Genetic Determinants of the Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a life-threatening lung condition that arises from multiple causes, including sepsis, pneumonia, trauma, and severe coronavirus disease 2019 (COVID-19). Given the heterogeneity of causes and the lack of specific therapeutic options, it is crucial to understand the genetic and molecular mechanisms that underlie this condition. The identification of genetic risks and pharmacogenetic loci, which are involved in determining drug responses, could help enhance early patient diagnosis, assist in risk stratification of patients, and reveal novel targets for pharmacological interventions, including possibilities for drug repositioning. Here, we highlight the basis and importance of the most common genetic approaches to understanding the pathogenesis of ARDS and its critical triggers. We summarize the findings of screening common genetic variation via genome-wide association studies and analyses based on other approaches, such as polygenic risk scores, multi-trait analyses, or Mendelian randomization studies. We also provide an overview of results from rare genetic variation studies using Next-Generation Sequencing techniques and their links with inborn errors of immunity. Lastly, we discuss the genetic overlap between severe COVID-19 and ARDS by other causes.

Ozone Eliminates SARS-CoV-2 from Difficult-to-Clean Office Supplies and Clinical Equipment.

(1) Background: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to cause profound health, economic, and social problems worldwide. The management and disinfection of materials used daily in health centers and common working environments have prompted concerns about the control of coronavirus disease 2019 (COVID-19) infection risk. Ozone is a powerful oxidizing agent that has been widely used in disinfection processes for decades. The aim of this study was to assess the optimal conditions of ozone treatment for the elimination of heat-inactivated SARS-CoV-2 from office supplies (personal computer monitors, keyboards, and computer mice) and clinical equipment (continuous positive airway pressure tubes and personal protective equipment) that are difficult to clean. (2) Methods: The office supplies and clinical equipment were contaminated in an area of 1 cm2 with 1 × 104 viral units of a heat-inactivated SARS-CoV-2 strain, then treated with ozone using two different ozone devices: a specifically designed ozonation chamber (for low-medium ozone concentrations over large volumes) and a clinical ozone generator (for high ozone concentrations over small volumes). SARS-CoV-2 gene detection was carried out using quantitative real-time polymerase chain reaction (RT-qPCR). (3) Results: At high ozone concentrations over small surfaces, the ozone eliminated SARS-CoV-2 RNA in short time periods-i.e., 10 min (at 4000 ppm) or less. The optimum ozone concentration over large volumes was 90 ppm for 120 min in ambient conditions (24 °C and 60-75% relative humidity). (4) Conclusions: This study showed that the appropriate ozone concentration and exposure time eliminated heat-inactivated SARS-CoV-2 RNA from the surfaces of different widely used clinical and office supplies, decreasing their risk of transmission, and improving their reutilization. Ozone may provide an additional tool to control the spread of the COVID-19 pandemic.

The PANDORA Study: Prevalence and Outcome of Acute Hypoxemic Respiratory Failure in the Pre-COVID-19 Era.

OBJECTIVES: To establish the epidemiological characteristics, ventilator management, and outcomes in patients with acute hypoxemic respiratory failure (AHRF), with or without acute respiratory distress syndrome (ARDS), in the era of lung-protective mechanical ventilation (MV). DESIGN: A 6-month prospective, epidemiological, observational study. SETTING: A network of 22 multidisciplinary ICUs in Spain. PATIENTS: Consecutive mechanically ventilated patients with AHRF (defined as Pao2/Fio2 ≤ 300 mm Hg on positive end-expiratory pressure [PEEP] ≥ 5 cm H2O and Fio2 ≥ 0.3) and followed-up until hospital discharge. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were prevalence of AHRF and ICU mortality. Secondary outcomes included prevalence of ARDS, ventilatory management, and use of adjunctive therapies. During the study period, 9,803 patients were admitted: 4,456 (45.5%) received MV, 1,271 (13%) met AHRF criteria (1,241 were included into the study: 333 [26.8%] met Berlin ARDS criteria and 908 [73.2%] did not). At baseline, tidal volume was 6.9 ± 1.1 mL/kg predicted body weight, PEEP 8.4 ± 3.1 cm H2O, Fio2 0.63 ± 0.22, and plateau pressure 21.5 ± 5.4 cm H2O. ARDS patients received higher Fio2 and PEEP than non-ARDS (0.75 ± 0.22 vs 0.59 ± 0.20 cm H2O and 10.3 ± 3.4 vs 7.7 ± 2.6 cm H2O, respectively [p < 0.0001]). Adjunctive therapies were rarely used in non-ARDS patients. Patients without ARDS had higher ventilator-free days than ARDS (12.2 ± 11.6 vs 9.3 ± 9.7 d; p < 0.001). All-cause ICU mortality was similar in AHRF with or without ARDS (34.8% [95% CI, 29.7-40.2] vs 35.5% [95% CI, 32.3-38.7]; p = 0.837). CONCLUSIONS: AHRF without ARDS is a very common syndrome in the ICU with a high mortality that requires specific studies into its epidemiology and ventilatory management. We found that the prevalence of ARDS was much lower than reported in recent observational studies.

Acute Hypoxemic Respiratory Failure in Children at the Start of COVID-19 Outbreak: A Nationwide Experience.

STUDY DESIGN: This is a prospective, multicenter, and observational study with the aim of describing physiological characteristics, respiratory management, and outcomes of children with acute hypoxemic respiratory failure (AHRF) from different etiologies receiving invasive mechanical ventilation (IMV) compared with those affected by SARS-CoV-2. METHODS AND MAIN RESULTS: Twenty-eight patients met the inclusion criteria: 9 patients with coronavirus disease 2019 (COVID-19) and 19 patients without COVID-19. Non-COVID-19 patients had more pre-existing comorbidities (78.9% vs. 44.4%) than COVID-19 patients. At AHRF onset, non-COVID-19 patients had worse oxygenation (PaO2/FiO2 = 95 mmHg (65.5-133) vs. 150 mmHg (105-220), p = 0.04), oxygenation index = 15.9 (11-28.4) vs. 9.3 (6.7-10.6), p = 0.01), and higher PaCO2 (48 mmHg (46.5-63) vs. 41 mmHg (40-45), p = 0.07, that remained higher at 48 h: 54 mmHg (43-58.7) vs. 41 (38.5-45.5), p = 0.03). In 12 patients (5 COVID-19 and 7 non-COVID-19), AHRF evolved to pediatric acute respiratory distress syndrome (PARDS). All non-COVID-19 patients had severe PARDS, while 3 out of 5 patients in the COVID-19 group had mild or moderate PARDS. Overall Pediatric Intensive Care Medicine (PICU) mortality was 14.3%. CONCLUSIONS: Children with AHRF due to SARS-CoV2 infection had fewer comorbidities and better oxygenation than patients with non-COVID-19 AHRF. In this study, progression to severe PARDS was rarely observed in children with COVID-19.

Predictors of failure with high-flow nasal oxygen therapy in COVID-19 patients with acute respiratory failure: a multicenter observational study.

PURPOSE: We aimed to describe the use of high-flow nasal oxygen (HFNO) in patients with COVID-19 acute respiratory failure and factors associated with a shift to invasive mechanical ventilation. METHODS: This is a multicenter, observational study from a prospectively collected database of consecutive COVID-19 patients admitted to 36 Spanish and Andorran intensive care units (ICUs) who received HFNO on ICU admission during a 22-week period (March 12-August 13, 2020). Outcomes of interest were factors on the day of ICU admission associated with the need for endotracheal intubation. We used multivariable logistic regression and mixed effects models. A predictive model for endotracheal intubation in patients treated with HFNO was derived and internally validated. RESULTS: From a total of 259 patients initially treated with HFNO, 140 patients (54%) required invasive mechanical ventilation. Baseline non-respiratory Sequential Organ Failure Assessment (SOFA) score [odds ratio (OR) 1.78; 95% confidence interval (CI) 1.41-2.35], and the ROX index calculated as the ratio of partial pressure of arterial oxygen to inspired oxygen fraction divided by respiratory rate (OR 0.53; 95% CI: 0.37-0.72), and pH (OR 0.47; 95% CI: 0.24-0.86) were associated with intubation. Hospital site explained 1% of the variability in the likelihood of intubation after initial treatment with HFNO. A predictive model including non-respiratory SOFA score and the ROX index showed excellent performance (AUC 0.88, 95% CI 0.80-0.96). CONCLUSIONS: Among adult critically ill patients with COVID-19 initially treated with HFNO, the SOFA score and the ROX index may help to identify patients with higher likelihood of intubation.

High-flow nasal oxygen in patients with COVID-19-associated acute respiratory failure.

PURPOSE: Whether the use of high-flow nasal oxygen in adult patients with COVID-19 associated acute respiratory failure improves clinically relevant outcomes remains unclear. We thus sought to assess the effect of high-flow nasal oxygen on ventilator-free days, compared to early initiation of invasive mechanical ventilation, on adult patients with COVID-19. METHODS: We conducted a multicentre cohort study using a prospectively collected database of patients with COVID-19 associated acute respiratory failure admitted to 36 Spanish and Andorran intensive care units (ICUs). Main exposure was the use of high-flow nasal oxygen (conservative group), while early invasive mechanical ventilation (within the first day of ICU admission; early intubation group) served as the comparator. The primary outcome was ventilator-free days at 28 days. ICU length of stay and all-cause in-hospital mortality served as secondary outcomes. We used propensity score matching to adjust for measured confounding. RESULTS: Out of 468 eligible patients, a total of 122 matched patients were included in the present analysis (61 for each group). When compared to early intubation, the use of high-flow nasal oxygen was associated with an increase in ventilator-free days (mean difference: 8.0 days; 95% confidence interval (CI): 4.4 to 11.7 days) and a reduction in ICU length of stay (mean difference: - 8.2 days; 95% CI - 12.7 to - 3.6 days). No difference was observed in all-cause in-hospital mortality between groups (odds ratio: 0.64; 95% CI: 0.25 to 1.64). CONCLUSIONS: The use of high-flow nasal oxygen upon ICU admission in adult patients with COVID-19 related acute hypoxemic respiratory failure may lead to an increase in ventilator-free days and a reduction in ICU length of stay, when compared to early initiation of invasive mechanical ventilation. Future studies should confirm our findings.

Early corticosteroids are associated with lower mortality in critically ill patients with COVID-19: a cohort study.

BACKGROUND: Critically ill patients with coronavirus disease 19 (COVID-19) have a high fatality rate likely due to a dysregulated immune response. Corticosteroids could attenuate this inappropriate response, although there are still some concerns regarding its use, timing, and dose. METHODS: This is a nationwide, prospective, multicenter, observational, cohort study in critically ill adult patients with COVID-19 admitted into Intensive Care Units (ICU) in Spain from 12th March to 29th June 2020. Using a multivariable Cox model with inverse probability weighting, we compared relevant outcomes between patients treated with early corticosteroids (before or within the first 48 h of ICU admission) with those who did not receive early corticosteroids (delayed group) or any corticosteroids at all (never group). Primary endpoint was ICU mortality. Secondary endpoints included 7-day mortality, ventilator-free days, and complications. RESULTS: A total of 691 patients out of 882 (78.3%) received corticosteroid during their hospital stay. Patients treated with early-corticosteroids (n = 485) had lower ICU mortality (30.3% vs. never 36.6% and delayed 44.2%) and lower 7-day mortality (7.2% vs. never 15.2%) compared to non-early treated patients. They also had higher number of ventilator-free days, less length of ICU stay, and less secondary infections than delayed treated patients. There were no differences in medical complications between groups. Of note, early use of moderate-to-high doses was associated with better outcomes than low dose regimens. CONCLUSION: Early use of corticosteroids in critically ill patients with COVID-19 is associated with lower mortality than no or delayed use, and fewer complications than delayed use.

Effects of Ozone Treatment on Personal Protective Equipment Contaminated with SARS-CoV-2.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing profound health, economic, and social problems worldwide. Management of personal protective equipment (PPE) and its potential limited availability have created concerns about the increased risks for healthcare professionals at hospitals and nursing homes. Ozone is a powerful oxidant agent. The objectives of this study were to examine the effects of ozone treatment on PPE contaminated with SARS-CoV-2, and to explore whether relative humidity could modify those effects. METHODS: PPE contaminated by heat-inactivated SARS-CoV-2 were treated with different ozone concentrations, exposure times, and relative humidity conditions. SARS-CoV-2 gene amplification was assessed by real-time polymerase chain reaction. RESULTS: There was no amplification of SARS-CoV-2 in PPE after the following ozone exposures: 30 s at 10,000 ppm (20 g/m3), 5 min at 4000 ppm, and 10 min at 2000 ppm. At lower ozone concentrations, 4-12 ppm (0.008-0.024 g/m3), the effects were highly dependent on the relative humidity conditions. CONCLUSIONS: Oxidative stress induced by ozone exposure eliminated heat-inactivated SARS-CoV-2 in different PPE components under appropriate exposure times, ozone concentrations, and relative humidity conditions. These findings could have implications in decreasing the risk of contamination associated with personal protective equipment management and in increasing its availability. Further research in the original SARS-CoV-2 strain is guaranteed.

Awake prone positioning does not reduce the risk of intubation in COVID-19 treated with high-flow nasal oxygen therapy: a multicenter, adjusted cohort study.

BACKGROUND: Awake prone positioning (awake-PP) in non-intubated coronavirus disease 2019 (COVID-19) patients could avoid endotracheal intubation, reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNO) with awake-PP prevents the need for intubation when compared to HFNO alone. METHODS: Prospective, multicenter, adjusted observational cohort study in consecutive COVID-19 patients with acute respiratory failure (ARF) receiving respiratory support with HFNO from 12 March to 9 June 2020. Patients were classified as HFNO with or without awake-PP. Logistic models were fitted to predict treatment at baseline using the following variables: age, sex, obesity, non-respiratory Sequential Organ Failure Assessment score, APACHE-II, C-reactive protein, days from symptoms onset to HFNO initiation, respiratory rate, and peripheral oxyhemoglobin saturation. We compared data on demographics, vital signs, laboratory markers, need for invasive mechanical ventilation, days to intubation, ICU length of stay, and ICU mortality between HFNO patients with and without awake-PP. RESULTS: A total of 1076 patients with COVID-19 ARF were admitted, of which 199 patients received HFNO and were analyzed. Fifty-five (27.6%) were pronated during HFNO; 60 (41%) and 22 (40%) patients from the HFNO and HFNO + awake-PP groups were intubated. The use of awake-PP as an adjunctive therapy to HFNO did not reduce the risk of intubation [RR 0.87 (95% CI 0.53-1.43), p = 0.60]. Patients treated with HFNO + awake-PP showed a trend for delay in intubation compared to HFNO alone [median 1 (interquartile range, IQR 1.0-2.5) vs 2 IQR 1.0-3.0] days (p = 0.055), but awake-PP did not affect 28-day mortality [RR 1.04 (95% CI 0.40-2.72), p = 0.92]. CONCLUSION: In patients with COVID-19 ARF treated with HFNO, the use of awake-PP did not reduce the need for intubation or affect mortality.

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis.

Importance: Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support. Objective: To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality. Design, Setting, and Participants: Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance-weighted fixed-effect analysis using risk ratios. Exposures: Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients). Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events. Results: A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as "low" for 6 of the 7 mortality results and as "some concerns" in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P < .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo. Conclusions and Relevance: In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

Corticosteroid therapy for critically ill patients with COVID-19: A structured summary of a study protocol for a prospective meta-analysis of randomized trials.

OBJECTIVES: Primary objective: To estimate the effect of corticosteroids compared with usual care or placebo on mortality up to 28 days after randomization. Secondary objectives: To examine whether the effect of corticosteroids compared with usual care or placebo on mortality up to 28 days after randomization varies between subgroups related to treatment characteristics, disease severity at the time of randomization, patient characteristics, or risk of bias. To examine the effect of corticosteroids compared with usual care or placebo on serious adverse events. STUDY DESIGN: Prospective meta-analysis of randomized controlled trials. Both placebo-controlled and open-label trials are eligible. PARTICIPANTS: Hospitalised, critically ill patients with suspected or confirmed COVID-19. INTERVENTION AND COMPARATOR: Intervention groups will have received therapeutic doses of a steroid (dexamethasone, hydrocortisone or methylprednisolone) with IV or oral administration immediately after randomization. The comparator groups will have received standard of care or usual care or placebo. MAIN OUTCOME: All-cause mortality up to 28 days after randomization. SEARCH METHODS: Systematic searching of clinicaltrials.gov , EudraCT, the WHO ISRCTN registry, and the Chinese clinical trials registry. Additionally, research and WHO networks will be asked for relevant trials. RISK OF BIAS ASSESSMENTS: These will be based on the Cochrane RoB 2 tool, and will use structured information provided by the trial investigators on a form designed for this prospective meta-analysis. We will use GRADE to assess the certainty of the evidence. STATISTICAL ANALYSES: Trial investigators will provide data on the numbers of participants who did and did not experience each outcome according to intervention group, overall and in specified subgroups. We will conduct fixed-effect (primary analysis) and random-effects (Paule-Mandel estimate of heterogeneity and Hartung-Knapp adjustment) meta-analyses. We will quantify inconsistency in effects between trials using I2 statistics. Evidence for subgroup effects will be quantified by ratios of odds ratios comparing effects in the subgroups, and corresponding interaction p-values. Comparisons between subgroups defined by trial characteristics will be made using random-effects meta-regression. Comparisons between subgroups defined by patient characteristics will be made by estimating trial-specific ratios of odds ratios comparing intervention effects between subgroups then combining these using random-effects meta-analysis. Steroid interventions will be classified as high or low dose according to whether the dose is greater or less than or equal to 400 mg hydrocortisone per day or equivalent. We will use network meta-analysis methods to make comparisons between the effects of high and low dose steroid interventions (because one trial randomized participants to both low and high dose steroid arms). PROSPERO REGISTRATION NUMBER: CRD42020197242 FULL PROTOCOL: The full protocol for this prospective meta-analysis is attached as an additional file, accessible from the Trials website (Additional file 1). To expedite dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol for the systematic review.

Efficacy of dexamethasone treatment for patients with the acute respiratory distress syndrome caused by COVID-19: study protocol for a randomized controlled superiority trial.

BACKGROUND: There are no specific generally accepted therapies for the coronavirus disease 2019 (COVID-19). The full spectrum of COVID-19 ranges from asymptomatic disease to mild respiratory tract illness to severe pneumonia, acute respiratory distress syndrome (ARDS), multisystem organ failure, and death. The efficacy of corticosteroids in viral ARDS remains unknown. We postulated that adjunctive treatment of established ARDS caused by COVID-19 with intravenous dexamethasone might change the pulmonary and systemic inflammatory response and thereby reduce morbidity, leading to a decrease in duration of mechanical ventilation and in mortality. METHODS/DESIGN: This is a multicenter, randomized, controlled, parallel, open-label, superiority trial testing dexamethasone in 200 mechanically ventilated adult patients with established moderate-to-severe ARDS caused by confirmed SARS-CoV-2 infection. Established ARDS is defined as maintaining a PaO2/FiO2 ≤ 200 mmHg on PEEP ≥ 10 cmH2O and FiO2 ≥ 0.5 after 12 ± 3 h of routine intensive care. Eligible patients will be randomly assigned to receive either dexamethasone plus standard intensive care or standard intensive care alone. Patients in the dexamethasone group will receive an intravenous dose of 20 mg once daily from day 1 to day 5, followed by 10 mg once daily from day 6 to day 10. The primary outcome is 60-day mortality. The secondary outcome is the number of ventilator-free days, defined as days alive and free from mechanical ventilation at day 28 after randomization. All analyses will be done according to the intention-to-treat principle. DISCUSSION: This study will assess the role of dexamethasone in patients with established moderate-to-severe ARDS caused by SARS-CoV-2. TRIAL REGISTRATION: ClinicalTrials.gov NCT04325061 . Registered on 25 March 2020 as DEXA-COVID19.

Clinical features, ventilatory management, and outcome of ARDS caused by COVID-19 are similar to other causes of ARDS.

PURPOSE: The main characteristics of mechanically ventilated ARDS patients affected with COVID-19, and the adherence to lung-protective ventilation strategies are not well known. We describe characteristics and outcomes of confirmed ARDS in COVID-19 patients managed with invasive mechanical ventilation (MV). METHODS: This is a multicenter, prospective, observational study in consecutive, mechanically ventilated patients with ARDS (as defined by the Berlin criteria) affected with with COVID-19 (confirmed SARS-CoV-2 infection in nasal or pharyngeal swab specimens), admitted to a network of 36 Spanish and Andorran intensive care units (ICUs) between March 12 and June 1, 2020. We examined the clinical features, ventilatory management, and clinical outcomes of COVID-19 ARDS patients, and compared some results with other relevant studies in non-COVID-19 ARDS patients. RESULTS: A total of 742 patients were analysed with complete 28-day outcome data: 128 (17.1%) with mild, 331 (44.6%) with moderate, and 283 (38.1%) with severe ARDS. At baseline, defined as the first day on invasive MV, median (IQR) values were: tidal volume 6.9 (6.3-7.8) ml/kg predicted body weight, positive end-expiratory pressure 12 (11-14) cmH2O. Values of respiratory system compliance 35 (27-45) ml/cmH2O, plateau pressure 25 (22-29) cmH2O, and driving pressure 12 (10-16) cmH2O were similar to values from non-COVID-19 ARDS patients observed in other studies. Recruitment maneuvers, prone position and neuromuscular blocking agents were used in 79%, 76% and 72% of patients, respectively. The risk of 28-day mortality was lower in mild ARDS [hazard ratio (RR) 0.56 (95% CI 0.33-0.93), p = 0.026] and moderate ARDS [hazard ratio (RR) 0.69 (95% CI 0.47-0.97), p = 0.035] when compared to severe ARDS. The 28-day mortality was similar to other observational studies in non-COVID-19 ARDS patients. CONCLUSIONS: In this large series, COVID-19 ARDS patients have features similar to other causes of ARDS, compliance with lung-protective ventilation was high, and the risk of 28-day mortality increased with the degree of ARDS severity.

Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial.

BACKGROUND: There is no proven specific pharmacological treatment for patients with the acute respiratory distress syndrome (ARDS). The efficacy of corticosteroids in ARDS remains controversial. We aimed to assess the effects of dexamethasone in ARDS, which might change pulmonary and systemic inflammation and result in a decrease in duration of mechanical ventilation and mortality. METHODS: We did a multicentre, randomised controlled trial in a network of 17 intensive care units (ICUs) in teaching hospitals across Spain in patients with established moderate-to-severe ARDS (defined by a ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen of 200 mm Hg or less assessed with a positive end-expiratory pressure of 10 cm H2O or more and FiO2 of 0·5 or more at 24 h after ARDS onset). Patients with brain death, terminal-stage disease, or receiving corticosteroids or immunosuppressive drugs were excluded. Eligible patients were randomly assigned based on balanced treatment assignments with a computerised randomisation allocation sequence using blocks of 10 opaque, sealed envelopes to receive immediate treatment with dexamethasone or continued routine intensive care (control group). Patients in the dexamethasone group received an intravenous dose of 20 mg once daily from day 1 to day 5, which was reduced to 10 mg once daily from day 6 to day 10. Patients in both groups were ventilated with lung-protective mechanical ventilation. Allocation concealment was maintained at all sites during the trial. Primary outcome was the number of ventilator-free days at 28 days, defined as the number of days alive and free from mechanical ventilation from day of randomisation to day 28. Secondary outcome was all-cause mortality 60 days after randomisation. All analyses were done according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT01731795. FINDINGS: Between March 28, 2013, and Dec 31, 2018, we enrolled 277 patients and randomly assigned 139 patients to the dexamethasone group and 138 to the control group. The trial was stopped by the data safety monitoring board due to low enrolment rate after enrolling more than 88% (277/314) of the planned sample size. The mean number of ventilator-free days was higher in the dexamethasone group than in the control group (between-group difference 4·8 days [95% CI 2·57 to 7·03]; p<0·0001). At 60 days, 29 (21%) patients in the dexamethasone group and 50 (36%) patients in the control group had died (between-group difference -15·3% [-25·9 to -4·9]; p=0·0047). The proportion of adverse events did not differ significantly between the dexamethasone group and control group. The most common adverse events were hyperglycaemia in the ICU (105 [76%] patients in the dexamethasone group vs 97 [70%] patients in the control group), new infections in the ICU (eg, pneumonia or sepsis; 33 [24%] vs 35 [25%]), and barotrauma (14 [10%] vs 10 [7%]). INTERPRETATION: Early administration of dexamethasone could reduce duration of mechanical ventilation and overall mortality in patients with established moderate-to-severe ARDS. FUNDING: Fundación Mutua Madrileña, Instituto de Salud Carlos III, The European Regional Development's Funds, Asociación Científica Pulmón y Ventilación Mecánica.