Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone. (Funded by Stryker Neurovascular; DAWN ClinicalTrials.gov number, NCT02142283 .).

Background Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. Methods In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care–level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d -dimer level. Results The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support–free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d -dimer cohort, 92.9% in the low d -dimer cohort, and 97.3% in the unknown d -dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. Conclusions In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589 , NCT04505774 , NCT04359277 , and NCT02735707 .)

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IMPORTANCE Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. OBJECTIVE To determine whether hydrocortisone improves outcome for patients with severe COVID-19. DESIGN, SETTING, AND PARTICIPANTS An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. INTERVENTIONS The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). MAIN OUTCOMES AND MEASURES The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned-1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). RESULTS After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR,-1 to 15), 0 (IQR,-1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. CONCLUSIONS AND RELEV...

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There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia (CAP). The trial uses a novel design entitled a randomized embedded multifactorial adaptive platform (REMAP). The design has 5 key features: i.) randomization, allowing robust causal inference; ii.) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; iii.) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; iv.) response-adaptive randomization with preferential assignment to those interventions that appear most favorable, and v.) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within 4 treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies and has capacity to address additional questions rapidly during pandemic respiratory infections.

Background. This study reports the epidemiologic features, survival rates, and neurologic outcomes of the largest population-based series of pediatric out-of-hospital cardiopulmonary arrest patients with prospectively collected data. Methods. Secondary analysis of data from a prospective, interventional trial of out-of-hospital pediatric airway management conducted from 1994 to 1997 (Gausche M, Lewis RJ, Stratton SJ, et al. JAMA. 2000;283:783-790). Consecutive out-of-hospital patients from 2 large urban counties in California <12 years old or 40 kg in bodyweight who were determined by paramedics to be pulseless and apneic were included. Main outcome measures included survival to hospital discharge, patient demographics, arrest etiology, arrest rhythm, event intervals, and neurologic outcomes. Results. In 599 patients, 601 events were studied (54% were <1 year old, 58% were male). Return of spontaneous circulation was achieved in 29%; 25% were admitted to the hospital, and 8.6% (51) survived to hospital discharge. The most prevalent etiologies were sudden infant death syndrome and trauma; these resulted in relatively higher mortality. Respiratory etiologies and submersions followed; these resulted in relatively lower mortality. Twenty-six percent of the arrests were witnessed by citizens, and an additional 8% were witnessed by rescue personnel. Witnessed arrests had a higher survival rate (16%). Thirty-one percent of patients received bystander cardiopulmonary resuscitation, which was not demonstrated to result in improved survival rates. Arrest rhythms were asystole (67%), pulseless electrical activity (24%), and ventricular fibrillation (9%); children with the latter 2 rhythms had better survival rates. One third of the survivors (16 of 51) had good neurologic outcome, none of whom received >3 doses of epinephrine or were resuscitated for >31 minutes in the emergency department. Conclusions. The 8.6% survival rate after out-of-hospital pediatric cardiopulmonary arrest is poor. Administration of >3 doses of epinephrine or prolonged resuscitation is futile.

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