Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

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 Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Using research to prepare for outbreaks of severe acute respiratory infection

Severe acute respiratory infections (SARI) remain one of the leading causes of mortality around the world in all age groups. There is large global variation in epidemiology, clinical management and outcomes, including mortality. We performed a short period observational data collection in critical care units distributed globally during regional peak SARI seasons from 1 January 2016 until 31 August 2017, using standardised data collection tools. Data were collected for 1 week on all admitted patients who met the inclusion criteria for SARI, with follow-up to hospital discharge. Proportions of patients across regions were compared for microbiology, management strategies and outcomes. Regions were divided geographically and economically according to World Bank definitions. Data were collected for 682 patients from 95 hospitals and 23 countries. The overall mortality was 9.5%. Of the patients, 21.7% were children, with case fatality proportions of 1% for those less than 5 years. The highest mortality was in those above 60 years, at 18.6%. Case fatality varied by region: East Asia and Pacific 10.2% (21 of 206), Sub-Saharan Africa 4.3% (8 of 188), South Asia 0% (0 of 35), North America 13.6% (25 of 184), and Europe and Central Asia 14.3% (9 of 63). Mortality in low-income and low-middle-income countries combined was 4% as compared with 14% in high-income countries. Organ dysfunction scores calculated on presentation in 560 patients where full data were available revealed Sequential Organ Failure Assessment (SOFA) scores on presentation were significantly associated with mortality and hospital length of stay. Patients in East Asia and Pacific (48%) and North America (24%) had the highest SOFA scores of >12. Multivariable analysis demonstrated that initial SOFA score and age were independent predictors of hospital survival. There was variability across regions and income groupings for the critical care management and outcomes of SARI. Intensive care unit-specific factors, geography and management features were less reliable than baseline severity for predicting ultimate outcome. These findings may help in planning future outbreak severity assessments, but more globally representative data are required

A quantitative tomotectonic plate reconstruction of Western North America and the Eastern Pacific Basin

Plate reconstructions since the breakup of Pangaea are mostly based on the preserved spreading history of ocean basins, within absolute reference frames that are constrained by a combination of age‐progressive hotspot tracks and palaeomagnetic data. The evolution of destructive plate margins is difficult to constrain from surface observations as much of the evidence has been subducted. Seismic tomography can directly constrain palaeo‐trench locations by imaging subducted lithosphere in the mantle. This new evidence, combined with the geological surface record of subduction, suggests that several intra‐oceanic arcs existed between the Farallon Ocean and North America during late Mesozoic times – in contrast to existing quantitative models that typically show long‐lived subduction of the Farallon plate beneath the continental margin. We present a continuously closing plate model for the eastern Pacific basin from 170 Ma to present, constrained using ‘tomotectonic analysis’ – the integration of surface and subsurface data. During the Middle to Late Jurassic, we show simultaneous eastward and westward subduction of oceanic plates under an archipelago composed of Cordilleran arc terranes. As North America drifts westward, it diachronously overrides the archipelago and its arcs, beginning in the latest Jurassic. During and post‐accretion, Cordilleran terranes are translated thousands of kilometers along the continental margin, as constrained by palaeomagnetic evidence. Final accretions to North America occur during the Eocene, ending ~100 million years of archipelago override. This model provides a detailed, quantitative tectonic history for the eastern Pacific domain, paving the way for tomotectonic analysis to be used in other palaeo‐oceanic regions

A Quantitative Tomotectonic Plate Reconstruction of Western North America and the Eastern Pacific Basin

Plate reconstructions since the breakup of Pangaea are mostly based on the preserved spreading history of ocean basins, within absolute reference frames that are constrained by a combination of age‐progressive hotspot tracks and palaeomagnetic data. The evolution of destructive plate margins is difficult to constrain from surface observations as much of the evidence has been subducted. Seismic tomography can directly constrain palaeo‐trench locations by imaging subducted lithosphere in the mantle. This new evidence, combined with the geological surface record of subduction, suggests that several intra‐oceanic arcs existed between the Farallon Ocean and North America during late Mesozoic times – in contrast to existing quantitative models that typically show long‐lived subduction of the Farallon plate beneath the continental margin. We present a continuously closing plate model for the eastern Pacific basin from 170 Ma to present, constrained using ‘tomotectonic analysis’ – the integration of surface and subsurface data. During the Middle to Late Jurassic, we show simultaneous eastward and westward subduction of oceanic plates under an archipelago composed of Cordilleran arc terranes. As North America drifts westward, it diachronously overrides the archipelago and its arcs, beginning in the latest Jurassic. During and post‐accretion, Cordilleran terranes are translated thousands of kilometers along the continental margin, as constrained by palaeomagnetic evidence. Final accretions to North America occur during the Eocene, ending ~100 million years of archipelago override. This model provides a detailed, quantitative tectonic history for the eastern Pacific domain, paving the way for tomotectonic analysis to be used in other palaeo‐oceanic regions