Strokes Averted by Intravenous Thrombolysis: A Secondary Analysis of a Prospective, Multicenter, Controlled Trial of Mobile Stroke Units.

OBJECTIVE: This study was undertaken to examine averted stroke in optimized stroke systems. METHODS: This secondary analysis of a multicenter trial from 2014 to 2020 compared patients treated by mobile stroke unit (MSU) versus standard management. The analytical cohort consisted of participants with suspected stroke treated with intravenous thrombolysis. The main outcome was a tissue-defined averted stroke, defined as a final diagnosis of stroke with resolution of presenting symptoms/signs by 24 hours attributed to thrombolysis and no acute infarction/hemorrhage on imaging. An additional outcome was stroke with early symptom resolution, defined as a final diagnosis of stroke with resolution of presenting symptoms/signs by 24 hours attributed to thrombolysis. RESULTS: Among 1,009 patients with a median last known well to thrombolysis time of 87 minutes, 159 (16%) had tissue-defined averted stroke and 276 (27%) had stroke with early symptom resolution. Compared with standard management, MSU care was associated with more tissue-defined averted stroke (18% vs 11%, adjusted odds ratio [aOR] = 1.82, 95% confidence interval [CI] = 1.13-2.98) and stroke with early symptom resolution (31% vs 21%, aOR = 1.74, 95% CI = 1.12-2.61). The relationships between thrombolysis treatment time and averted/early recovered stroke appeared nonlinear. Most models indicated increased odds for stroke with early symptom resolution but not tissue-defined averted stroke with earlier treatment. Additionally, younger age, female gender, hyperlipidemia, lower National Institutes of Health Stroke Scale, lower blood pressure, and no large vessel occlusion were associated with both tissue-defined averted stroke and stroke with early symptom resolution. INTERPRETATION: In optimized stroke systems, 1 in 4 patients treated with thrombolysis recovered within 24 hours and 1 in 6 had no demonstrable brain injury on imaging. ANN NEUROL 2024;95:347-361.

Prospective, Multicenter, Controlled Trial of Mobile Stroke Units.

BACKGROUND: Mobile stroke units (MSUs) are ambulances with staff and a computed tomographic scanner that may enable faster treatment with tissue plasminogen activator (t-PA) than standard management by emergency medical services (EMS). Whether and how much MSUs alter outcomes has not been extensively studied. METHODS: In an observational, prospective, multicenter, alternating-week trial, we assessed outcomes from MSU or EMS management within 4.5 hours after onset of acute stroke symptoms. The primary outcome was the score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes according to a patient value system, derived from scores on the modified Rankin scale of 0 to 6, with higher scores indicating more disability). The main analysis involved dichotomized scores on the utility-weighted modified Rankin scale (≥0.91 or <0.91, approximating scores on the modified Rankin scale of ≤1 or >1) at 90 days in patients eligible for t-PA. Analyses were also performed in all enrolled patients. RESULTS: We enrolled 1515 patients, of whom 1047 were eligible to receive t-PA; 617 received care by MSU and 430 by EMS. The median time from onset of stroke to administration of t-PA was 72 minutes in the MSU group and 108 minutes in the EMS group. Of patients eligible for t-PA, 97.1% in the MSU group received t-PA, as compared with 79.5% in the EMS group. The mean score on the utility-weighted modified Rankin scale at 90 days in patients eligible for t-PA was 0.72 in the MSU group and 0.66 in the EMS group (adjusted odds ratio for a score of ≥0.91, 2.43; 95% confidence interval [CI], 1.75 to 3.36; P<0.001). Among the patients eligible for t-PA, 55.0% in the MSU group and 44.4% in the EMS group had a score of 0 or 1 on the modified Rankin scale at 90 days. Among all enrolled patients, the mean score on the utility-weighted modified Rankin scale at discharge was 0.57 in the MSU group and 0.51 in the EMS group (adjusted odds ratio for a score of ≥0.91, 1.82; 95% CI, 1.39 to 2.37; P<0.001). Secondary clinical outcomes generally favored MSUs. Mortality at 90 days was 8.9% in the MSU group and 11.9% in the EMS group. CONCLUSIONS: In patients with acute stroke who were eligible for t-PA, utility-weighted disability outcomes at 90 days were better with MSUs than with EMS. (Funded by the Patient-Centered Outcomes Research Institute; BEST-MSU ClinicalTrials.gov number, NCT02190500.).

Golden Hour Treatment With tPA (Tissue-Type Plasminogen Activator) in the BEST-MSU Study.

BACKGROUND: Treatment of patients with acute ischemic stroke on mobile stroke units (MSUs) improves outcomes compared with management by standard emergency medical services ambulances and is associated with more patients treated with intravenous tPA (tissue-type plasminogen activator) in the first golden hour after last known normal. We explored the predictors and outcomes of first-hour treatment (FHT) compared with later treatment in an alternating-week cluster-controlled trial of MSUs. METHODS: We analyzed all patients treated with intravenous tPA in the BEST-MSU Study (Benefits of Stroke Treatment Delivered by a Mobile Stroke Unit Compared to Standard Management by Emergency Medical Services). After stratifying by treatment timeframe, we identified factors associated with FHT. We performed adjusted analyses of the association between FHT and clinical outcome and modeled the shape of the relationship between last known normal-to-treatment time and excellent outcome. RESULTS: Among 941 tPA-treated patients, 206 (21.8%) had lytic started within 60 minutes. Treatment on the MSU, older age, male sex, alert by 911, faster arrival on-scene and imaging, more severe stroke, atrial fibrillation, and absence of heart failure and pretreatment antihypertensive treatment were associated with FHT. Compared with later treatment, FHT was associated with higher adjusted odds ratio for 90-day modified Rankin Scale score of 0 to 1 (odds ratio, 1.87 [95% CI, 1.25-2.84]; P=0.003). Among FHT patients, 68% achieved a 90-day modified Rankin Scale of 0 or 1 or returned to their baseline status. FHT was not associated with higher risk of hemorrhage and was associated with reduced risk of treating neurovascular mimics. CONCLUSIONS: FHT almost doubles the odds of excellent clinical outcome without increased risk compared with later treatment, which supports the use of MSUs.

Hemorrhage Enlargement Is More Frequent in the First 2 Hours: A Prehospital Mobile Stroke Unit Study.

BACKGROUND: Hematoma enlargement (HE) after intracerebral hemorrhage (ICH) is a therapeutic target for improving outcomes. Hemostatic therapies to prevent HE may be more effective the earlier they are attempted. An understanding of HE in first 1 to 2 hours specifically in the prehospital setting would help guide future treatment interventions in this time frame and setting. METHODS: Patients with spontaneous ICH within 4 hours of symptom onset were prospectively evaluated between May 2014 and April 2020 as a prespecified substudy within a multicenter trial of prehospital mobile stroke unit versus standard management. Baseline computed tomography scans obtained <1, 1 to 2, and 2 to 4 hours postsymptom onset on the mobile stroke unit in the prehospital setting were compared with computed tomography scans repeated 1 hour later and at 24 hours in the hospital. HE was defined as >6 mL if baseline ICH volume was <20 mL and 33% increase if baseline volume >20 mL. The association between time from symptom onset to baseline computed tomography (hours) and HE was investigated using Wilcoxon rank-sum test when time was treated as a continuous variable and using Fisher exact test when time was categorized. Kruskal-Wallis and Wilcoxon rank-sum tests evaluated differences in baseline volumes and HE. Univariable and multivariable logistic regression analyses were conducted to identify factors associated with HE and variable selection was performed using cross-validated L1-regularized (Lasso regression). This study adhered to STROBE guidelines (Strengthening the Reporting of Observational Studies in Epidemiology) for cohort studies. RESULTS: One hundred thirty-nine patients were included. There was no difference between baseline ICH volumes obtained <1 hour (n=43) versus 1 to 2 hour (n=51) versus >2 hours (n=45) from symptom onset (median [interquartile range], 13 mL [6-24] versus 14 mL [6-30] versus 12 mL [4-19]; P=0.65). However, within the same 3 time epochs, initial hematoma growth (volume/time from onset) was greater with earlier baseline scanning (median [interquartile range], 17 mL/hour [9-35] versus 9 mL/hour [5-23]) versus 4 mL/hour [2-7]; P<0.001). Forty-nine patients had repeat scans 1 hour after baseline imaging (median, 2.3 hours [interquartile range. 1.9-3.1] after symptom onset). Eight patients (16%) had HE during that 1-hour interval; all of these occurred in patients with baseline imaging within 2 hours of onset (5/18=28% with baseline imaging within 1 hour, 3/18=17% within 1-2 hour, 0/13=0% >2 hours; P=0.02). HE did not occur between the scans repeated at 1 hour and 24 hours. No association between baseline variables and HE was detected in multivariable analyses. CONCLUSIONS: HE in the next hour occurs in 28% of ICH patients with baseline imaging within the first hour after symptom onset, and in 17% of those with baseline imaging between 1 and 2 hours. These patients would be a target for ultraearly hemostatic intervention.

Machine Learning Automated Detection of Large Vessel Occlusion From Mobile Stroke Unit Computed Tomography Angiography.

BACKGROUND: Prehospital automated large vessel occlusion (LVO) detection in Mobile Stroke Units (MSUs) could accelerate identification and treatment of patients with LVO acute ischemic stroke. Here, we evaluate the performance of a machine learning (ML) model on CT angiograms (CTAs) obtained from 2 MSUs to detect LVO. METHODS: Patients evaluated on MSUs in Houston and Los Angeles with out-of-hospital CTAs were identified. Anterior circulation LVO was defined as an occlusion of the intracranial internal carotid artery, middle cerebral artery (M1 or M2), or anterior cerebral artery vessels and determined by an expert human reader. A ML model to detect LVO was trained and tested on independent data sets consisting of in-hospital CTAs and then tested on MSU CTA images. Model performance was determined using area under the receiver-operator curve statistics. RESULTS: Among 68 patients with out-of-hospital MSU CTAs, 40% had an LVO. The most common occlusion location was the middle cerebral artery M1 segment (59%), followed by the internal carotid artery (30%), and middle cerebral artery M2 (11%). Median time from last known well to CTA imaging was 88.0 (interquartile range, 59.5-196.0) minutes. After training on 870 in-hospital CTAs, the ML model performed well in identifying LVO in a separate in-hospital data set of 441 images with area under receiver-operator curve of 0.84 (95% CI, 0.80-0.87). ML algorithm analysis time was under 1 minute. The performance of the ML model on the MSU CTA images was comparable with area under receiver-operator curve 0.80 (95% CI, 0.71-0.89). There was no significant difference in performance between the Houston and Los Angeles MSU CTA cohorts. CONCLUSIONS: In this study of patients evaluated on MSUs in 2 cities, a ML algorithm was able to accurately and rapidly detect LVO using prehospital CTA acquisitions.

Prevalence and Financial Burden of Digestive Diseases in a Commercially Insured Population.

BACKGROUND & AIMS: Digestive diseases represent a diverse group of clinical conditions that impact the population. Their heterogeneity in classification, presentation, acuity, chronicity, and need for drug therapy presents a challenge when comparing and contrasting the burden associated with these conditions. Prior studies use an outdated classification system and aggregate costs at the population level or focus on specific diseases, limiting the ability to characterize the overall landscape. Our aim was to provide the most up-to-date assessment of cost, utilization, and prevalence associated with digestive diseases. METHODS: We examined digestive disease claims and payment data for a commercially insured adult population between 2016 and 2018 to provide a comprehensive summary of costs, utilization, and prevalence across 38 conditions. Outcome variables included point prevalence and relative prevalence, annualized all-cause medical and drug costs, digestive disease-specific average medical cost, digestive disease-specific cost per fill, and utilization by clinical setting and by clinical condition. RESULTS: A total of 7,297,435 individuals with a digestive disease diagnosis were included in the study. The point prevalence of having a digestive disease in the total population was 24%. Annualized total costs by clinical category ranged from $10,038 (eosinophilic esophagitis) to $107,007 (hepatitis C), with medical costs accounting for most of the expenditures in a majority of conditions. Annualized total costs for common conditions included $39,653 for alcoholic liver disease, $42,554 for acute pancreatitis, $62,735 for Crohn's disease, $13,948 for functional gastrointestinal disorders, $53,214 for nonalcoholic cirrhosis, and $36,441 for ulcerative colitis. Average cost of inpatient stays ranged from $12,218 (noninfectious gastroenteritis/colitis) to $78,259 (nonalcoholic steatohepatitis). Outpatient visits ranged from $784 (gastrointestinal infection) to $4629 (gallbladder and biliary tract disease). Average drug cost per fill ranged from $83 (gastroesophageal reflux disease) to $1458 (hepatitis C). A total of 27,429,046 clinical encounters occurred across all conditions during the study period, with 90% taking place as outpatient visits. Abdominal pain was the single largest contributor to outpatient visits and emergency department to home encounters. Inpatient stays were considerably more heterogeneous, with no condition accounting for more than 12% (gallbladder and biliary tract disease) of the total. CONCLUSIONS: The results demonstrate digestive diseases are common, heterogeneous in cost and utilization, and collectively exact a significant financial burden on the U.S. adult population.

How Frequent is the One-Hour tPA Infusion Interrupted or Delayed?

BACKGROUND AND PURPOSE: Tissue plasminogen activator (tPA) requires a one-hour infusion after the bolus. The frequency of delay or interruption of the tPA infusion may be useful in weighing the advantages of Tenecteplase (TNKase, TNK) which does not require an infusion. METHODS: Utilizing the Benefits of Stroke Treatment Delivered Using a Mobile Stroke Unit Compared to Standard Management by Emergency Medical Services study database, we calculated the frequency and magnitude of tPA infusion delay or interruption. RESULTS: Of 497 patients treated with tPA on the Houston Mobile Stroke Unit (MSU), 41 (8.3%) had delay or interruption of the infusion for reasons that did not reflect a side effect of, or contraindication to, tPA. Nine received less than 90% of their calculated dose (median 62%, range 28-88%), and eleven had more than a 10% prolongation of their infusion (median 19 min, range 7-210 min). Six patients (1.2%) had infusion stopped for a valid concern for tPA side effect or contraindication. CONCLUSIONS: Interruption or discontinuation of the tPA infusion occurs in 8% of patients treated on a MSU providing an opportunity for more complete and faster treatment with TNK.

Retrospectively Collected EQ-5D-5L Data as Valid Proxies for Imputing Missing Information in Longitudinal Studies.

OBJECTIVES: Studies face challenges with missing 5-level EQ-5D (EQ-5D-5L) data, often because of the need for longitudinal EQ-5D-5L data collection. There is a dearth of validated methodologies for dealing with missing EQ-5D-5L data in the literature. This study, for the first time, examined the possibility of using retrospectively collected EQ-5D-5L data as proxies for the missing data. METHODS: Participants who had prospectively completed a 3rd month postdischarge EQ-5D-5L instrument (in-the-moment collection) were randomly interviewed to respond to a 2nd "retrospective collection" of their 3rd month EQ-5D-5L at 6th, 9th, or 12th month after hospital discharge. A longitudinal single imputation was also used to assess the relative performance of retrospective collection compared with the longitudinal single imputation. Concordances between the in-the-moment, retrospective, and imputed measures were assessed using intraclass correlation coefficients and weighted kappa statistics. RESULTS: Considerable agreement was observed on the basis of weighted kappa (range 0.72-0.95) between the mobility, self-care, and usual activities dimensions of EQ-5D-5L collected in-the-moment and retrospectively. Concordance based on intraclass correlation coefficients was good to excellent (range 0.79-0.81) for utility indices computed, and excellent (range 0.93-0.96) for quality-adjusted life-years computed using in-the-moment compared with retrospective EQ-5D-5L. The longitudinal single imputation did not perform as well as the retrospective collection method. CONCLUSIONS: This study demonstrates that retrospective collection of EQ-5D-5L has high concordance with "in-the-moment" EQ-5D-5L and could be a valid and attractive alternative for data imputation when longitudinally collected EQ-5D-5L data are missing. Future studies examining this method for other disease areas and populations are required to provide more generalizable evidence.

Mobile Stroke Unit Computed Tomography Angiography Substantially Shortens Door-to-Puncture Time.

Background and Purpose- Endovascular thrombectomy (ET) door-to-puncture time (DTPT) is a modifiable metric. One of the most important, yet time-consuming steps, is documentation of large vessel occlusion by computed tomography angiography (CTA). We hypothesized that obtaining CTA on board a Mobile Stroke Unit and direct alert of the ET team shortens DTPT by over 30 minutes. Methods- We compared DTPT between patients having CTA onboard the Mobile Stroke Unit then subsequent ET from September 2018 to November 2019 and patients in Mobile Stroke Unit from August 2014 to August 2018, when onboard CTA was not yet being used. We also correlated DTPT with change in National Institutes of Health Stroke Scale between baseline and 24 hours. Results- Median DTPT was 53.5 (95% CI, 35-67) minutes shorter with onboard CTA and direct ET team notification: 41 minutes (interquartile range, 30.0-63.5) versus 94.5 minutes (interquartile range, 69.8-117.3; P<0.001). Median on-scene time was 31.5 minutes (interquartile range, 28.8-35.5) versus 27.0 minutes (interquartile range, 23.0-31.0) (P<0.001). Shorter DTPT correlated with greater improvement of National Institutes of Health Stroke Scale (correlation=-0.2, P=0.07). Conclusions- Prehospital Mobile Stroke Unit management including on-board CTA and ET team alert substantially shortens DTPT. Registration- URL: https://clinicaltrials.gov; Unique identifier: NCT02190500.

Impact of Initial Imaging Protocol on Likelihood of Endovascular Stroke Therapy.

BACKGROUND AND PURPOSE: Noncontrast head CT and CT perfusion (CTP) are both used to screen for endovascular stroke therapy (EST), but the impact of imaging strategy on likelihood of EST is undetermined. Here, we examine the influence of CTP utilization on likelihood of EST in patients with large vessel occlusion (LVO). METHODS: We identified patients with acute ischemic stroke at 4 comprehensive stroke centers. All 4 hospitals had 24/7 CTP and EST capability and were covered by a single physician group (Neurology, NeuroIntervention, NeuroICU). All centers performed noncontrast head CT and CT angiography in the initial evaluation. One center also performed CTP routinely with high CTP utilization (CTP-H), and the others performed CTP optionally with lower utilization (CTP-L). Primary outcome was likelihood of EST. Multivariable logistic regression was used to determine whether facility type (CTP-H versus CTP-L) was associated with EST adjusting for age, prestroke mRS, National Institutes of Health Stroke Scale, Alberta Stroke Program Early CT Score, LVO location, time window, and intravenous tPA (tissue-type plasminogen activator). RESULTS: Among 3107 patients with acute ischemic stroke, 715 had LVO, of which 403 (56%) presented to CTP-H and 312 (44%) presented to CTP-L. CTP utilization among LVO patients was greater at CTP-H centers (72% versus 18%, CTP-H versus CTP-L, P<0.01). In univariable analysis, EST rates for patients with LVO were similar between CTP-H versus CTP-L (46% versus 49%). In multivariable analysis, patients with LVO were less likely to undergo EST at CTP-H (odds ratio, 0.59 [0.41-0.85]). This finding was maintained in multiple patient subsets including late time window, anterior circulation LVO, and direct presentation patients. Ninety-day functional independence (odds ratio, 1.04 [0.70-1.54]) was not different, nor were rates of post-EST PH-2 hemorrhage (1% versus 1%). CONCLUSIONS: We identified an increased likelihood for undergoing EST in centers with lower CTP utilization, which was not associated with worse clinical outcomes or increased hemorrhage. These findings suggest under-treatment bias with routine CTP.

Exome sequencing compared with standard genetic tests for critically ill infants with suspected genetic conditions.

PURPOSE: As exome sequencing (ES) is increasingly used as a diagnostic tool, we aimed to compare ES with status quo genetic diagnostic workup for infants with suspected genetic disorders in terms of identifying diagnoses, survival, and cost of care. METHODS: We studied newborns and infants admitted to intensive care with a suspected genetic etiology within the first year of life at a US quaternary-referral children's hospital over 5 years. In this propensity-matched cohort study using electronic medical record data, we compared patients who received ES as part of a diagnostic workup (ES cohort, n = 368) with clinically similar patients who did not receive ES (No-ES cohort, n = 368). RESULTS: Diagnostic yield (27.4% ES, 25.8% No-ES; p = 0.62) and 1-year survival (80.2% ES, 84.8% No-ES; p = 0.10) were no different between cohorts. ES cohort patients had higher cost of admission, diagnostic investigation, and genetic testing (all p < 0.01). CONCLUSION: ES did not differ from status quo genetic testing collectively in terms of diagnostic yield or patient survival; however, it had high yield as a single test, led to complementary classes of diagnoses, and was associated with higher costs. Further work is needed to define the most efficient use of diagnostic ES for critically ill newborns and infants.

Elicitation of prior probability distributions for a proposed Bayesian randomized clinical trial of whole blood for trauma resuscitation.

BACKGROUND: Whole blood trauma resuscitation is conceptually appealing and increasingly used but lacks evidence. A randomized controlled trial is needed but challenging to design. A Bayesian approach might be more efficient and more interpretable than a conventional frequentist design. We report the results on an elicitation meeting to create prior probability distributions to help develop such a trial. METHODS: In-person expert elicitation meeting, based on Sheffield Elicitation Framework methodology. We used an interactive graphical tool to elicit the quantities of interest (24-hour mortality and certainty required). Two rounds were conducted, with an intervening discussion of deidentified responses. Individual responses were aggregated into probability distributions. RESULTS: Fifteen experts participated. The pooled belief was that the median 24-hour mortality of trauma patients with hemorrhagic shock treated with component therapy (the current standard of care) was 19% (95% credible interval [CrI], 6%-45%), and the median 24-hour mortality of those treated with whole blood, 16% (95% CrI, 5%-39%). The pooled prior distribution for the relative risk had a median of 0.84 (95% CrI, 0.26-3.1), indicating that the expert group had a 64% prior belief that whole blood decreases 24-hour mortality compared to component therapy. CONCLUSIONS: Experts had moderately strong beliefs that whole blood reduces the 24-hour mortality of trauma patients with hemorrhagic shock. These data will assist with the design and planning of a Bayesian trial of whole blood resuscitation, which will help to answer a key question in contemporary transfusion practice.

Retrospective collection of 90-day modified Rankin Scale is accurate.

BACKGROUND: The 90-day modified Rankin Scale is a widely used outcome after stroke but is sometimes hard to ascertain due to loss to follow-up. Missing outcomes can result in biased and/or inefficient estimates in clinical trials. The aim of this study is to assess the validity of acquiring the 90-day modified Rankin Scale at a later point of time when the patient has been lost at 90 days to impute the missing value. METHODS: Participants who had prospectively completed a 90-day modified Rankin Scale questionnaire on their own in the Benefits of Stroke Treatment Using a Mobile Stroke Unit study were randomly interviewed to recall the 90-day modified Rankin Scale at 6, 9, or 12 months after hospital discharge over the phone. Concordance between the two scores was assessed using kappa and weighted kappa statistics. Logistic regression was used to identify factors associated with inconsistent reporting of the 90-day modified Rankin Scale. RESULTS: Substantial agreement was observed between in-the-moment and retrospective 90-day modified Rankin Scale recalled at 6, 9, or 12 months (weighted kappa = 0.93, 95% confidence interval: 0.89-0.98; weighted kappa = 0.93, 95% confidence interval: 0.85-1.00 and weighted kappa = 0.89, 95% confidence interval: 0.82-0.95, respectively). CONCLUSION: Retrospective recall of 90-day modified Rankin Scale at a later time point is a valid means to impute missing data in stroke clinical trials.

Vasopressor treatment and mortality following nontraumatic subarachnoid hemorrhage: a nationwide electronic health record analysis.

OBJECTIVE: Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular condition, not only due to the effect of initial hemorrhage, but also due to the complication of delayed cerebral ischemia (DCI). While hypertension facilitated by vasopressors is often initiated to prevent DCI, which vasopressor is most effective in improving outcomes is not known. The objective of this study was to determine associations between initial vasopressor choice and mortality in patients with nontraumatic SAH. METHODS: The authors conducted a retrospective cohort study using a large, national electronic medical record data set from 2000-2014 to identify patients with a new diagnosis of nontraumatic SAH (based on ICD-9 codes) who were treated with the vasopressors dopamine, phenylephrine, or norepinephrine. The relationship between the initial choice of vasopressor therapy and the primary outcome, which was defined as in-hospital death or discharge to hospice care, was examined. RESULTS: In total, 2634 patients were identified with nontraumatic SAH who were treated with a vasopressor. In this cohort, the average age was 56.5 years, 63.9% were female, and 36.5% of patients developed the primary outcome. The incidence of the primary outcome was higher in those initially treated with either norepinephrine (47.6%) or dopamine (50.6%) than with phenylephrine (24.5%). After adjusting for possible confounders using propensity score methods, the adjusted OR of the primary outcome was higher with dopamine (OR 2.19, 95% CI 1.70-2.81) and norepinephrine (OR 2.24, 95% CI 1.80-2.80) compared with phenylephrine. Sensitivity analyses using different variable selection procedures, causal inference models, and machine-learning methods confirmed the main findings. CONCLUSIONS: In patients with nontraumatic SAH, phenylephrine was significantly associated with reduced mortality in SAH patients compared to dopamine or norepinephrine. Prospective randomized clinical studies are warranted to confirm this finding.

Enhanced dispatch and rendezvous doubles the catchment area and number of patients treated on a mobile stroke unit.

INTRODUCTION: Mobile Stroke Units (MSUs) deliver acute stroke treatment on-scene in coordination with Emergency Medical Services (EMS). One criticism of the MSU approach is the limited range of a single MSU. The Houston MSU is evaluating MSU implementation, and we developed a rendezvous approach as an innovative solution to expand the range and number of patients treated. METHODS: In addition to direct 911 dispatch of our MSU to the scene within our 7-mile catchment area, we empowered more distant EMS units to activate the MSU. We also monitored EMS radio communications to identify possible patients. For these distant patients, the MSU met the EMS unit en route to the stroke center and treated the patient at that intermediate location. The distribution of the distance from MSU base station to site of stroke and time from 911 alert to tissue plasminogen activator (tPA) bolus were compared between patients treated on-scene and by rendezvous using Wilcoxon rank sum test. RESULTS: Over 4 years, 338 acute ischemic stroke patients were treated with tPA on our MSU. Of these, 169 (50%) were treated on-scene after MSU dispatch at a median of 6.4 miles (IQR 6.4 miles) from MSU base station. 169 (50%) were treated by 'rendezvous' pathway with assessment and treatment of stroke a median of 12.4 miles from base (IQR 5.5 miles) (p< 0.0001). Time (min) from MSU alert to tPA bolus did not differ: 36.0 ± 10.0 for on-scene vs 37.0 ± 10.0 with rendezvous (p=0.65). 13% of patients alerted via direct 911 dispatch were treated vs 44% of rendezvous patients. CONCLUSION: Adding a rendezvous approach to an MSU dispatch pathway doubles the range of operations and the number of patients treated by an MSU in an urban area, without incurring delay.

Emergency Department Door-to-Puncture Time Since 2014.

Background and Purpose- The impact of a mobile stroke unit (MSU) on access to intraarterial thrombectomy (IAT) is a prespecified BEST-MSU substudy (Benefits of Stroke Treatment Delivered Using a Mobile Stroke Unit Compared to Standard Management by Emergency Medical Services). On the MSU, IAT decision-making steps, such as computed tomography, neurological exam, and tPA (tissue-type plasminogen activator) treatment are completed before emergency department arrival. We hypothesized that such pre-ED assessment of potential IAT patients on an MSU improves the time from ED arrival to skin puncture time (door-to-puncture-time, DTPT). Methods- BEST-MSU is a prospective comparative effectiveness study of MSU versus standard management by emergency medical services (EMS). We compared ED DTPT among the following groups of MSU and EMS patients: all IAT patients, IAT patients post-tPA, and IAT patients post-tPA meeting thrombolytic adjudication criteria over the first 4 years of the study. Results- From August 2014 to July 2018, a total of 161 patients underwent IAT. Ninety-four patients presented to the ED via the MSU and 67 by EMS. One hundred forty patients received tPA before IAT, 85 in the MSU arm, and 55 in the EMS arm. One hundred twenty-six patients received tPA within thrombolytic adjudication criteria: 76 MSU and 50 EMS. DTPT in minutes was shorter for MSU patients (all IAT MSU versus EMS 89 versus 99, P=0.01; IAT post-tPA MSU versus EMS 93 versus 100, P=0.03; and IAT post-tPA within adjudicated criteria MSU versus EMS 93 versus 99.5, P=0.03). From 2014 to 2018, DTPT decreased at a faster rate for EMS compared with MSU-managed patients, improving by about an hour. Conclusions- Pre-ED IAT evaluation on an MSU results in faster DTPT compared with arrival by EMS. Since 2014, dramatic improvement in ED IAT metrics has attenuated this difference. However, DTPT in all groups indicates substantial room for improvement.

Clinical Application of Genome and Exome Sequencing as a Diagnostic Tool for Pediatric Patients: a Scoping Review of the Literature.

PURPOSE: Availability of clinical genomic sequencing (CGS) has generated questions about the value of genome and exome sequencing as a diagnostic tool. Analysis of reported CGS application can inform uptake and direct further research. This scoping literature review aims to synthesize evidence on the clinical and economic impact of CGS. METHODS: PubMed, Embase, and Cochrane were searched for peer-reviewed articles published between 2009 and 2017 on diagnostic CGS for infant and pediatric patients. Articles were classified according to sample size and whether economic evaluation was a primary research objective. Data on patient characteristics, clinical setting, and outcomes were extracted and narratively synthesized. RESULTS: Of 171 included articles, 131 were case reports, 40 were aggregate analyses, and 4 had a primary economic evaluation aim. Diagnostic yield was the only consistently reported outcome. Median diagnostic yield in aggregate analyses was 33.2% but varied by broad clinical categories and test type. CONCLUSION: Reported CGS use has rapidly increased and spans diverse clinical settings and patient phenotypes. Economic evaluations support the cost-saving potential of diagnostic CGS. Multidisciplinary implementation research, including more robust outcome measurement and economic evaluation, is needed to demonstrate clinical utility and cost-effectiveness of CGS.

Characterizing red blood cell age exposure in massive transfusion therapy: the scalar age of blood index (SBI).

BACKGROUND: The mortality of trauma patients requiring massive transfusion to treat hemorrhagic shock approaches 17% at 24 hours and 26% at 30 days. The use of stored RBCs is limited to less than 42 days, so older RBCs are delivered first to rapidly bleeding trauma patients. Patients who receive a greater quantity of older RBCs may have a higher risk for mortality. METHODS AND MATERIALS: Characterizing blood age exposure requires accounting for the age of each RBC unit and the quantity of transfused units. To address this challenge, a novel Scalar Age of Blood Index (SBI) that represents the relative distribution of RBCs received is introduced and applied to a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized controlled trial (NCT01545232, https://clinicaltrials.gov/ct2/show/NCT01545232). The effect of the SBI is assessed on the primary PROPPR outcome, 24-hour and 30-day mortality. RESULTS: The distributions of blood storage ages successfully maps to a parameter (SBI) that fully defines the blood age curve for each patient. SBI was a significant predictor of 24-hour and 30-day mortality in an adjusted model that had strong predictive ability (odds ratio, 1.15 [1.01-1.29], p = 0.029, C-statistic, 0.81; odds ratio, 1.14 [1.02-1.28], p = 0.019, C-statistic, 0.88, respectively). CONCLUSION: SBI is a simple scalar metric of blood age that accounts for the relative distribution of RBCs among age categories. Transfusion of older RBCs is associated with 24-hour and 30-day mortality, after adjustment for total units and clinical covariates.

Adaptive group-sequential design with population enrichment in phase 3 randomized controlled trials with two binary co-primary endpoints.

The use of co-primary endpoints in drug development allows investigators to capture an experimental intervention's multidimensional effect more comprehensively than a single primary endpoint. We propose the theoretical basis and development of an adaptive population enrichment design with co-primary endpoints, provide stage-wise boundary values for futility and efficacy, and discuss power under different efficacy configurations, subgroup prevalence, and analysis times using a pre-specified decision criterion. We considered a two-arm, two-stage, parallel group design where population enrichment occurs at the interim analysis by dropping any non-responsive subgroups. A test for efficacy is conducted only in the enriched population. Two binary endpoints are evaluated as co-primary endpoints. Our trial objective is to determine whether the experimental intervention is superior to the control intervention, with superiority required in both endpoints. We define the stopping boundary using alpha spending functions. Using a 0.025 significance level for each endpoint, we obtain the stage I threshold boundary values for futility and efficacy as -0.1040 and 2.2761, respectively, and the stage II boundary value for futility and efficacy is 2.2419. We show that in the presence of substantial heterogeneity of treatment effect, we gain more power to observe an effect in the subgroup where the benefits are greater. By allowing the dropping of non-responsive subgroups at an early stage, our design reduces the likelihood of obtaining false-negative results due to inclusion of the heterogeneous treatment effects of both subgroups, which would dilute the responsive subgroup's results.