%]; P = .16; [97.5% 1-sided confidence limit for harm, 10.2%]; P = .84). There was no statistically significant difference in 28-day mortality between the tranexamic acid groups vs the placebo group (14% vs 17%; difference, -2.9% [95% CI, -7.9% to 2.1%]; P = .26), 6-month Disability Rating Scale score (6.8 vs 7.6; difference, -0.9 [95% CI, -2.5 to 0.7]; P = .29), or progression of intracranial hemorrhage (16% vs 20%; difference, -5.4% [95% CI, -12.8% to 2.1%]; P = .16). Conclusions and Relevance: Among patients with moderate to severe TBI, out-of-hospital tranexamic acid administration within 2 hours of injury compared with placebo did not significantly improve 6-month neurologic outcome as measured by the Glasgow Outcome Scale-Extended. Trial Registration: ClinicalTrials.gov Identifier: NCT01990768.

Novel method to collect medication adverse events in juvenile arthritis: results from the childhood arthritis and rheumatology research alliance enhanced drug safety surveillance project.

OBJECTIVE: Few data are available regarding the rates of serious adverse events (SAEs) and important medical events (IMEs) outside of product-based registries and clinical trials for juvenile idiopathic arthritis (JIA). The Enhanced Drug Safety Surveillance Project (EDSSP) was developed to pilot a novel system to collect SAEs/IMEs in children with JIA. This analysis reports the results from this 4-year (2008-2012) EDSSP. METHODS: Participating physicians were surveyed monthly to ascertain whether their JIA patients experienced an SAE or IME. Sites were surveyed every 6 months to determine the number of unique JIA patients seen at each site during that 6-month period. Reporting rates were calculated per 100 person-years and 95% confidence intervals (95% CIs) were calculated based on a Poisson distribution. RESULTS: Thirty-seven Childhood Arthritis and Rheumatology Research Alliance sites with 115 physicians participated. The mean response rate to the monthly surveys was 65%. There were 147 total SAEs and 145 total IMEs. The largest proportion of SAEs and IMEs occurred in children with polyarticular JIA (39% and 37%, respectively). The majority of SAEs and IMEs were reported for patients receiving therapy with biologic agents (76% and 69%, respectively). The total event rate for SAEs and IMEs combined was 1.07 events per 100 person-years (95% CI 0.95-1.19). The rates for SAEs and IMEs were 0.54 per 100 person-years (95% CI 0.45-0.63) and 0.53 per 100 person-years (95% CI 0.49-0.62), respectively. CONCLUSION: The EDSSP provided a simple tool for SAE/IME reporting within an established research network and resulted in a similar range of reported events as captured by a traditional product-based registry.

Extension study of participants from the trial of early aggressive therapy in juvenile idiopathic arthritis.

OBJECTIVE: To follow children with juvenile idiopathic arthritis (JIA) who had completed at least 6 months of the TRial of Early Aggressive Therapy (TREAT) clinical study for an additional 2 years, describing safety of early aggressive treatment, disease activity, function, and duration of clinical inactive disease (CID) during followup. METHODS: Children were treated as per provider's discretion. Physician, patient/parent, and laboratory measures of disease status as well as safety information were collected at clinic visits every 3 months for up to 2 years. RESULTS: Forty-eight children were followed for a mean of 28 months (range 12-42) beyond the end of the TREAT study. Half of patients were in CID for > 50% of their followup time. Overall, 88% of patients achieved CID at > 1 study visit and 54% achieved clinical remission while taking medication. Six patients were in CID for the duration of the study, and, of those, 2 achieved a full year of clinical remission while not taking medication. Active disease was mild: mean physician's global assessment 2.4, active joint count 3.5, parent global evaluation 2.4, Childhood Health Assessment Questionnaire 0.32, erythrocyte sedimentation rate 19 mm/h, and morning stiffness 23 min. There were no serious adverse events or adverse events reported at grade 3 or higher of Common Terminology Criteria for Adverse Events. CONCLUSION: Early aggressive therapy in this cohort of patients with polyarticular JIA who had high initial disease activity was associated with prolonged periods of CID in the majority of patients during followup. Those not in CID had low levels of disease activity.

Prevalence of narcolepsy in King County, Washington, USA.

BACKGROUND: Relatively few epidemiologic studies have focused on narcolepsy, a disabling sleep disorder with a strong association with HLA-DQB1 *0602. METHODS: We sought to estimate the prevalence of narcolepsy using multiple overlapping techniques to identify residents of King County, WA who were 18 years or older with physician-diagnosed narcolepsy. Patients were entered into a registry and recruited into an epidemiologic study entailing interview and buccal scrapings to determine HLA-DQB1 *0602 status. Missing values were imputed to allow prevalence to be estimated based on all 425 patients entered into the registry between 2001 and 2005, whether they were recruited into the epidemiologic study (n=279) or not (n=146). RESULTS: As of July 01, 2001, estimated prevalence per 100,000 of physician-diagnosed narcolepsy with cataplexy was 21.8 (95% confidence interval (CI): 18.8-24.8), similar to prior studies. The median age of onset was 14 (interquartile range: 10-18). For narcolepsy with HLA-DQB1 *0602, prevalence was 15.3 (95% CI: 12.8-17.9). Estimated prevalence was higher in women than men and in African-Americans than other racial groups. CONCLUSIONS: These differences could reflect problems in identification and recruitment or may provide etiologic clues about narcolepsy. This study illustrates the challenges in performing population-based studies of narcolepsy.

The epidemiology of narcolepsy.

Much has been learned about the pathophysiology of narcolepsy over the last several decades. It is likely that hypocretin-producing cells in the lateral hypothalamus are selectively destroyed in genetically susceptible individuals carrying 1 or more alleles of HLA DQB1*0602. Despite advances, the causes of narcolepsy and how to prevent it remain elusive. Classic epidemiology aims not only to enumerate occurrence of disease in populations, but also to identify etiologic risk factors. This review details what the application of classic epidemiology has taught us so far about narcolepsy and suggests directions for future studies to clarify its etiology. The prevalence of narcolepsy with cataplexy has been examined in many studies and falls between 25 and 50 per 100,000 people. Information on incidence is limited, with 1 study finding the incidence of narcolepsy with cataplexy to be 0.74 per 100,000 person-years. The search for etiologic risk factors has yet to yield important associations. Factors most thoroughly examined include body mass index, immune responses, and stressful life events. Such associations may reflect a consequence rather than a cause of disease. As with other diseases characterized by selective cell loss, such as Parkinson disease or type 1 diabetes mellitus, narcolepsy is likely caused by environmental exposures before the age of onset in genetically susceptible individuals. Matching efforts in these other diseases and using large well-designed epidemiologic studies of narcolepsy, investigators must intensify the search for these exposures, focusing on the first 2 decades of life. Identification of modifiable risk factors will help to prevent this disease.

Ex vivo measures of LDL oxidative susceptibility predict carotid artery disease.

AIM: The purpose of the study was to assess whether ex vivo measures of low-density lipoprotein (LDL) oxidation improved prediction of carotid artery disease (CAAD) case-control status compared to standard lipid and smoking measures. METHODS: One hundred and forty cases with a high degree of carotid artery stenosis aged 40-83 years and an equal number of controls without stenosis or other vascular disease were matched by censored age within 2 years. Matched logistic regression evaluated the significance of copper-induced oxidative measures with and without covariates. The relationship of LDL oxidation measures with statin use and current smoking was also evaluated. RESULTS: Logistic regression demonstrated a significant effect of the three correlated measures of oxidative susceptibility (lag time, oxidation rate and maximal rate of oxidation) separately on disease prediction (all p<0.05). These oxidative measures remained significant predictors of case-control status when other cardiovascular disease predictors (age; LDL-C, HDL-C and ApoAI levels; current smoking, ever smoking and pack-years smoked) were jointly considered. This relationship was not attributable to the effects of statin use on LDL oxidation. CONCLUSIONS: Ex vivo measures of oxidation improved the prediction of carotid artery disease status, suggesting that this is an important determinant of atherosclerotic risk in this older population.

Weight change and the risk of gestational diabetes in obese women.

BACKGROUND: Obesity is an established risk factor for gestational diabetes. It is not known whether this risk might be reduced through weight loss between pregnancies. We sought to determine whether weight loss between pregnancies reduced the risk of gestational diabetes among obese women. METHODS: We conducted a population-based cohort study of 4102 women with 2 or more singleton live births in Washington State between 1992 and 1998. All subjects were nondiabetic and obese (at least 200 lbs) at their first birth during these years. Weight change was calculated as the difference between prepregnancy weight for the 2 pregnancies. We estimated relative risks of gestational diabetes at the subsequent delivery through stratified analyses and Mantel-Haenszel estimates. RESULTS: Thirty-two percent of women lost weight between pregnancies, with a mean weight loss of 23 lbs. Women who lost at least 10 lbs between pregnancies had a decreased risk of gestational diabetes relative to women whose weight changed by less than 10 lbs (relative risk = 0.63; 95% confidence interval = 0.38-1.02, adjusted for age and weight gain during each pregnancy). Of the 61% of women who gained weight between pregnancies, the mean weight gain was 22 lbs. Women who gained at least 10 lbs had an increased risk of gestational diabetes (1.47; 1.05-2.04). CONCLUSIONS: Even moderate changes in prepregnancy weight can apparently affect the risk of gestational diabetes among obese women. This may offer further motivation for interventions aimed at reducing obesity among women of reproductive age.