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

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Décret concernant la mise en liberté de trois officiers de la garnison de Valence, lors de la séance du 31 mai 1790

Vieillard Pierre-Jacques. Décret concernant la mise en liberté de trois officiers de la garnison de Valence, lors de la séance du 31 mai 1790. In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XVI - Du 31 mai au 8 juillet 1790. Paris : Librairie Administrative P. Dupont, 1883. p. 1

Adresse de l'académie de peinture et de sculpture concernant la vente des biens ecclésiastiques, lors de la séance du 6 octobre 1790

Vieillard Pierre-Jacques. Adresse de l'académie de peinture et de sculpture concernant la vente des biens ecclésiastiques, lors de la séance du 6 octobre 1790. In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XIX - Du 16 septembre au 23 octobre 1790. Paris : Librairie Administrative P. Dupont, 1884. p. 472

Lecture du procès-verbal de la séance du 15 septembre 1790, lors de la séance du 16 septembre 1790

Vieillard Pierre-Jacques. Lecture du procès-verbal de la séance du 15 septembre 1790, lors de la séance du 16 septembre 1790. In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XIX - Du 16 septembre au 23 octobre 1790. Paris : Librairie Administrative P. Dupont, 1884. p. 18

Rapport sur l’affaire de la municipalité de Doullens, lors de la séance du 2 décembre 1790

Vieillard Pierre Jacques. Rapport sur l’affaire de la municipalité de Doullens, lors de la séance du 2 décembre 1790. In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XXI - Du 26 novembre 1790 au 2 janvier 1791. Paris : Librairie Administrative P. Dupont, 1885. p. 179

Décret exonérant les quittances de liquidation du droit d’enregistrement, lors de la séance du 10 février 1791

Vieillard Pierre Jacques. Décret exonérant les quittances de liquidation du droit d’enregistrement, lors de la séance du 10 février 1791. In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XXIII - Du 6 février 1791 au 9 mars 1791. Paris : Librairie Administrative P. Dupont, 1886. pp. 112-113

Reprise du rapport du comité des rapports sur une contestation entre les corps administratifs et l'université de Poitiers, lors de la séance du 3 février 1791

Vieillard Pierre Jacques. Reprise du rapport du comité des rapports sur une contestation entre les corps administratifs et l'université de Poitiers, lors de la séance du 3 février 1791. In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XXII - Du 3 janvier au 5 février 1791. Paris : Librairie Administrative P. Dupont, 1885. pp. 735-736

Décret exonérant les quittances de liquidation du droit d’enregistrement, lors de la séance du 10 février 1791

Vieillard Pierre-Jacques. Décret exonérant les quittances de liquidation du droit d’enregistrement, lors de la séance du 10 février 1791. In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XXIII - Du 6 février 1791 au 9 mars 1791. Paris : Librairie Administrative P. Dupont, 1886. pp. 112-113

Adoption de l'avis du comité concernant la non discussion de la pétition des citoyens de Mautauban, lors de la séance du 18 août 1790

Vieillard Pierre Jacques. Adoption de l'avis du comité concernant la non discussion de la pétition des citoyens de Mautauban, lors de la séance du 18 août 1790. In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XVIII - Du 12 aout au 15 septembre 1790. Paris : Librairie Administrative P. Dupont, 1884. p. 141