Static Compliance and Driving Pressure are Associated with ICU Mortality in Intubated COVID-19 ARDS (preprint)

Background: ascertaining whether respiratory system static compliance (Crs), driving pressure (DP), and tidal volume normalized for ideal body weight (VT/kg IBW) at the 1st day of controlled mechanical ventilation (CMV) are associated with intensive care unit (ICU) mortality in COVID-19 acute respiratory distress syndrome (ARDS).Methods: observational multicenter cohort study. All consecutive COVID-19 adult patients admitted to 25 ICUs belonging to the COVID-19 VENETO ICU network (February 28th-April 28th, 2020), who received CMV, were screened. Only patients fulfilling ARDS criteria and with complete records of Crs, DP and VT/kg IBW within the 1st day of CMV were included. Crs, DP and VT/kg IBW were collected in sedated, paralyzed and supine patients.Results: 704 COVID-19 patients were screened and 241 enrolled. Seventy-one patients (29%) died in ICU. The logistic regression analysis showed that: i) Crs was not linearly associated with ICU mortality (p-value for non-linearity=0.01), with a greater risk of death for values <48 ml/cmH2O; ii) the association between DP and ICU mortality was linear (p-value for non-linearity=0.68), and increasing DP from 10 to 14 cmH2O caused significant higher odds of in-ICU death (OR 1.45, 95%CI 1.06-1.99); iii) VT/kg IBW was not associated with a significant increase of the risk of death (OR 0.92, 95%CI 0.55-1.52). Multivariable analysis confirmed these findings.Conclusions: Crs <48 ml/cmH2O was associated with ICU mortality, while DP was linearly associated with mortality. DP should be kept as low as possible, even in the case of relatively preserved Crs, irrespective of VT/kg IBW, to reduce the risk of death. 

Prone Position in Intubated, Mechanically Ventilated Patients with Coronavirus Disease-19. (preprint)

Background: Limited data are available on the use of prone position in intubated, invasively ventilated patients with Coronavirus disease-19 (COVID-19). Aim of this study is to investigate the use and effect of prone position in this population during the first 2020 pandemic wave.Methods: Retrospective, multicentre, national cohort study conducted between February 24 and June 14, 2020 in 24 Italian Intensive Care Units (ICU) on adult patients needing invasive mechanical ventilation for respiratory failure caused by COVID-19.Clinical data were collected on the day of ICU admission. Information regarding the use of prone position were collected daily. Follow-up for patient outcomes was performed on July 15, 2020. The respiratory effects of the first prone position were studied in a subset of 78 patients. Patients were classified as Responders if the PaO2/FiO2 ratio increased ≥ 20 mmHg during prone position. Results:  Of 1057 included patients, mild, moderate and severe ARDS was present in 15, 50 and 35% of patients, respectively and had a resulting mortality of 25, 33 and 41%. Prone position was applied in 61% of the patients. Patients placed prone had a more severe disease and died significantly more (45% vs 33%, p<0.001). Overall, prone position induced a significant increase in PaO2/FiO2 ratio, while no change in respiratory system compliance was observed. Seventy-eight % of patients were Responders to prone position. Non-Responders had a more severe respiratory failure and died more often in the ICU (65% vs. 38%, p=0.047).Conclusions: During the COVID-19 pandemic, prone position has been widely adopted to treat mechanically ventilated patients with respiratory failure. The majority of patients improved their oxygenation during prone position, most likely due to a better ventilation perfusion matching.Trial registration: clinicaltrials.gov  number: NCT04388670

Sustained Oxygenation Improvement After First Prone Positioning Is Associated with Liberation from Mechanical Ventilation and Survival in Critically Ill COVID-19 Patients: A Cohort Study (preprint)

Background: Prone positioning (PP) has been used to improve oxygenation in patients affected by the SARS-CoV-2 disease (COVID-19). Several mechanisms, including lung recruitment and better lung ventilation/perfusion matching, make a relevant rationale for using PP. However, not all patients maintain the oxygenation improvement after returning to supine position. Nevertheless, no evidence exists that a sustained oxygenation response after PP is associated to outcome in mechanically ventilated COVID-19 patients.Methods: We analyzed data from 191 patients affected by COVID-19 related acute respiratory distress syndrome undergoing PP for clinical reasons. Clinical history, severity scores and respiratory mechanics were analyzed. Patients were classified as responders (≥50% PaO2/FiO2 increase) or non-responders (<50% PaO2/FiO2 increase) based on the PaO2/FiO2 increase after returning to supine position from the first PP session. Differences among the groups in physiological variables, complication rates and outcome were evaluated. A competing risk regression analysis was conducted to evaluate if PaO2/FiO2 response after the first pronation cycle was associated to liberation from mechanical ventilation.Findings: No differences in demographics, comorbidities, ventilatory treatment and PaO2/FiO2 before PP were found between responders (91/191) and non-responders (98/191). Despite no differences in ICU length of stay, non-responders had a higher rate of tracheostomy (49·5 vs 68·4%, P=0·008) and mortality (53·1% vs 33·3%, p=0·006), as compared to responders. Moreover, oxygenation response after the first PP was independently associated to liberation from mechanical ventilation at 28 days.Interpretation: Sustained oxygenation improvement after first PP session is independently associated to improved survival and reduced duration of mechanical ventilation in critically ill COVID-19 patients.Trial Registration: The study was registered in ClinicalTrials.gov (NCT04411459).Funding Statement: None.Declaration of Interests: None.Ethics Approval Statement: The study was approved by the Institutional Review Board of the study coordinator center (Maggiore Hospital, Bologna, Italy, approval number: 273/2020/OSS/AUSLBO) and by each institutional review committee of the participating hospitals. Informed consent was partially waived according to the approval of the local Ethics committee and analysis was conducted on anonymized individual data.

Glucocorticoids inhibit type I IFN beta signaling and the upregulation of CD73 in human lung (preprint)

Purpose Glucocorticoids are widely used to treat acute respiratory distress syndrome (ARDS) despite its use is highly controversial based on randomized controlled trials and meta-analyses. As type I interferons (IFNs) are our first line of defense against severe viral respiratory infections, we explored whether glucocorticoids interfere with IFN signaling and whether their use associates to outcome of IFN beta treatment of ARDS. Methods We performed a propensity-matched post-hoc-analysis using data from the recent randomized INTEREST-trial comparing IFN beta-1a to placebo in ARDS patients. Based on the results of these analyses we utilized human lung tissue and human pulmonary endothelial cell cultures to investigate the effect of hydrocortisone on IFN nuclear signaling and the protein transcription of CD73, a molecule responsible for vascular integrity. Results We found that hydrocortisone reduces the production, and prevents the nuclear translocation of IRF9, that is required for IFN beta-dependent signaling of multiple IFN-induced genes. In addition, hydrocortisone inhibits IFN beta-dependent upregulation of CD73 in human lung tissue. Additionally, we found that use of glucocorticoids with IFN beta-1a was independently associated with increased mortality (OR 5.4, 95% CI 2.1–13.9, P< 0.001) in the INTEREST-trial. Conclusions Glucocorticoids inhibit type I IFN beta signaling and the upregulation of CD73 in human lung. This provides the mechanistic basis for the harmful association of glucocorticoids in IFN beta treated patients in the INTEREST-trial. Most importantly, it strongly speaks against the use of glucocorticoids in viral-induced ARDS such as in the current corona virus pandemia. Take home message Glucocorticoids inhibit type I interferon beta signaling and the upregulation of CD73 that is a key molecule preventing vascular leakage and harmful leukocyte infiltration into the lungs. This work provides the mechanistic basis for the need to avoid glucocorticoids in viral-induced ARDS, in which endogenous interferon is needed to combat the infection and its consequences.