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Purpose: The novel coronavirus disease (COVID-19) has revived the debate on the optimal tidal volume during acute respiratory distress syndrome (ARDS). Some experts recommend 6 mL/kg of predicted body weight (PBW) for all patients, while others suggest 7-9 mL/kg PBW for those with compliance >50 mL/cmH 2 O. We investigated whether a tidal volume ≥ 7 ml/kg PBW may be safe in COVID-19 patients, particularly those with compliance >50 mL/cmH 2 O., Materials and Methods: This secondary analysis of a multicenter study compares the Intensive Care Unit (ICU) mortality among 600 patients ventilated with <7 or ≥ 7 mL/kg PBW. Compliance was categorized as <40, 40-50, or > 50 mL/cmH 2 O., Results: 346 patients were ventilated with <7 (6.2 ± 0.5) mL/kg PBW and 254 with ≥7 (7.9 ± 0.9) mL/kg PBW. ICU mortality was 33 % and 29 % in the two groups (p = 0.272). At multivariable regression analysis, tidal volume ≥ 7 mL/kg PBW was associated with lower ICU mortality in the overall population (odds ratio: 0.62 [95 %-confidence interval: 0.40-0.95]) and in each compliance category., Conclusions: A tidal volume ≥ 7 (up to 9) mL/kg PBW was associated with lower ICU mortality in these COVID-19 patients, including those with compliance <40 mL/cmH 2 O. This finding should be interpreted cautiously due to the retrospective study design., Trial Registration: ClinicalTrails.govNCT04388670., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Giacomo Grasselli and Alberto Zanella report financial support was provided by the Italian Ministry of Health (“Ricerca Corrente” funding to the Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico di Milano, Milan, Italy). The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

During COVID-19 pandemic, vaccination has been strongly recommended and advocated to prevent COVID-19 infection and adverse outcomes, particularly among at-risk populations. The vaccination against SARS-CoV-2 (COVAC) occurred at off-site locations capable of accommodating large crowds, distinct from the hospital setting, where a team of intensivists, emergency physicians, and nurses, ensuring prompt medical attention (medical occurrences, MO) in cases of adverse event following immunization. Our aims were to estimate the incidence of MO, and to assess its association with demographics, and vaccine characteristics. Our retrospective cohort study included all subject aged 12 years and older who received vaccinations at two large out-of-hospital vaccination hubs (Fiera Milano City, Palazzo delle Scintille), between April 12th and August 31st, 2021. Nine hundred and ninety-five thousand and twenty-eight vaccinations were administrated. MOs incidence rate was 278/100,000 doses (95% confidence interval (CI) 268-289). Most MOs were mild (86.27%) and mainly observed in subjects who received the Comirnaty vaccine; 92 MOs (3.32%) were severe and mostly occurred in recipients of the Vaxzeria vaccine. The incidence rate for hospital transfers following vaccination was 4.7/100,000 doses (95% CI 3.5-6.2) and any level of anaphylaxis occurred in 0.4 cases per 100,000 administrated doses (95% CI 0.3.-0.7). Sex, age, type of vaccine and first dose were associated with incidence of MO. Our results showed a low incidence rate in MOs after COVAC, mainly mild and support the feasibility, effectiveness and safety of vaccinations administered in hubs with a dedicated SEU located outside of the hospital setting., (© 2024. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Objectives: Although respiratory failure is the most common feature in coronavirus disease 2019 (COVID-19), abdominal organ involvement is likewise frequently observed. To investigate visceral and thoracic circulation and abdominal organ damage in COVID-19 patients., Materials and Methods: A monocentric observational study was carried on. In COVID-19 patients affected by acute respiratory distress syndrome (ARDS) (n = 31) or mild pneumonia (n = 60) thoracoabdominal circulation was evaluated using Doppler-ultrasound and computed tomography. The study also included non-COVID-19 patients affected by ARDS (n = 10) or portal hypertension (n = 10) for comparison of the main circulatory changes., Results: Patients affected by COVID-19 ARDS showed hyperdynamic visceral flow and increased portal velocity, hepatic artery resistance-index, and spleen diameter relative to those with mild-pneumonia (p = 0.001). Splanchnic circulatory parameters significantly correlated with the main respiratory indexes (p < 0.001) and pulmonary artery diameter (p = 0.02). The chest and abdominal vascular remodeling pattern of COVID-19 ARDS patients resembled the picture observed in the PH group, while differed from that of the non-COVID ARDS group. A more severe COVID-19 presentation was associated with worse liver dysfunction and enhanced inflammatory activation; these parameters both correlated with abdominal (p = 0.04) and chest imaging measures (p = 0.03)., Conclusion: In COVID-19 ARDS patients there are abdominal and lung vascular modifications that depict a portal hypertension-like pattern. The correlation between visceral vascular remodeling, pulmonary artery enlargement, and organ damage in these critically ill patients is consistent with a portal hyperlfow-like syndrome that could contribute to the peculiar characteristics of respiratory failure in these patients., Clinical Relevance Statement: our data suggest that the severity of COVID-19 lung involvement is directly related to the development of a portal hyperflow-like syndrome. These observations should help in defining the need for a closer monitoring, but also to develop dedicated therapeutic strategies., Competing Interests: Declaration of competing interest All authors declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: This study aimed to investigate the effects of inspired oxygen fraction (FiO 2 ) and positive end-expiratory pressure (PEEP) on gas exchange in mechanically ventilated patients with COVID-19. Methods: Two FiO 2 (100%, 40%) were tested at 3 decreasing levels of PEEP (15, 10, and 5 cmH 2 O). At each FiO 2 and PEEP, gas exchange, respiratory mechanics, hemodynamics, and the distribution of ventilation and perfusion were assessed with electrical impedance tomography. The impact of FiO 2 on the intrapulmonary shunt (delta shunt) was analyzed as the difference between the calculated shunt at FiO 2 100% (shunt) and venous admixture at FiO 2 40% (venous admixture). Results: Fourteen patients were studied. Decreasing PEEP from 15 to 10 cmH 2 O did not change shunt (24 [21-28] vs 27 [24-29]%) or venous admixture (18 [15-26] vs 23 [18-34]%) while partial pressure of arterial oxygen (FiO 2 100%) was higher at PEEP 15 (262 [198-338] vs 256 [147-315] mmHg; P  < .05). Instead when PEEP was decreased from 10 to 5 cmH 2 O, shunt increased to 36 [30-39]% ( P  < .05) and venous admixture increased to 33 [30-43]% ( P  < .05) and partial pressure of arterial oxygen (100%) decreased to 109 [76-177] mmHg ( P  < .05). At PEEP 15, administration of 100% FiO 2 resulted in a shunt greater than venous admixture at 40% FiO 2, ((24 [21-28] vs 18 [15-26]%, P  = .005), delta shunt 5.5% (2.3-8.8)). Compared to PEEP 10, PEEP of 5 and 15 cmH 2 O resulted in decreased global and pixel-level compliance. Cardiac output at FiO 2 100% resulted higher at PEEP 5 (5.4 [4.4-6.5]) compared to PEEP 10 (4.8 [4.1-5.5], P  < .05) and PEEP 15 cmH 2 O (4.7 [4.5-5.4], P  < .05). Conclusion: In this study, PEEP of 15 cmH 2 O, despite resulting in the highest oxygenation, was associated with overdistension. PEEP of 5 cmH 2 O was associated with increased shunt and alveolar collapse. Administration of 100% FiO 2 was associated with an increase in intrapulmonary shunt in the setting of high PEEP. Trial registration: NCT05132933., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AMP reports personal fees from Baxter, Maquet, Boehringer Ingelheim, and Xenios outside the submitted work. GG reports consultation fees from Getinge, Draeger, Pfizer, Thermo Fisher, MSD, and Gilead. The remaining authors declare that they have no conflicts of interest.

Background: No univocal recommendation exists for microbiological diagnosis of ventilator-associated pneumonia (VAP). Sampling of either proximal or distal respiratory tract likely impacts on the broad range of VAP incidence between cohorts. Immune biomarkers to rule-in/rule-out VAP diagnosis, although promising, have not yet been validated. COVID-19-induced ARDS made VAP recognition even more challenging, often leading to overdiagnosis and overtreatment. We evaluated the impact of different respiratory samples and laboratory techniques on VAP incidence and microbiological findings in COVID-19 patients., Methods: Prospective single-centre cohort study conducted among COVID-19 mechanically ventilated patients in Policlinico Hospital (Milan, Italy) from January 2021 to May 2022. Microbiological confirmation of suspected VAP (sVAP) was based on concomitant endotracheal aspirates (ETA) and bronchoalveolar lavage (BAL). Conventional and fast microbiology (FILMARRAY® Pneumonia Panel plus, BAL FAPPP ) as well as immunological markers (immune cells and inflammatory cytokines) was analysed., Results: Seventy-nine patients were included. Exposure to antibiotics and steroid therapy before ICU admission occurred in 51/79 (64.6%) and 60/79 (65.9%) patients, respectively. Median duration of MV at VAP suspicion was 6 (5-9) days. Incidence rate of microbiologically confirmed VAP was 33.1 (95% CI 22.1-44.0) and 20.1 (95% CI 12.5-27.7) according to ETA and BAL, respectively. Concordance between ETA and BAL was observed in 35/49 (71.4%) cases, concordance between BAL FAPPP and BAL in 39/49 (79.6%) cases. With BAL as reference standard, ETA showed 88.9% (95% CI 70.8-97.7) sensitivity and 50.0% (95% CI 28.2-71.8) specificity (Cohen's Kappa 0.40, 95% CI 0.16-0.65). BAL FAPPP showed 95.0% (95% CI 75.1-99.9) sensitivity and 69% (95% CI 49.2-84.7) specificity (Cohen's Kappa 0.60, 95% CI 0.39-0.81). BAL IL-1β differed significantly between VAP (135 (IQR 11-450) pg/ml) and no-VAP (10 (IQR 2.9-105) pg/ml) patients (P = 0.03)., Conclusions: In COVID-19 ICU patients, differences in microbial sampling at VAP suspicion could lead to high variability in VAP incidence and microbiological findings. Concordance between ETA and BAL was mainly limited by over 20% of ETA positive and BAL negative samples, while BAL FAPPP showed high sensitivity but limited specificity when evaluating in-panel targets only. These factors should be considered when comparing results of cohorts with different sampling. BAL IL-1β showed potential in discriminating microbiologically confirmed VAP., Clinical Trial Registration: NCT04766983, registered on February 23, 2021., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerging infectious disease pandemic developed in Lombardy (northern Italy) during the last week of February 2020 with a progressive increase of patients presenting with serious clinical findings. Despite the efforts of the Central Italian Government, regional resources were rapidly at capacity. The solution was to plan the medical evacuation (MEDEVAC) of 119 critically ill patients (median age 61 years) to in-patient intensive care units in other Italian regions (77) and Germany (42). Once surviving patients were deemed suitable, the repatriation process concluded the assignment. The aim of this report is to underline the importance of a rapid organization and coordination process between different nodes of an effective national and international network during an emerging infectious disease outbreak and draw lessons learned from similar published reports.

Few data are available on incidence of multidrug-resistant organism (MDRO) colonization and infections in mechanically ventilated patients, particularly during the COVID-19 pandemic. We retrospectively evaluated all patients admitted to the COVID-19 intensive care unit (ICU) of Hub Hospital in Milan, Italy, during October 2020‒May 2021. Microbiologic surveillance was standardized with active screening at admission and weekly during ICU stay. Of 435 patients, 88 (20.2%) had MDROs isolated ≤48 h after admission. Of the remaining patients, MDRO colonization was diagnosed in 173 (51.2%), MDRO infections in 95 (28.1%), and non-MDRO infections in 212 (62.7%). Non-MDRO infections occurred earlier than MDRO infections (6 days vs. 10 days; p<0.001). Previous exposure to antimicrobial drugs within the ICU was higher in MDRO patients than in non-MDRO patients (116/197 [58.9%] vs. 18/140 [12.9%]; p<0.001). Our findings might serve as warnings for future respiratory viral pandemics and call for increased measures of antimicrobial stewardship and infection control.

The aim of these guidelines is to update the 2017 clinical practice guideline (CPG) of the European Society of Intensive Care Medicine (ESICM). The scope of this CPG is limited to adult patients and to non-pharmacological respiratory support strategies across different aspects of acute respiratory distress syndrome (ARDS), including ARDS due to coronavirus disease 2019 (COVID-19). These guidelines were formulated by an international panel of clinical experts, one methodologist and patients' representatives on behalf of the ESICM. The review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and grade recommendations and the quality of reporting of each study based on the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) network guidelines. The CPG addressed 21 questions and formulates 21 recommendations on the following domains: (1) definition; (2) phenotyping, and respiratory support strategies including (3) high-flow nasal cannula oxygen (HFNO); (4) non-invasive ventilation (NIV); (5) tidal volume setting; (6) positive end-expiratory pressure (PEEP) and recruitment maneuvers (RM); (7) prone positioning; (8) neuromuscular blockade, and (9) extracorporeal life support (ECLS). In addition, the CPG includes expert opinion on clinical practice and identifies the areas of future research., (© 2023. The Author(s).)

Objective: To explore recurrent themes in diaries kept by intensive care unit (ICU) staff during the coronavirus disease 2019 (COVID-19) pandemic., Design: Qualitative study., Setting: Two ICUs in a tertiary level hospital (Milan, Italy) from January to December 2021., Methods: ICU staff members wrote a digital diary while caring for adult patients hospitalized in the intensive care unit for >48 hours. A thematic analysis was performed., Findings: Diary entries described what happened and expressed emotions. Thematic analysis of 518 entries gleaned from 48 diaries identified four themes (plus ten subthemes): Presenting (Places and people; Diary project), Intensive Care Unit Stay (Clinical events; What the patient does; Patient support), Outside the Hospital (Family and topical events; The weather), Feelings and Thoughts (Encouragement and wishes; Farewell; Considerations)., Conclusion: The themes were similar to published findings. They offer insight into care in an intensive care unit during a pandemic, with scarce resources and no family visitors permitted, reflecting on the patient as a person and on daily care. The staff wrote farewell entries to dying patients even though no one would read them., Implications for Clinical Practice: The implementation of digital diaries kept by intensive care unit staff is feasible even during the COVID-19 pandemic. Diaries kept by staff can provide a tool to humanize critical care. Staff can improve their work by reflecting on diary records., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: It has been reported that people with COVID-19 and pre-existing autoantibodies against type I interferons are likely to develop an inflammatory cytokine storm responsible for severe respiratory symptoms. Since interleukin 6 (IL-6) is one of the cytokines released during this inflammatory process, IL-6 blocking agents have been used for treating people with severe COVID-19., Objectives: To update the evidence on the effectiveness and safety of IL-6 blocking agents compared to standard care alone or to a placebo for people with COVID-19., Search Methods: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform, the Living OVerview of Evidence (L·OVE) platform, and the Cochrane COVID-19 Study Register to identify studies on 7 June 2022., Selection Criteria: We included randomized controlled trials (RCTs) evaluating IL-6 blocking agents compared to standard care alone or to placebo for people with COVID-19, regardless of disease severity., Data Collection and Analysis: Pairs of researchers independently conducted study selection, extracted data and assessed risk of bias. We assessed the certainty of evidence using the GRADE approach for all critical and important outcomes. In this update we amended our protocol to update the methods used for grading evidence by establishing minimal important differences for the critical outcomes., Main Results: This update includes 22 additional trials, for a total of 32 trials including 12,160 randomized participants all hospitalized for COVID-19 disease. We identified a further 17 registered RCTs evaluating IL-6 blocking agents without results available as of 7 June 2022.  The mean age range varied from 56 to 75 years; 66.2% (8051/12,160) of enrolled participants were men. One-third (11/32) of included trials were placebo-controlled. Twenty-two were published in peer-reviewed journals, three were reported as preprints, two trials had results posted only on registries, and results from five trials were retrieved from another meta-analysis. Eight were funded by pharmaceutical companies.  Twenty-six included studies were multicenter trials; four were multinational and 22 took place in single countries. Recruitment of participants occurred between February 2020 and June 2021, with a mean enrollment duration of 21 weeks (range 1 to 54 weeks). Nineteen trials (60%) had a follow-up of 60 days or more. Disease severity ranged from mild to critical disease. The proportion of participants who were intubated at study inclusion also varied from 5% to 95%. Only six trials reported vaccination status; there were no vaccinated participants included in these trials, and 17 trials were conducted before vaccination was rolled out. We assessed a total of six treatments, each compared to placebo or standard care. Twenty trials assessed tocilizumab, nine assessed sarilumab, and two assessed clazakizumab. Only one trial was included for each of the other IL-6 blocking agents (siltuximab, olokizumab, and levilimab). Two trials assessed more than one treatment. Efficacy and safety of tocilizumab and sarilumab compared to standard care or placebo for treating COVID-19 At day (D) 28, tocilizumab and sarilumab probably result in little or no increase in clinical improvement (tocilizumab: risk ratio (RR) 1.05, 95% confidence interval (CI) 1.00 to 1.11; 15 RCTs, 6116 participants; moderate-certainty evidence; sarilumab: RR 0.99, 95% CI 0.94 to 1.05; 7 RCTs, 2425 participants; moderate-certainty evidence). For clinical improvement at ≥ D60, the certainty of evidence is very low for both tocilizumab (RR 1.10, 95% CI 0.81 to 1.48; 1 RCT, 97 participants; very low-certainty evidence) and sarilumab (RR 1.22, 95% CI 0.91 to 1.63; 2 RCTs, 239 participants; very low-certainty evidence). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score (WHO-CPS) of level 7 or above remains uncertain at D28 (RR 0.90, 95% CI 0.72 to 1.12; 13 RCTs, 2117 participants; low-certainty evidence) and that for sarilumab very uncertain (RR 1.10, 95% CI 0.90 to 1.33; 5 RCTs, 886 participants; very low-certainty evidence). Tocilizumab reduces all cause-mortality at D28 compared to standard care/placebo (RR 0.88, 95% CI 0.81 to 0.94; 18 RCTs, 7428 participants; high-certainty evidence). The evidence about the effect of sarilumab on this outcome is very uncertain (RR 1.06, 95% CI 0.86 to 1.30; 9 RCTs, 3305 participants; very low-certainty evidence). The evidence is uncertain for all cause-mortality at ≥ D60 for tocilizumab (RR 0.91, 95% CI 0.80 to 1.04; 9 RCTs, 2775 participants; low-certainty evidence) and very uncertain for sarilumab (RR 0.95, 95% CI 0.84 to 1.07; 6 RCTs, 3379 participants; very low-certainty evidence). Tocilizumab probably results in little to no difference in the risk of adverse events (RR 1.03, 95% CI 0.95 to 1.12; 9 RCTs, 1811 participants; moderate-certainty evidence). The evidence about adverse events for sarilumab is uncertain (RR 1.12, 95% CI 0.97 to 1.28; 4 RCT, 860 participants; low-certainty evidence).  The evidence about serious adverse events is very uncertain for tocilizumab (RR 0.93, 95% CI 0.81 to 1.07; 16 RCTs; 2974 participants; very low-certainty evidence) and uncertain for sarilumab (RR 1.09, 95% CI 0.97 to 1.21; 6 RCTs; 2936 participants; low-certainty evidence). Efficacy and safety of clazakizumab, olokizumab, siltuximab and levilimab compared to standard care or placebo for treating COVID-19 The evidence about the effects of clazakizumab, olokizumab, siltuximab, and levilimab comes from only one or two studies for each blocking agent, and is uncertain or very uncertain., Authors' Conclusions: In hospitalized people with COVID-19, results show a beneficial effect of tocilizumab on all-cause mortality in the short term and probably little or no difference in the risk of adverse events compared to standard care alone or placebo. Nevertheless, both tocilizumab and sarilumab probably result in little or no increase in clinical improvement at D28. Evidence for an effect of sarilumab and the other IL-6 blocking agents on critical outcomes is uncertain or very uncertain. Most of the trials included in our review were done before the waves of different variants of concern and before vaccination was rolled out on a large scale. An additional 17 RCTs of IL-6 blocking agents are currently registered with no results yet reported. The number of pending studies and the number of participants planned is low. Consequently, we will not publish further updates of this review., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

This multicenter observational study included 171 COVID-19 adult patients hospitalized in the ICUs of nine hospitals in Lombardy (Northern Italy) from December, 1st 2021, to February, 9th 2022. During the study period, the Delta/Omicron variant ratio of cases decreased with a delay of two weeks in ICU patients compared to that in the community; a higher proportion of COVID-19 unvaccinated patients was infected by Delta than by Omicron whereas a higher rate of COVID-19 boosted patients was Omicron-infected. A higher number of comorbidities and a higher comorbidity score in ICU critically COVID-19 inpatients was positively associated with the Omicron infection as well in vaccinated individuals. Although people infected by Omicron have a lower risk of severe disease than those infected by Delta variant, the outcome, including the risk of ICU admission and the need for mechanical ventilation due to infection by Omicron versus Delta, remains uncertain. The continuous monitoring of the circulating SARS-CoV-2 variants remains a milestone to counteract this pandemic., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 SPLF and Elsevier Masson SAS. All rights reserved.)

Objectives: To determine the prevalence and outcomes associated with hemorrhage, disseminated intravascular coagulopathy, and thrombosis (HECTOR) complications in ICU patients with COVID-19., Design: Prospective, observational study., Setting: Two hundred twenty-nine ICUs across 32 countries., Patients: Adult patients (≥ 16 yr) admitted to participating ICUs for severe COVID-19 from January 1, 2020, to December 31, 2021., Interventions: None., Measurements and Main Results: HECTOR complications occurred in 1,732 of 11,969 study eligible patients (14%). Acute thrombosis occurred in 1,249 patients (10%), including 712 (57%) with pulmonary embolism, 413 (33%) with myocardial ischemia, 93 (7.4%) with deep vein thrombosis, and 49 (3.9%) with ischemic strokes. Hemorrhagic complications were reported in 579 patients (4.8%), including 276 (48%) with gastrointestinal hemorrhage, 83 (14%) with hemorrhagic stroke, 77 (13%) with pulmonary hemorrhage, and 68 (12%) with hemorrhage associated with extracorporeal membrane oxygenation (ECMO) cannula site. Disseminated intravascular coagulation occurred in 11 patients (0.09%). Univariate analysis showed that diabetes, cardiac and kidney diseases, and ECMO use were risk factors for HECTOR. Among survivors, ICU stay was longer (median days 19 vs 12; p < 0.001) for patients with versus without HECTOR, but the hazard of ICU mortality was similar (hazard ratio [HR] 1.01; 95% CI 0.92-1.12; p = 0.784) overall, although this hazard was identified when non-ECMO patients were considered (HR 1.13; 95% CI 1.02-1.25; p = 0.015). Hemorrhagic complications were associated with an increased hazard of ICU mortality compared to patients without HECTOR complications (HR 1.26; 95% CI 1.09-1.45; p = 0.002), whereas thrombosis complications were associated with reduced hazard (HR 0.88; 95% CI 0.79-0.99, p = 0.03)., Conclusions: HECTOR events are frequent complications of severe COVID-19 in ICU patients. Patients receiving ECMO are at particular risk of hemorrhagic complications. Hemorrhagic, but not thrombotic complications, are associated with increased ICU mortality., Competing Interests: Dr. J. P. Fanning received funding from the Australian-American Fulbright Commission and Metro North Clinical Research Fellowship, Queensland Government, Australia. Drs. Suen, Li Bassi, and Fraser received support for article research from the Bill and Melinda Gates Foundation. Dr. Cho is funded by National Heart, Lung, and Blood Institute 1K23HL157610. Dr. Rando received funding from the American Heart Association. Dr. Whitman disclosed that he is 50% owner of a patent for a medical device for GWBN, LLC and that he received funding from Cellphire/Avania as principal investigator for a national study. Dr. Arora received funding from Edwards LifeSciences and Avir Pharma. Dr. Grasselli received funding from Getinge, Fisher & Paykel, Draeger Medical, Merck Sharp and Dohme, Cook Medical, and GlaxoSmithKline. Dr. Usman received support for article research from the National Institutes of Health. Drs. Suen’s and Li Bassi’s institutions received funding from The Bill and Melinda Gates Foundation. Dr. Suen is funded by the Advance Queensland fellowship program, Queensland Government, Australia. Dr. Li Bassi’s institution received funding from Fisher & Paykel. Dr. Li Bassi is a recipient of the Biomedical international training research programme for excellent clinician-scientists (BITRECS) fellowship; the “BITRECS” project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 754550 and from the “La Caixa” Foundation (ID 100010434), under the agreement LCF/PR/GN18/50310006. Dr. Dalton received funding from extracorporeal membrane oxygenation concepts, entegrion, and hemocue. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Objectives: The aim of this study was to investigate the potential benefits of using an energy-dense, high-protein (HP) formula enriched with β-hydroxy-β-methylbutyrate (HMB), fructo-oligosaccharide (FOS), and vitamin D (VitD) for enteral feeding in the intensive care unit (ICU)., Methods: This was a nested case-control multicenter study. Mechanically ventilated patients with COVID-19 in whom enteral nutrition was not contraindicated and receiving an energy-dense, HP-HMB-FOS-VitD formula (1.5 kcal/mL; 21.5% of calories from protein; n = 53) were matched (1:1) by age (±1 y), sex, body mass index (±1 kg/m 2 ) and Sequential Organ Failure Assessment score (±1 point) and compared with patients fed with a standard HP, fiber-free formula (1.25-1.3 kcal/mL; 20% of calories from protein; n = 53). The primary end point was daily protein intake (g/kg) on day 4. Protein-calorie intake on day 7, gastrointestinal intolerance, and clinical outcomes were addressed as secondary end points., Results: The use of a HP-HMB-FOS-VitD formula resulted in higher protein intake on days 4 and 7 (P = 0.006 and P = 0.013, respectively), with similar energy intake but higher provision of calories from enteral nutrition at both times (P <0 .001 and P = 0.017, respectively). Gastrointestinal tolerance was superior, with fewer patients fed with a HP-HMB-FOS-VitD formula reporting at least one symptom of intolerance (55 versus 74%; odds ratio [OR], 0.43; 95% confidence interval [CI], 0.18-0.99; P = 0.046) and constipation (38 versus 66%; OR, 0.27; 95% CI, 0.12-0.61; P = 0.002). A lower rate of ICU-acquired infections was also observed (42 versus 72%; OR, 0.29; 95% CI, 0.13-0.65; P = 0.003), although no difference was found in mortality, ICU length of stay, and ventilation-free survival., Conclusions: An energy-dense, HP-HMB-FOS-VitD formula provided a more satisfactory protein intake and a higher provision of caloric intake from enteral nutrition than a standard HP formula in mechanically ventilated patients with COVID-19. Lower rates of gastrointestinal intolerance and ICU-acquired infections were also observed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: To inform future research and practice, we aimed to investigate the outcomes of patients who received extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) due to different variants of SARS-CoV-2., Methods: This retrospective study included consecutive adult patients with laboratory-confirmed SARS-CoV-2 infection who received ECMO for ARDS in 21 experienced ECMO centres in eight European countries (Austria, Belgium, England, France, Germany, Italy, Portugal, and Spain) between Jan 1, 2020, and Sept 30, 2021. We collected data on patient characteristics, clinical status, and management before and after the initiation of ECMO. Participants were grouped according to SARS-CoV-2 variant (wild type, alpha, delta, or other) and period of the pandemic (first [Jan 1-June 30] and second [July 1-Dec 31] semesters of 2020, and first [Jan 1-June 30] and second [July 1-Sept 30] semesters of 2021). Descriptive statistics and Kaplan-Meier survival curves were used to analyse evolving characteristics, management, and patient outcomes over the first 2 years of the pandemic, and independent risk factors of mortality were determined using multivariable Cox regression models. The primary outcome was mortality 90 days after the initiation of ECMO, with follow-up to Dec 30, 2021., Findings: ECMO was initiated in 1345 patients. Patient characteristics and management were similar for the groups of patients infected with different variants, except that those with the delta variant had a younger median age and less hypertension and diabetes. 90-day mortality was 42% (569 of 1345 patients died) overall, and 43% (297/686) in patients infected with wild-type SARS-CoV-2, 39% (152/391) in those with the alpha variant, 40% (78/195) in those with the delta variant, and 58% (42/73) in patients infected with other variants (mainly beta and gamma). Mortality was 10% higher (50%) in the second semester of 2020, when the wild-type variant was still prevailing, than in other semesters (40%). Independent predictors of mortality were age, immunocompromised status, a longer time from intensive care unit admission to intubation, need for renal replacement therapy, and higher Sequential Organ Failure Assessment haemodynamic component score, partial pressure of arterial carbon dioxide, and lactate concentration before ECMO. After adjusting for these variables, mortality was significantly higher with the delta variant than with the other variants, the wild-type strain being the reference., Interpretation: Although crude mortality did not differ between variants, adjusted risk of death was highest for patients treated with ECMO infected with the delta variant of SARS-CoV-2. The higher virulence and poorer outcomes associated with the delta strain might relate to higher viral load and increased inflammatory response syndrome in infected patients, reinforcing the need for a higher rate of vaccination in the population and updated selection criteria for ECMO, should a new and highly virulent strain of SARS-CoV-2 emerge in the future. Mortality was noticeably lower than in other large, multicentre series of patients who received ECMO for COVID-19, highlighting the need to concentrate resources at experienced centres., Funding: None., Competing Interests: Declaration of interests MS reports lecture fees from Getinge, Drager, and Xenios, outside of the submitted work. AM-D reports grants from Addmedica, Baxter, Ferring, Fisher & Paykel, and Philips, and personal fees from Air Liquide, outside of the submitted work. PSc reports lecture fees from Getinge and scientific grants from the European Society of Intensive Medicine (ESICM) and the European Commission (Horizon 2020 Fast Track to Innovation; NCT04115709), and has co-organised an ARDS fellowship for the ESICM sponsored by Medtronic. BL reports fees from Abiomed, Getinge, Baxter, Novartis, Sanofi, Amomed, and Orion, outside of the submitted work. GG has received personal fees (payment for lectures) from Getinge, Draeger Medical, Biotest, GSK, Pfizer, Fisher & Paykel, and Cook Medical, and research grants from MSD and Fisher & Paykel. CG reports fees from Xenios, outside of the submitted work. JR reports lecture fees from Werfen and Gilead, and advisory fees from Medtronic, outside of the submitted work. AC reports grants from Getinge, and personal fees from Getinge, Baxter, and Xenios, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: During the Coronavirus disease 2019 (COVID-19) pandemic, hospital visits were suspended and video calls were offered to connect patients with their family members, especially toward the end of life (EoL)., Aim: The primary aim was to describe EoL care for COVID-19 patients dying in an intensive care unit (ICU). The secondary aim was to explore whether making video calls and allowing visits was associated with lower death-related stress in family members., Design: Single centre cross-sectional study. The setting was the ICU of a COVID-19 center in northern Italy, during the first year of the pandemic. Data on patients who died in the ICU were collected; death-related stress on their family members was measured using the Impact of Event Scale-Revised (IES-R). The statistical association was tested by means of logistic regression., Results: The study sample included 70 patients and 56 family members. All patients died with mechanical ventilation, hydration, nutrition, analgesia and sedation ongoing. Resuscitation procedures were performed in 5/70 patients (7.1%). Only 6/56 (10.7%) of the family members interviewed had visited their loved ones in the ICU and 28/56 (50%) had made a video call. EoL video calls were judged useful by 53/56 family members (94.6%) but all (56/56, 100%) wished they could have visited the patient. High-stress levels were found in 38/56 family members (67.9%), regardless of whether they were allowed ICU access or made a video call. Compared with other degrees of kinship, patients' offspring were less likely to show a positive IES-R score (odds ratio [OR] 0.22, 95% confidence interval [CI] 0.05 to 0.89)., Conclusions: During the first year of the COVID-19 pandemic, patients died without their family members at the bedside while on life-sustaining treatment. Stress levels were high in most family members, especially in patients' spouses. Video calls or ICU visits were judged favourably by family members but insufficient to alleviate death-related stress., Relevance for Clinical Practice: During a pandemic, ICU access by patients' family members should be considered, particularly as the time of death approaches. Although generally appreciated by family members, EoL video calls should be arranged together with other measures to alleviate death-related stress, especially for the patient's spouse., (© 2022 The Authors. Nursing in Critical Care published by John Wiley & Sons Ltd on behalf of British Association of Critical Care Nurses.)

Background: Different forms of vaccines have been developed to prevent the SARS-CoV-2 virus and subsequent COVID-19 disease. Several are in widespread use globally.  OBJECTIVES: To assess the efficacy and safety of COVID-19 vaccines (as a full primary vaccination series or a booster dose) against SARS-CoV-2., Search Methods: We searched the Cochrane COVID-19 Study Register and the COVID-19 L·OVE platform (last search date 5 November 2021). We also searched the WHO International Clinical Trials Registry Platform, regulatory agency websites, and Retraction Watch., Selection Criteria: We included randomized controlled trials (RCTs) comparing COVID-19 vaccines to placebo, no vaccine, other active vaccines, or other vaccine schedules., Data Collection and Analysis: We used standard Cochrane methods. We used GRADE to assess the certainty of evidence for all except immunogenicity outcomes.  We synthesized data for each vaccine separately and presented summary effect estimates with 95% confidence intervals (CIs).  MAIN RESULTS: We included and analyzed 41 RCTs assessing 12 different vaccines, including homologous and heterologous vaccine schedules and the effect of booster doses. Thirty-two RCTs were multicentre and five were multinational. The sample sizes of RCTs were 60 to 44,325 participants. Participants were aged: 18 years or older in 36 RCTs; 12 years or older in one RCT; 12 to 17 years in two RCTs; and three to 17 years in two RCTs. Twenty-nine RCTs provided results for individuals aged over 60 years, and three RCTs included immunocompromized patients. No trials included pregnant women. Sixteen RCTs had two-month follow-up or less, 20 RCTs had two to six months, and five RCTs had greater than six to 12 months or less. Eighteen reports were based on preplanned interim analyses. Overall risk of bias was low for all outcomes in eight RCTs, while 33 had concerns for at least one outcome. We identified 343 registered RCTs with results not yet available.  This abstract reports results for the critical outcomes of confirmed symptomatic COVID-19, severe and critical COVID-19, and serious adverse events only for the 10 WHO-approved vaccines. For remaining outcomes and vaccines, see main text. The evidence for mortality was generally sparse and of low or very low certainty for all WHO-approved vaccines, except AD26.COV2.S (Janssen), which probably reduces the risk of all-cause mortality (risk ratio (RR) 0.25, 95% CI 0.09 to 0.67; 1 RCT, 43,783 participants; high-certainty evidence). Confirmed symptomatic COVID-19 High-certainty evidence found that BNT162b2 (BioNtech/Fosun Pharma/Pfizer), mRNA-1273 (ModernaTx), ChAdOx1 (Oxford/AstraZeneca), Ad26.COV2.S, BBIBP-CorV (Sinopharm-Beijing), and BBV152 (Bharat Biotect) reduce the incidence of symptomatic COVID-19 compared to placebo (vaccine efficacy (VE): BNT162b2: 97.84%, 95% CI 44.25% to 99.92%; 2 RCTs, 44,077 participants; mRNA-1273: 93.20%, 95% CI 91.06% to 94.83%; 2 RCTs, 31,632 participants; ChAdOx1: 70.23%, 95% CI 62.10% to 76.62%; 2 RCTs, 43,390 participants; Ad26.COV2.S: 66.90%, 95% CI 59.10% to 73.40%; 1 RCT, 39,058 participants; BBIBP-CorV: 78.10%, 95% CI 64.80% to 86.30%; 1 RCT, 25,463 participants; BBV152: 77.80%, 95% CI 65.20% to 86.40%; 1 RCT, 16,973 participants). Moderate-certainty evidence found that NVX-CoV2373 (Novavax) probably reduces the incidence of symptomatic COVID-19 compared to placebo (VE 82.91%, 95% CI 50.49% to 94.10%; 3 RCTs, 42,175 participants). There is low-certainty evidence for CoronaVac (Sinovac) for this outcome (VE 69.81%, 95% CI 12.27% to 89.61%; 2 RCTs, 19,852 participants). Severe or critical COVID-19 High-certainty evidence found that BNT162b2, mRNA-1273, Ad26.COV2.S, and BBV152 result in a large reduction in incidence of severe or critical disease due to COVID-19 compared to placebo (VE: BNT162b2: 95.70%, 95% CI 73.90% to 99.90%; 1 RCT, 46,077 participants; mRNA-1273: 98.20%, 95% CI 92.80% to 99.60%; 1 RCT, 28,451 participants; AD26.COV2.S: 76.30%, 95% CI 57.90% to 87.50%; 1 RCT, 39,058 participants; BBV152: 93.40%, 95% CI 57.10% to 99.80%; 1 RCT, 16,976 participants). Moderate-certainty evidence found that NVX-CoV2373 probably reduces the incidence of severe or critical COVID-19 (VE 100.00%, 95% CI 86.99% to 100.00%; 1 RCT, 25,452 participants). Two trials reported high efficacy of CoronaVac for severe or critical disease with wide CIs, but these results could not be pooled. Serious adverse events (SAEs) mRNA-1273, ChAdOx1 (Oxford-AstraZeneca)/SII-ChAdOx1 (Serum Institute of India), Ad26.COV2.S, and BBV152 probably result in little or no difference in SAEs compared to placebo (RR: mRNA-1273: 0.92, 95% CI 0.78 to 1.08; 2 RCTs, 34,072 participants; ChAdOx1/SII-ChAdOx1: 0.88, 95% CI 0.72 to 1.07; 7 RCTs, 58,182 participants; Ad26.COV2.S: 0.92, 95% CI 0.69 to 1.22; 1 RCT, 43,783 participants); BBV152: 0.65, 95% CI 0.43 to 0.97; 1 RCT, 25,928 participants). In each of these, the likely absolute difference in effects was fewer than 5/1000 participants. Evidence for SAEs is uncertain for BNT162b2, CoronaVac, BBIBP-CorV, and NVX-CoV2373 compared to placebo (RR: BNT162b2: 1.30, 95% CI 0.55 to 3.07; 2 RCTs, 46,107 participants; CoronaVac: 0.97, 95% CI 0.62 to 1.51; 4 RCTs, 23,139 participants; BBIBP-CorV: 0.76, 95% CI 0.54 to 1.06; 1 RCT, 26,924 participants; NVX-CoV2373: 0.92, 95% CI 0.74 to 1.14; 4 RCTs, 38,802 participants). For the evaluation of heterologous schedules, booster doses, and efficacy against variants of concern, see main text of review., Authors' Conclusions: Compared to placebo, most vaccines reduce, or likely reduce, the proportion of participants with confirmed symptomatic COVID-19, and for some, there is high-certainty evidence that they reduce severe or critical disease. There is probably little or no difference between most vaccines and placebo for serious adverse events. Over 300 registered RCTs are evaluating the efficacy of COVID-19 vaccines, and this review is updated regularly on the COVID-NMA platform (covid-nma.com). Implications for practice Due to the trial exclusions, these results cannot be generalized to pregnant women, individuals with a history of SARS-CoV-2 infection, or immunocompromized people. Most trials had a short follow-up and were conducted before the emergence of variants of concern. Implications for research Future research should evaluate the long-term effect of vaccines, compare different vaccines and vaccine schedules, assess vaccine efficacy and safety in specific populations, and include outcomes such as preventing long COVID-19. Ongoing evaluation of vaccine efficacy and effectiveness against emerging variants of concern is also vital., (Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Background & Aims: The aim of this study was to evaluate the nutritional support management in mechanically ventilated coronavirus disease 2019 (COVID-19) patients and explore the association between early caloric deficit and mortality, taking possible confounders (i.e. obesity) into consideration., Methods: This was a prospective study carried out during the first pandemic wave in the intensive care units (ICUs) of two referral University Hospitals in Lombardy, Italy. Two hundred twenty-two consecutive mechanically ventilated COVID-19 patients were evaluated during the ICU stay. In addition to major demographic and clinical data, we recorded information on the route and amount of nutritional support provided on a daily basis., Results: Among patients still in the ICUs and alive on day 4 (N = 198), 129 (65.2%) and 72 (36.4%) reached a satisfactory caloric and protein intake, respectively, mainly by enteral route. In multivariable analysis, a satisfactory caloric intake on day 4 was associated with lower mortality (HR = 0.46 [95%CI, 0.42-0.50], P < 0.001). Mild obesity (body mass index [BMI] ≥30 and < 35 kg/m 2 ) was associated with higher mortality (HR = 1.99 [95%CI, 1.07-3.68], P = 0.029), while patients with moderate-severe obesity (BMI≥35 kg/m 2 ) were less likely to be weaned from invasive mechanical ventilation (HR = 0.71 [95%CI, 0.62-0.82], P < 0.001)., Conclusions: This study confirmed the negative prognostic and clinical role of obesity in mechanically ventilated COVID-19 patients and suggested that early caloric deficit may independently contribute to worsen survival in this patients' population. Therefore, any effort should be made to implement an adequate timely nutritional support in all COVID-19 patients during the ICU stay., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Coronavirus Disease (COVID-19) can be considered as a human pathological model of inflammation combined with hypoxia. In this setting, both erythropoiesis and iron metabolism appear to be profoundly affected by inflammatory and hypoxic stimuli, which act in the opposite direction on hepcidin regulation. The impact of low blood oxygen levels on erythropoiesis and iron metabolism in the context of human hypoxic disease (e.g., pneumonia) has not been fully elucidated. This multicentric observational study was aimed at investigating the prevalence of anemia, the alterations of iron homeostasis, and the relationship between inflammation, hypoxia, and erythropoietic parameters in a cohort of 481 COVID-19 patients admitted both to medical wards and intensive care units (ICU). Data were collected on admission and after 7 days of hospitalization. On admission, nearly half of the patients were anemic, displaying mild-to-moderate anemia. We found that hepcidin levels were increased during the whole period of observation. The patients with a higher burden of disease (i.e., those who needed intensive care treatment or had a more severe degree of hypoxia) showed lower hepcidin levels, despite having a more marked inflammatory pattern. Erythropoietin (EPO) levels were also lower in the ICU group on admission. After 7 days, EPO levels rose in the ICU group while they remained stable in the non-ICU group, reflecting that the initial hypoxic stimulus was stronger in the first group. These findings strengthen the hypothesis that, at least in the early phases, hypoxia-driven stimuli prevail over inflammation in the regulation of hepcidin and, finally, of erythropoiesis., (© 2022 Wiley Periodicals LLC.)

Importance: Data on the association of COVID-19 vaccination with intensive care unit (ICU) admission and outcomes of patients with SARS-CoV-2-related pneumonia are scarce., Objective: To evaluate whether COVID-19 vaccination is associated with preventing ICU admission for COVID-19 pneumonia and to compare baseline characteristics and outcomes of vaccinated and unvaccinated patients admitted to an ICU., Design, Setting, and Participants: This retrospective cohort study on regional data sets reports: (1) daily number of administered vaccines and (2) data of all consecutive patients admitted to an ICU in Lombardy, Italy, from August 1 to December 15, 2021 (Delta variant predominant). Vaccinated patients received either mRNA vaccines (BNT162b2 or mRNA-1273) or adenoviral vector vaccines (ChAdOx1-S or Ad26.COV2). Incident rate ratios (IRRs) were computed from August 1, 2021, to January 31, 2022; ICU and baseline characteristics and outcomes of vaccinated and unvaccinated patients admitted to an ICU were analyzed from August 1 to December 15, 2021., Exposures: COVID-19 vaccination status (no vaccination, mRNA vaccine, adenoviral vector vaccine)., Main Outcomes and Measures: The incidence IRR of ICU admission was evaluated, comparing vaccinated people with unvaccinated, adjusted for age and sex. The baseline characteristics at ICU admission of vaccinated and unvaccinated patients were investigated. The association between vaccination status at ICU admission and mortality at ICU and hospital discharge were also studied, adjusting for possible confounders., Results: Among the 10 107 674 inhabitants of Lombardy, Italy, at the time of this study, the median [IQR] age was 48 [28-64] years and 5 154 914 (51.0%) were female. Of the 7 863 417 individuals who were vaccinated (median [IQR] age: 53 [33-68] years; 4 010 343 [51.4%] female), 6 251 417 (79.5%) received an mRNA vaccine, 550 439 (7.0%) received an adenoviral vector vaccine, and 1 061 561 (13.5%) received a mix of vaccines and 4 497 875 (57.2%) were boosted. Compared with unvaccinated people, IRR of individuals who received an mRNA vaccine within 120 days from the last dose was 0.03 (95% CI, 0.03-0.04; P < .001), whereas IRR of individuals who received an adenoviral vector vaccine after 120 days was 0.21 (95% CI, 0.19-0.24; P < .001). There were 553 patients admitted to an ICU for COVID-19 pneumonia during the study period: 139 patients (25.1%) were vaccinated and 414 (74.9%) were unvaccinated. Compared with unvaccinated patients, vaccinated patients were older (median [IQR]: 72 [66-76] vs 60 [51-69] years; P < .001), primarily male individuals (110 patients [79.1%] vs 252 patients [60.9%]; P < .001), with more comorbidities (median [IQR]: 2 [1-3] vs 0 [0-1] comorbidities; P < .001) and had higher ratio of arterial partial pressure of oxygen (Pao2) and fraction of inspiratory oxygen (FiO2) at ICU admission (median [IQR]: 138 [100-180] vs 120 [90-158] mm Hg; P = .007). Factors associated with ICU and hospital mortality were higher age, premorbid heart disease, lower Pao2/FiO2 at ICU admission, and female sex (this factor only for ICU mortality). ICU and hospital mortality were similar between vaccinated and unvaccinated patients., Conclusions and Relevance: In this cohort study, mRNA and adenoviral vector vaccines were associated with significantly lower risk of ICU admission for COVID-19 pneumonia. ICU and hospital mortality were not associated with vaccinated status. These findings suggest a substantial reduction of the risk of developing COVID-19-related severe acute respiratory failure requiring ICU admission among vaccinated people.

Purpose: COVID-19 disease frequently affects the lungs leading to bilateral viral pneumonia, progressing in some cases to severe respiratory failure requiring ICU admission and mechanical ventilation. Risk stratification at ICU admission is fundamental for resource allocation and decision making. We assessed performances of three machine learning approaches to predict mortality in COVID-19 patients admitted to ICU using early operative data from the Lombardy ICU Network., Methods: This is a secondary analysis of prospectively collected data from Lombardy ICU network. A logistic regression, balanced logistic regression and random forest were built to predict survival on two datasets: dataset A included patient demographics, medications before admission and comorbidities, and dataset B included respiratory data the first day in ICU., Results: Models were trained on 1484 patients on four outcomes (7/14/21/28 days) and reached the greatest predictive performance at 28 days (F1-score: 0.75 and AUC: 0.80). Age, number of comorbidities and male gender were strongly associated with mortality. On dataset B, mode of ventilatory assistance at ICU admission and fraction of inspired oxygen were associated with an increase in prediction performances., Conclusions: Machine learning techniques might be useful in emergency phases to reach good predictive performances maintaining interpretability to gain knowledge on complex situations and enhance patient management and resources., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: To assess the impact of treatment with steroids on the incidence and outcome of ventilator-associated pneumonia (VAP) in mechanically ventilated COVID-19 patients., Design: Propensity-matched retrospective cohort study from February 24 to December 31, 2020, in 4 dedicated COVID-19 Intensive Care Units (ICU) in Lombardy (Italy)., Patients: Adult consecutive mechanically ventilated COVID-19 patients were subdivided into two groups: (1) treated with low-dose corticosteroids (dexamethasone 6 mg/day intravenous for 10 days) (DEXA+); (2) not treated with corticosteroids (DEXA-). A propensity score matching procedure (1:1 ratio) identified patients' cohorts based on: age, weight, PEEP Level, PaO 2 /FiO 2 ratio, non-respiratory Sequential Organ Failure Assessment (SOFA) score, Charlson Comorbidity Index (CCI), C reactive protein plasma concentration at admission, sex and admission hospital (exact matching)., Intervention: Dexamethasone 6 mg/day intravenous for 10 days from hospital admission., Measurements and Main Results: Seven hundred and thirty-nine patients were included, and the propensity-score matching identified two groups of 158 subjects each. Eighty-nine (56%) DEXA+ versus 55 (34%) DEXA- patients developed a VAP (RR 1.61 (1.26-2.098), p = 0.0001), after similar time from hospitalization, ICU admission and intubation. DEXA+ patients had higher crude VAP incidence rate (49.58 (49.26-49.91) vs. 31.65 (31.38-31.91)VAP*1000/pd), (IRR 1.57 (1.55-1.58), p < 0.0001) and risk for VAP (HR 1.81 (1.31-2.50), p = 0.0003), with longer ICU LOS and invasive mechanical ventilation but similar mortality (RR 1.17 (0.85-1.63), p = 0.3332). VAPs were similarly due to G+ bacteria (mostly Staphylococcus aureus) and G- bacteria (mostly Enterobacterales). Forty-one (28%) VAPs were due to multi-drug resistant bacteria. VAP was associated with almost doubled ICU and hospital LOS and invasive mechanical ventilation, and increased mortality (RR 1.64 [1.02-2.65], p = 0.040) with no differences among patients' groups., Conclusions: Critically ill COVID-19 patients are at high risk for VAP, frequently caused by multidrug-resistant bacteria, and the risk is increased by corticosteroid treatment., Trial Registration: NCT04388670, retrospectively registered May 14, 2020., (© 2022. The Author(s).)

Purpose: To accommodate the unprecedented number of critically ill patients with pneumonia caused by coronavirus disease 2019 (COVID-19) expansion of the capacity of intensive care unit (ICU) to clinical areas not previously used for critical care was necessary. We describe the global burden of COVID-19 admissions and the clinical and organizational characteristics associated with outcomes in critically ill COVID-19 patients., Methods: Multicenter, international, point prevalence study, including adult patients with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) and a diagnosis of COVID-19 admitted to ICU between February 15th and May 15th, 2020., Results: 4994 patients from 280 ICUs in 46 countries were included. Included ICUs increased their total capacity from 4931 to 7630 beds, deploying personnel from other areas. Overall, 1986 (39.8%) patients were admitted to surge capacity beds. Invasive ventilation at admission was present in 2325 (46.5%) patients and was required during ICU stay in 85.8% of patients. 60-day mortality was 33.9% (IQR across units: 20%-50%) and ICU mortality 32.7%. Older age, invasive mechanical ventilation, and acute kidney injury (AKI) were associated with increased mortality. These associations were also confirmed specifically in mechanically ventilated patients. Admission to surge capacity beds was not associated with mortality, even after controlling for other factors., Conclusions: ICUs responded to the increase in COVID-19 patients by increasing bed availability and staff, admitting up to 40% of patients in surge capacity beds. Although mortality in this population was high, admission to a surge capacity bed was not associated with increased mortality. Older age, invasive mechanical ventilation, and AKI were identified as the strongest predictors of mortality., (© 2022. The Author(s).)

Non-invasive ventilation (NIV) or invasive mechanical ventilation (MV) is frequently needed in patients with acute hypoxemic respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. While NIV can be delivered in hospital wards and nonintensive care environments, intubated patients require intensive care unit (ICU) admission and support. Thus, the lack of ICU beds generated by the pandemic has often forced the use of NIV in severely hypoxemic patients treated outside the ICU. In this context, awake prone positioning has been widely adopted to ameliorate oxygenation during noninvasive respiratory support. Still, the incidence of NIV failure and the role of patient self-induced lung injury on hospital outcomes of COVID-19 subjects need to be elucidated. On the other hand, endotracheal intubation is indicated when gas exchange deterioration, muscular exhaustion, and/or neurological impairment ensue. Yet, the best timing for intubation in COVID-19 is still widely debated, as it is the safest use of neuromuscular blocking agents. Not differently from other types of acute respiratory distress syndrome, the aim of MV during COVID-19 is to provide adequate gas exchange while avoiding ventilator-induced lung injury. At the same time, the use of rescue therapies is advocated when standard care is unable to guarantee sufficient organ support. Nevertheless, the general shortage of health care resources experienced during SARS-CoV-2 pandemic might affect the utilization of high-cost, highly specialized, and long-term supports. In this article, we describe the state-of-the-art of NIV and MV setting and their usage for acute hypoxemic respiratory failure of COVID-19 patients., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To evaluate the muscle strength and functional level of patients discharged from intensive care unit (ICU) in relation to the swimmer position as a nurse intervention during pronation., Methods: Prospective study conducted in the hub COVID-19 center in Milan (Italy), between March and June 2020. All patients with COVID-19 discharged alive from ICU who received invasive mechanical ventilation were included. Forward continuation ratio model was fitted to explore the statistical association between muscle strength grades and body positioning during ICU stay., Results: Over the 128 patients admitted to ICU, 87 patients were discharged alive from ICU, with available follow-up measures at hospital discharge. Thirty-four patients (39.1%) were treated with prone positioning as rescue therapy, for a total of 106 pronation cycles with a median duration of 72 (IQR 60-83) hours. Prone positioning did not influence the odds of showing particular level of muscle strength, in any of the evaluated districts, namely shoulder (OR 1.34, 95%CI:0.61-2.97), elbow (OR 1.10, 95%CI:0.45-2.68) and wrist (OR 0.97, 95%CI:0.58-1.63). Only in the shoulder district, age showed evidence of association with strength (OR 1.06, 95%CI:1.02-1.10), affecting people as they get older. No significant sequalae related to swimmer position were reported by physiotherapists or nurses., Conclusion: Swimmer position adopted during prone ventilation is not associated with worse upper limb strength or poor mobility level in COVID-19 survivors after hospital discharge., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rationale: The "Berlin definition" of acute respiratory distress syndrome (ARDS) does not allow inclusion of patients receiving high-flow nasal oxygen (HFNO). However, several articles have proposed that criteria for defining ARDS should be broadened to allow inclusion of patients receiving HFNO. Objectives: To compare the proportion of patients fulfilling ARDS criteria during HFNO and soon after intubation, and 28-day mortality between patients treated exclusively with HFNO and patients transitioned from HFNO to invasive mechanical ventilation (IMV). Methods: From previously published studies, we analyzed patients with coronavirus disease (COVID-19) who had Pa O 2 /Fi O 2 of ⩽300 while treated with ⩾40 L/min HFNO, or noninvasive ventilation (NIV) with positive end-expiratory pressure of ⩾5 cm H 2 O (comparator). In patients transitioned from HFNO/NIV to invasive mechanical ventilation (IMV), we compared ARDS severity during HFNO/NIV and soon after IMV. We compared 28-day mortality in patients treated exclusively with HFNO/NIV versus patients transitioned to IMV. Measurements and Main Results: We analyzed 184 and 131 patients receiving HFNO or NIV, respectively. A total of 112 HFNO and 69 NIV patients transitioned to IMV. Of those, 104 (92.9%) patients on HFNO and 66 (95.7%) on NIV continued to have Pa O 2 /Fi O 2 ⩽300 under IMV. Twenty-eight-day mortality in patients who remained on HFNO was 4.2% (3/72), whereas in patients transitioned from HFNO to IMV, it was 28.6% (32/112) ( P  < 0.001). Twenty-eight-day mortality in patients who remained on NIV was 1.6% (1/62), whereas in patients who transitioned from NIV to IMV, it was 44.9% (31/69) ( P  < 0.001). Overall mortality was 19.0% (35/184) and 24.4% (32/131) for HFNO and NIV, respectively ( P  = 0.2479). Conclusions: Broadening the ARDS definition to include patients on HFNO with Pa O 2 /Fi O 2 ⩽300 may identify patients at earlier stages of disease but with lower mortality.

Background: Extracorporeal membrane oxygenation (ECMO) has become an established rescue therapy for severe acute respiratory distress syndrome (ARDS) in several etiologies including influenza A H1N1 pneumonia. The benefit of receiving ECMO in coronavirus disease 2019 (COVID-19) is still uncertain. The aim of this analysis was to compare the outcome of patients who received veno-venous ECMO for COVID-19 and Influenza A H1N1 associated ARDS., Methods: This was a multicenter retrospective cohort study including adults with ARDS, receiving ECMO for COVID-19 and influenza A H1N1 pneumonia between 2009 and 2021 in seven Italian ICU. The primary outcome was any-cause mortality at 60 days after ECMO initiation. We used a multivariable Cox model to estimate the difference in mortality accounting for patients' characteristics and treatment factors before ECMO was started. Secondary outcomes were mortality at 90 days, ICU and hospital length of stay and ECMO associated complications., Results: Data from 308 patients with COVID-19 (N = 146) and H1N1 (N = 162) associated ARDS who had received ECMO support were included. The estimated cumulative mortality at 60 days after initiating ECMO was higher in COVID-19 (46%) than H1N1 (27%) patients (hazard ratio 1.76, 95% CI 1.17-2.46). When adjusting for confounders, specifically age and hospital length of stay before ECMO support, the hazard ratio decreased to 1.39, 95% CI 0.78-2.47. ICU and hospital length of stay, duration of ECMO and invasive mechanical ventilation and ECMO-associated hemorrhagic complications were higher in COVID-19 than H1N1 patients., Conclusion: In patients with ARDS who received ECMO, the observed unadjusted 60-day mortality was higher in cases of COVID-19 than H1N1 pneumonia. This difference in mortality was not significant after multivariable adjustment; older age and longer hospital length of stay before ECMO emerged as important covariates that could explain the observed difference., Trial Registration Number: NCT05080933 , retrospectively registered., (© 2022. The Author(s).)

Early physiotherapy could play an important role in the management of severe COVID-19 subjects with consequences of prolonged ICU stay, although its effectiveness is still unclear. Aim of this study is to describe physiotherapy performed in severe COVID-19 patients and to evaluate its safety and feasibility. Consecutive adults with confirmed SARS-CoV-2 infection, admitted to the ICU, needing invasive mechanical ventilation for >24 hours and receiving early physiotherapy, have been enrolled. Adverse events occurred during physiotherapy sessions and timing and type of physiotherapy delivered were analysed, to identify the interventions most frequently performed and to determine the time taken to first mobilize, stand and walk. Functional and clinical assessment of patients was also performed at hospital discharge. Eighty-four severe COVID-19 subjects were enrolled. Few minor adverse events were recorded. Active mobilization was promoted over passive mobilization and independence in daily life activities was supported. Time interval from patients' intubation to the first physiotherapy treatment was 13 days and to walking was 27 days. Forty-eight (57.1%) subjects returned at home, whereas 29 (34.5%) were discharged to in-patient rehabilitation. Patients with tracheostomy experienced a delay in time from ICU admission until sit out of bed and ambulation, if compared with subjects without tracheostomy, although no differences were found in 6MWT and 1m-STST performances. This study reporting early physiotherapy during pandemic suggests that this intervention is feasible and safe for severe COVID-19 subjects, as well as healthcare workers, although delayed compared to other critically ill patients.

During the spring of 2020, the coronavirus disease 2019 (COVID-19) epidemic caused an unprecedented demand for intensive-care resources in the Lombardy region of Italy. Using data on 43,538 hospitalized patients admitted between February 21 and July 12, 2020, we evaluated variations in intensive care unit (ICU) admissions and mortality over the course of 3 periods: the early phase of the pandemic (February 21-March 13), the period of highest pressure on the health-care system (March 14-April 25, when numbers of COVID-19 patients exceeded prepandemic ICU bed capacity), and the declining phase (April 26-July 12). Compared with the early phase, patients aged 70 years or more were less often admitted to an ICU during the period of highest pressure on the health-care system (odds ratio (OR) = 0.47, 95% confidence interval (CI): 0.41, 0.54), with longer ICU delays (incidence rate ratio = 1.82, 95% CI: 1.52, 2.18) and lower chances of dying in the ICU (OR = 0.47, 95% CI: 0.34, 0.64). Patients under 56 years of age had more limited changes in the probability of (OR = 0.65, 95% CI: 0.56, 0.76) and delay to (incidence rate ratio = 1.16, 95% CI: 0.95, 1.42) ICU admission and increased mortality (OR = 1.43, 95% CI: 1.00, 2.07). In the declining phase, all quantities decreased for all age groups. These patterns may suggest that limited health-care resources during the peak phase of the epidemic in Lombardy forced a shift in ICU admission criteria to prioritize patients with higher chances of survival., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In the night of February 20, 2020, the first epidemic of the novel coronavirus disease (COVID-19) outside Asia was uncovered by the identification of its first patient in Lombardy region, Italy. In the following weeks, Lombardy experienced a sudden increase in the number of ascertained infections and strict measures were imposed to contain the epidemic spread., Methods: We analyzed official records of cases occurred in Lombardy to characterize the epidemiology of SARS-CoV-2 during the early phase of the outbreak. A line list of laboratory-confirmed cases was set up and later retrospectively consolidated, using standardized interviews to ascertained cases and their close contacts. We provide estimates of the serial interval, of the basic reproduction number, and of the temporal variation of the net reproduction number of SARS-CoV-2., Results: Epidemiological investigations detected over 500 cases (median age: 69, IQR: 57-78) before the first COVID-19 diagnosed patient (February 20, 2020), and suggested that SARS-CoV-2 was already circulating in at least 222 out of 1506 (14.7%) municipalities with sustained transmission across all the Lombardy provinces. We estimated the mean serial interval to be 6.6 days (95% CrI, 0.7-19). Our estimates of the basic reproduction number range from 2.6 in Pavia (95% CI, 2.1-3.2) to 3.3 in Milan (95% CI, 2.9-3.8). A decreasing trend in the net reproduction number was observed following the detection of the first case., Conclusions: At the time of first case notification, COVID-19 was already widespread in the entire Lombardy region. This may explain the large number of critical cases experienced by this region in a very short timeframe. The slight decrease of the reproduction number observed in the early days after February 20, 2020 might be due to increased population awareness and early interventions implemented before the regional lockdown imposed on March 8, 2020., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Understanding the risk factors associated with hospital burden of COVID-19 is crucial for healthcare planning for any future waves of infection., Methods: An observational cohort study is performed, using data on all PCR-confirmed cases of COVID-19 in Regione Lombardia, Italy, during the first wave of infection from February-June 2020. A multi-state modelling approach is used to simultaneously estimate risks of progression through hospital to final outcomes of either death or discharge, by pathway (via critical care or not) and the times to final events (lengths of stay). Logistic and time-to-event regressions are used to quantify the association of patient and population characteristics with the risks of hospital outcomes and lengths of stay respectively., Results: Risks of severe outcomes such as ICU admission and mortality have decreased with month of admission (for example, the odds ratio of ICU admission in June vs March is 0.247 [0.120-0.508]) and increased with age (odds ratio of ICU admission in 45-65 vs 65 + age group is 0.286 [0.201-0.406]). Care home residents aged 65 + are associated with increased risk of hospital mortality and decreased risk of ICU admission. Being a healthcare worker appears to have a protective association with mortality risk (odds ratio of ICU mortality is 0.254 [0.143-0.453] relative to non-healthcare workers) and length of stay. Lengths of stay decrease with month of admission for survivors, but do not appear to vary with month for non-survivors., Conclusions: Improvements in clinical knowledge, treatment, patient and hospital management and public health surveillance, together with the waning of the first wave after the first lockdown, are hypothesised to have contributed to the reduced risks and lengths of stay over time., (© 2021. The Author(s).)

Background: COVID-19 patients developing the acute respiratory distress syndrome (ARDS) show increased production of pro-inflammatory cytokines, including interleukin-6 (IL-6). The use of humanized monoclonal antibody against interleukin-6 receptor (IL-6R) may represent a potential treatment strategy. We analyzed the effects of compassionate use of tocilizumab and sarilumab on clinical outcome of patients affected by ARDS due COVID-19., Methods: This single-center, observational, exploratory study was performed during the acute phase of COVID-19 outbreak, between March 7 th and April 21 st , 2020 in a University Hospital in Rome, Italy. All consecutive adult patients admitted to the intensive care unit with laboratory-confirmed COVID-19 and fulfilling ARDS criteria were enrolled. Patients who were treated with anti-IL-6R therapy were compared to those who were not, as per clinical decision. Inverse probability weights were applied to weight individual's contribution to survival curves and in the multivariate regression model., Results: Among 105 ARDS patients, 65 received compassionate treatment with anti-IL-6R therapy (43 [66%] Tocilizumab [Hoffmann-La Roche, Basel, Switzerland] and 22 [34%] Sarilumab, respectively], with oxygenation improvement. In the multivariable Cox proportional regression hazards model with propensity score inverse probability weighting, patients who received anti-IL-6R treatment had lower risk of death compared to those who did not, with a hazard ration of 0.34 [95% confidence interval 0.17-0.74], P=0.001., Conclusions: Our data suggested that immune modulator therapy based on anti-human IL-6 receptor monoclonal antibodies might lead to improved outcome in patients with ARDS due to COVID-19. These data support the need for confirmatory randomized trials to assess the effect of immune modulator therapies on mortality.

Background: Lombardy was the epicenter in Italy of the first wave of COVID-19 pandemic. To face the contagion growth, from March 8 to May 8, 2020, a regional law redesigned the hub-and-spoke system for time-dependent diseases to better allocate resources for COVID-19 patients., Methods: We report the reorganization of the major hospital in Lombardy during COVID-19 pandemic, including the rearrangement of its ICU beds to face COVID-19 pandemic and fulfill its role as extended hub for time-dependent diseases while preserving transplant activity. To highlight the impact of the emergently planned hub-and-spoke system, all patients admitted to a COVID-19-free ICU hub for trauma, neurosurgical emergencies and stroke during the two-month period were retrospectively collected and compared to 2019 cohort. Regional data on organ procurement was retrieved. Observed-to-expected (OE) in-ICU mortality ratios were computed to test the impact of the pandemic on patients affected by time-dependent diseases., Results: Dynamic changes in ICU resource allocation occurred according to local COVID-19 epidemiology/trends of patients referred for time-dependent diseases. The absolute increase of admissions for trauma, neurosurgical emergencies and stroke was roughly two-fold. Patients referred to the hub were older and characterized by more severe conditions. An increase in crude mortality was observed, though OE ratios for in-ICU mortality were not statistically different when comparing 2020 vs. 2019. An increase in local organ procurement was observed, limiting the debacle of regional transplant activity., Conclusions: We described the effects of a regional emergently planned hub-and-spoke system for time-dependent diseases settled in the epicenter of COVID-19 pandemic in Italy.

Background: The aim of this study is to quantify the hospital burden of COVID-19 during the first wave and how it changed over calendar time; to interpret the results in light of the emergency measures introduced to manage the strain on secondary healthcare., Methods: This is a cohort study of hospitalised confirmed cases of COVID-19 admitted from February-June 2020 and followed up till 17th July 2020, analysed using a mixture multi-state model. All hospital patients with confirmed COVID-19 disease in Regione Lombardia were involved, admitted from February-June 2020, with non-missing hospital of admission and non-missing admission date., Results: The cohort consists of 40,550 patients hospitalised during the first wave. These patients had a median age of 69 (interquartile range 56-80) and were more likely to be men (60%) than women (40%). The hospital-fatality risk, averaged over all pathways through hospital, was 27.5% (95% CI 27.1-28.0%); and steadily decreased from 34.6% (32.5-36.6%) in February to 7.6% (6.3-10.6%) in June. Among surviving patients, median length of stay in hospital was 11.8 (11.6-12.3) days, compared to 8.1 (7.8-8.5) days in non-survivors. Averaged over final outcomes, median length of stay in hospital decreased from 21.4 (20.5-22.8) days in February to 5.2 (4.7-5.8) days in June., Conclusions: The hospital burden, in terms of both risks of poor outcomes and lengths of stay in hospital, has been demonstrated to have decreased over the months of the first wave, perhaps reflecting improved treatment and management of COVID-19 cases, as well as reduced burden as the first wave waned. The quantified burden allows for planning of hospital beds needed for current and future waves of SARS-CoV-2 i., (© 2021. The Author(s).)

Purpose: To evaluate the daily values and trends over time of relevant clinical, ventilatory and laboratory parameters during the intensive care unit (ICU) stay and their association with outcome in critically ill patients with coronavirus disease 19 (COVID-19)., Methods: In this retrospective-prospective multicentric study, we enrolled COVID-19 patients admitted to Italian ICUs from February 22 to May 31, 2020. Clinical data were daily recorded. The time course of 18 clinical parameters was evaluated by a polynomial maximum likelihood multilevel linear regression model, while a full joint modeling was fit to study the association with ICU outcome., Results: 1260 consecutive critically ill patients with COVID-19 admitted in 24 ICUs were enrolled. 78% were male with a median age of 63 [55-69] years. At ICU admission, the median ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO 2 /FiO 2 ) was 122 [89-175] mmHg. 79% of patients underwent invasive mechanical ventilation. The overall mortality was 34%. Both the daily values and trends of respiratory system compliance, PaO 2 /FiO 2 , driving pressure, arterial carbon dioxide partial pressure, creatinine, C-reactive protein, ferritin, neutrophil, neutrophil-lymphocyte ratio, and platelets were associated with survival, while for lactate, pH, bilirubin, lymphocyte, and urea only the daily values were associated with survival. The trends of PaO 2 /FiO 2 , respiratory system compliance, driving pressure, creatinine, ferritin, and C-reactive protein showed a higher association with survival compared to the daily values., Conclusion: Daily values or trends over time of parameters associated with acute organ dysfunction, acid-base derangement, coagulation impairment, or systemic inflammation were associated with patient survival., (© 2021. The Author(s).)

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2021. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2021 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.springer.com/bookseries/8901 ., (© 2021. Grasselli et al.)

Background:  Coronavirus disease 2019 (COVID-19) is associated with systemic inflammation, which may dysregulate platelet function. Total Thrombus-Formation Analysis System (T-TAS) is a flow-chamber device that analyses platelet-mediated thrombus formation in capillary channels through the following parameters: (1) the area under the flow-pressure curve (AUC), (2) occlusion start time (OST), time needed to reach OST, and (3) occlusion time (OT), time needed to reach the occlusion pressure., Methods and Findings:  Sixty-one COVID-19 patients admitted to intensive, subintensive, and low intensive care were prospectively enrolled according to the time of admission: group A (up to 8 days) ( n  = 18); group B (from 9 to 21 days) ( n  = 19), and group C ( > 21 days) ( n  = 24). T-TAS measurements were performed at enrolment and after 7 days. Median OST was similar among groups. AUC was lower in group A compared to B ( p  = 0.001) and C ( p  = 0.033). OT was longer in group A compared to B ( p  = 0.001) and C ( p  = 0.028). Platelet count (PC) was higher in group B compared to A ( p  = 0.024). The linear regression showed that OT and AUC were independent from PC in group A (OT: 0.149 [95% confidence interval [CI]: -0.326 to 0.624], p  = 0.513 and AUC: 0.005 [95% CI: -0.008 to 0.017], p  = 0,447). In contrast, in group B, PC was associated with OT (-0.019 [-0.028 to 0.008], p  = 0.023) and AUC (0.749 [0.358-1.139], p  = 0,015), similarly to group C. Conversely, patients with different illness severity had similar T-TAS parameters., Conclusion:  COVID-19 patients display an impaired platelet thrombus formation in the early phase of the disease compared to later stages and controls, independently from illness severity., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Few small studies have described hospital-acquired infections (HAIs) occurring in patients with COVID-19., Research Question: What characteristics in critically ill patients with COVID-19 are associated with HAIs and how are HAIs associated with outcomes in these patients?, Study Design and Methods: Multicenter retrospective analysis of prospectively collected data including adult patients with severe COVID-19 admitted to eight Italian hub hospitals from February 20, 2020, through May 20, 2020. Descriptive statistics and univariate and multivariate Weibull regression models were used to assess incidence, microbial cause, resistance patterns, risk factors (ie, demographics, comorbidities, exposure to medication), and impact on outcomes (ie, ICU discharge, length of ICU and hospital stays, and duration of mechanical ventilation) of microbiologically confirmed HAIs., Results: Of the 774 included patients, 359 patients (46%) demonstrated 759 HAIs (44.7 infections/1,000 ICU patient-days; 35% multidrug-resistant [MDR] bacteria). Ventilator-associated pneumonia (VAP; n = 389 [50%]), bloodstream infections (BSIs; n = 183 [34%]), and catheter-related BSIs (n = 74 [10%]) were the most frequent HAIs, with 26.0 (95% CI, 23.6-28.8) VAPs per 1,000 intubation-days, 11.7 (95% CI, 10.1-13.5) BSIs per 1,000 ICU patient-days, and 4.7 (95% CI, 3.8-5.9) catheter-related BSIs per 1,000 ICU patient-days. Gram-negative bacteria (especially Enterobacterales) and Staphylococcus aureus caused 64% and 28% of cases of VAP, respectively. Variables independently associated with infection were age, positive end expiratory pressure, and treatment with broad-spectrum antibiotics at admission. Two hundred thirty-four patients (30%) died in the ICU (15.3 deaths/1,000 ICU patient-days). Patients with HAIs complicated by septic shock showed an almost doubled mortality rate (52% vs 29%), whereas noncomplicated infections did not affect mortality. HAIs prolonged mechanical ventilation (median, 24 days [interquartile range (IQR), 14-39 days] vs 9 days [IQR, 5-13 days]; P < .001), ICU stay (24 days [IQR, 16-41 days] vs 9 days [IQR, 6-14 days]; P = .003), and hospital stay (42 days [IQR, 25-59 days] vs 23 days [IQR, 13-34 days]; P < .001)., Interpretation: Critically ill patients with COVID-19 are at high risk for HAIs, especially VAPs and BSIs resulting from MDR organisms. HAIs prolong mechanical ventilation and hospitalization, and HAIs complicated by septic shock almost double mortality., Trial Registry: ClinicalTrials.gov; No.: NCT04388670; URL: www.clinicaltrials.gov., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

To describe radiographic key patterns on Chest X-ray (CXR) in patients with SARS-CoV-2 infection, assessing the prevalence of radiographic signs of interstitial pneumonia. To evaluate pattern variation between a baseline and a follow-up CXR. 1117 patients tested positive for SARS-CoV-2 infection were retrospectively enrolled from four centers in Lombardy region. All patients underwent a CXR at presentation. Follow-up CXR was performed when clinically indicated. Two radiologists in each center reviewed images and classified them as suggestive or not for interstitial pneumonia, recording the presence of ground-glass opacity (GGO), reticular pattern or consolidation and their distribution. Pearson's χ 2 test for categorical variables and McNemar test (χ 2 for paired data) were performed. Patients mean age 63.3 years, 767 were males (65.5%). The main result is the large proportion of positive CXR in COVID-19 patients. Baseline CXR was positive in 940 patients (80.3%), with significant differences in age and sex distribution between patients with positive and negative CXR. 382 patients underwent a follow-up CXR. The most frequent pattern on baseline CXR was the GGO (66.1%), on follow-up was consolidation (53.4%). The most common distributions were peripheral and middle-lower lung zone. We described key-patterns and their distribution on CXR in a large cohort of COVID-19 patients: GGO was the most frequent finding on baseline CXR, while we found an increase in the proportion of lung consolidation on follow-up CXR. CXR proved to be a reliable tool in our cohort obtaining positive results in 80.3% of the baseline cases., (© 2020. The Author(s).)

Background: Noninvasive respiratory support (NIRS) has been diffusely employed outside the intensive care unit (ICU) to face the high request of ventilatory support due to the massive influx of patients with acute respiratory failure (ARF) caused by coronavirus-19 disease (COVID-19). We sought to summarize the evidence on clinically relevant outcomes in COVID-19 patients supported by NIV outside the ICU., Methods: We searched PUBMED®, EMBASE®, and the Cochrane Controlled Clinical trials register, along with medRxiv and bioRxiv repositories for pre-prints, for observational studies and randomized controlled trials, from inception to the end of February 2021. Two authors independently selected the investigations according to the following criteria: (1) observational study or randomized clinical trials enrolling ≥ 50 hospitalized patients undergoing NIRS outside the ICU, (2) laboratory-confirmed COVID-19, and (3) at least the intra-hospital mortality reported. Preferred Reporting Items for Systematic reviews and Meta-analysis guidelines were followed. Data extraction was independently performed by two authors to assess: investigation features, demographics and clinical characteristics, treatments employed, NIRS regulations, and clinical outcomes. Methodological index for nonrandomized studies tool was applied to determine the quality of the enrolled studies. The primary outcome was to assess the overall intra-hospital mortality of patients under NIRS outside the ICU. The secondary outcomes included the proportions intra-hospital mortalities of patients who underwent invasive mechanical ventilation following NIRS failure and of those with 'do-not-intubate' (DNI) orders., Results: Seventeen investigations (14 peer-reviewed and 3 pre-prints) were included with a low risk of bias and a high heterogeneity, for a total of 3377 patients. The overall intra-hospital mortality of patients receiving NIRS outside the ICU was 36% [30-41%]. 26% [21-30%] of the patients failed NIRS and required intubation, with an intra-hospital mortality rising to 45% [36-54%]. 23% [15-32%] of the patients received DNI orders with an intra-hospital mortality of 72% [65-78%]. Oxygenation on admission was the main source of between-study heterogeneity., Conclusions: During COVID-19 outbreak, delivering NIRS outside the ICU revealed as a feasible strategy to cope with the massive demand of ventilatory assistance., Registration: PROSPERO, https://www.crd.york.ac.uk/prospero/ , CRD42020224788, December 11, 2020., (© 2021. The Author(s).)

Since the lockdown because of the pandemic, family members have been prohibited from visiting their loved ones in hospital. While it is clearly complicated to implement protocols for the admission of family members, we believe precise strategic goals are essential and operational guidance is needed on how to achieve them. Even during the pandemic, we consider it a priority to share strategies adapted to every local setting to allow family members to enter intensive care units and all the other hospital wards.

Purpose: Aim of the study is to evaluate the incidence of DVT in COVID-19 patients and its correlation with the severity of the disease and with clinical and laboratory findings., Methods: 234 symptomatic patients with COVID-19, diagnosed according to the World Health Organization guidelines, were included in the study. The severity of the disease was classified as moderate, severe and critical. Doppler ultrasound (DUS) was performed in all patients. DUS findings, clinical, laboratory's and therapeutic variables were investigated by contingency tables, Pearson chi square test and by Student t test and Fisher's exact test. ROC curve analysis was applied to study significant continuous variables., Results: Overall incidence of DVT was 10.7% (25/234): 1.6% (1/60) among moderate cases, 13.8% (24/174) in severely and critically ill patients. Prolonged bedrest and intensive care unit admission were significantly associated with the presence of DVT (19.7%). Fraction of inspired oxygen, P/F ratio, respiratory rate, heparin administration, D-dimer, IL-6, ferritin and CRP showed correlation with DVT., Conclusion: DUS may be considered a useful and valid tool for early identification of DVT. In less severely affected patients, DUS as screening of DVT might be unnecessary. High rate of DVT found in severe patients and its correlation with respiratory parameters and some significant laboratory findings suggests that these can be used as a screening tool for patients who should be getting DUS.

Italy was the first western country facing an outbreak of coronavirus disease 2019 (COVID-19). The first Italian patient diagnosed with COVID-19 was admitted, on Feb. 20, 2020, to the intensive care unit (ICU) in Codogno (Lodi, Lombardy, Italy), and the number of reported positive cases increased to 36 in the next 24 hours, and then exponentially for 18 days. This triggered a response that resulted in a massive surge in ICU bed capacity. The COVID19 Lombardy Network organized a structured logistic response and provided scientific evidence to highlight information on COVID-19 associated respiratory failure., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Rationale: Treatment with noninvasive ventilation (NIV) in coronavirus disease (COVID-19) is frequent. Shortage of intensive care unit (ICU) beds led clinicians to deliver NIV also outside ICUs. Data about the use of NIV in COVID-19 is limited. Objectives: To describe the prevalence and clinical characteristics of patients with COVID-19 treated with NIV outside the ICUs. To investigate the factors associated with NIV failure (need for intubation or death). Methods: In this prospective, single-day observational study, we enrolled adult patients with COVID-19 who were treated with NIV outside the ICU from 31 hospitals in Lombardy, Italy. Results: We collected data on demographic and clinical characteristics, ventilatory management, and patient outcomes. Of 8,753 patients with COVID-19 present in the hospitals on the study day, 909 (10%) were receiving NIV outside the ICU. A majority of patients (778/909; 85%) patients were treated with continuous positive airway pressure (CPAP), which was delivered by helmet in 617 (68%) patients. NIV failed in 300 patients (37.6%), whereas 498 (62.4%) patients were discharged alive without intubation. Overall mortality was 25%. NIV failure occurred in 152/284 (53%) patients with an arterial oxygen pressure (Pa O 2 )/fraction of inspired oxygen (Fi O 2 ) ratio <150 mm Hg. Higher C-reactive protein and lower Pa O 2 /Fi O 2 and platelet counts were independently associated with increased risk of NIV failure. Conclusions: The use of NIV outside the ICUs was common in COVID-19, with a predominant use of helmet CPAP, with a rate of success >60% and close to 75% in full-treatment patients. C-reactive protein, Pa O 2 /Fi O 2 , and platelet counts were independently associated with increased risk of NIV failure.Clinical trial registered with ClinicalTrials.gov (NCT04382235).

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 was 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 Oxygen Responders if the PaO 2 /FiO 2 ratio increased ≥ 20 mmHg during prone position and as Carbon Dioxide Responders if the ventilatory ratio was reduced 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 PaO 2 /FiO 2 ratio, while no change in respiratory system compliance or ventilatory ratio was observed. Seventy-eight % of the subset of 78 patients were Oxygen Responders. Non-Responders had a more severe respiratory failure and died more often in the ICU (65% vs. 38%, p = 0.047). Forty-seven % of patients were defined as Carbon Dioxide Responders. These patients were older and had more comorbidities; however, no difference in terms of ICU mortality was observed (51% vs. 37%, p = 0.189 for Carbon Dioxide Responders and Non-Responders, respectively)., 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.