Evaluation of the efficacy and safety of TREM-1 inhibition with nangibotide in patients with COVID-19 receiving respiratory support: the ESSENTIAL randomised, double-blind trial

Background Activation of the TREM-1 pathway is associated with outcome in life threatening COVID-19. Data suggest that modulation of this pathway with nangibotide, a TREM-1 modulator may improve survival in TREM-1 activated patients (identified using the biomarker sTREM-1). Methods Phase 2 double-blind randomized controlled trial assessing efficacy, safety, and optimum treatment population of nangibotide (1.0 mg/kg/h) compared to placebo. Patients aged 18–75 years were eligible within 7 days of SARS-CoV-2 documentation and within 48 h of the onset of invasive or non-invasive respiratory support because of COVID-19-related ARDS. Patients were included from September 2020 to April 2022, with a pause in recruitment between January and August 2021. Primary outcome was the improvement in clinical status defined by a seven-point ordinal scale in the overall population with a planned sensitivity analysis in the subgroup of patients with a sTREM-1 level above the median value at baseline (high sTREM-1 group). Secondary endpoints included safety and all-cause 28-day and day 60 mortality. The study was registered in EudraCT (2020-001504-42) and ClinicalTrials.gov (NCT04429334). Findings The study was stopped after 220 patients had been recruited. Of them, 219 were included in the mITT analysis. Nangibotide therapy was associated with an improved clinical status at day 28. Fifty-two (52.0%) of patients had improved in the placebo group compared to 77 (64.7%) of the nangibotide treated population, an odds ratio (95% CI) for improvement of 1.79 (1.02–3.14), p = 0.043. In the high sTREM-1 population, 18 (32.7%) of placebo patients had improved by day 28 compared to 26 (48.1%) of treated patients, an odds ratio (95% CI) of 2.17 (0.96–4.90), p = 0.063 was observed. In the overall population, 28 (28.0%) of placebo treated patients were not alive at the day 28 visit compared to 19 (16.0%) of nangibotide treated patients, an absolute improvement (95% CI) in all-cause mortality at day 28, adjusted for baseline clinical status of 12.1% (1.18–23.05). In the high sTREM-1 population (n = 109), 23 (41.8%) of patients in the placebo group and 12 (22.2%) of patients in the nangibotide group were not alive at day 28, an adjusted absolute reduction in mortality of 19.9% (2.78–36.98). The rate of treatment emergent adverse events was similar in both placebo and nangibotide treated patients. Interpretation Whilst the study was stopped early due to low recruitment rate, the ESSENTIAL study demonstrated that TREM-1 modulation with nangibotide is safe in COVID-19, and results in a consistent pattern of improved clinical status and mortality compared to placebo. The relationship between sTREM-1 and both risk of death and treatment response merits further evaluation of nangibotide using precision medicine approaches in life threatening viral pneumonitis. Funding The study was sponsored by Inotrem SA.

Hydrocortisone in Severe Community-Acquired Pneumonia.

BACKGROUND: Whether the antiinflammatory and immunomodulatory effects of glucocorticoids may decrease mortality among patients with severe community-acquired pneumonia is unclear. METHODS: In this phase 3, multicenter, double-blind, randomized, controlled trial, we assigned adults who had been admitted to the intensive care unit (ICU) for severe community-acquired pneumonia to receive intravenous hydrocortisone (200 mg daily for either 4 or 7 days as determined by clinical improvement, followed by tapering for a total of 8 or 14 days) or to receive placebo. All the patients received standard therapy, including antibiotics and supportive care. The primary outcome was death at 28 days. RESULTS: A total of 800 patients had undergone randomization when the trial was stopped after the second planned interim analysis. Data from 795 patients were analyzed. By day 28, death had occurred in 25 of 400 patients (6.2%; 95% confidence interval [CI], 3.9 to 8.6) in the hydrocortisone group and in 47 of 395 patients (11.9%; 95% CI, 8.7 to 15.1) in the placebo group (absolute difference, -5.6 percentage points; 95% CI, -9.6 to -1.7; P = 0.006). Among the patients who were not undergoing mechanical ventilation at baseline, endotracheal intubation was performed in 40 of 222 (18.0%) in the hydrocortisone group and in 65 of 220 (29.5%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.40 to 0.86). Among the patients who were not receiving vasopressors at baseline, such therapy was initiated by day 28 in 55 of 359 (15.3%) of the hydrocortisone group and in 86 of 344 (25.0%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.43 to 0.82). The frequencies of hospital-acquired infections and gastrointestinal bleeding were similar in the two groups; patients in the hydrocortisone group received higher daily doses of insulin during the first week of treatment. CONCLUSIONS: Among patients with severe community-acquired pneumonia being treated in the ICU, those who received hydrocortisone had a lower risk of death by day 28 than those who received placebo. (Funded by the French Ministry of Health; CAPE COD ClinicalTrials.gov number, NCT02517489.).

Pneumopathie sévère a SARS-CoV-2: aspects TDM à 6 mois

RÉSUMÉ Introduction – Depuis le début de la pandémie Covid-19, la TDM thoracique a joué un rôle clé dans le diagnostic, l'évaluation pronostique et le suivi de la pneumonie virale à SARS-CoV-2. Données récentes – La persistance de lésions pulmonaires sur la TDM de suivi d'une pneumopathie à Covid-19 grave concerne environ 60 % des patients. L'aspect TDM à 6 mois peut varier d'une résolution radiologique complète à des lésions fibrosantes pouvant imiter des pathologies interstitielles connues. Conclusion – Cet article illustre, à partir des images TDM de la cohorte Recovery from Covid-19 ardS (RECOVIDS) les aspects caractéristiques observés au suivi à 6 mois d'une pneumopathie sévère à SARS-CoV-2. En s'appuyant sur la présence de fibrose et le profil lésionnel prédominant, les radiologues peuvent reconnaître et intégrer ces images dans le diagnostic différentiel d'autres pneumopathies de présentations cliniques et TDM proches. SUMMARY Introduction- Since the beginning of the COVID-19 pandemic, chest computed tomography (CT) has played a key role in the diagnosis, prognostic evaluation, and follow-up of severe SARS-COVD-2 viral pneumonia. Recent Findings- Approximately 60 % of patients with severe COVID-19 exhibit persistent lung lesions on follow-up chest CT. The chest CT appearance at 6-month follow-up can range from complete resolution to severe fibrotic changes that may mimic known interstitial lung diseases. Conclusion- This article illustrates the typical appearance at 6-month using Chest-CT images from the "Recovery from COVID-19 ARDS” (RECOVIDS) cohort. An approach based on the presence of fibrosis and the predominant pattern will enable radiologists to recognize and incorporate these aspects into the differential diagnosis of other interstitial lung diseases that may present with similar clinical and CT features.

Limitation of life-sustaining therapies in critically ill patients with COVID-19: a descriptive epidemiological investigation from the COVID-ICU study.

BACKGROUND: Limitations of life-sustaining therapies (LST) practices are frequent and vary among intensive care units (ICUs). However, scarce data were available during the COVID-19 pandemic when ICUs were under intense pressure. We aimed to investigate the prevalence, cumulative incidence, timing, modalities, and factors associated with LST decisions in critically ill COVID-19 patients. METHODS: We did an ancillary analysis of the European multicentre COVID-ICU study, which collected data from 163 ICUs in France, Belgium and Switzerland. ICU load, a parameter reflecting stress on ICU capacities, was calculated at the patient level using daily ICU bed occupancy data from official country epidemiological reports. Mixed effects logistic regression was used to assess the association of variables with LST limitation decisions. RESULTS: Among 4671 severe COVID-19 patients admitted from February 25 to May 4, 2020, the prevalence of in-ICU LST limitations was 14.5%, with a nearly six-fold variability between centres. Overall 28-day cumulative incidence of LST limitations was 12.4%, which occurred at a median of 8 days (3-21). Median ICU load at the patient level was 126%. Age, clinical frailty scale score, and respiratory severity were associated with LST limitations, while ICU load was not. In-ICU death occurred in 74% and 95% of patients, respectively, after LST withholding and withdrawal, while median survival time was 3 days (1-11) after LST limitations. CONCLUSIONS: In this study, LST limitations frequently preceded death, with a major impact on time of death. In contrast to ICU load, older age, frailty, and the severity of respiratory failure during the first 24 h were the main factors associated with decisions of LST limitations.

Rapid rEcognition of COrticosteRoiD resistant or sensitive Sepsis (RECORDS): study protocol for a multicentre, placebo-controlled, biomarker-guided, adaptive Bayesian design basket trial.

INTRODUCTION: Corticosteroids affect variably survival in sepsis trials, suggesting heterogeneity in patients' response to corticosteroids. The RECORDS (Rapid rEcognition of COrticosteRoiD resistant or sensitive Sepsis) trial aimed at defining endotypes associated with adults with sepsis responsiveness to corticosteroids. METHODS AND ANALYSIS: RECORDS, a multicentre, placebo-controlled, biomarker-guided, adaptive Bayesian design basket trial, will randomly assign to a biomarker stratum 1800 adults with community-acquired pneumonia, vasopressor-dependent sepsis, septic shock or acute respiratory distress syndrome. In each stratum, patients will be randomly assigned to receive a 7-day course of hydrocortisone and fludrocortisone or their placebos. Patients with COVID-19 will be treated with a 10-day standard course of dexamethasone and randomised to fludrocortisone or its placebo. Primary outcome will be 90-day death or persistent organ dysfunction. Large simulation study will be performed across a range of plausible scenarios to foresee power to detect a 5%-10% absolute difference with corticosteroids. We will assess subset-by-treatment interaction by estimating in a Bayesian framework two quantities: (1) measure of influence, relying on the value of the estimation of corticosteroids' effect in each subset, and (2) measure of interaction. ETHICS AND DISSEMINATION: The protocol was approved by the Ethics Committee (Comité de Protection des Personnes, Dijon, France), on 6 April 2020. Trial results will be disseminated at scientific conferences and results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04280497).

Endotracheal tube biofilm in critically ill patients during the COVID-19 pandemic : description of an underestimated microbiological compartment.

Biofilm (BF) growth is believed to play a major role in the development of ventilator-associated pneumonia (VAP) in the intensive care unit. Despite concerted efforts to understand the potential implication of endotracheal tube (ETT)-BF dispersal, clinically relevant data are lacking to better characterize the impact of its mesostructure and microbiological singularity on the occurrence of VAP. We conducted a multicenter, retrospective observational study during the third wave of the COVID-19 pandemic, between March and May 2021. In total, 64 ETTs collected from 61 patients were included in the present BIOPAVIR study. Confocal microscopy acquisitions revealed two main morphological aspects of ETT-deposited BF: (1) a thin, continuous ribbon-shaped aspect, less likely monobacterial and predominantly associated with Enterobacter spp., Streptococcus pneumoniae or Viridans streptococci, and (2) a thicker, discontinuous, mushroom-shaped appearance, more likely characterized by the association of bacterial and fungal species in respiratory samples. The microbiological characterization of ETT-deposited BF found higher acquired resistance in more than 80% of analyzed BF phenotypes, compared to other colonization sites from the patient's environment. These findings reveal BF as a singular microbiological compartment, and are of added clinical value, with a view to future ETT-deposited BF-based antimicrobial stewardship in critically ill patients. Trial registration NCT04926493. Retrospectively registered 15 June 2021.

Crise de la Covid-19 : les professionnels des établissements de santé en souffrance

Alors que l'infection au Sars-CoV-2 s'est rapidement propagée au niveau mondial, on a assisté à une mobilisation massive des établissements de santé pour accueillir l'afflux important de patients. La majorité des recherches ayant étudié l'impact psychologique de la crise sanitaire dans les établissements de santé se sont centrées sur les professionnels de première ligne. Mais, dans les faits, c'est l'ensemble des professionnels qui ont été affectés. Dans cet article, nous proposons d'effectuer une mise au point sur le vécu de ces professionnels dans les établissements de santé durant les premiers mois de la crise de la Covid-19. L'objectif de notre étude était d'identifier les facteurs de stress spécifiques, mais aussi communs à chacune des professions, en nous basant sur le discours de ces professionnels.Alternate :Since 2019, Covid-19 has rapidly spread worldwide, generating a pandemic. Healthcare organizations have been massively engaged in dealing with the large influx of patients. Most studies that considered the psychological impact of this crisis in health establishments focused on front-line professionals. However, recent literature showed that all professionals in healthcare organizations have been affected by the different stressors associated with this situation. Our research provides an update on the affective experience of these workers in French healthcare organizations during the first months of the COVID-19 crisis. Specifically, from a qualitative approach, we identified the common and specific stressors among the main stakeholders of such organizations.

Anticipating need for intensive care in the healthcare trajectory of patients with chronic disease: A qualitative study among specialists.

INTRODUCTION: We investigated the reflections and perceptions of non-ICU physicians about anticipating the need for ICU admission in case of acute decompensation in patients with chronic disease. METHODS: We performed a qualitative multicentre study using semi-structured interviews among non-ICU specialist physicians. The interview guide, developed in advance, focused on 3 questions: (1) What is your perception of ICU care? (2) How do you think advance directives can be integrated into the patient's healthcare goals? and (3) How can the possibility of a need for ICU admission be integrated into the patient's healthcare goals? Interviews were recorded, transcribed and analysed by thematic analysis. Interviews were performed until theoretical saturation was reached. RESULTS: In total, 16 physicians (8 women, 8 men) were interviewed. The main themes related to intensive care being viewed as a distinct specialty, dispensing very technical care, and with major human and ethical challenges, especially regarding end-of-life issues. The participants also mentioned the difficulty in anticipating an acute decompensation, and the choices that might have to be made in such situations. The timing of discussions about potential decompensation of the patient, the medical culture and the presence of advance directives are issues that arise when attempting to anticipate the question of ICU admission in the patient's healthcare goals or wishes. CONCLUSION: This study describes the perceptions that physicians treating patients with chronic disease have of intensive care, notably that it is a distinct and technical specialty that presents challenging medical and ethical situations. Our study also opens perspectives for actions that could promote a pluridisciplinary approach to anticipating acute decompensation and ICU requirements in patients with chronic disease.

A qualitative study of the perceptions and experiences of healthcare providers caring for critically ill patients during the first wave of the COVID-19 pandemic: A PsyCOVID-ICU substudy.

BACKGROUND: Intensive care unit (ICU) staff have faced unprecedented levels of stress, in the context of profound upheaval of their working environment due to the COVID-19 pandemic. We explored the perceptions of frontline ICU staff about the first wave of the COVID-19 pandemic, and how this experience impacted their personal and professional lives. METHODS: In a qualitative study as part of the PsyCOVID-ICU project, we conducted semi-structured interviews with a random sample of nurses and nurses' aides from 5 centres participating in the main PsyCOVID study. Interviews were recorded and fully transcribed, and analysed by thematic analysis. RESULTS: A total of 18 interviews were performed from 13 August to 6 October 2020; 13 were nurses, and 5 were nurses' aides. Thematic analysis revealed three major themes, namely: (1) Managing the home life; (2) Conditions in the workplace; and (3) the meaning of their profession. CONCLUSION: In this qualitative study investigating the experiences and perceptions of healthcare workers caring for critically ill patients during the first COVID-19 wave in France, the participants reported that the crisis had profound repercussions on both their personal and professional lives. The main factors affecting the participants were a fear of contamination, and the re-organisation of working conditions, against a background of a media "infodemic".

Nicotine patches in patients on mechanical ventilation for severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial.

PURPOSE: Epidemiologic studies have documented lower rates of active smokers compared to former or non-smokers in symptomatic patients affected by coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of nicotine administered by a transdermal patch in critically ill patients with COVID-19 pneumonia. METHODS: In this multicentre, double-blind, placebo-controlled trial conducted in 18 intensive care units in France, we randomly assigned adult patients (non-smokers, non-vapers or who had quit smoking/vaping for at least 12 months) with proven COVID-19 pneumonia receiving invasive mechanical ventilation for up to 72 h to receive transdermal patches containing either nicotine at a daily dose of 14 mg or placebo until 48 h following successful weaning from mechanical ventilation or for a maximum of 30 days, followed by 3-week dose tapering by 3.5 mg per week. Randomization was stratified by centre, non- or former smoker status and Sequential Organ Function Assessment score (< or ≥ 7). The primary outcome was day-28 mortality. Main prespecified secondary outcomes included 60-day mortality, time to successful extubation, days alive and free from mechanical ventilation, renal replacement therapy, vasopressor support or organ failure at day 28. RESULTS: Between November 6th 2020, and April 2nd 2021, 220 patients were randomized from 18 active recruiting centers. After excluding 2 patients who withdrew consent, 218 patients (152 [70%] men) were included in the analysis: 106 patients to the nicotine group and 112 to the placebo group. Day-28 mortality did not differ between the two groups (30 [28%] of 106 patients in the nicotine group vs 31 [28%] of 112 patients in the placebo group; odds ratio 1.03 [95% confidence interval, CI 0.57-1.87]; p = 0.46). The median number of day-28 ventilator-free days was 0 (IQR 0-14) in the nicotine group and 0 (0-13) in the placebo group (with a difference estimate between the medians of 0 [95% CI -3-7]). Adverse events likely related to nicotine were rare (3%) and similar between the two groups. CONCLUSION: In patients having developed severe COVID-19 pneumonia requiring invasive mechanical ventilation, transdermal nicotine did not significantly reduce day-28 mortality. There is no indication to use nicotine in this situation.

Les vieux, le tri et le réanimateur

Résumé En France, la pandémie COVID-19 a révélé la fragilité d’un système de santé pourtant réputé insubmersible. Rationnées depuis trois décennies, les ressources humaines et matérielles de nos hôpitaux ont été épuisées en moins de deux semaines, tandis que les responsables de cette précarité et leurs successeurs plastronnaient dans les médias. Les soignants ont alors redoublé d’efforts et d’initiatives pour ne jamais abandonner les patients, parfois au détriment de leur vie personnelle et de leur propre santé. Les capacités d’accueil des unités de réanimation ont été accrues en proportion des surfaces et du matériel disponibles (les respirateurs surtout). Les locaux et les personnels d’autres spécialités (blocs opératoires, plateaux techniques, soins intensifs) ont également été mobilisés, entraînant la déprogrammation d’actes chirurgicaux ou exploratoires considérés comme non urgents. Conséquence de l’afflux massif de patients et de la pénurie des ressources, la question de l’accès aux soins critiques des personnes âgées s’est rapidement invitée dans le débat public. À l’écart de toute polémique, il existait, bien avant la crise, un corpus de travaux scientifiques évaluant le bénéfice ou les risques d’un séjour en réanimation pour nos aînés, selon des critères médicaux spécifiques et une approche multidimensionnelle du grand âge. Summary In France, the COVID-19 pandemic revealed the frailty of a health system that was considered unsinkable. Rationed for three decades, the human and material resources of our hospitals have been exhausted in less than two weeks, while those responsible for this precariousness and their successors were swaggering in the media. Caregivers then redoubled their efforts and initiatives to never abandon patients, sometimes to the detriment of their personal lives and their own health. The capacity of the intensive care units has been increased in proportion to the space and equipment available (especially respirators). The facilities and personnel of other specialties (operating rooms, technical platforms, intermediate care units) were also mobilized, leading to the deprogramming of surgical or exploratory procedures deemed non-urgent. As a result of the massive surge of patients and the scarcity of resources, the issue of access to critical care for the elderly has emerged early in the public debate. Apart from any controversy, well before the crisis, there was a body of scientific work evaluating the benefits or risks of a stay in intensive care for our elderly, according to specific medical criteria and a multidimensional approach to old age.

Mental Health Support for Hospital Staff during the COVID-19 Pandemic: Characteristics of the Services and Feedback from the Providers.

French authorities created mental health support services to accompany HCWs during the pandemic. We aimed to obtain feedback from staff providing these mental health support services within French hospitals to identify positive and negative features and avenues for improvement. A mixed-methods study was performed between 1 April and 30 June 2020. We contacted 77 centres to identify those providing mental health support services. We developed a questionnaire containing questions about the staff providing the service (quantitative part), with open questions to enable feedback from service providers (qualitative part). Of the 77 centres, 36 had mental health support services; 77.8% were created specifically for the epidemic. Services were staffed principally by psychologists, mainly used a telephone platform, and had a median opening time of 8 h/day. Thirty-seven professionals provided feedback, most aged 35-49 years. For 86.5%, it was their first time providing such support. Median self-reported comfort level was 8 (interquartiles 3-10), and 95% would do it again. Respondents reported (i) difficulties with work organisation, clinical situations, and lack of recognition and (ii) a desire for training. This study suggests that mental health support needs to be adapted to the needs of HCWs, both in terms of the content of the service and the timing of delivery.

A qualitative study of reinforcement workers' perceptions and experiences of working in intensive care during the COVID-19 pandemic: A PsyCOVID-ICU substudy.

PURPOSE: During the COVID pandemic, many hospitals had to mobilize reinforcement healthcare workers, especially in intensive care (ICUs). We investigated the perceptions and experiences of reinforcement workers deployed to ICUs, and the impact of deployment on their personal and professional lives. METHODS: For this qualitative study, a random sample of 30 reinforcement workers was drawn from 4 centres participating in the larger PsyCOVID-ICU study. Individual semi-structured interviews were held, recorded, transcribed and analyzed by thematic analysis. RESULTS: Thirty interviews were performed from April to May 2021 (22 nurses, 2 anesthesiology nurses, 6 nurses' aides). Average age was 36.8±9.5 years; 7 participants had no ICU experience. Four major themes emerged, namely: (1) Difficulties with integration, especially for those with no ICU experience; (2) lack of training; (3) difficulties with management, notably a feeling of insufficient communication; (4) Mental distress relating to the unusual work and fear of contaminating their entourage. CONCLUSION: Healthcare workers deployed as reinforcements to ICUs at the height of the pandemic had a unique experience of the crisis, and identified important gaps in organisation and preparation. They also suffered from a marked lack of training, given the stakes in the management of critically ill patients in the ICU.

Septic patients without obvious signs of infection at baseline are more likely to die in the ICU.

OBJECTIVE: Early identification of sepsis is mandatory. However, clinical presentation is sometimes misleading given the lack of infection signs. The objective of the study was to evaluate the impact on the 28-day mortality of the so-called "vague" presentation of sepsis. DESIGN: Single centre retrospective observational study. SETTING: One teaching hospital Intensive Care Unit. SUBJECTS: All the patients who presented at the Emergency Department (ED) and were thereafter admitted to the Intensive Care Unit (ICU) with a final diagnosis of sepsis were included in this retrospective observational three-year study. They were classified as having exhibited either "vague" or explicit presentation at the ED according to previously suggested criteria. Baseline characteristics, infection main features and sepsis management were compared. The impact of a vague presentation on 28-day mortality was then evaluated. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 348 included patients, 103 (29.6%) had a vague sepsis presentation. Underlying chronic diseases were more likely in those patients [e.g., peripheral arterial occlusive disease: adjusted odd ratio (aOR) = 2.01, (1.08-3.77) 95% confidence interval (CI); p = 0.028], but organ failure was less likely at the ED [SOFA score value: 4.7 (3.2) vs. 5.2 (3.1), p = 0.09]. In contrast, 28-day mortality was higher in the vague presentation group (40.8% vs. 26.9%, p = 0.011), along with longer time-to-diagnosis [18 (31) vs. 4 (11) h, p < 0.001], time-to-antibiotics [20 (32) vs. 7 (12) h, p < 0.001] and time to ICU admission [71 (159) vs. 24 (69) h, p < 0.001]. Whatever, such a vague presentation independently predicted 28-day mortality [aOR = 2.14 (1.24-3.68) 95% CI; p = 0.006]. CONCLUSIONS: Almost one third of septic patient requiring ICU had a vague presentation at the ED. Despite an apparent lower level of severity when initially assessed, those patients had an increased risk of mortality that could not be fully explained by delayed diagnosis and management of sepsis.

Association of COVID-19 Acute Respiratory Distress Syndrome With Symptoms of Posttraumatic Stress Disorder in Family Members After ICU Discharge.

IMPORTANCE: Persistent physical and mental disorders are frequent in survivors of COVID-19-related acute respiratory distress syndrome (ARDS). However, data on these disorders among family members are scarce. OBJECTIVE: To determine the association between patient hospitalization for COVID-19 ARDS vs ARDS from other causes and the risk of posttraumatic stress disorder (PTSD)-related symptoms in family members. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study in 23 intensive care units (ICUs) in France (January 2020 to June 2020 with final follow-up ending in October 2020). ARDS survivors and family members (1 family member per patient) were enrolled. EXPOSURES: Family members of patients hospitalized for ARDS due to COVID-19 vs ARDS due to other causes. MAIN OUTCOMES AND MEASURES: The primary outcome was family member symptoms of PTSD at 90 days after ICU discharge, measured by the Impact of Events Scale-Revised (score range, 0 [best] to 88 [worst]; presence of PTSD symptoms defined by score >22). Secondary outcomes were family member symptoms of anxiety and depression at 90 days assessed by the Hospital Anxiety and Depression Scale (score range, 0 [best] to 42 [worst]; presence of anxiety or depression symptoms defined by subscale scores ≥7). Multivariable logistic regression models were used to determine the association between COVID-19 status and outcomes. RESULTS: Among 602 family members and 307 patients prospectively enrolled, 517 (86%) family members (median [IQR] age, 51 [40-63] years; 72% women; 48% spouses; 26% bereaved because of the study patient's death; 303 [50%] family members of COVID-19 patients) and 273 (89%) patients (median [IQR] age, 61 [50-69] years; 34% women; 181 [59%] with COVID-19) completed the day-90 assessment. Compared with non-COVID-19 ARDS, family members of patients with COVID-19 ARDS had a significantly higher prevalence of symptoms of PTSD (35% [103/293] vs 19% [40/211]; difference, 16% [95% CI, 8%-24%]; P < .001), symptoms of anxiety (41% [121/294] vs 34% [70/207]; difference, 8% [95% CI, 0%-16%]; P= .05), and symptoms of depression (31% [91/291] vs 18% [37/209]; difference, 13% [95% CI, 6%-21%]; P< .001). In multivariable models adjusting for age, sex, and level of social support, COVID-19 ARDS was significantly associated with increased risk of PTSD-related symptoms in family members (odds ratio, 2.05 [95% CI, 1.30 to 3.23]). CONCLUSIONS AND RELEVANCE: Among family members of patients hospitalized in the ICU with ARDS, COVID-19 disease, as compared with other causes of ARDS, was significantly associated with increased risk of symptoms of PTSD at 90 days after ICU discharge. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04341519.

Risk and protective factors for the possible development of post-traumatic stress disorder among intensive care professionals in France during the first peak of the COVID-19 epidemic Factores de riesgo y factores protectores para el posible desarrollo de un trastorno de estrés postraumático en profesionales de cuidados intensivos en Francia durante la primera ola de la pandemia por la COVID-19 在 COVID-19 疫情第一个高峰期间, 法国重症监护专业人员可能发生创伤后应激障碍的风险和保护因素

Background Intensive care units (ICU) are among the healthcare services most affected by the COVID-19 crisis. Stressors related to insecurity, unpredictability, patient death and family distress are significant, and put healthcare workers (HCWs) at high risk of post-traumatic stress disorder (PTSD). The aims of this study were to measure the prevalence of post-traumatic stress disorder in HCWs and to identify risk factors and protective factors during the epidemic in France. Methods During the first peak of the epidemic (from 22 April to 13 May 2020), we assessed sources of stress (PS-ICU scale), mental health (GHQ-12) and coping strategies (Brief-COPE). Three months later (03 June to 6 July 2020), PTSD was assessed using the IES-R scale, with additional questions about sources of support. Data were collected using self-report questionnaires administered online. Results Among 2153 professionals who participated in the study, 20.6% suffered from potential PTSD, mostly intrusion symptoms. Risk factors for the development of PTSD were having experienced additional difficult events during the crisis, having a high level of psychological distress, a high level of perceived stress related to the workload and human resources issues, the emotional burden related to the patient and family, and stressors specific to COVID-19 during the first peak of the crisis. The use of positive thinking coping strategies decreased the relationship between perceived stress and the presence of PTSD, while social support seeking strategies increased the relationship. Finally, the HCWs preferred to use support from colleagues, relatives and/or a psychologist, and very few used the telephone hotlines. Conclusion The epidemic has had a strong traumatic impact on intensive care HCWs. Given the risk of PTSD, we need to consider implementing easily-accessible support services that focus on positive thinking coping strategies, during and after the crisis. HIGHLIGHTS The risk of PTSD is high among intensive care professionals. Perceived stress and psychological distress during the first peak of crisis increased the likelihood of subsequent PTSD. Support for professionals should be easily available and focused on positive thinking strategies.

Risk and protective factors for the possible development of post-traumatic stress disorder among intensive care professionals in France during the first peak of the COVID-19 epidemic.

Background: Intensive care units (ICU) are among the healthcare services most affected by the COVID-19 crisis. Stressors related to insecurity, unpredictability, patient death and family distress are significant, and put healthcare workers (HCWs) at high risk of post-traumatic stress disorder (PTSD). The aims of this study were to measure the prevalence of post-traumatic stress disorder in HCWs and to identify risk factors and protective factors during the epidemic in France. Methods: During the first peak of the epidemic (from 22 April to 13 May 2020), we assessed sources of stress (PS-ICU scale), mental health (GHQ-12) and coping strategies (Brief-COPE). Three months later (03 June to 6 July 2020), PTSD was assessed using the IES-R scale, with additional questions about sources of support. Data were collected using self-report questionnaires administered online. Results: Among 2153 professionals who participated in the study, 20.6% suffered from potential PTSD, mostly intrusion symptoms. Risk factors for the development of PTSD were having experienced additional difficult events during the crisis, having a high level of psychological distress, a high level of perceived stress related to the workload and human resources issues, the emotional burden related to the patient and family, and stressors specific to COVID-19 during the first peak of the crisis. The use of positive thinking coping strategies decreased the relationship between perceived stress and the presence of PTSD, while social support seeking strategies increased the relationship. Finally, the HCWs preferred to use support from colleagues, relatives and/or a psychologist, and very few used the telephone hotlines. Conclusion: The epidemic has had a strong traumatic impact on intensive care HCWs. Given the risk of PTSD, we need to consider implementing easily-accessible support services that focus on positive thinking coping strategies, during and after the crisis.

Antecedentes: Las unidades de cuidados intensivos (UCIs) se encuentran dentro de los servicios de salud más comprometidos por la crisis de la COVID-19. Los factores estresantes asociados a la inseguridad, la impredecibilidad, el fallecimiento de pacientes y la angustia familiar son considerables y colocan a los trabajadores de salud (TS) en un alto riesgo de trastorno de estrés postraumático (TEPT). Los objetivos de este estudio fueron el determinar la prevalencia del trastorno por estrés postraumático en TS e identificar los factores de riesgo y los factores protectores durante la epidemia en Francia.Métodos: Durante la primera ola de la epidemia (del 22 de abril al 13 de mayo del 2020) evaluamos fuentes de estrés (mediante la escala de percepción de factores estresantes en la UCI; PS-ICU en sus siglas en inglés), salud mental (mediante el cuestionario de salud general de 12 ítems; GHQ-12 en sus siglas en inglés) y estrategias de afrontamiento (mediante el inventario de la orientación del afrontamiento ante los problemas experimentados; Brief-COPE en sus siglas en inglés). Tres meses después (del 3 de junio al 6 de julio del 2020) se evaluó el TEPT mediante la escala de impacto del evento (IES-R en sus siglas en inglés) y con preguntas adicionales respecto a las fuentes de soporte. Se recolectó la información mediante cuestionarios de autoreporte realizados en línea.Resultados: De los 2.153 profesionales que participaron en el estudio, 20,6% padecían un potencial TEPT, predominando los síntomas intrusivos. Los factores de riesgo para el desarrollo del TEPT fueron el haber experimentado eventos difíciles adicionales durante la crisis, el tener un nivel elevado de angustia psicológica, un nivel alto de estrés percibido asociado a la carga laboral y a situaciones asociadas a los recursos humanos, la carga emocional relacionada al paciente y su familia, y los factores estresantes específicos de la COVID-19 durante la primera ola de la crisis. El uso del pensamiento positivo como estrategia de afrontamiento disminuía la relación entre el estrés percibido y la presencia del TEPT, mientras que las estrategias relacionadas con la búsqueda de soporte social incrementaban esta relación. Finalmente, los TS preferían emplear el soporte brindado por sus colegas, familiares y/o un psicólogo, mientras que muy pocos preferían el uso de líneas telefónicas de crisis.Conclusión: La epidemia ha tenido un fuerte impacto traumático sobre los TS de las UCIs. Dado el riesgo de TEPT, se necesita considerar la implementación de servicios de apoyo de fácil acceso que se enfoquen en el empleo del pensamiento positivo como estrategia de afrontamiento, tanto durante como después de la crisis.

Inhaled amikacin versus placebo to prevent ventilator-associated pneumonia: the AMIKINHAL double-blind multicentre randomised controlled trial protocol.

INTRODUCTION: Pre-emptive inhaled antibiotics may be effective to reduce the occurrence of ventilator-associated pneumonia among critically ill patients. Meta-analysis of small sample size trials showed a favourable signal. Inhaled antibiotics are associated with a reduced emergence of antibiotic resistant bacteria. The aim of this trial is to evaluate the benefit of a 3-day course of inhaled antibiotics among patients undergoing invasive mechanical ventilation for more than 3 days on the occurrence of ventilator-associated pneumonia. METHODS AND ANALYSIS: Academic, investigator-initiated, parallel two group arms, double-blind, multicentre superiority randomised controlled trial. Patients invasively ventilated more than 3 days will be randomised to receive 20 mg/kg inhaled amikacin daily for 3 days or inhaled placebo (0.9% Sodium Chloride). Occurrence of ventilator-associated pneumonia will be recorded based on a standardised diagnostic framework from randomisation to day 28 and adjudicated by a centralised blinded committee. ETHICS AND DISSEMINATION: The protocol and amendments have been approved by the regional ethics review board and French competent authorities (Comité de protection des personnes Ouest I, No.2016-R29). All patients will be included after informed consent according to French law. Results will be disseminated in international scientific journals. TRIAL REGISTRATION NUMBERS: EudraCT 2016-001054-17 and NCT03149640.

Specific Features of the Coagulopathy Signature in Severe COVID-19 Pneumonia.

Rationale: COVID-19 displays distinct characteristics that suggest a unique pathogenesis. The objective of this study was to compare biomarkers of coagulopathy and outcomes in COVID-19 and non-COVID-19 patients with severe pneumonia. Methods: Thirty-six non-COVID-19 and 27 COVID-19 non-immunocompromised patients with severe pneumonia were prospectively enrolled, most requiring intensive care. Clinical and biological characteristics (including plasma biomarkers of coagulopathy) were compared. Results: At similar baseline severity, COVID-19 patients required mechanical ventilation (MV) for significantly longer than non-COVID-19 patients (p = 0.0049) and more frequently developed venous thrombotic complications (p = 0.031). COVID-19 patients had significantly higher plasma concentrations of soluble VCAM1 (sVCAM1) (5,739 ± 3,293 vs. 3,700 ± 2,124 ng/ml; p = 0.009), but lower levels of D-dimers, vWF-A2, sICAM1, sTREM1, VEGF, and P-selectin, compared to non-COVID-19 patients. Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariable regression analysis confirmed that sVCAM1 rising levels were independently associated with a longer duration of MV. Finally, we identified close correlations between sVCAM1 and some features of COVID-19 immune dysregulation (ie. CXCL10, GM-CSF, and IL-10). Conclusion: We identified specific features of the coagulopathy signature in severe COVID-19 patients, with higher plasma sVCAM1 levels, that were independently associated with the longer duration of mechanical ventilation. Clinical Trial Registration:ClinicalTrials.gov, identifier: NCT03505281.