Factors Associated With Prolonged Ventilation in Patients Receiving Prone Positioning Protocol With Muscle Relaxants for Severe COVID-19 Pneumonia.

BACKGROUND: Prone positioning and neuromuscular blocking agents (NMBAs) are frequently used to treat severe respiratory failure from COVID-19 pneumonia. Prone positioning has shown to improve mortality, whereas NMBAs are used to prevent ventilator asynchrony and reduce patient self-inflicted lung injury. However, despite the use of lung-protective strategies, high death rates in this patient population have been reported. METHODS: We retrospectively examined the factors affecting prolonged mechanical ventilation in patients receiving prone positioning plus muscle relaxants. The medical records of 170 patients were reviewed. Subjects were divided into 2 groups according to ventilator-free days (VFDs) at day 28. Whereas subjects with VFDs < 18 d were defined as prolonged mechanical ventilation, subjects with VFDs ≥18 d were defined as short-term mechanical ventilation. Subjects' baseline status, status at ICU admission, therapy before ICU admission, and treatment in the ICU were studied. RESULTS: Under the proning protocol for COVID-19, the mortality rate in our facility was 11.2%. The prognosis may be improved by avoiding lung injury in the early stages of mechanical ventilation. According to multifactorial logistic regression analysis, persistent SARS-CoV-2 viral shedding in blood (P = .027), higher daily corticosteroid use before ICU admission (P = .007), delayed recovery of lymphocyte count (P < .001), and higher maximal fibrinogen degradation products (P = .039) were associated with prolonged mechanical ventilation. A significant relationship was found between daily corticosteroid use before admission and VFDs by squared regression analysis (y = -0.00008522x2 + 0.01338x + 12.8; x: daily corticosteroids dosage before admission [prednisolone mg/d]; y: VFDs/28 d, R2 = 0.047, P = .02). The peak point of the regression curve was 13.4 d at 78.5 mg/d of the equivalent prednisolone dose, which corresponded to the longest VFDs. CONCLUSIONS: Persistent SARS-CoV-2 viral shedding in blood, high corticosteroid dose from the onset of symptoms to ICU admission, slow recovery of lymphocyte counts, and high levels of fibrinogen degradation products after admission were associated with prolonged mechanical ventilation in subjects with severe COVID-19 pneumonia.

Effect of Tocilizumab on "Ventilator Free Days" Composite Outcome in SARS-CoV-2 Patients: A Retrospective Competing Risk Analysis.

Background: SARS-CoV-2 infection demonstrates a wide range of severity. More severe cases demonstrate a cytokine storm with elevated serum interleukin-6, hence IL-6 receptor antibody tocilizumab was tried for the management of severe cases. Aims: Effect of tocilizumab on ventilator-free days among critically ill SARS-CoV-2 patients. Method: Retrospective propensity score matching study, comparing mechanically ventilated patients who received tocilizumab to a control group. Results: 29 patients in the intervention group were compared to 29 controls. Matched groups were similar. Ventilator-free days were more numerous in the intervention group (SHR 2.7, 95% CI: 1.2 - 6.3; p = 0.02), ICU mortality rate was not different (37.9% versus 62%, p = 0.1), actual ventilator-free periods were significantly longer in tocilizumab group (mean difference 4.7 days; p = 0.02). Sensitivity analysis showed a significantly lower hazard ratio of death in tocilizumab group (HR 0.49, 95% CI: 0.25 - 0.97; p = 0.04). There was no difference in positive cultures among groups (55.2% in tocilizumab group versus 34.5% in the control; p = 0.1). Conclusion: Tocilizumab may improve the composite outcome of ventilator-free days at day 28 among mechanically ventilated SARS-CoV-2 patients; it is associated with significantly longer actual ventilator-free periods, and insignificantly lower mortality and higher superinfection.

Association of ventilator-free days with respiratory physiotherapy in critically ill patients with Coronavirus Disease 2019 (COVID-19) during the first pandemic wave. A propensity score-weighted analysis.

Background: Respiratory physiotherapy is reported as safe and feasible in mechanically ventilated patients with severe Coronavirus Disease (COVID-19) admitted to Intensive Care Unit (ICU), but the short-term benefits remain unclear. Methods: We performed a retrospective observational study in four ICUs in Northern Italy. All patients with COVID-19 admitted to ICU and under invasive mechanical ventilation (MV) between March 1st and May 30th, 2020, were enrolled into the study. Overlap weighting based on the propensity score was used to adjust for confounding in the comparison of patients who had or had not been treated by physiotherapists. The primary outcome was the number of days alive and ventilator-free (VFDs). The secondary outcomes were arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio (P/F) at ICU discharge, ICU length of stay, ICU and hospital mortality, and survival at 90 days. The trial protocol was registered on clinicaltrials.gov (NCT05067907). Results: A total of 317 patients were included in the analysis. The median VFDs was 18 days [interquartile range (IQR) 10; 24] in patients performing physiotherapy and 21 days (IQR 0; 26) in the group without physiotherapy [incidence rate ratio (IRR) 0.86, 95% confidence interval (CI): 0.78; 0.95]. The chance of 0 VFDs was lower for patients treated by physiotherapists compared to those who were not [odds ratio (OR) = 0.36, 95% CI: 0.18-0.71]. Survival at 90 days was 96.0% in the physiotherapy group and 70.6% in patients not performing physiotherapy [hazard ratio (HR) = 0.14, 95% CI: 0.03-0.71]. Number of VFDs was not associated with body mass index (BMI), sex, or P/F at ICU admission for individuals with at least 1 day off the ventilator. Conclusion: In patients with COVID-19 admitted to ICU during the first pandemic wave and treated by physiotherapists, the number of days alive and free from MV was lower compared to patients who did not perform respiratory physiotherapy. Survival at 90 days in the physiotherapy group was greater compared to no physiotherapy. These findings may be the starting point for further investigation in this setting.

"Ventilator-free days" composite outcome in patients with SARS-CoV-2 infection treated with tocilizumab: A retrospective competing risk analysis.

BACKGROUND: SARS-CoV-2 infection demonstrates a wide range of severity, with more severe cases presenting with a cytokine storm with elevated serum interleukin-6; hence, the interleukin-6 receptor antibody tocilizumab was used for the management of severe cases. OBJECTIVE: To explore the effect of tocilizumab on ventilator-free day composite outcomes among critically ill patients with SARS-CoV-2 infection. METHODS: This retrospective propensity score-matching study compared mechanically ventilated patients who received tocilizumab to a control group. RESULTS: Twenty-nine patients in the intervention group were compared to 29 controls. The matched groups were similar. The ventilator-free days composite outcome was higher in the intervention group (sub-distribution hazard ratio 2.7, 95% confidence interval [CI]: 1.2-6.3; p = 0.02), the mortality rate in the intensive care unit was not different (37.9% vs 62%, p = 0.1), and actual ventilator-free days were significantly longer in the tocilizumab group (mean difference 4.7 days; p = 0.02). Sensitivity analysis showed a significantly lower hazard ratio for death in the tocilizumab group (HR 0.49, 95% CI: 0.25-0.97; p = 0.04). Positive cultures were not significantly different among the groups (55.2% vs 34.5% in the tocilizumab and control groups, respectively; p = 0.1). CONCLUSIONS: Tocilizumab may improve the composite outcome of ventilator-free days at day 28 among mechanically ventilated patients with SARS-CoV-2 infection. It is associated with significantly longer actual ventilator-free days, insignificantly lower mortality, and higher superinfection.

Effect of dexamethasone in patients with ARDS and COVID-19 - prospective, multi-centre, open-label, parallel-group, randomised controlled trial (REMED trial): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The primary objective of this study is to test the hypothesis that administration of dexamethasone 20 mg is superior to a 6 mg dose in adult patients with moderate or severe ARDS due to confirmed COVID-19. The secondary objective is to investigate the efficacy and safety of dexamethasone 20 mg versus dexamethasone 6 mg. The exploratory objective of this study is to assess long-term consequences on mortality and quality of life at 180 and 360 days. TRIAL DESIGN: REMED is a prospective, phase II, open-label, randomised controlled trial testing superiority of dexamethasone 20 mg vs 6 mg. The trial aims to be pragmatic, i.e. designed to evaluate the effectiveness of the intervention in conditions that are close to real-life routine clinical practice. PARTICIPANTS: The study is multi-centre and will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. INCLUSION CRITERIA: Subjects will be eligible for the trial if they meet all of the following criteria: 1. Adult (≥18 years of age) at time of enrolment; 2. Present COVID-19 (infection confirmed by RT-PCR or antigen testing); 3. Intubation/mechanical ventilation or ongoing high-flow nasal cannula (HFNC) oxygen therapy; 4. Moderate or severe ARDS according to Berlin criteria: • Moderate - PaO2/FiO2 100-200 mmHg; • Severe - PaO2/FiO2 < 100 mmHg; 5. Admission to ICU in the last 24 hours. EXCLUSION CRITERIA: Subjects will not be eligible for the trial if they meet any of the following criteria: 1. Known allergy/hypersensitivity to dexamethasone or excipients of the investigational medicinal product (e.g. parabens, benzyl alcohol); 2. Fulfilled criteria for ARDS for ≥14 days at enrolment; 3. Pregnancy or breastfeeding; 4. Unwillingness to comply with contraception measurements from enrolment until at least 1 week after the last dose of dexamethasone (sexual abstinence is considered an adequate contraception method); 5. End-of-life decision or patient is expected to die within next 24 hours; 6. Decision not to intubate or ceilings of care in place; 7. Immunosuppression and/or immunosuppressive drugs in medical history: a) Systemic immunosuppressive drugs or chemotherapy in the past 30 days; b) Systemic corticosteroid use before hospitalization; c) Any dose of dexamethasone during the present hospital stay for COVID-19 for ≥5 days before enrolment; d) Systemic corticosteroids during present hospital stay for conditions other than COVID-19 (e.g. septic shock); 8. Current haematological or generalized solid malignancy; 9. Any contraindication for corticosteroid administration, e.g. • intractable hyperglycaemia; • active gastrointestinal bleeding; • adrenal gland disorders; • presence of superinfection diagnosed with locally established clinical and laboratory criteria without adequate antimicrobial treatment; 10. Cardiac arrest before ICU admission; 11. Participation in another interventional trial in the last 30 days. INTERVENTION AND COMPARATOR: Dexamethasone solution for injection/infusion is the investigational medicinal product as well as the comparator. The trial will assess two doses, 20 mg (investigational) vs 6 mg (comparator). Patients in the intervention group will receive dexamethasone 20 mg intravenously once daily on day 1-5, followed by dexamethasone 10 mg intravenously once daily on day 6-10. Patients in the control group will receive dexamethasone 6 mg day 1-10. All authorized medicinal products containing dexamethasone in the form of solution for i.v. injection/infusion can be used. MAIN OUTCOMES: Primary endpoint: Number of ventilator-free days (VFDs) at 28 days after randomisation, defined as being alive and free from mechanical ventilation. SECONDARY ENDPOINTS: a) Mortality from any cause at 60 days after randomisation; b) Dynamics of inflammatory marker (C-Reactive Protein, CRP) change from Day 1 to Day 14; c) WHO Clinical Progression Scale at Day 14; d) Adverse events related to corticosteroids (new infections, new thrombotic complications) until Day 28 or hospital discharge; e) Independence at 90 days after randomisation assessed by Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days through telephone structured interviews using the Barthel Index. RANDOMISATION: Randomisation will be carried out within the electronic case report form (eCRF) by the stratified permuted block randomisation method. Allocation sequences will be prepared by a statistician independent of the study team. Allocation to the treatment arm of an individual patient will not be available to the investigators before completion of the whole randomisation process. The following stratification factors will be applied: • Age <65 and ≥ 65; • Charlson Comorbidity index (CCI) <3 and ≥3; • CRP <150 mg/L and ≥150 mg/L • Trial centre. Patients will be randomised in a 1 : 1 ratio into one of the two treatment arms. Randomisation through the eCRF will be available 24 hours every day. BLINDING (MASKING): This is an open-label trial in which the participants and the study staff will be aware of the allocated intervention. Blinded pre-planned statistical analysis will be performed. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size is calculated to detect the difference of 3 VFDs at 28 days (primary efficacy endpoint) between the two treatment arms with a two-sided type I error of 0.05 and power of 80%. Based on data from a multi-centre randomised controlled trial in COVID-19 ARDS patients in Brazil and a multi-centre observational study from French and Belgian ICUs regarding moderate to severe ARDS related to COVID-19, investigators assumed a standard deviation of VFD at 28 days as 9. Using these assumptions, a total of 142 patients per treatment arm would be needed. After adjustment for a drop-out rate, 150 per treatment arm (300 patients per study) will be enrolled. TRIAL STATUS: This is protocol version 1.1, 15.01.2021. The trial is due to start on 2 February 2021 and recruitment is expected to be completed by December 2021. TRIAL REGISTRATION: The study protocol was registered on EudraCT No.:2020-005887-70, and on December 11, 2020 on ClinicalTrials.gov (Title: Effect of Two Different Doses of Dexamethasone in Patients With ARDS and COVID-19 (REMED)) Identifier: NCT04663555 with a last update posted on February 1, 2021. FULL PROTOCOL: The full protocol (version 1.1) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the standard formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Ivermectin administration is associated with lower gastrointestinal complications and greater ventilator-free days in ventilated patients with COVID-19: A propensity score analysis.

INTRODUCTION: COVID-19 patients have been reported to have digestive symptoms with poor outcome. Ivermectin, an antiparasitic drug, has been used in COVID-19 patients. The objective of this study was to evaluate whether ivermectin has effects on gastrointestinal complications and ventilator-free days in ventilated patients with COVID-19. METHODS: COVID-19 patients who were mechanically ventilated in the ICU were included in this study. The ventilated patients who received ivermectin within 3 days after admission were assigned to the Ivermectin group, and the others were assigned to the Control group. Patients in the Ivermectin group received ivermectin 200 µg/kg via nasal tube. The incidence of gastrointestinal complications and ventilator-free days within 4 weeks from admission were evaluated as clinical outcomes using a propensity score with the inverse probability weighting method. RESULTS: We included 88 patients in this study, of whom 39 patients were classified into the Ivermectin group, and 49 patients were classified into the Control group. The hazard ratio for gastrointestinal complications in the Ivermectin group as compared with the Control group was 0.221 (95% confidence interval [CI], 0.057 to 0.855; p = 0.029) in a Cox proportional-hazard regression model. The odds ratio for ventilator-free days as compared with the Control group was 1.920 (95% CI, 1.076 to 3.425; p = 0.027) in a proportional odds logistic regression model. CONCLUSIONS: Ivermectin improved gastrointestinal complications and the number of ventilator-free days in severe COVID-19 patients undergoing mechanical ventilation. Prevention of gastrointestinal symptoms by SARS-Cov-2 might be associated with COVID-19 outcome.

Effects of Methylprednisolone on Ventilator-Free Days in Mechanically Ventilated Patients with Acute Respiratory Distress Syndrome and COVID-19: A Retrospective Study.

Objectives: There are limited data regarding the efficacy of methylprednisolone in patients with acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) requiring invasive mechanical ventilation. We aimed to determine whether methylprednisolone is associated with increases in the number of ventilator-free days (VFDs) among these patients. Design: Retrospective single-center study. Setting: Intensive care unit. Patients: All patients with ARDS due to confirmed SARS-CoV-2 infection and requiring invasive mechanical ventilation between 1 March and 29 May 2020 were included. Interventions: None. Measurements and Main Results: The primary outcome was ventilator-free days (VFDs) for the first 28 days. Defined as being alive and free from mechanical ventilation. The primary outcome was analyzed with competing-risks regression based on Fine and Gray's proportional sub hazards model. Death before day 28 was considered to be the competing event. A total of 77 patients met the inclusion criteria. Thirty-two patients (41.6%) received methylprednisolone. The median dose was 1 mg·kg-1 (IQR: 1-1.3 mg·kg-1) and median duration for 5 days (IQR: 5-7 days). Patients who received methylprednisolone had a mean 18.8 VFDs (95% CI, 16.6-20.9) during the first 28 days vs. 14.2 VFDs (95% CI, 12.6-16.7) in patients who did not receive methylprednisolone (difference, 4.61, 95% CI, 1.10-8.12, p = 0.001). In the multivariable competing-risks regression analysis and after adjusting for potential confounders (ventilator settings, prone position, organ failure support, severity of the disease, tocilizumab, and inflammatory markers), methylprednisolone was independently associated with a higher number of VFDs (subhazards ratio: 0.10, 95% CI: 0.02-0.45, p = 0.003). Hospital mortality did not differ between the two groups (31.2% vs. 28.9%, p = 0.82). Hospital length of stay was significantly shorter in the methylprednisolone group (24 days [IQR: 15-41 days] vs. 37 days [IQR: 23-52 days], p = 0.046). The incidence of positive blood cultures was higher in patients who received methylprednisolone (37.5% vs. 17.8%, p = 0.052). However, 81% of patients who received methylprednisolone also received tocilizumab. The number of days with hyperglycemia was similar in the two groups. Conclusions: Methylprednisolone was independently associated with increased VFDs and shortened hospital length of stay. The combination of methylprednisolone and tocilizumab was associated with a higher rate of positive blood cultures. Further trials are needed to evaluate the benefits and safety of methylprednisolone in moderate or severe COVID-19 ARDS.

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.

PRactice of VENTilation in Patients with Novel Coronavirus Disease (PRoVENT-COVID): rationale and protocol for a national multicenter observational study in The Netherlands.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is rapidly expanding across the world, with more than 100,000 new cases each day as of end-June 2020. Healthcare workers are struggling to provide the best care for COVID-19 patients. Approaches for invasive ventilation vary widely between and within countries and new insights are acquired rapidly. We aim to investigate invasive ventilation practices and outcome in COVID-19 patients in the Netherlands. METHODS: PRoVENT-COVID ('study of PRactice of VENTilation in COVID-19') is an investigator-initiated national, multicenter observational study to be undertaken in intensive care units (ICUs) in The Netherlands. Consecutive COVID-19 patients aged 18 years or older, who are receiving invasive ventilation in the participating ICUs, are to be enrolled during a 10-week period, with a daily follow-up of 7 days. The primary outcome is ventilatory management (including tidal volume expressed as mL/kg predicted body weight and positive end-expiratory pressure expressed as cmH2O) during the first 3 days of ventilation. Secondary outcomes include other ventilatory variables, use of rescue therapies for refractory hypoxemia such as prone positioning and extracorporeal membrane oxygenation, use of sedatives, vasopressors and inotropes; daily cumulative fluid balances; acute kidney injury; ventilator-free days and alive at day 28 (VFD-28), duration of ICU and hospital stay, and ICU, hospital and 90-day mortality. DISCUSSION: PRoVENT-COVID will be the largest observational study to date, with high density ventilatory data and major outcomes. There is urgent need for a better understanding of ventilation practices, and the effects of ventilator settings on outcomes in COVID-19 patients. The results of PRoVENT-COVID will be rapidly disseminated through electronic presentations, such as webinars and electronic conferences, and publications in international peer-reviewed journals. Access to source data will be made available through local, regional and national anonymized datasets on request, and after agreement of the PRoVENT-COVID steering committee. TRIAL REGISTRATION: PRoVENT-COVID is registered at clinicaltrials.gov (identifier NCT04346342).

Helmet continuous positive airway pressure versus high-flow nasal cannula in COVID-19: a pragmatic randomised clinical trial (COVID HELMET).

BACKGROUND: Patients with COVID-19 and hypoxaemia despite conventional low-flow oxygen therapy are often treated with high-flow nasal cannula (HFNC) in line with international guidelines. Oxygen delivery by helmet continuous positive airway pressure (CPAP) is a feasible option that enables a higher positive end-expiratory pressure (PEEP) and may theoretically reduce the need for intubation compared to HFNC but direct comparative evidence is lacking. METHODS: We plan to perform an investigator-initiated, pragmatic, randomised trial at an intermediate-level COVID-19 cohort ward in Helsingborg Hospital, southern Sweden. We have estimated a required sample size of 120 patients randomised 1:1 to HFNC or Helmet CPAP to achieve 90% power to detect superiority at a 0.05 significance level regarding the primary outcome of ventilator free days (VFD) within 28 days using a Mann-Whitney U test. Patient recruitment is planned to being June 2020 and be completed in the first half of 2021. DISCUSSION: We hypothesise that the use of Helmet CPAP will reduce the need for invasive mechanical ventilation compared to the use of HFNC without having a negative effect on survival. This could have important implications during the current COVID-19 epidemic. TRIAL REGISTRATION: ClinicalTrials.gov NCT04395807 . Registered on 20 May 2020.

A prospective, randomised, double blind placebo-controlled trial to evaluate the efficacy and safety of tocilizumab in patients with severe COVID-19 pneumonia (TOC-COVID): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: SARS-CoV2 infection leads to a concomitant pulmonary inflammation. This inflammation is supposed to be the main driver in the pathogenesis of lung failure (Acute Respiratory Distress Syndrome) in COVID-19. Objective of this study is to evaluate the efficacy and safety of a single dose treatment with Tocilizumab in patients with severe COVID-19. We hypothesize that Tocilizumab slows down the progression of SARS-CoV-2 induced pneumonia and inflammation. We expect an improvement in pulmonary function compared to placebo-treated patients. Desirable outcomes would be that tocilizumab reduces the number of days that patients are dependent on mechanical ventilation and reduces the invasiveness of breathing assistance. Furthermore, this treatment might result in fewer admissions to intensive care units. Next to these efficacy parameters, safety of a therapy with Tocilizumab in COVID-19 patients has to be monitored closely, since immunosuppression could lead to an increased rate of bacterial infections, which could negatively influence the patient's outcome. TRIAL DESIGN: Multicentre, prospective, 2-arm randomised (ratio 1:1), double blind, placebo-controlled trial with parallel group design. PARTICIPANTS: Inclusion criteria 1.Proof of SARS-CoV2 (Symptoms and positive polymerase chain reaction (PCR))2.Severe respiratory failure: a.Ambient air SpO2 ≤ 92% orb.Need of ≥ 6l O2/min orc.NIV (non-invasive ventilation) ord.IMV (invasive mechanical ventilation)3.Age ≥ 18 years Exclusion criteria 1.Non-invasive or invasive mechanical ventilation ≥ 48 hours2.Pregnancy or breast feeding3.Liver injury or failure (AST/ALT ≥ 5x ULN)4.Leukocytes < 2 × 103/µl5.Thrombocytes < 50 × 103/µl6.Severe bacterial infection (PCT > 3ng/ml)7.Acute or chronic diverticulitis8.Immunosuppressive therapy (e.g. mycophenolate, azathioprine, methotrexate, biologicals, prednisolone >10mg/d; exceptions are: prednisolone ≤ 10mg/d, sulfasalazine or hydroxychloroquine)9.Known active or chronic tuberculosis10.Known active or chronic viral hepatitis11.Known allergic reactions to tocilizumab or its ingredients12.Life expectation of less than 1 year (independent of COVID-19)13.Participation in any other interventional clinical trial within the last 30 days before the start of this trial14.Simultaneous participation in other interventional trials (except for participation in COVID-19 trials) which could interfere with this trial; simultaneous participation in registry and diagnostic trials is allowed15.Failure to use one of the following safe methods of contraception: female condoms, diaphragm or coil, each used in combination with spermicides; intra-uterine device; hormonal contraception in combination with a mechanical method of contraception. The data collection of the primary follow up (28 days after randomisation) takes place during the hospital stay. Subsequently, a telephone interview on the quality of life is conducted after 6 and 12 months. Participants will be recruited from inpatients at ten medical centres in Germany. INTERVENTION AND COMPARATOR: Intervention arm: Application of 8mg/kg body weight (BW) Tocilizumab i.v. once immediately after randomisation (12 mg/kg for patients with <30kg BW; total dose should not exceed 800 mg) AND conventional treatment. Control arm: Placebo (NaCl) i.v. once immediately after randomisation AND conventional treatment. MAIN OUTCOMES: Primary endpoint is the number of ventilator free days (d) (VFD) in the first 28 days after randomisation. Non-invasive ventilation (NIV), Invasive mechanical ventilation (IMV) and extracorporeal membrane oxygenation (ECMO) are defined as ventilator days. VFD's are counted as zero if the patient dies within the first 28 days. RANDOMISATION: The randomisation code will be generated by the CTU (Clinical Trials Unit, ZKS Freiburg) using the following procedure to ensure that treatment assignment is unbiased and concealed from patients and investigator staff. Randomisation will be stratified by centre and will be performed in blocks of variable length in a ratio of 1:1 within each centre. The block lengths will be documented separately and will not be disclosed to the investigators. The randomisation code will be produced by validated programs based on the Statistical Analysis System (SAS). BLINDING (MASKING): Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 100 participants will be randomised to each group (thus 200 participants in total). TRIAL STATUS: Protocol Version: V 1.2, 16.04.2020. Recruitment began 27th April 2020 and is anticipated to be completed by December 2020. TRIAL REGISTRATION: The trial was registered before trial start in trial registries (EudraCT: No. 2020-001408-41, registered 21st April 2020, and DRKS: No. DRKS00021238, registered 22nd April 2020). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.