Ventilatory associated barotrauma in COVID-19 patients: A multicenter observational case control study (COVI-MIX-study).

BACKGROUND: The risk of barotrauma associated with different types of ventilatory support is unclear in COVID-19 patients. The primary aim of this study was to evaluate the effect of the different respiratory support strategies on barotrauma occurrence; we also sought to determine the frequency of barotrauma and the clinical characteristics of the patients who experienced this complication. METHODS: This multicentre retrospective case-control study from 1 March 2020 to 28 February 2021 included COVID-19 patients who experienced barotrauma during hospital stay. They were matched with controls in a 1:1 ratio for the same admission period in the same ward of treatment. Univariable and multivariable logistic regression (OR) were performed to explore which factors were associated with barotrauma and in-hospital death. RESULTS: We included 200 cases and 200 controls. Invasive mechanical ventilation was used in 39.3% of patients in the barotrauma group, and in 20.1% of controls (p<0.001). Receiving non-invasive ventilation (C-PAP/PSV) instead of conventional oxygen therapy (COT) increased the risk of barotrauma (OR 5.04, 95% CI 2.30 - 11.08, p<0.001), similarly for invasive mechanical ventilation (OR 6.24, 95% CI 2.86-13.60, p<0.001). High Flow Nasal Oxygen (HFNO), compared with COT, did not significantly increase the risk of barotrauma. Barotrauma frequency occurred in 1.00% [95% CI 0.88-1.16] of patients; these were older (p=0.022) and more frequently immunosuppressed (p=0.013). Barotrauma was shown to be an independent risk for death (OR 5.32, 95% CI 2.82-10.03, p<0.001). CONCLUSIONS: C-PAP/PSV compared with COT or HFNO increased the risk of barotrauma; otherwise HFNO did not. Barotrauma was recorded in 1.00% of patients, affecting mainly patients with more severe COVID-19 disease. Barotrauma was independently associated with mortality. TRIAL REGISTRATION: this case-control study was prospectively registered in clinicaltrial.gov as NCT04897152 (on 21 May 2021).

Quality of Life in COVID-Related ARDS Patients One Year after Intensive Care Discharge (Odissea Study): A Multicenter Observational Study.

BACKGROUND: Investigating the health-related quality of life (HRQoL) after intensive care unit (ICU) discharge is necessary to identify possible modifiable risk factors. The primary aim of this study was to investigate the HRQoL in COVID-19 critically ill patients one year after ICU discharge. METHODS: In this multicenter prospective observational study, COVID-19 patients admitted to nine ICUs from 1 March 2020 to 28 February 2021 in Italy were enrolled. One year after ICU discharge, patients were required to fill in short-form health survey 36 (SF-36) and impact of event-revised (IES-R) questionnaire. A multivariate linear or logistic regression analysis to search for factors associated with a lower HRQoL and post-traumatic stress disorded (PTSD) were carried out, respectively. RESULTS: Among 1003 patients screened, 343 (median age 63 years [57-70]) were enrolled. Mechanical ventilation lasted for a median of 10 days [2-20]. Physical functioning (PF 85 [60-95]), physical role (PR 75 [0-100]), emotional role (RE 100 [33-100]), bodily pain (BP 77.5 [45-100]), social functioning (SF 75 [50-100]), general health (GH 55 [35-72]), vitality (VT 55 [40-70]), mental health (MH 68 [52-84]) and health change (HC 50 [25-75]) describe the SF-36 items. A median physical component summary (PCS) and mental component summary (MCS) scores were 45.9 (36.5-53.5) and 51.7 (48.8-54.3), respectively, considering 50 as the normal value of the healthy general population. In all, 109 patients (31.8%) tested positive for post-traumatic stress disorder, also reporting a significantly worse HRQoL in all SF-36 domains. The female gender, history of cardiovascular disease, liver disease and length of hospital stay negatively affected the HRQoL. Weight at follow-up was a risk factor for PTSD (OR 1.02, p = 0.03). CONCLUSIONS: The HRQoL in COVID-19 ARDS (C-ARDS) patients was reduced regarding the PCS, while the median MCS value was slightly above normal. Some risk factors for a lower HRQoL have been identified, the presence of PTSD is one of them. Further research is warranted to better identify the possible factors affecting the HRQoL in C-ARDS.

VENTILATORY ASSOCIATED BAROTRAUMA IN COVID-19 PATIENTS: A MULTICENTER OBSERVATIONAL CASE CONTROL STUDY (COVI-MIX-STUDY)

Background The risk of barotrauma associated with different types of ventilatory support is unclear in COVID-19 patients. The primary aim of this study was to evaluate the effect of the different respiratory support strategies on barotrauma occurrence;we also sought to determine the frequency of barotrauma and the clinical characteristics of the patients who experienced this complication. Methods This multicentre retrospective case-control study from 1 March 2020 to 28 February 2021 included COVID-19 patients who experienced barotrauma during hospital stay. They were matched with controls in a 1:1 ratio for the same admission period in the same ward of treatment. Univariable and multivariable logistic regression (OR) were performed to explore which factors were associated with barotrauma and in-hospital death. Results We included 200 cases and 200 controls. Invasive mechanical ventilation was used in 39.3% of patients in the barotrauma group, and in 20.1% of controls (p<0.001). Receiving non-invasive ventilation (C-PAP/PSV) instead of conventional oxygen therapy (COT) increased the risk of barotrauma (OR 5.04, 95% CI 2.30 - 11.08, p<0.001), similarly for invasive mechanical ventilation (OR 6.24, 95% CI 2.86-13.60, p<0.001). High Flow Nasal Oxygen (HFNO), compared with COT, did not significantly increase the risk of barotrauma. Barotrauma frequency occurred in 1.00% [95% CI 0.88-1.16] of patients;these were older (p=0.022) and more frequently immunosuppressed (p=0.013). Barotrauma was shown to be an independent risk for death (OR 5.32, 95% CI 2.82-10.03, p<0.001). Conclusions C-PAP/PSV compared with COT or HFNO increased the risk of barotrauma;otherwise HFNO did not. Barotrauma was recorded in 1.00% of patients, affecting mainly patients with more severe COVID-19 disease. Barotrauma was independently associated with mortality. Trial registration this case-control study was prospectively registered in clinicaltrial.gov as NCT04897152 (on 21 May 2021).

Reorganization of Intensive Care Units for the COVID-19 pandemic: effects on nursing sensitive outcomes.

Background: Since the first months of 2020 COVID-19 patients who were seriously ill due to the development of ARDS, required admission to the intensive care unit to ensure potentially life-saving mechanical ventilation and support for vital functions. To cope with this emergency, an extremely rapid reorganization of premises, services and staff, to dedicate an entire intensive care unit exclusively to SARS-CoV-2 patients and increasing the number of beds was essential. The aim of the study was to evaluate the effects of reorganization of the COVID-19 intensive care unit in terms of nursing sensitive outcomes. Methods: a retrospective observational study was conducted to compare nursing sensitive outcomes between pre-COVID period and COVID period. Results: Falls (0.0 and 0.4%, respectively), physical restraint (1.8 and 1.1%, respectively), and pressure ulcers (8.0 and 3.0%, respectively) were similar in the COVID and in the pre-COVID group. After adjusting for gender, age, BMI, and number of comorbidities, the incidence of bloodstream infections was significantly higher in the COVID group than in the pre-COVID group. There were no statistically significant differences in the incidence between the two groups regarding other evaluated outcomes. Conclusion: The selected nursing sensitive outcomes maintained similar values in the pre-COVID and COVID patient groups. Healthcare-related infections rate must be considered an important alarm signal of quality of nursing care especially in conditions of excessive workload, stress and the presence of less experienced staff increase.

Level of Diffusion and Training of Lung Ultrasound during the COVID-19 Pandemic - A National Online Italian Survey (ITALUS) from the Lung Ultrasound Working Group of the Italian Society of Anesthesia, Analgesia, Resuscitation, and Intensive Care (SIAARTI).

PURPOSE: The goal of this survey was to describe the use and diffusion of lung ultrasound (LUS), the level of training received before and during the COVID-19 pandemic, and the clinical impact LUS has had on COVID-19 cases in intensive care units (ICU) from February 2020 to May 2020. MATERIALS AND METHODS: The Italian Lung Ultrasound Survey (ITALUS) was a nationwide online survey proposed to Italian anesthesiologists and intensive care physicians carried out after the first wave of the COVID-19 pandemic. It consisted of 27 questions, both quantitative and qualitative. RESULTS: 807 responded to the survey. The median previous LUS experience was 3 years (IQR 1.0-6.0). 473 (60.9 %) reported having attended at least one training course on LUS before the COVID-19 pandemic. 519 (73.9 %) reported knowing how to use the LUS score. 404 (52 %) reported being able to use LUS without any supervision. 479 (68.2 %) said that LUS influenced their clinical decision-making, mostly with respect to patient monitoring. During the pandemic, the median of patients daily evaluated with LUS increased 3-fold (p < 0.001), daily use of general LUS increased from 10.4 % to 28.9 % (p < 0.001), and the daily use of LUS score in particular increased from 1.6 % to 9.0 % (p < 0.001). CONCLUSION: This survey showed that LUS was already extensively used during the first wave of the COVID-19 pandemic by anesthesiologists and intensive care physicians in Italy, and then its adoption increased further. Residency programs are already progressively implementing LUS teaching. However, 76.7 % of the sample did not undertake any LUS certification.

Diaphragm ultrasound evaluation during weaning from mechanical ventilation in COVID-19 patients: a pragmatic, cross-section, multicenter study.

BACKGROUND: Diaphragmatic dysfunction is a major factor responsible for weaning failure in patients that underwent prolonged invasive mechanical ventilation for acute severe respiratory failure from COVID-19. This study hypothesizes that ultrasound measured diaphragmatic thickening fraction (DTF) could provide corroborating information for weaning COVID-19 patients from mechanical ventilation. METHODS: This was an observational, pragmatic, cross-section, multicenter study in 6 Italian intensive care units. DTF was assessed in COVID-19 patients undergoing weaning from mechanical ventilation from 1st March 2020 to 30th June 2021. Primary aim was to evaluate whether DTF is a predictive factor for weaning failure. RESULTS: Fifty-seven patients were enrolled, 25 patients failed spontaneous breathing trial (44%). Median length of invasive ventilation was 14 days (IQR 7-22). Median DTF within 24 h since the start of weaning was 28% (IQR 22-39%), RASS score (- 2 vs - 2; p = 0.031); Kelly-Matthay score (2 vs 1; p = 0.002); inspiratory oxygen fraction (0.45 vs 0.40; p = 0.033). PaO2/FiO2 ratio was lower (176 vs 241; p = 0.032) and length of intensive care stay was longer (27 vs 16.5 days; p = 0.025) in patients who failed weaning. The generalized linear regression model did not select any variables that could predict weaning failure. DTF was correlated with pH (RR 1.56 × 1027; p = 0.002); Kelly-Matthay score (RR 353; p < 0.001); RASS (RR 2.11; p = 0.003); PaO2/FiO2 ratio (RR 1.03; p = 0.05); SAPS2 (RR 0.71; p = 0.005); hospital and ICU length of stay (RR 1.22 and 0.79, respectively; p < 0.001 and p = 0.004). CONCLUSIONS: DTF in COVID-19 patients was not predictive of weaning failure from mechanical ventilation, and larger studies are needed to evaluate it in clinical practice further. Registered: ClinicalTrial.gov (NCT05019313, 24 August 2021).

Incidence and types of laryngotracheal sequelae of prolonged invasive ventilation in COVID-19 patients.

PURPOSE: The COVID-19 outbreak has led to an increasing number of acute laryngotracheal complications in patients subjected to prolonged mechanical ventilation, but their incidence in the short and mid-term after ICU discharge is still unknown. The main objective of this study is to evaluate the incidence of these complications in a COVID-19 group of patients and to compare these aspects with non-COVID-19 matched controls. METHODS: In this cohort study, we retrospectively selected patients from November 1 to December 31, 2020, according to specific inclusion and exclusion criteria. The follow-up visits were planned after 6 months from discharge. All patients were subjected to an endoscopic evaluation and completed two questionnaires (VHI-10 score and MDADI score). RESULTS: Thirteen men and three women were enrolled in the COVID-19 group while nine men and seven women were included in the control group. The median age was 60 [56-66] years in the COVID-19 group and 64 [58-69] years in the control group. All the patients of the control group showed no laryngotracheal lesions, while five COVID-19 patients had different types of lesions, two located in the vocal folds and three in the trachea. No difference was identified between the two groups regarding the VHI-10 score, while the control group showed a significantly worse MDADI score. CONCLUSIONS: COVID-19 patients subjected to prolonged invasive ventilation are more likely to develop a laryngotracheal complication in the short and medium term. A rigorous clinical follow-up to allow early identification and management of these complications should be set up after discharge.

Ten conditions where lung ultrasonography may fail: limits, pitfalls and lessons learned from a computer-aided algorithmic approach.

Lung ultrasonography provides relevant information on morphological and functional changes occurring in the lungs. However, it correlates weakly with pulmonary congestion and extra vascular lung water. Moreover, there is lack of consensus on scoring systems and acquisition protocols. The automation of this technique may provide promising easy-to-use clinical tools to reduce inter- and intra-observer variability and to standardize scores, allowing faster data collection without increased costs and patients risks.

Inflammatory Profiles of Tracheal Biopsies From SARS-CoV-2 Patients.

Purpose: An increasing number of laryngotracheal complications in mechanically ventilated COVID-19 patients has been reported in the last few months. Many etiopathogenetic hypotheses were proposed but no clear explanation of these complications was identified. In this paper we evaluated the possibility that the tracheal mucosa could be a high viral replication site that could weaken the epithelium itself. Methods: Subjects for the COVID-19 group and the control group were selected retrospectively according to specific criteria. Patients' basic and clinical data were recorded and analyzed. Tracheal samples of both groups were collected during surgical tracheostomies and then analyzed from a histological and genetic-transcriptional point of view. Results: Four COVID-19 patients were enrolled in this study and compared with four non-COVID-19 patients. No laryngotracheal complications were identified in both groups. The SARS-CoV-2 was detected in one out of four COVID-19 samples. A subepithelial inflammatory lymphomonocyte infiltrate was observed in all patients but two cases of the COVID-19 group showed vasculitis of small subepithelial vessels associated with foci of coagulative necrosis. Two gene sets (HALLMARK_INFLAMMATORY_RESPONSE and HALLMARK_ESTROGEN_RESPONSE_LATE) were significantly deregulated in COVID-19 patients compared to the control group. Conclusion: The altered inflammatory response of the COVID-19 patients could be another possible explanation of the increasing number of laryngotracheal complications.

Ictogenesis of viral pneumonia: A comparison between SARS-CoV-2 and H1N1/H3N2.

Several studies reported acute symptomatic seizures as a possible neurological complication of COVID-19 pneumonia. Apart from metabolic imbalances, hypoxia, and fever, other ictogenic mechanisms are likely related to an immune-mediated damage. The same mechanisms are shared by other respiratory viruses. Since neurotropic properties of SARS-CoV-2 have been questioned, we investigated whether SARS-CoV-2 has a similar ictogenic potential to other respiratory non-neurotropic viruses. We conducted a retrospective study identifying 1141 patients with SARS-CoV-2 pneumonia and 146 patients with H1N1/H3N2 pneumonia. We found a similar prevalence of seizures in the two viral pneumonia (1.05% with SARS-CoV-2 vs 2.05% with influenza; p = 0.26). We detailed clinical, electroencephalographic, and neuroradiological features of each patient, together with the hypothesized pathogenesis of seizures. Previous epilepsy or pre-existing predisposing conditions (i.e., Alzheimer's disease, stroke, cerebral neoplasia) were found in one-third of patients that experienced seizures, while two-thirds of patients had seizures without known risk factors other than pneumonia in both groups. The prevalence of pre-existing predisposing conditions and disease severity indexes was similar in SARS-CoV-2 and H1N1/H3N2 pneumonia, thus excluding they could act as potential confounders. Considering all the patients with viral pneumonia together, previous epilepsy (p < 0.001) and the need for ventilatory support (p < 0.001), but not the presence of pre-existing predisposing conditions (p = 0.290), were associated with seizure risk. Our study showed that SARS-CoV-2 and influenza viruses share a similar ictogenic potential. In both these infections, seizures are rare but serious events, and can manifest without pre-existing predisposing conditions, in particular when pneumonia is severe, thus suggesting an interplay between disease severity and host response as a major mechanism of ictogenesis, rather than a virus-specific mechanism.

Italian Society of Anesthesia, Analgesia, Resuscitation, and Intensive Care expert consensus statement on the use of lung ultrasound in critically ill patients with coronavirus disease 2019 (ITACO).

BACKGROUND: To produce statements based on the available evidence and an expert consensus (as members of the Lung Ultrasound Working Group of the Italian Society of Analgesia, Anesthesia, Resuscitation, and Intensive Care, SIAARTI) on the use of lung ultrasound for the management of patients with COVID-19 admitted to the intensive care unit. METHODS: A modified Delphi method was applied by a panel of anesthesiologists and intensive care physicians expert in the use of lung ultrasound in COVID-19 intensive critically ill patients to reach a consensus on ten clinical questions concerning the role of lung ultrasound in the following: COVID-19 diagnosis and monitoring (with and without invasive mechanical ventilation), positive end expiratory pressure titration, the use of prone position, the early diagnosis of pneumothorax- or ventilator-associated pneumonia, the process of weaning from invasive mechanical ventilation, and the need for radiologic chest imaging. RESULTS: A total of 20 statements were produced by the panel. Agreement was reached on 18 out of 20 statements (scoring 7-9; "appropriate") in the first round of voting, while 2 statements required a second round for agreement to be reached. At the end of the two Delphi rounds, the median score for the 20 statements was 8.5 [IQR 8.9], and the agreement percentage was 100%. CONCLUSION: The Lung Ultrasound Working Group of the Italian Society of Analgesia, Anesthesia, Resuscitation, and Intensive Care produced 20 consensus statements on the use of lung ultrasound in COVID-19 patients admitted to the ICU. This expert consensus strongly suggests integrating lung ultrasound findings in the clinical management of critically ill COVID-19 patients.

The effects of the reorganisation of an intensive care unit due to COVID-19 on nurses' wellbeing: An observational cross-sectional study.

OBJECTIVES: To evaluate the effects of the reorganisation of an intensive care unit for COVID-19 patients in the context of the SARS-CoV-2 pandemic on wellbeing perceived by nurses. METHODS: An observational cross-sectional study was conducted to evaluate wellbeing perceived by nurses who during the study were on duty in the COVID-19 intensive care unit. The "Covid-19-Nurse Well-being at Work (NWB) scale" questionnaire consisting of 72 items divided into 13 sections, was validated and used to collect data. RESULTS: The level of wellbeing perceived by the nurses was very good (4.77; SD 0.83). Differences in the of level of perceived wellbeing were found for "years of experience" and the various levels of competence. We found a positive correlation between "female gender" and "nurses' togetherness and collaboration", a negative correlation between "male gender" and "satisfactory practical organisation of work, and a negative correlation between "work experience" and the overall "level of wellbeing at work. CONCLUSIONS: The reorganisation had positive effects in terms of wellbeing perceived by the nurses. The factors that contributed mostly to the perception of wellbeing were in the area of "support", "communication, and "socializing with colleagues". It is appropriate to consider "gender differences", "work experience" and "levels of competence" when implementing this type of reorganisation to respond to a pandemic or a health emergency.

A pandemic recap: lessons we have learned.

On January 2020, the WHO Director General declared that the outbreak constitutes a Public Health Emergency of International Concern. The world has faced a worldwide spread crisis and is still dealing with it. The present paper represents a white paper concerning the tough lessons we have learned from the COVID-19 pandemic. Thus, an international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making. With the present paper, international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making.

JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.

Cefiderocol as Rescue Therapy for Acinetobacter baumannii and Other Carbapenem-resistant Gram-negative Infections in Intensive Care Unit Patients.

Ten critically ill patients with either bacteremia or ventilator-associated pneumonia caused by carbapenem-resistant Acinetobacter baumannii, Stenotrophomonas maltophilia, or New Delhi metallo-ß-lactamase-producing Klebsiella pneumoniae received cefiderocol. All strains had minimum inhibitory concentration ≤2 µg/mL. Thirty-day clinical success and survival rates were 70% and 90%, respectively. Two patients had a microbiological failure. Future prospective studies are warranted.

Rationale for Polyclonal Intravenous Immunoglobulin Adjunctive Therapy in COVID-19 Patients: Report of a Structured Multidisciplinary Consensus.

INTRODUCTION: Adjunctive therapy with polyclonal intravenous immunoglobins (IVIg) is currently used for preventing or managing infections and sepsis, especially in immunocompromised patients. The pathobiology of COVID-19 and the mechanisms of action of Ig led to the consideration of this adjunctive therapy, including in patients with respiratory failure due to the SARS-CoV-2 infection. This manuscript reports the rationale, the available data and the results of a structured consensus on intravenous Ig therapy in patients with severe COVID-19. METHODS: A panel of multidisciplinary experts defined the clinical phenotypes of COVID-19 patients with severe respiratory failure and, after literature review, voted for the agreement on the rationale and the potential role of IVIg therapy for each phenotype. Due to the scarce evidence available, a modified RAND/UCLA appropriateness method was used. RESULTS: Three different phenotypes of COVID-19 patients with severe respiratory failure were identified: patients with an abrupt and dysregulated hyperinflammatory response (early phase), patients with suspected immune paralysis (late phase) and patients with sepsis due to a hospital-acquired superinfection (sepsis by bacterial superinfection). The rationale for intravenous Ig therapy in the early phase was considered uncertain whereas the panelists considered its use in the late phase and patients with sepsis/septic shock by bacterial superinfection appropriate. CONCLUSION: As with other immunotherapies, IVIg adjunctive therapy may have a potential role in the management of COVID-19 patients. The ongoing trials will clarify the appropriate target population and the true effectiveness.

Preventing Severe Acute Respiratory Syndrome Coronavirus-2 Exhalation Upon Tracheal Extubation in the Intensive Care Unit: A Case Series.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly infectious virus transmitted by inhalation of infected matter containing live virus or by exposure from contaminated surfaces. Aerosol-generating procedures (AGPs) create an increased risk of airborne transmission of infection. Tracheal extubation of coronavirus disease 2019 (COVID-19) patients in the intensive care unit (ICU) is a risky AGP procedure owing to the proximity of the staff members to the patients' mouths and the exposure to airway secretions. We describe the use of a disposable openable mask (Janus Mask, Biomedical Srl, Florence, Italy) that might limit aerosol generation in the periextubation phase of COVID-19 cardiac surgical patients.

Adjunctive IgM-enriched immunoglobulin therapy with a personalised dose based on serum IgM-titres versus standard dose in the treatment of septic shock: a randomised controlled trial (IgM-fat trial).

INTRODUCTION: In patients with septic shock, low levels of circulating immunoglobulins are common and their kinetics appear to be related to clinical outcome. The pivotal role of immunoglobulins in the host immune response to infection suggests that additional therapy with polyclonal intravenous immunoglobulins may be a promising option in patients with septic shock. Immunoglobulin preparations enriched with the IgM component have largely been used in sepsis, mostly at standard dosages (250 mg/kg per day), regardless of clinical severity and without any dose adjustment based on immunoglobulin serum titres or other biomarkers. We hypothesised that a personalised dose of IgM enriched preparation based on patient IgM titres and aimed to achieve a specific threshold of IgM titre is more effective in decreasing mortality than a standard dose. METHODS AND ANALYSIS: The study is designed as a multicentre, interventional, randomised, single-blinded, prospective, investigator sponsored, two-armed study. Patients with septic shock and IgM titres <60 mg/dL will be randomly assigned to an IgM titre-based treatment or a standard treatment group in a ratio of 1:1. The study will involve 12 Italian intensive care units and 356 patients will be enrolled. Patients assigned to the IgM titre-based treatment will receive a personalised daily dose based on an IgM serum titre aimed at achieving serum titres above 100 mg/dL up to discontinuation of vasoactive drugs or day 7 after enrolment. Patients assigned to the IgM standard treatment group will receive IgM enriched preparation daily for three consecutive days at the standard dose of 250 mg/kg. The primary endpoint will be all-cause mortality at 28 days. ETHICS AND DISSEMINATION: The study protocol was approved by the ethics committees of the coordinating centre (Comitato Etico dell'Area Vasta Emilia Nord) and collaborating centres. The results of the trial will be published within 12 months from the end of the study and the steering committee has the right to present them at public symposia and conferences. TRIAL REGISTRATION DETAILS: The trial protocol and information documents have received a favourable opinion from the Area Vasta Emilia Nord Ethical Committee on 12 September 2019. The trial protocol has been registered on EudraCT (2018-001613-33) on 18 April 2018 and on ClinicalTrials.gov (NCT04182737) on 2 December 2019.

Low diaphragm muscle mass predicts adverse outcome in patients hospitalized for COVID-19 pneumonia: an exploratory pilot study.

BACKGROUND: The aim of this study was to evaluate whether measurement of diaphragm thickness (DT) by ultrasonography may be a clinically useful noninvasive method for identifying patients at risk of adverse outcomes defined as need of invasive mechanical ventilation or death. METHODS: We prospectively enrolled 77 patients with laboratory-confirmed COVID-19 infection admitted to our intermediate care unit in Pisa between March 5 and March 30, 2020, with follow-up until hospital discharge or death. Logistic regression was used identify variables potentially associated with adverse outcomes and those P<0.10 were entered into a multivariate logistic regression model. Cumulative probability for lack of adverse outcomes in patients with or without low baseline diaphragm muscle mass was calculated with the Kaplan-Meier product-limit estimator. RESULTS: The main findings of this study are that: 1) patients who developed adverse outcomes had thinner diaphragm than those who did not (2.0 vs. 2.2 mm, P=0.001); and 2) DT and lymphocyte count were independent significant predictors of adverse outcomes, with end-expiratory DT being the strongest (ß=-708; OR=0.492; P=0.018). CONCLUSIONS: Diaphragmatic ultrasound may be a valid tool to evaluate the risk of respiratory failure. Evaluating the need of mechanical ventilation treatment should be based not only on PaO2/FiO2, but on a more comprehensive assessment including DT because if the lungs become less compliant a thinner diaphragm, albeit free of intrinsic abnormality, may become exhausted, thus contributing to severe respiratory failure.