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

Stable isotopc record of ODP Site 114-704

We report a near-continuous, stable isotopic record for the Pliocene-Pleistocene (4.8 to 0.8 Ma) from Ocean Drilling Program Site 704 in the sub-Antarctic South Atlantic (47°S, 7°E). During the early to middle Pliocene (4.8 to 3.2 Ma), variation in delta18O was less than ~0.5 per mil, and absolute values were generally less than those of the Holocene. These results indicate some warming and minor deglaciation of Antarctica during intervals of the Pliocene but are inconsistent with scenarios calling for major warming and deglaciation of the Antarctic ice sheet. The climate System operated within relatively narrow limits prior to ~3.2 Ma, and the Antarctic cryosphere probably did not fluctuate on a large scale until the late Pliocene. Benthic oxygen isotopic values exceeded 3 per mil for the first time at 3.16 Ma. The amplitude and mean of the delta18O signal increased at 2.7 Ma, suggesting a shift in climate mode during the latest Gauss. The greatest delta18O values of the Gaus anti Gilbert chrons occurred at ~2.6 Ma, just below a hiatus that removed the interval from ~2.6 to 2.3 Ma in Site 704. These results agree with those from Subantarctic Site 514, which suggest that the latest Gauss (2.68 to 2.47 Ma) was the time of greatest change in Neogene climate in the northern Antarctic and Subanthtic regions. During this period, surface water cooled as the Polar Front Zone (PFZ) migrated north and perennial sea ice Cover expanded into the Subantarctic region. Antarctic ice volume increased and the ventilation rate of Southern Ocean deep water decreased during glacial events after 2.7 Ma. We suggest that these changes in the Southern Ocean were related to a gradual lowering of sea level and a reduction in the flux of North Atlantic Deep Water (NADW) with the Initiation of ice growth in the northern hemisphere. The early Matuyama Chron (~ 2.3 to 1.7 Ma) was marked by relatively warm climates in the Southern Ocean except for strong glacial events associated with isotopic stages 82 (2.027 Ma), 78 (1.941 Ma), and 70 (1.782 Ma). At 1.67 Ma (stage 65/64 transition), surface waters cooled as the PFZ migrated equatorward and oscillated about a far northerly position for a prolonged interval between 1.67 and 1.5 Ma (stages 65 to 57). Beginning at ~1.42 Ma (stage 52), all parameters (delta18O, delta13C, %opal, %CaCO3) in Hole 704 become highly correlated with each other and display a very strong 41-kyr cyclicity. This increase in the importance of the 41-kyr cycle is attributed to an increase in the amplitude of the Earth's obliquity cycle that was likely reinforced by increased glacial suppression of NADW, which may explain the tightly coupled response that developed between the Southern Ocean and the North Atlantic beginning at ~1.42 Ma (stage 52)

Plio-Pleistocene age-depth points and occurrence of hiatuses in ODP sites of the Southern Ocean

Changes in Atlantic deep water circulation were reconstructed by comparing the benthic foraminiferal delta13C record at ODP Site 1090 in the South Atlantic with similar records from the North Atlantic (Sites 982, 607, 925, 929) and deep Pacific (Site 849) oceans. Important deep water circulation changes occurred in the early Pleistocene at 1.55 Myr and during the Mid-Pleistocene Transition at 0.9 Myr. At 1.55 Myr, glacial delta13C values in the Southern Ocean became significantly lower than those in the deep Pacific, establishing a pattern that persisted throughout the late Pleistocene. We propose that the lowering of delta13C values of Southern Component Water (SCW) at this time resulted from expansion of sea ice and reduced ventilation of deep water during glacial periods after marine isotope stage 52. Accompanying this change in Southern Ocean deep water circulation was enhanced interhemispheric coupling between the North and South Atlantic after 1.55 Myr. At ~0.9 Myr, the magnitude of glacial-to-interglacial variabilityin delta13C increased and shifted to a longer frequency (100 kyr) along with oceanic delta18O (ice volume). Calculation of percent Northern Component Water (NCW) using Site 1090 as the SCW end member yielded 20-30% less reduction of NCW during glacial periods of the late Pleistocene. Also, a trend toward reduced glacial suppression of NCW during the past 400 kyr is not evident. The apparent decoupling of ice volume and deep water circulation reported previously maybe an artifact of using a Pacific, rather than a Southern Ocean, carbon isotopic record to calculate past mixing ratios of NCW and SCW