; for the COALITION COVID-19 Brazil III Investigators IMPORTANCE Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) is associated with substantial mortality and use of health care resources. Dexamethasone use might attenuate lung injury in these patients. OBJECTIVE To determine whether intravenous dexamethasone increases the number of ventilator-free days among patients with COVID-19-associated ARDS. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, open-label, clinical trial conducted in 41 intensive care units (ICUs) in Brazil. Patients with COVID-19 and moderate to severe ARDS, according to the Berlin definition, were enrolled from April 17 to June 23, 2020. Final follow-up was completed on July 21, 2020. The trial was stopped early following publication of a related study before reaching the planned sample size of 350 patients. INTERVENTIONS Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard care (n =151) or standard care alone (n = 148). MAIN OUTCOMES AND MEASURES The primary outcome was ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death), ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) at 48 hours, 72 hours, and 7 days. RESULTS A total of 299 patients (mean [SD] age, 61 [14] years; 37% women) were enrolled and all completed follow-up. Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days (95% CI, 5.0-8.2) during the first 28 days vs 4.0 ventilator-free days (95% CI, 2.9-5.4) in the standard care group (difference, 2.26; 95% CI, 0.2-4.38; P = .04). At 7 days, patients in the dexamethasone group had a mean SOFA score of 6.1 (95% CI, 5.5-6.7) vs 7.5 (95% CI, 6.9-8.1) in the standard care group (difference, −1.16; 95% CI, −1.94 to −0.38; P = .004). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. Thirty-three patients (21.9%) in the dexamethasone group vs 43 (29.1%) in the standard care group experienced secondary infections, 47 (31.1%) vs 42 (28.3%) needed insulin for glucose control, and 5 (3.3%) vs 9 (6.1%) experienced other serious adverse events. CONCLUSIONS AND RELEVANCE Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days.

Background Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited. Methods We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed. Results A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P=1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P=1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. Conclusions Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123 .)

Objective To determine whether tocilizumab improves clinical outcomes for patients with severe or critical coronavirus disease 2019 (covid-19). Design Randomised, open label trial. Setting Nine hospitals in Brazil, 8 May to 17 July 2020. Participants Adults with confirmed covid-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (C reactive protein, D dimer, lactate dehydrogenase, or ferritin). The data monitoring committee recommended stopping the trial early, after 129 patients had been enrolled, because of an increased number of deaths at 15 days in the tocilizumab group. Interventions Tocilizumab (single intravenous infusion of 8 mg/kg) plus standard care (n=65) versus standard care alone (n=64). Main outcome measure The primary outcome, clinical status measured at 15 days using a seven level ordinal scale, was analysed as a composite of death or mechanical ventilation because the assumption of odds proportionality was not met. Results A total of 129 patients were enrolled (mean age 57 (SD 14) years; 68% men) and all completed follow-up. All patients in the tocilizumab group and two in the standard care group received tocilizumab. 18 of 65 (28%) patients in the tocilizumab group and 13 of 64 (20%) in the standard care group were receiving mechanical ventilation or died at day 15 (odds ratio 1.54, 95% confidence interval 0.66 to 3.66; P=0.32). Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group (odds ratio 6.42, 95% confidence interval 1.59 to 43.2). Adverse events were reported in 29 of 67 (43%) patients who received tocilizumab and 21 of 62 (34%) who did not receive tocilizumab. Conclusions In patients with severe or critical covid-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality. Trial registration ClinicalTrials.gov NCT04403685 .

The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group IMPORTANCE Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.OBJECTIVE To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.DATA SOURCES Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.STUDY SELECTION Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. DATA EXTRACTION AND SYNTHESISIn this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I 2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. MAIN OUTCOMES AND MEASURESThe primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.RESULTS A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). CONCLUSIONS AND RELEVANCEIn this prospective meta-analysis of clinical trials of patients hosp...

BackgroundPrevious studies showed higher sepsis mortality rates in Brazil compared to other developed or developing countries. Moreover, another trial demonstrated an increased mortality rate in public hospitals compared to private hospitals in Brazil. The reasons for these findings may include delayed recognition and inadequate treatment of sepsis in public facilities. We designed this study to evaluate the factors associated with mortality in septic patients admitted to intensive care units in a network of public and private institutions.Materials and MethodsThis study is a retrospective analysis of a prospective cohort of sepsis patients in 19 private and public institutions in Brazil. We analyzed data from the original database and collected additional data to assess compliance to the treatment guidelines and to determine the time from the onset of organ dysfunction and the sepsis diagnosis by the healthcare team.ResultsA total of 396 patients were analyzed. Patients in public hospitals were younger, had a greater number of dysfunctional organs at baseline and a lower chance to have sepsis diagnosed within two hours of the onset of organ dysfunction. Private hospitals had a better compliance to lactate and blood culture sampling and maintenance of glycemic control. The multivariate analysis showed that age, disease severity at baseline and being treated at a public hospital were independent risk factors for mortality. A delay in the sepsis diagnosis of longer than two hours was associated with mortality only in the public setting.ConclusionsWe confirmed a lower sepsis mortality rate in the private hospitals of this network. Being treated in a public hospital was an independent factor for mortality. Delayed recognition of sepsis was more frequent in public institutions and this might have been associated with a higher mortality. Improving sepsis recognition and early diagnosis may be important targets in public institutions.

for the BaSICS investigators and the BRICNet members IMPORTANCE Intravenous fluids are used for almost all intensive care unit (ICU) patients. Clinical and laboratory studies have questioned whether specific fluid types result in improved outcomes, including mortality and acute kidney injury.OBJECTIVE To determine the effect of a balanced solution vs saline solution (0.9% sodium chloride) on 90-day survival in critically ill patients. DESIGN, SETTING, AND PARTICIPANTS Double-blind, factorial, randomized clinical trial conducted at 75 ICUs in Brazil. Patients who were admitted to the ICU with at least 1 risk factor for worse outcomes, who required at least 1 fluid expansion, and who were expected to remain in the ICU for more than 24 hours were randomized between May 29, 2017, and March 2, 2020; follow-up concluded on October 29, 2020. Patients were randomized to 2 different fluid types (a balanced solution vs saline solution reported in this article) and 2 different infusion rates (reported separately).INTERVENTIONS Patients were randomly assigned 1:1 to receive either a balanced solution (n = 5522) or 0.9% saline solution (n = 5530) for all intravenous fluids. MAIN OUTCOMES AND MEASURESThe primary outcome was 90-day survival. RESULTS Among 11 052 patients who were randomized, 10 520 (95.2%) were available for the analysis (mean age, 61.1 [SD, 17] years; 44.2% were women). There was no significant interaction between the 2 interventions (fluid type and infusion speed; P = .98). Planned surgical admissions represented 48.4% of all patients. Of all the patients, 60.6% had hypotension or vasopressor use and 44.3% required mechanical ventilation at enrollment. Patients in both groups received a median of 1.5 L of fluid during the first day after enrollment. By day 90, 1381 of 5230 patients (26.4%) assigned to a balanced solution died vs 1439 of 5290 patients (27.2%) assigned to saline solution (adjusted hazard ratio, 0.97 [95% CI, 0.90-1.05]; P = .47). There were no unexpected treatment-related severe adverse events in either group.CONCLUSION AND RELEVANCE Among critically ill patients requiring fluid challenges, use of a balanced solution compared with 0.9% saline solution did not significantly reduce 90-day mortality. The findings do not support the use of this balanced solution.

BackgroundIn the later stages of circulatory shock, monitoring should help to avoid fluid overload. In this setting, volume expansion is ideally indicated only for patients in whom the cardiac index (CI) is expected to increase. Crystalloids are usually the choice for fluid replacement. As previous studies evaluating the hemodynamic effect of crystalloids have not distinguished responders from non-responders, the present study was designed to evaluate the duration of the hemodynamic effects of crystalloids according to the fluid responsiveness status.MethodsThis is a prospective observational study conducted after the initial resuscitation phase of circulatory shock (>6 h vasopressor use). Critically ill, sedated adult patients monitored with a pulmonary artery catheter who received a fluid challenge with crystalloids (500 mL infused over 30 min) were included. Hemodynamic variables were measured at baseline (T0) and at 30 min (T1), 60 min (T2), and 90 min (T3) after a fluid bolus, totaling 90 min of observation. The patients were analyzed according to their fluid responsiveness status (responders with CI increase >15% and non-responders ≤15% at T1). The data were analyzed by repeated measures of analysis of variance.ResultsTwenty patients were included, 14 of whom had septic shock. Overall, volume expansion significantly increased the CI: 3.03 ± 0.64 L/min/m2 to 3.58 ± 0.66 L/min/m2 (p < 0.05). From this period, there was a progressive decrease: 3.23 ± 0.65 L/min/m2 (p < 0.05, T2 versus T1) and 3.12 ± 0.64 L/min/m2 (p < 0.05, period T3 versus T1). Similar behavior was observed in responders (13 patients), 2.84 ± 0.61 L/min/m2 to 3.57 ± 0.65 L/min/m2 (p < 0.05) with volume expansion, followed by a decrease, 3.19 ± 0.69 L/min/m2 (p < 0.05, T2 versus T1) and 3.06 ± 0.70 L/min/m2 (p < 0.05, T3 versus T1). Blood pressure and cardiac filling pressures also decreased significantly after T1 with similar findings in both responders and non-responders.ConclusionsThe results suggest that volume expansion with crystalloids in patients with circulatory shock after the initial resuscitation has limited success, even in responders.

Automatized ΔPP accurately predicted fluid responsiveness in septic patients ventilated with low TV.