Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.

BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CONCLUSIONS: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.)

Mild Hypercapnia or Normocapnia after Out-of-Hospital Cardiac Arrest

Background Guidelines recommend normocapnia for adults with coma who are resuscitated after out-of-hospital cardiac arrest. However, mild hypercapnia increases cerebral blood flow and may improve neurologic outcomes. Methods We randomly assigned adults with coma who had been resuscitated after out-of-hospital cardiac arrest of presumed cardiac or unknown cause and admitted to the intensive care unit (ICU) in a 1:1 ratio to either 24 hours of mild hypercapnia (target partial pressure of arterial carbon dioxide [Paco₂], 50 to 55 mm Hg) or normocapnia (target Paco₂, 35 to 45 mm Hg). The primary outcome was a favorable neurologic outcome, defined as a score of 5 (indicating lower moderate disability) or higher, as assessed with the use of the Glasgow Outcome Scale–Extended (range, 1 [death] to 8, with higher scores indicating better neurologic outcome) at 6 months. Secondary outcomes included death within 6 months. Results A total of 1700 patients from 63 ICUs in 17 countries were recruited, with 847 patients assigned to targeted mild hypercapnia and 853 to targeted normocapnia. A favorable neurologic outcome at 6 months occurred in 332 of 764 patients (43.5%) in the mild hypercapnia group and in 350 of 784 (44.6%) in the normocapnia group (relative risk, 0.98; 95% confidence interval [CI], 0.87 to 1.11; P=0.76). Death within 6 months after randomization occurred in 393 of 816 patients (48.2%) in the mild hypercapnia group and in 382 of 832 (45.9%) in the normocapnia group (relative risk, 1.05; 95% CI, 0.94 to 1.16). The incidence of adverse events did not differ significantly between groups. Conclusions In patients with coma who were resuscitated after out-of-hospital cardiac arrest, targeted mild hypercapnia did not lead to better neurologic outcomes at 6 months than targeted normocapnia.Glenn Eastwood, Alistair D. Nichol, Carol Hodgson, Rachael L. Parke, Shay McGuinness, Niklas Nielsen, Stephen Bernard, Markus B. Skrifvars, Dion Stub, Fabio S. Taccone, John Archer, Demetrios Kutsogiannis, Josef Dankiewicz, Gisela Lilja, Tobias Cronberg, Hans Kirkegaard, Gilles Capellier, Giovanni Landoni, Janneke Horn, Theresa Olasveengen, Yaseen Arabi, Yew Woon Chia, Andrej Markota, Matthias Hænggi, Matt P. Wise, Anders M. Grejs, Steffen Christensen, Heidi Munk-Andersen, Asger Granfeldt, Geir Ø. Andersen, Eirik Qvigstad, Arnljot Flaa, Matthew Thomas, Katie Sweet, Jeremy Bewley, Minna Bäcklund, Marjaana Tiainen, Manuela Iten, Anja Levis, Leah Peck, James Walsham, Adam Deane, Angajendra Ghosh, Filippo Annoni, Yan Chen, David Knight, Eden Lesona, Haytham Tlayjeh, Franc Svenšek, Peter J. McGuigan, Jade Cole, David Pogson, Matthias P. Hilty, Joachim P. Düring, Michael J. Bailey, Eldho Paul, Bridget Ady, Kate Ainscough, Anna Hunt, Sinéad Monahan, Tony Trapani, Ciara Fahey, and Rinaldo Bellomo, for the TAME Study Investigator