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Studies that investigate the performance of prognostic and predictive biomarkers are commonplace in medicine. Evaluating the performance of biomarkers is challenging in traumatic brain injury (TBI) and other conditions when both the time factor (i.e. time from injury to biomarker measurement) and different levels or doses of treatments are in play. Such factors need to be accounted for when assessing the biomarker’s performance in relation to a clinical outcome. The Hyperbaric Oxygen in Brain Injury Treatment (HOBIT) trial, a phase II randomized control clinical trial seeks to determine the dose of hyperbaric oxygen therapy (HBOT) for treating severe TBI that has the highest likelihood of demonstrating efficacy in a phase III trial. Hyperbaric Oxygen in Brain Injury Treatment will study up to 200 participants with severe TBI. This paper discusses the statistical approaches to assess the prognostic and predictive performance of the biomarkers studied in this trial, where prognosis refers to the association between a biomarker and the clinical outcome while the predictiveness refers to the ability of the biomarker to identify patient subgroups that benefit from therapy. Analyses based on initial biomarker levels accounting for different levels of HBOT and other baseline clinical characteristics, and analyses of longitudinal changes in biomarker levels are discussed from a statistical point of view. Methods for combining biomarkers that are of complementary nature are also considered and the relevant algorithms are illustrated in detail along with an extensive simulation study that assesses the performance of the statistical methods. Even though the discussed approaches are motivated by the HOBIT trial, their applications are broader. They can be applied in studies assessing the predictiveness and prognostic ability of biomarkers in relation to a well-defined therapeutic intervention and clinical outcome.

We describe a subset of patients with toxin-related precipitants of seizures/status epilepticus enrolled in the Established Status Epilepticus Treatment Trial (ESETT).The ESETT was a prospective, double-blinded, adaptive trial evaluating levetiracetam, valproate, and fosphenytoin as second-line agents in benzodiazepine-refractory status epilepticus in adults and children. The primary outcome was the absence of seizures and improvement in the level of consciousness 1 hour after study drug administration. In this post hoc analysis, the safety and efficacy of second-line agents in a subset of patients with toxin-related seizures are described.A total of 249 adults and 229 children were enrolled in the ESETT. Toxin-related seizures occurred in 29 (11.6%) adults and 1 child (0.4%). In adults, men were more likely to have toxin-related seizures than women (25 of 145, 17.2% versus 4 of 104, 3.9%). The most common toxin-related precipitants were alcohol withdrawal and cocaine, 11(37%) of 30 patients each. Cocaine was used with other substances by most patients 10 (91%) of 11, most commonly with an opioid 7 (64%) of 11. For alcohol withdrawal-related seizures, treatment successes with levetiracetam, valproate, and fosphenytoin were 3 (100%) of 3, 3 (50%) of 6, and 1 (50%) of 2, respectively. For cocaine-related seizures, treatment success was 1 (14%) of 7 for levetiracetam, 0 (0%) of 1 for valproate, and 1 (33%) of 3 for fosphenytoin. One patient who used cocaine and an opioid received fosphenytoin and developed life-threatening hypotension.In the ESETT, approximately 1 in 10 adult patients with status epilepticus presented with a toxin-related seizure. Alcohol withdrawal and cocaine/opioid use were the most common toxin-related precipitants. Toxin-related benzodiazepine-refractory status epilepticus was successfully treated with a single dose of second-line antiseizure medication in 42% of the patients.

Introduction This project aimed to retrospectively obtain, review, and extract key safety data from medical records of participants enrolled in RAMPART, the NIH-supported Rapid Anticonvulsant Medication Prior to ARrival Trial of intramuscular midazolam versus intravenous lorazepam for pre-hospital treatment of status epilepticus, to support a US new drug application (NDA) for intramuscular midazolam. Methods A collaborative partnership was established between the NDA sponsor, the RAMPART trial lead academic institution, US government agencies, and contract research organizations to retrieve, review, and extract relevant safety data from the medical records of RAMPART participants and summarize those data to include in an NDA submitted to the US Food and Drug Administration (FDA). Results Key data in the medical records of 890 RAMPART trial participants (1020 enrollments, including 130 repeat enrollments) were reviewed and extracted into a project database. Safety events occurred in 771 (86.6%) participants, and included additional information not collected in the RAMPART trial. This database also enabled subgroup analyses based on medical history and prior/concurrent medications, building upon previous analyses according to age, sex, and race. No previously unrecognized safety patterns were identified, and no association was observed between efficacy and medical history or medication usage. Conclusions The use of unstructured real-world retrospective medical record data can effectively support an NDA submission in place of conducting another interventional clinical trial. This retrospective medical records review and extraction of additional safety data contributed to the FDA approval of intramuscular midazolam for the pre-hospital treatment of status epilepticus in 2018. ClinicalTrials.gov NCT00809146.

Background/Aims Fibrinolytic therapy with tenecteplase has been proposed for patients with pulmonary embolism but the optimal dose is unknown. Higher-than-necessary dosing is likely to cause excess bleeding. We designed an adaptive clinical trial to identify the minimum and assumed safest dose of tenecteplase that maintains efficacy. Methods We propose a Bayesian adaptive, placebo-controlled, group-sequential dose-finding trial using response-adaptive randomization to preferentially allocate subjects to the most promising doses, dual analyses strategies (continuous and dichotomized) using a gatekeeping approach to maximize clinical impact, and interim stopping rules to efficiently address competing trial objectives. The operating characteristics of the proposed design were evaluated using Monte Carlo simulation across multiple hypothetical efficacy scenarios. Results Simulation demonstrated response-adaptive randomization can preferentially allocate subjects to doses which appear to be performing well based on interim data. Interim decision-making, including the interim evaluation of both analysis strategies with gatekeeping, allows the trial to continue enrollment when success with the dichotomized analysis strategy appears sufficiently likely and to stop enrollment and declare superiority based on the continuous analysis strategy when there is little chance of ultimately declaring superiority with the dichotomized analysis. Conclusion The proposed design allows evaluation of a greater number of dose levels than would be possible with a non-adaptive design and avoids the need to choose either the continuous or the dichotomized analysis strategy for the primary endpoint.

Early treatment of moderate/severe traumatic brain injury (TBI) with progesterone does not improve clinical outcomes. This is in contrast with findings from pre-clinical studies of progesterone in TBI. To understand the reasons for the negative clinical trial, we investigated whether progesterone treatment has the desired biological effect of decreasing brain cell death. We quantified brain cell death using serum levels of biomarkers of glial and neuronal cell death (glial fibrillary acidic protein [GFAP], ubiquitin carboxy-terminal hydrolase-L1 [UCH-L1], S100 calcium-binding protein B [S100B], and Alpha II Spectrin Breakdown Product 150 [SBDP]) in the Biomarkers of Injury and Outcome–Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (BIO-ProTECT) study. Serum levels of GFAP, UCHL1, S100B, and SBDP were measured at baseline (≤4 h post-injury and before administration of study drug) and at 24 and 48 h post-injury. Serum progesterone levels were measured at 24 and 48 h post-injury. The primary outcome of ProTECT was based on the Glasgow Outcome Scale-Extended assessed at 6 months post-randomization. We found that at baseline, there were no differences in biomarker levels between subjects randomized to progesterone treatment and those randomized to placebo (p > 0.10). Similarly, at 24 and 48 h post-injury, there were no differences in biomarker levels in the progesterone versus placebo groups (p > 0.15). There was no statistically significant correlation between serum progesterone concentrations and biomarker values obtained at 24 and 48 h. When examined as a continuous variable, baseline biomarker levels did not modify the association between progesterone treatment and neurological outcome (p of interaction term >0.39 for all biomarkers). We conclude that progesterone treatment does not decrease levels of biomarkers of glial and neuronal cell death during the first 48 h post-injury.

Study objective Outcomes of extracorporeal cardiopulmonary resuscitation (ECPR) for out-of-hospital cardiac arrest depend on time to therapy initiation. We hypothesize that it would be feasible to select refractory out-of-hospital cardiac arrest patients for expedited transport based on real-time estimates of the 911 call to the emergency department (ED) arrival interval, and for emergency physicians to rapidly initiate ECPR in eligible patients. Methods In a 2-tiered emergency medical service with an ECPR-capable primary destination hospital, adults with refractory shockable or witnessed out-of-hospital cardiac arrest were randomized 4:1 to expedited transport or standard care if the predicted 911 call to ED arrival interval was less than or equal to 30 minutes. The primary outcomes were the proportion of subjects with 911 call to ED arrival less than or equal to 30 minutes and ED arrival to ECPR flow less than or equal to 30 minutes. Results Of 151 out-of-hospital cardiac arrest 911 calls, 15 subjects (10%) were enrolled. Five of 12 subjects randomized to expedited transport had an ED arrival time of less than or equal to 30 minutes (overall mean 32.5 minutes [SD 7.1]), and 5 were eligible for and treated with ECPR. Three of 5 ECPR-treated subjects had flow initiated in less than or equal to 30 minutes of ED arrival (overall mean 32.4 minutes [SD 10.9]). No subject in either group survived with a good neurologic outcome. Conclusion The Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest trial did not meet predefined feasibility outcomes for selecting out-of-hospital cardiac arrest patients for expedited transport and initiating ECPR in the ED. Additional research is needed to improve the accuracy of predicting the 911 call to ED arrival interval, optimize patient selection, and reduce the ED arrival to ECPR flow interval.

ObjectiveTo investigate whether receiving a second-line anticonvulsant medication that is part of a patient's home regimen influences outcomes in benzodiazepine-refractory convulsive status epilepticus.MethodsUsing the Established Status Epilepticus Treatment Trial data, allocation to a study drug included in the patient's home anticonvulsant medication regimen was compared to receipt of an alternative second-line study medication. The primary outcome was cessation of clinical seizures with improved consciousness by 60 minutes after study drug initiation. Secondary outcomes were seizure cessation adjudicated from medical records and adverse events. We performed inverse probability of treatment-weighted (IPTW) logistic regressions.ResultsOf 462 patients, 232 (50%) were taking 1–2 of the 3 study medications at home. The primary outcome was observed in 39/89 (44%) patients allocated to their home medication vs 76/143 (53%) allocated to a nonhome medication (IPTW odds ratio [OR] 0.66, 95% confidence interval [CI] 0.39–1.14). The adjudicated outcome occurred in 37/89 (42%) patients vs 82/143 (57%), respectively (IPTW OR 0.52, 95% CI 0.30–0.89). There was no interaction between study levetiracetam and home levetiracetam and there were no differences in adverse events.ConclusionThere was no difference in the primary outcome for patients who received a home medication vs nonhome medication. However, the retrospective evaluation suggested an association between receiving a nonhome medication and seizure cessation.Classification of EvidenceThis study provides Class II evidence that for patients with refractory convulsive status epilepticus, use of a home second-line anticonvulsant compared to a nonhome anticonvulsant did not significantly affect the probability of stopping seizures.

Estimating early exposure of drugs used for the treatment of emergent conditions is challenging because blood sampling to measure concentrations is difficult. The objective of this work was to evaluate predictive performance of two early concentrations and prior pharmacokinetic (PK) information for estimating early exposure. The performance of a modeling approach was compared with a noncompartmental analysis (NCA). A simulation study was performed using literature‐based models for phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA). These models were used to simulate rich concentration‐time profiles from 0 to 2 h. Profiles without residual unexplained variability (RUV) were used to obtain the true partial area under the curve (pAUC) until 2 h after the start of drug infusion. From the profiles with the RUV, two concentrations per patient were randomly selected. These concentrations were analyzed under a population model to obtain individual population PK (PopPK) pAUCs. The NCA pAUCs were calculated using a linear trapezoidal rule. Percent prediction errors (PPEs) for the PopPK pAUCs and NCA pAUCs were calculated. A PPE within ±20% of the true value was considered a success and the number of successes was obtained for 100 simulated datasets. For PHT, LEV, and VPA, respectively, the median value of the success statistics obtained using the PopPK approach of 81%, 92%, and 88% were significantly higher than the 72%, 80%, and 67% using the NCA approach (p

We present the rationale for testing ketamine as an add-on therapy for treating benzodiazepine refractory (established) status epilepticus. In animal studies, ketamine terminates benzodiazepine refractory status epilepticus by interfering with the pathophysiological mechanisms and is a neuroprotectant. Ketamine does not suppress respiration when used for sedation and anesthesia. A Series of reports suggest that ketamine can help terminate refractory and super refractory status epilepticus. We propose to use 1 or 3 mg/Kg ketamine intravenously based on animal-to-human conversion and pharmacokinetic studies. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.

Lessons learned from the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) and Established Status Epilepticus Treatment Trial (ESETT) trials are considered in three ways. First, by asking about the questions the trials were primarily designed to answer, then about the context of the intervention and characteristics of the patients described in secondary analyses, and finally, about what was learned about how to conduct trials in this space. The talk concludes with suggestions and a vision for how to best conduct future trials investigating status epilepticus. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.

Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses particularly in young children. The Established Status Epilepticus Treatment Trial (ESETT), a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients ≥ 2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomized to FOS, LEV or VPA infused over 10 minutes. A sparse blood sampling approach was used, with up to two samples collected per patient within two hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5, 6.5) years were enrolled. The total plasma concentrations ranged from 69-151.3 μg/mL for LEV, 11.3-26.7 μg/mL for PHT and 126-223 μg/mL for VPA. Free fraction ranged from 4-19% for PHT and 17-51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition. This article is protected by copyright. All rights reserved.

Background Early administration of convalescent plasma obtained from blood donors who have recovered from coronavirus disease 2019 (Covid-19) may prevent disease progression in acutely ill, high-risk patients with Covid-19. Methods In this randomized, multicenter, single-blind trial, we assigned patients who were being treated in an emergency department for Covid-19 symptoms to receive either one unit of convalescent plasma with a high titer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or placebo. All the patients were either 50 years of age or older or had one or more risk factors for disease progression. In addition, all the patients presented to the emergency department within 7 days after symptom onset and were in stable condition for outpatient management. The primary outcome was disease progression within 15 days after randomization, which was a composite of hospital admission for any reason, seeking emergency or urgent care, or death without hospitalization. Secondary outcomes included the worst severity of illness on an 8-category ordinal scale, hospital-free days within 30 days after randomization, and death from any cause. Results A total of 511 patients were enrolled in the trial (257 in the convalescent-plasma group and 254 in the placebo group). The median age of the patients was 54 years; the median symptom duration was 4 days. In the donor plasma samples, the median titer of SARS-CoV-2 neutralizing antibodies was 1:641. Disease progression occurred in 77 patients (30.0%) in the convalescent-plasma group and in 81 patients (31.9%) in the placebo group (risk difference, 1.9 percentage points; 95% credible interval, −6.0 to 9.8; posterior probability of superiority of convalescent plasma, 0.68). Five patients in the plasma group and 1 patient in the placebo group died. Outcomes regarding worst illness severity and hospital-free days were similar in the two groups. Conclusions The administration of Covid-19 convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of Covid-19 did not prevent disease progression. (SIREN-C3PO ClinicalTrials.gov number, NCT04355767.)

New onset motor seizures, especially generalized convulsive seizures, are common but frightening to patients and bystanders, and typically result in evaluation in the emergency department (ED). Emergency physicians are challenged to confirm whether the event precipitating the visit was indeed a seizure rather than a mimic such as stroke, syncope, non-epileptic spell, or migraine. When a true seizure is suspected, the next step is to identify a precipitating cause.

Rapid risk-stratification of patients with acute traumatic brain injury (TBI) would inform management decisions and prognostication. The objective of this serum biomarker study (Biomarkers of Injury and Outcome [BIO]-Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment [ProTECT]) was to test the hypothesis that serum biomarkers of structural brain injury, measured at a single, very early time-point, add value beyond relevant clinical covariates when predicting unfavorable outcome 6 months after moderate-to-severe acute TBI. BIO-ProTECT utilized prospectively collected samples obtained from subjects with moderate-to-severe TBI enrolled in the ProTECT III clinical trial of progesterone. Serum samples were obtained within 4 h after injury. Glial fibrillary acidic protein (GFAP), S100B, αII-spectrin breakdown product of molecular weight 150 (SBDP150), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) were measured. The association between log-transformed biomarker levels and poor outcome, defined by a Glasgow Outcome Scale-Extended (GOS-E) score of 1–4 at 6 months post-injury, were estimated via logistic regression. Prognostic models and a biomarker risk score were developed using bootstrapping techniques. Of 882 ProTECT III subjects, samples were available for 566. Each biomarker was associated with 6-month GOS-E (p

Benzodiazepines, including diazepam (DZP), lorazepam (LZP), and midazolam (MDZ), are considered the initial drugs of choice for status epilepticus (SE) treatment. A number of trials have demonstrated their safety and efficacy; however, the failure rate ranges from 10‐55%.1,2 This may be attributable, in part, to sub‐optimal benzodiazepine dosing and timing of administration.\ud \ud The Neurocritical Care Society (NCS) and American Epilepsy Society (AES) have published evidence‐based guidelines for benzodiazepine use in SE that specify drugs, doses, and routes of administration.

BACKGROUND: Exception from informed consent (EFIC) regulations for research in emergency settings contain unique requirements for community consultation and public disclosure. These requirements address ethical challenges intrinsic to this research context. Multiple approaches have evolved to accomplish these activities that may reflect and advance different aims. This scoping review was designed to identify areas of consensus and lingering uncertainty in the literature. METHODS: Scoping review methodology was used. Conceptual and empirical literature related to community consultation and public disclosure for EFIC research was included and identified through a structured search using Embase, HEIN Online, PubMed, and Web of Science. Data were extracted using a standardized tool with domains for major literature categories. RESULTS: Among 84 manuscripts, major domains included conceptual or policy issues, reports of community consultation processes and results, and reports of public disclosure processes and results. Areas of consensus related to community consultation included the need for a two-way exchange of information and use of multiple methods. Public acceptance of personal EFIC enrollment is commonly 64% to 85%. There is less consensus regarding how to assess attitudes, what “communities” to prioritize, and how to determine adequacy for individual projects. Core goals of public disclosure are less well developed; no metrics exist for assessing adequacy. CONCLUSIONS: Multiple methods are used to meet community consultation and public disclosure requirements. There remain no settled norms for assessing adequacy of public disclosure, and there is lingering debate about needed breadth and depth of community consultation.

Objective\ud This study was undertaken to describe patterns of benzodiazepine use as first‐line treatment of status epilepticus (SE) and test the association of benzodiazepine doses with response to second‐line agents in patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT).\ud \ud Methods\ud Patients refractory to an adequate dose of benzodiazepines for the treatment of SE were enrolled in ESETT. Choice of benzodiazepine, doses given prior to administration of second‐line agent, route of administration, setting, and patient weight were characterized. These were compared with guideline‐recommended dosing. Logistic regression was used to determine the association of the first dose of benzodiazepine and the cumulative benzodiazepine dose with the response to second‐line agent.\ud \ud Results\ud Four hundred sixty patients were administered 1170 doses of benzodiazepines (669 lorazepam, 398 midazolam, 103 diazepam). Lorazepam was most frequently administered intravenously in the emergency department, midazolam intramuscularly or intravenously by the emergency medical services personnel, and diazepam rectally prior to ambulance arrival. The first dose of the first benzodiazepine (N = 460) was lower than guideline recommendations in 76% of midazolam administrations and 81% of lorazepam administrations. Among all administrations, >85% of midazolam and >76% of lorazepam administrations were lower than recommended. Higher first or cumulative benzodiazepine doses were not associated with better outcomes or clinical seizure cessation in response to second‐line medications in these benzodiazepine‐refractory seizures.\ud \ud Significance\ud Benzodiazepines as first‐line treatment of SE, particularly midazolam and lorazepam, are frequently underdosed throughout the United States. This broad and generalizable cohort confirms prior single site reports that underdosing is both pervasive and difficult to remediate. (ESETT ClinicalTrials.gov identifier: NCT01960075.)

Purpose It is unknown how often and how early EEG is obtained in patients presenting with status epilepticus. The Established Status Epilepticus Treatment Trial enrolled patients with benzodiazepine-refractory seizures and randomized participants to fosphenytoin, levetiracetam, or valproate. The use of early EEG, including frequency of electrographic seizures, was determined in Established Status Epilepticus Treatment Trial participants. Methods Secondary analysis of 475 enrollments at 58 hospitals to determine the frequency of EEG performed within 24 hours of presentation. The EEG type, the prevalence of electrographic seizures, and characteristics associated with obtaining early EEG were recorded. Chi-square and Wilcoxon rank-sum tests were calculated as appropriate for univariate and bivariate comparisons. Odds ratios are reported with 95% confidence intervals. Results A total of 278 of 475 patients (58%) in the Established Status Epilepticus Treatment Trial cohort underwent EEG within 24 hours (median time to EEG: 5 hours [interquartile range: 3-10]). Electrographic seizure prevalence was 14% (95% confidence interval, 10%-19%; 39/278) in the entire cohort and 13% (95% confidence interval, 7%-21%) in the subgroup of patients meeting the primary outcome of the Established Status Epilepticus Treatment Trial (clinical treatment success within 60 minutes of randomization). Among subjects diagnosed with electrographic seizures (39), 15 (38%; 95% confidence interval, 25%-54%) had no clinical correlate on the video EEG recording. Conclusions Electrographic seizures may occur in patients who stop seizing clinically after treatment of convulsive status epilepticus. Clinical correlates might not be present during electrographic seizures. These findings support early initiation of EEG recordings in patients suffering from convulsive status epilepticus, including those with clinical evidence of treatment success.

Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) for out-of-hospital cardiac arrest (OHCA) is promising but is unproven, and outcomes are strongly dependent on time to initiation of therapy. Expedited transport may facilitate opportunities for ECPR in clinical practice and future trials. Hypotheses: We hypothesized that a real-time dispatch-based computer algorithm could select refractory OHCA patients who could be reliably transported to the emergency department (ED) within 30 min of the 911 call, and that Emergency Medicine physicians could initiate ECPR in eligible patients within 30 min of ED arrival. Methods: In a 2-tiered EMS system serving a US city of 100k in 29 square miles with an ECPR capable primary destination hospital, adults with refractory shockable or witnessed OHCA were randomized 4:1 to expedited transport (ET) or standard prehospital care (SC) if the predicted 911 to ED arrival time was Results: Out of 156 cardiac arrest runs, 15 participants (10%) were randomized prior to ending the trial for slow accrual. Five of 12 patients randomized to expedited transport had an ED arrival time of Conclusions: EROCA demonstrated a functional model for selecting patients with refractory OHCA for ET in an ECPR capable system but did not meet predefined time-interval targets. These results provide important insight into the feasibility of ECPR clinical trials and clinical practice based on selected target intervals.

The Glasgow Outcome Scale-Extended (GOS-E), an ordinal scale measuring global outcome, is used commonly as the primary outcome measure in clinical trials of traumatic brain injury. Analysis is often based on a dichotomization and thus has inherent statistical limitations, including loss of information related to the collapse of adjacent categories. A fixed dichotomization defines favorable outcome consistently for all subjects, whereas a sliding dichotomy tailors the definition of favorable outcome according to baseline prognosis/severity. Literature indicates that the sliding dichotomy is more statistically efficient than the fixed dichotomy; however, the sliding dichotomy still collapses categories and therefore discards information. We propose an alternative, a sliding scoring system for the GOS-E, intended to address the limitations of the sliding dichotomy. The score is assigned based on the number of levels between the achieved score and the favorable cut-point. The proposed scoring system reflects the magnitude of change, where change is defined according to each subject's baseline prognosis. Because the score is approximately continuous, statistical methods can rely on the normal distribution, both for analysis and study design. Two examples show the corresponding potential for improved power. A sliding score approach allows for quantification of the magnitude of change while still accounting for prognosis. Scientific advantages include increased power and an intuitive interpretation.

The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75kg. Hence, patients weighing >75kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75kg, ≤ or >90kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75kg and >75kg, respectively. Using univariate analyses, the likelihood of success for those >75kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75kg or ≤90kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings.

Summary Background Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups. Methods In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group ( 65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov , NCT01960075 . Findings Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged 65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41–62) of children, 44% (33–55) of adults, and 37% (19–59) of older adults; with fosphenytoin in 49% (38–61) of children, 46% (34–59) of adults, and 35% (17–59) of older adults; and with valproate in 52% (41–63) of children, 46% (34–58) of adults, and 47% (25–70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group. Interpretation Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus. Funding National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Although informed consent is important in clinical research, questions persist regarding when it is necessary, what it requires, and how it should be obtained. The standard view in research ethics is that the function of informed consent is to respect individual autonomy. However, consent processes are multidimensional and serve other ethical functions as well. These functions deserve particular attention when barriers to consent exist. We argue that consent serves seven ethically important and conceptually distinct functions. The first four functions pertain principally to individual participants: (1) providing transparency; (2) allowing control and authorization; (3) promoting concordance with participants' values; and (4) protecting and promoting welfare interests. Three other functions are systemic or policy focused: (5) promoting trust; (6) satisfying regulatory requirements; and (7) promoting integrity in research. Reframing consent around these functions can guide approaches to consent that are context sensitive and that maximize achievable goals.

OBJECTIVE: Traumatic brain injury (TBI) causes more than 2.5 million emergency department visits, hospitalizations, or deaths annually. Prehospital endotracheal intubation has been associated with poor outcomes in patients with TBI in several retrospective observational studies. We evaluated the relationship between prehospital intubation, functional outcomes, and mortality using high quality data on clinical practice collected prospectively during a randomized multicenter clinical trial. METHODS: ProTECT III was a multicenter randomized, double-blind, placebo-controlled trial of early administration of progesterone in 882 patients with acute moderate to severe nonpenetrating TBI. Patients were excluded if they had an index GCS of 3 and nonreactive pupils, those with withdrawal of life support on arrival, and if they had documented prolonged hypotension and/or hypoxia. Prehospital intubation was performed as per local clinical protocol in each participating EMS system. Models for favorable outcome and mortality included prehospital intubation, method of transport, index GCS, age, race, and ethnicity as independent variables. Significance was set at α = 0.05. Favorable outcome was defined by a stratified dichotomy of the GOS-E scores in which the definition of favorable outcome depended on the severity of the initial injury. RESULTS: Favorable outcome was more frequent in the 349 subjects with prehospital intubation (57.3%) than in the other 533 patients (46.0%, p = 0.003). Mortality was also lower in the prehospital intubation group (13.8% v. 19.5%, p = 0.03). Logistic regression analysis of prehospital intubation and mortality, adjusted for index GCS, showed that odds of dying for those with prehospital intubation were 47% lower than for those that were not intubated (OR = 0.53, 95% CI = 0.36–0.78). 279 patients with prehospital intubation were transported by air. Modeling transport method and mortality, adjusted for index GCS, showed increased odds of dying in those transported by ground compared to those transported by air (OR = 2.10, 95% CI = 1.40–3.15). Decreased odds of dying trended among those with prehospital intubation adjusted for transport method, index GCS score at randomization, age, and race/ethnicity (OR = 0.70, 95% CI = 0.37–1.31). CONCLUSIONS: In this study that excluded moribund patients, prehospital intubation was performed primarily in patients transported by air. Prehospital intubation and air medical transport together were associated with favorable outcomes and lower mortality. Prehospital intubation was not associated with increased morbidity or mortality regardless of transport method or severity of injury.

A Phase III, double-blind, placebo-controlled trial (ProTECT III) found that administration of progesterone did not reduce mortality or improve functional outcome as measured by the Glasgow Outcome Scale Extended (GOSE) in subjects with moderate to severe traumatic brain injury. We conducted a secondary analysis of neuropsychological outcomes to evaluate whether progesterone is associated with improved recovery of cognitive and motor functioning. ProTECT III was conducted at 49 level I trauma centers in the United States. Adults with moderate to severe TBI were randomized to receive intravenous progesterone or placebo within 4 h of injury for a total of 4 days. At 6 months, subjects underwent evaluation of memory, attention, executive functioning, language, and fine motor coordination/dexterity. Chi-square analysis revealed no significant difference in the proportion of subjects (263/280 progesterone, 283/295 placebo) with Galveston Orientation and Amnesia Test scores ≥75. Analyses of covariance did not reveal significant treatment effects for memory (Buschke immediate recall, p = 0.53; delayed recall, p = 0.94), attention (Trails A speed, p = 0.81 and errors, p = 0.22; Digit Span Forward length, p = 0.66), executive functioning (Trails B speed, p = 0.97 and errors, p = 0.93; Digit Span Backward length, p = 0.60), language (timed phonemic fluency, p = 0.05), and fine motor coordination/dexterity (Grooved Pegboard dominant hand time, p = 0.75 and peg drops, p = 0.59; nondominant hand time, p = 0.74 and peg drops, p = 0.61). Pearson Product Moment Correlations demonstrated significant (p

Background\ud The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied.\ud \ud Methods\ud In a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous anticonvulsive agents — levetiracetam, fosphenytoin, and valproate — in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death.\ud \ud Results\ud A total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant.\ud \ud Conclusions\ud In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075. opens in new tab.)

Background Informed consent for acute myocardial infarction and stroke research is challenging. Time for enrollment decisions is limited, patients and family are usually stressed, and being asked to participate in research is often unexpected. Despite these barriers, patients and surrogates have reported a preference for prospective involvement in research decisions and generally positive views of the consent process. It is unknown what drives positive or negative consent experiences. These data are crucial to making consent processes more context appropriate. Methods and Results We conducted a qualitative interview study with 27 patients and surrogates enrolled in acute myocardial infarction and stroke trials in the past 5 years. Purposive sampling from the P‐CARE (Patient‐Centered Approaches to Research Enrollment) study was based on participant characteristics and responses to initial patient‐centered interviews. In‐depth interviews used open‐ended questions to explore factors influencing consent experiences. Qualitative descriptive analysis was performed utilizing a multilevel coding strategy. Participants identified specific researcher behaviors as important, including expressions of respect, professionalism, and nonpressuring communication. Participants preferred consent conversations focused on risks/benefits and the trial protocol. They had varying views of consent forms and communicated several reasons the form was valuable unrelated to informational content. Participants also valued postenrollment interactions as opportunities to ask questions and learn about the study. Conclusions Barriers to consent in acute myocardial infarction and stroke trials are unavoidable, but participants identified productive ways to demonstrate respect for patients during enrollment conversations. These include key researcher behaviors, concentrating consent discussions on what participants find most important, and structured postenrollment follow‐up.

Convulsive status epilepticus (SE) is a relatively common emergency condition affecting individuals of all ages. The primary goal of treatment is prompt termination of seizures. Where first-line treatment with benzodiazepine has failed to achieve this, a condition known as established SE (ESE), there is uncertainty about which agent to use next. The Established Status Epilepticus Treatment Trial (ESETT) is a 3-arm (valproate (VPA), fosphenytoin (FOS), levetiracetam (LEV)), phase III, double-blind randomized comparative effectiveness study in patients aged 2 years and above with established convulsive SE. Enrollment was completed in January 2019, and the results are expected later this year. We discuss lessons learnt during the conduct of the study in relation to the following: ethical considerations; trial design and practical implementation in emergency settings, including pediatric and adult populations; quality assurance; and outcome determination where treating emergency clinicians may lack specialist expertise. We consider that the ESETT is already informing both clinical practice and future trial design. This article is part of the Special Issue “Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures"

OBJECTIVES: To estimate the impact of goal-directed therapy on outcome after traumatic brain injury, our team applied goal-directed therapy to standardize care in patients with moderate to severe traumatic brain injury, who were enrolled in a large multicenter clinical trial. DESIGN: Planned secondary analysis of data from Progesterone for the Treatment of Traumatic Brain Injury III, a large, prospective, multicenter clinical trial. SETTING: Forty-two trauma centers within the Neurologic Emergencies Treatment Trials network. PATIENTS: Eight-hundred eighty-two patients were enrolled within 4 hours of injury after nonpenetrating traumatic brain injury characterized by Glasgow Coma Scale score of 4–12. MEASUREMENTS AND MAIN RESULTS: Physiologic goals were defined a priori in order to standardize care across 42 sites participating in Progesterone for the Treatment of Traumatic Brain Injury III. Physiologic data collection occurred hourly; laboratory data were collected according to local ICU protocols and at a minimum of once per day. Physiologic transgressions were predefined as substantial deviations from the normal range of goal-directed therapy. Each hour where goal-directed therapy was not achieved was classified as a “transgression.” Data were adjudicated electronically and via expert review. Six-month outcomes included mortality and the stratified dichotomy of the Glasgow Outcome Scale-Extended. For each variable, the association between outcome and either: 1) the occurrence of a transgression or 2) the proportion of time spent in transgression was estimated via logistic regression model. RESULTS: For the 882 patients enrolled in Progesterone for the Treatment of Traumatic Brain Injury III, mortality was 12.5%. Prolonged time spent in transgression was associated with increased mortality in the full cohort for hemoglobin less than 8 gm/dL (p = 0.0006), international normalized ratio greater than 1.4 (p < 0.0001), glucose greater than 180 mg/dL (p = 0.0003), and systolic blood pressure less than 90 mm Hg (p < 0.0001). In the patient subgroup with intracranial pressure monitoring, prolonged time spent in transgression was associated with increased mortality for intracranial pressure greater than or equal to 20 mm Hg (p < 0.0001), glucose greater than 180 mg/dL (p = 0.0293), hemoglobin less than 8 gm/dL (p = 0.0220), or systolic blood pressure less than 90 mm Hg (p = 0.0114). Covariates inversely related to mortality included: a single occurrence of mean arterial pressure less than 65 mm Hg (p = 0.0051) or systolic blood pressure greater than 180 mm Hg (p = 0.0002). CONCLUSIONS: The Progesterone for the Treatment of Traumatic Brain Injury III clinical trial rigorously monitored compliance with goal-directed therapy after traumatic brain injury. Multiple significant associations between physiologic transgressions, morbidity, and mortality were observed. These data suggest that effective goal-directed therapy in traumatic brain injury may provide an opportunity to improve patient outcomes.

Study objective It is important for researchers interested in trials using the exception from informed consent to understand the views and experiences of enrolled individuals. Previous studies have shown that patient and surrogate attitudes are generally positive. These studies were small and did not include pediatric patients, and interviews were often conducted long after trial enrollment. This study sought to explore attitudes toward exception from informed consent in a larger sample and more contemporaneous setting. Methods A 10-item paper-and-pencil survey was integrated into the Established Status Epilepticus Treatment Trial, a randomized trial of 3 treatments for benzodiazepine-refractory status epilepticus in pediatric and adult patients. Primary domains included attitudes toward trial enrollment, exception from informed consent, and community consultation. Simple descriptive statistics, χ2, and Fisher's exact tests were conducted. Results Of 317 patients and surrogates, 90% agreed with or were neutral about the statement "I am glad that I/my family member was included in the Established Status Epilepticus Treatment Trial research study," whereas 10% disagreed. Twenty-seven percent disagreed with enrollment in the study without prospective consent. Black participants were more likely than white, other race, and unknown-race participants to disagree with enrollment without prospective consent (36% versus 23%, 14%, and 14%, respectively). Participants indicated that patients (81%), their families (65%), and those at risk for seizures (51%) were most important to include in community consultation. Conclusion This study aimed to explore attitudes toward exception from informed consent enrollment among participants at all sites in a large, multicenter exception from informed consent trial. General acceptance of trial enrollment was high; acceptance of exception from informed consent specifically was somewhat lower, especially among black participants. Our findings provide further support for targeted community consultation focusing on individuals with connections to the disease under study. Future research should focus on communication in the postenrollment period, especially with individuals who may have concerns about exception from informed consent.

Background Emergent informed consent for clinical trials in acute myocardial infarction (AMI) and stroke is challenging. The role and value of consent are controversial, and insufficient data exist regarding patients’ and surrogates’ experiences. Methods and Results We conducted structured interviews with patients (or surrogates) enrolled in AMI or acute stroke trials at 6 sites between 2011 and 2016. Primary domains included trial recall, consent experiences, and preferences regarding involvement. Descriptive and test statistics were used to characterize responses and explore relationships between key domains and characteristics. Multivariable logistic regression was used to examine associations between key covariates and consent preferences. There were 176 (84 stroke, 92 AMI) completed interviews. Most stroke respondents (82%) were surrogates; all AMI respondents were patients. Average time from trial enrollment to interview was 1.9 years (stroke) and 2.8 years (AMI); 89% of stroke and 62% of AMI respondents remembered being in the trial, and among these respondents, 80% (stroke) and 44% (AMI) remembered reading some of the consent form. Over 90% reported not feeling pressure to enroll, being treated in a caring way, and being treated with dignity. A minority (16% stroke and 26% AMI) reported they would have preferred not to be asked for consent. Just over half (61% stroke and 53% AMI) recalled a postenrollment conversation about the study. Conclusions Most respondents felt they were treated respectfully and were glad they had been asked for consent. Trial recall was relatively low, and many respondents recalled little postenrollment discussion. Further development of context‐sensitive approaches to consent is important.

The goals of phase II clinical trials are to gain important information about the performance of novel treatments and decide whether to conduct a larger phase III trial. This can be complicated in cases when the phase II trial objective is to identify a novel treatment having several factors. Such multifactor treatment scenarios can be explored using fixed sample size trials. However, the alternative design could be response adaptive randomization with interim analyses and additionally, longitudinal modeling whereby more data could be used in the estimation process. This combined approach allows a quicker and more responsive adaptation to early estimates of later endpoints. Such alternative clinical trial designs are potentially more powerful, faster, and smaller than fixed randomized designs. Such designs are particularly challenging, however, because phase II trials tend to be smaller than subsequent confirmatory phase III trials. The phase II trial may need to explore a large number of treatment variations to ensure that the efficacy of optimal clinical conditions is not overlooked. Adaptive trial designs need to be carefully evaluated to understand how they will perform and to take full advantage of their potential benefits. This manuscript discusses a Bayesian response adaptive randomization design with a longitudinal model that uses a multifactor approach for predicting phase III study success via the phase II data. The approach is based on an actual clinical trial design for the hyperbaric oxygen brain injury treatment trial. Specific details of the thought process and the models informing the trial design are provided. Copyright © 2016 John Wiley & Sons, Ltd.

Barriers to informed consent are ubiquitous in the conduct of emergency care research across a wide range of conditions and clinical contexts. They are largely unavoidable; can be related to time constraints, physical symptoms, emotional stress, and cognitive impairment; and affect patients and surrogates. US regulations permit an exception from informed consent for certain clinical trials in emergency settings, but these regulations have generally been used to facilitate trials in which patients are unconscious and no surrogate is available. Most emergency care research, however, involves conscious patients, and surrogates are often available. Unfortunately, there is neither clear regulatory guidance nor established ethical standards in regard to consent in these settings. In this report—the result of a workshop convened by the National Institutes of Health Office of Emergency Care Research and Department of Bioethics to address ethical challenges in emergency care research—we clarify potential gaps in ethical understanding and federal regulations about research in emergency care in which limited involvement of patients or surrogates in enrollment decisions is possible. We propose a spectrum of approaches directed toward realistic ethical goals and a research and policy agenda for addressing these issues to facilitate clinical research necessary to improve emergency care.

Importance The safety and efficacy of intensive systolic blood pressure reduction in patients with intracerebral hemorrhage who present with systolic blood pressure greater than 220 mm Hg appears to be unknown. Objective To evaluate the differential outcomes of intensive (goal, 110-139 mm Hg) vs standard (goal, 140-179 mm Hg) systolic blood pressure reduction in patients with intracerebral hemorrhage and initial systolic blood pressure of 220 mm Hg or more vs less than 220 mm Hg. Design, Setting, and Participants This post hoc analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage-II trial was performed in November 2019 on data from the multicenter randomized clinical trial, which was conducted between May 2011 to September 2015. Patients with intracerebral hemorrhage and initial systolic blood pressure of 180 mm Hg or more, randomized within 4.5 hours after symptom onset, were included. Interventions Intravenous nicardipine infusion titrated to goals. Main Outcomes and Measures Neurological deterioration and hematoma expansion within 24 hours and death or severe disability at 90 days, plus kidney adverse events and serious adverse events until day 7 or hospital discharge. Results A total of 8532 patients were screened, and 999 individuals (mean [SD] age, 62.0 [13.1] years; 620 men [62.0%]) underwent randomization and had an initial SBP value. Among 228 participants with initial systolic blood pressures of 220 mm Hg or more, the rate of neurological deterioration within 24 hours was higher in those who underwent intensive (vs standard) systolic blood pressure reduction (15.5% vs 6.8%; relative risk, 2.28 [95% CI, 1.03-5.07];P = .04). The rate of death and severe disability (39.0% vs 38.4%; relative risk, 1.02 [95% CI, 0.73-1.78];P = .92) was not significantly different between the 2 groups. There was a significantly higher rate of kidney adverse events in participants randomized to intensive systolic blood pressure reduction (13.6% vs 4.2%; relative risk, 3.22 [95% CI, 1.21-8.56];P = .01), but no difference was observed in the rate of kidney serious adverse events. Conclusions and Relevance The higher rate of neurological deterioration within 24 hours associated with intensive treatment in patients with intracerebral hemorrhage and initial systolic blood pressure of 220 mm Hg or more, without any benefit in reducing hematoma expansion at 24 hours or death or severe disability at 90 days, warrants caution against generalization of recommendations for intensive systolic blood pressure reduction.

Introduction: Relatively minimal data exist regarding perspectives of patients (or surrogate decision-makers) after enrollment in clinical trials using the exception from informed consent (EFIC) for emergency research, a regulation essential for resuscitation research. Prior studies have shown that attitudes are generally positive but have enrolled a small proportion of participants and may have been subject to selection bias. Methods: As part of the study protocol, a 10-item paper-and-pencil survey was integrated into the protocol for all sites of the Established Status Epilepticus Treatment Trial (ESETT) trial, a randomized trial of three treatments for benzodiazepine-refractory status epilepticus in pediatric and adult patients. All patients (or surrogate) were given the survey after being asked for consent to continue in ESETT. Primary domains included acceptance of trial enrollment, acceptance of EFIC, and views on which population to include in community consultation. Response items primarily used a 5-point Likert scale. Simple descriptive statistics were tabulated. Results: In total, 317 of 443 patients/surrogates completed the survey (71.6% response). Only 7.3% (23/317) disagreed with the statement “I am glad that my family member/I was included in the ESETT research study,” and 24.9% (79/317) disagreed with being included under EFIC. When asked whom researchers should consult during community consultation, 81.1% (257/317) said patients who have had seizures, 64.7% (205/317) said their family members, and individuals at particular risk for seizures (50.8%) (161/317) were most frequently chosen. Only 26.5% (84/317) felt that members of the general public should be consulted. Conclusions: This is the largest study to date of participants’ perspectives on being enrolled in an EFIC trial. Rates of enrollment acceptance were relatively high; acceptance of EFIC specifically was slightly lower. There is much greater support for consulting individuals with connections to the disease under study than the general public or other groups. These findings further suggest that targeted community consultation may be appropriate and the importance of clear communication with participants after enrollment regarding reasons for EFIC use.

For a variety of reasons including cheap computing, widespread adoption of electronic medical records, digitalization of imaging and biosignals, and rapid development of novel technologies, the amount of health care data being collected, recorded, and stored is increasing at an exponential rate. Yet despite these advances, methods for the valid, efficient, and ethical utilization of these data remain underdeveloped. Emergency care research, in particular, poses several unique challenges in this rapidly evolving field. A group of content experts was recently convened to identify research priorities related to barriers to the application of data science to emergency care research. These recommendations included: 1) developing methods for cross-platform identification and linkage of patients; 2) creating central, deidentified, open-access databases; 3) improving methodologies for visualization and analysis of intensively sampled data; 4) developing methods to identify and standardize electronic medical record data quality; 5) improving and utilizing natural language processing; 6) developing and utilizing syndrome or complaint-based based taxonomies of disease; 7) developing practical and ethical framework to leverage electronic systems for controlled trials; 8) exploring technologies to help enable clinical trials in the emergency setting; and 9) training emergency care clinicians in data science and data scientists in emergency care medicine. The background, rationale, and conclusions of these recommendations are included in the present article.