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Abstract Background Therapeutic plasma exchanges (TPE), which affect the humoral response, are often performed in combination with immunosuppressive drugs. For this reason, TPE may be associated with an increased susceptibility to infections. We aimed to describe blood stream infection (BSI) incidence in ICU patients treated with TPE and to identify associated risk factors. Methods We retrospectively included patients that had received at least one session of TPE in the ICU of one of the 4 participating centers (all in Paris, France) between January 1st 2010 and December 31th 2019. Patients presenting with a BSI during ICU stay were compared to patients without such an infection. Risk factors for BSI were identified by a multivariate logistic regression model. Results Over 10 years in the 4 ICUs, 387 patients were included, with a median of 5 [2–7] TPE sessions per patient. Most frequent indications for TPE were thrombotic microangiopathy (47%), central nervous system inflammatory disorders (11%), hyperviscosity syndrome (11%) and ANCA associated vasculitis (8.5%). Thirty-one patients (8%) presented with a BSI during their ICU stay, a median of 7 [3–11] days after start of TPE. In a multivariate logistic regression model, diabetes (OR 3.32 [1.21–8.32]) and total number of TPE sessions (OR 1.14 [1.08–1.20]) were independent risk factors for BSI. There was no difference between TPE catheter infection related BSI (n = 11 (35%)) and other sources of BSI (n = 20 (65%)) regarding catheter insertion site (p = 0.458) or rate of TPE catheter related deep vein thrombosis (p = 0.601). ICU course was severe in patients presenting with BSI when compared to patients without BSI, with higher need for mechanical ventilation (45% vs 18%, p = 0.001), renal replacement therapy (42% vs 20%, p = 0.011), vasopressors (32% vs 12%, p = 0.004) and a higher mortality (19% vs 5%, p = 0.010). Conclusion Blood stream infections are frequent in patients receiving TPE in the ICU, and are associated with a severe ICU course. Vigilant monitoring is crucial particularly for patients receiving a high number of TPE sessions.

Abstract Background Morphine relieves dyspnea in various clinical circumstances. Whether or not this applies to patients admitted to intensive care units (ICUs) for acute respiratory failure (ARF) is unknown. We evaluated the efficacy and safety of low-dose morphine on dyspnea in patients admitted to the ICU for ARF. Methods In this single-center, double-blind, phase 2, randomized, controlled trial, we assigned non-intubated adults admitted to the ICU for ARF with severe dyspnea, defined by a visual analog scale for dyspnea (dyspnea-VAS) from zero (no dyspnea) to 100 mm (worst imaginable dyspnea) ≥40 mm, to receive a low dose of Morphine Hydrochloride (intravenous titration followed by subcutaneous relay) or Placebo. All patients received standard therapy, including etiological treatment and non-invasive respiratory support. Results Twenty-two patients were randomized, 11 in each group. The average dyspnea (median [interquartile range]) over 24 hours did not significantly differ between the two groups (40 [25 – 43] mm in the Morphine group vs. 40 [36 – 49] mm in the Placebo group, p=0.411). Dyspnea-VAS was lower in the Morphine group than in the Placebo group at the end of intravenous titration (30 [11 – 30] vs. 35 [30 – 44], p=0.044) and four hours later (18 [10 – 29] vs. 50 [30 – 60], p=0.043). The cumulative probability of intubation was higher in the Morphine group than in the Placebo group (p=0.046) Conclusion In this phase 2 pilot trial, morphine did not improve 24-hour average dyspnea in adult patients with ARF, even though it had a statistically significant immediate effect. Of concern, Morphine use was associated with a higher intubation rate. Trial registration The protocol was declared on the ClinicalTrial.gov database (no. NCT04358133) and was published in September 2022.

Abstract Background Alongside the recent worldwide expansion of hypervirulent Klebsiella pneumoniae (KP) infections, the available literature regarding cases of community acquired pneumonias (KP-CAP) remains scarce but reports a strikingly high and early mortality. We performed a retrospective multicenter study (7 ICU in France) between 2015 and 2019, comparing prognosis and severity of KP-CAP versus Streptococcus pneumoniae - CAP (SP-CAP). Methods For each KP-CAP, three SP-CAP admitted in ICUs within the same center and within the same 6-month window were selected. When available, KP strains were studied, and bacterial virulence was genetically assessed for virulence factors. The primary outcome was in-hospital mortality. Associations between clinical outcomes and type of infection were tested using univariate and multivariate logistic regressions, adjusted for pairing variables. Results Twenty-seven KP-CAP and 81 SP-CAP were included. Respective in-hospital mortality rates were 59% (n = 16) and 17% (n = 14, p

Abstract Background During the first COVID-19 pandemic wave, COVID-19-associated pulmonary aspergillosis (CAPA) has been reported in up to 11–28% of critically ill COVID-19 patients and associated with increased mortality. As new SARS-CoV-2 variants emerged, the characteristics of critically ill COVID-19 patients have evolved, particularly in the era of Omicron. The purpose of this study is to investigate the characteristics of CAPA in the era of new variants. Methods This is a prospective multicenter observational cohort study conducted in France in 36 participating intensive care units (ICU), between December 7th, 2021 and April 26th 2023. Diagnosis criteria of CAPA relied on European Confederation of Medical Mycology (ECMM)/International Society for Human & Animal Mycology (ISHAM) consensus criteria. Results 566 patients were included over the study period. The prevalence of CAPA was 5.1% [95% CI 3.4–7.3], and rose to 9.1% among patients who required invasive mechanical ventilation (IMV). Univariable analysis showed that CAPA patients were more frequently immunosuppressed and required more frequently IMV support, vasopressors and renal replacement therapy during ICU stay than non-CAPA patients. SAPS II score at ICU admission, immunosuppression, and a SARS-CoV-2 Delta variant were independently associated with CAPA in multivariable logistic regression analysis. Although CAPA was not significantly associated with day-28 mortality, patients with CAPA experienced a longer duration of mechanical ventilation and ICU stay. Conclusion This study contributes valuable insights into the prevalence, characteristics, and outcomes of CAPA in the era of Delta and Omicron variants. We report a lower prevalence of CAPA (5.1%) among critically-ill COVID-19 patients than previously reported, mainly affecting intubated-patients. Duration of mechanical ventilation and ICU stay were significantly longer in CAPA patients.

Abstract Background The STROMA-CoV-2 study was a French phase 2b, multicenter, double-blind, randomized, placebo-controlled clinical trial that did not identify a significant efficacy of umbilical cord-derived mesenchymal stromal cells in patients with SARS-CoV-2-induced acute respiratory distress syndrome. Safety on day 28 was found to be good. The aim of our extended study was to assess the 6- and 12-month safety of UC-MSCs administration in the STROMA-CoV-2 cohort. Methods A detailed multi-domain assessment was conducted at 6 and 12 months following hospital discharge focusing on adverse events, lung computed tomography-scan, pulmonary and muscular functional status, and quality of life in the STROMA-CoV-2 cohort including SARS–CoV-2-related early (

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Abstract We aimed to explore the relationships between specific viral mutations/mutational patterns and ventilator-associated pneumonia (VAP) occurrence in COVID-19 patients admitted in intensive care units between October 1, 2020, and May 30, 2021. Full-length SARS-CoV-2 genomes were sequenced by means of next-generation sequencing. In this prospective multicentre cohort study, 259 patients were included. 222 patients (47%) had been infected with pre-existing ancestral variants, 116 (45%) with variant α, and 21 (8%) with other variants. 153 patients (59%) developed at least one VAP. There was no significant relationship between VAP occurrence and a specific SARS CoV-2 lineage/sublineage or mutational pattern.

Abstract Background The extent of the consequences of an episode of severe acute kidney injury (AKI) on long-term outcome of critically ill patients remain debated. We conducted a prospective follow-up of patients included in a large multicenter clinical trial of renal replacement therapy (RRT) initiation strategy during severe AKI (the Artificial Kidney Initiation in Kidney Injury, AKIKI) to investigate long-term survival, renal outcome and health related quality of life (HRQOL). We also assessed the influence of RRT initiation strategy on these outcomes. Results Follow-up of patients extended from 60 days to a median of 3.35 years [interquartile range (IQR), 1.89 to 4.09] after the end of initial study. Of the 619 patients included in the AKIKI trial, 316 survived after 60 days. The overall survival rate at 3 years from inclusion was 39.4% (95% CI 35.4 to 43.4). A total of 46 patients (on the 175 with available data on long-term kidney function) experienced worsening of renal function (WRF) at the time of follow-up [overall incidence of 26%, cumulative incidence at 4 years: 20.6% (CI 95% 13.0 to 28.3)]. Fifteen patients required chronic dialysis (5% of patients who survived after day 90). Among the 226 long-term survivors, 80 (35%) answered the EQ-5D questionnaire. The median index value reported was 0.67 (IQR 0.40 to 1.00) indicating a noticeable alteration of quality of life. Initiation strategy for RRT had no effect on any long-term outcome. Conclusion Severe AKI in critically ill patients was associated with a high proportion of death within the first 2 months but less so during long-term follow-up. A quarter of long-term survivors experienced a WRF and suffered from a noticeable impairment of quality of life. Renal replacement therapy initiation strategy was not associated with mortality outcome. Graphical Abstract

Abstract Background Sepsis prognosis correlates with antibiotic adequacy at the early phase. This adequacy is dependent on antibacterial spectrum, bacterial resistance profile and antibiotic dosage. Optimal efficacy of beta-lactams mandates concentrations above the minimal inhibitory concentration (MIC) of the targeted bacteria for the longest time possible over the day. Septic acute kidney injury (AKI) is the most common AKI syndrome in ICU and often mandates renal replacement therapy (RRT) initiation. Both severe AKI and RRT may increase outside target antibiotic concentrations and ultimately alter patient’s prognosis. Patients and methods This is a secondary analysis of a randomized controlled trial that compared an early RRT initiation strategy with a delayed one in 620 critically ill patients undergoing severe AKI (defined by KDIGO 3). We compared beta-lactam trough concentrations between the two RRT initiation strategies. The primary outcome was the proportion of patients with sufficient trough plasma concentration of beta-lactams defined by trough concentration above 4 times the MIC. We hypothesized that early initiation of RRT could be associated with an insufficient antibiotic plasma trough concentration compared to patients allocated to the delayed strategy. Results One hundred and twelve patients were included: 53 in the early group and 59 in the delayed group. Eighty-three patients (74%) had septic shock on inclusion. Trough beta-lactam plasma concentration was above 4 times the MIC breakpoint in 80.4% (n = 90) of patients of the whole population, without differences between the early and the delayed groups (79.2% vs. 81.4%, respectively, p = 0.78). On multivariate analysis, the presence of septic shock and a higher mean arterial pressure were significantly associated with a greater probability of adequate antibiotic trough concentration [OR 3.95 (1.14;13.64), p = 0.029 and OR 1.05 (1.01;1.10), p = 0.013, respectively). Evolution of procalcitonin level and catecholamine-free days as well as mortality did not differ whether beta-lactam trough concentration was above 4 times the MIC or not. Conclusions In this secondary analysis of a randomized controlled trial, renal replacement therapy initiation strategy did not significantly influence plasma trough concentrations of beta-lactams in ICU patients with severe AKI. Presence of septic shock on inclusion was the main variable associated with a sufficient beta-lactam concentration. Trial registration: The AKIKI trial was registered on ClinicalTrials.gov (Identifier: NCT01932190) before the inclusion of the first patient.

BackgroundCardiac arrest is the most life-threatening complication of attempted suicide by hanging. However, data are scarce on its characteristics and outcome predictors.MethodsThis retrospective observational multicentre study in 31 hospitals included consecutive adults admitted after cardiac arrest induced by suicidal hanging. Factors associated with in-hospital mortality were identified by multivariate logistic regression with multiple imputations for missing data and adjusted to the temporal trends over the study period.ResultsOf 450 patients (350 men, median age, 43 [34–52] years), 305 (68%) had a psychiatric history, and 31 (6.9%) attempted hanging while hospitalized. The median time from unhanging to cardiopulmonary resuscitation was 0 [0–5] min, and the median time to return of spontaneous circulation (ROSC) was 20 [10–30] min. Seventy-nine (18%) patients survived to hospital discharge. Three variables were independently associated with higher in-hospital mortality: time from collapse or unhanging to ROSC>20 min (odds ratio [OR], 4.71; 95% confidence intervals [95%CIs], 2.02–10.96; p = 0.0004); glycaemia >1.4 g/L at admission (OR, 6.38; 95%CI, 2.60–15.66; p < 0.0001); and lactate >3.5 mmol/L at admission (OR, 6.08; 95%CI, 1.71–21.06; p = 0.005). A Glasgow Coma Scale (GCS) score of >5 at admission was associated with lower in-hospital mortality (OR, 0.009; 95%CI, 0.02–0.37; p = 0.0009).ConclusionIn patients with hanging-induced cardiac arrest, time from collapse or unhanging to return of spontaneous circulation, glycaemia, arterial lactate, and coma depth at admission were independently associated with survival to hospital discharge. Knowledge of these risk factors may help guide treatment decisions in these patients at high risk of hospital mortality.

Abstract Background Auto-antibodies (auto-Abs) neutralizing type I interferons (IFN) have been found in about 15% of critical cases COVID-19 pneumonia and less than 1% of mild or asymptomatic cases. Determining whether auto-Abs influence presentation and outcome of critically ill COVID-19 patients could lead to specific therapeutic interventions. Our objectives were to compare the severity at admission and the mortality of patients hospitalized for critical COVID-19 in ICU with versus without auto-Abs. Results We conducted a prospective multicentre cohort study including patients admitted in 11 intensive care units (ICUs) from Great Paris area hospitals with proven SARS-CoV-2 infection and acute respiratory failure. 925 critically ill COVID-19 patients were included. Auto-Abs neutralizing type I IFN-α2, β and/or ω were found in 96 patients (10.3%). Demographics and comorbidities did not differ between patients with versus without auto-Abs. At ICU admission, Auto-Abs positive patients required a higher FiO2 (100% (70–100) vs. 90% (60–100), p = 0.01), but were not different in other characteristics. Mortality at day 28 was not different between patients with and without auto-Abs (18.7 vs. 23.7%, p = 0.279). In multivariable analysis, 28-day mortality was associated with age (adjusted odds ratio (aOR) = 1.06 [1.04–1.08], p

SARS-CoV-2 variant Omicron has been suggested to cause less severe disease. This prospective study shows that the clinical phenotype in patients infected with Omicron differs from patients infected with Delta but no association between Delta and Omicron including sublineages and mortality was observed.

IntroductionIncreasing evidence has shown that coronavirus disease 19 (COVID-19) severity is driven by a dysregulated immunological response. Previous studies have demonstrated that natural killer (NK) cell dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of NK cell markers as a driver of death in the most critically ill patients.MethodsWe enrolled 50 non-vaccinated hospitalized patients infected with the initial virus or the alpha variant of SARS-CoV-2 with moderate or severe illness, to evaluate phenotypic and functional features of NK cells.ResultsHere, we show that, consistent with previous studies, evolution NK cells from COVID-19 patients are more activated, with the decreased activation of natural cytotoxicity receptors and impaired cytotoxicity and IFN-γ production, in association with disease regardless of the SARS-CoV-2 strain. Fatality was observed in 6 of 17 patients with severe disease; NK cells from all of these patients displayed a peculiar phenotype of an activated memory-like phenotype associated with massive TNF-α production.DiscussionThese data suggest that fatal COVID-19 infection is driven by an uncoordinated inflammatory response in part mediated by a specific subset of activated NK cells.

Abstract Rationale Dyspnea, a key symptom of acute respiratory failure, is not among the criteria for spontaneous breathing trial (SBT) failure. Here, we sought (1) to determine whether dyspnea is a reliable failure criterion for SBT failure; (2) to quantify the relationship between dyspnea and the respective electromyographic activity of the diaphragm (EMGdi), the parasternal (EMGpa) and the Alae nasi (EMGan). Methods Mechanically ventilated patients undergoing an SBT were included. Dyspnea intensity was measured by the Dyspnea-Visual Analogic Scale (Dyspnea-VAS) at the initiation and end of the SBT. During the 30-min SBT or until SBT failure, the EMGdi was continuously measured with a multi-electrode nasogastric catheter and the EMGan and EMGpa with surface electrodes. Results Thirty-one patients were included, SAPS 2 (median [interquartile range]) 53 (37‒74), mechanically ventilated for 6 (3‒10) days. Seventeen patients (45%) failed the SBT. The increase in Dyspnea-VAS along the SBT was higher in patients who failed (6 [4‒8] cm) than in those who passed (0 [0‒1] cm, p = 0.01). The area under the receiver operating characteristics curve for Dyspnea-VAS was 0.909 (0.786–1.032). The increase in Dyspnea-VAS was significantly correlated to the increase in EMGan (Rho = 0.42 [0.04‒0.70], p

Abstract Background Whether dyspnea is present before starting a spontaneous breathing trial (SBT) and whether it may affect the outcome of the SBT is unknown. Mechanical Ventilation—Respiratory Distress Observation Scale (MV-RDOS) has been proposed as a reliable surrogate of dyspnea in non-communicative intubated patients. In the present study, we sought (1) to describe the evolution of the MV-RDOS during a SBT and (2) to investigate whether MV-RDOS can predict the outcome of the SBT. Methods Prospective, single-center study in a twenty-two bed ICU in a tertiary center. Patients intubated since more 48 h who had failed a first SBT were eligible if they meet classical readiness to wean criteria. The MV-RDOS was assessed before, at 2-min, 15-min and 30-min (end) of the SBT. The presence of clinically important dyspnea was inferred by a MV-RDOS value ≥ 2.6. Results Fifty-eight patients (age 63 [51–70], SAPS II 66 [51–76]; med [IQR]) were included. Thirty-three (57%) patients failed the SBT, whose 18 (55%) failed before 15-min. Twenty-five (43%) patients successfully passed the SBT. A MV-RDOS ≥ 2.6 was present in ten (17%) patients before to start the SBT. All these ten patients subsequently failed the SBT. A MV-RDOS ≥ 2.6 at 2-min predicted a SBT failure with a 51% sensibility and a 88% specificity (AUC 0.741 95% confidence interval [CI] 0.616–0.866, p = 0.002). Best cut-off value at 2-min was 4.3 and predicted SBT failure with a 27% sensibility and a 96% specificity. Conclusion Despite patients met classical readiness to wean criteria, respiratory distress assessed with the MV-RDOS was frequent at the beginning of SBT. Measuring MV-RDOS before to initiate a SBT could avoid undue procedure and reduce patient’s exposure to unnecessary mechanical ventilation weaning failure and distress.

Abstract Background Varicella-zoster virus (VZV) is one of the main viruses responsible of acute encephalitis. However, data on the prognosis and neurologic outcome of critically ill patients with VZV encephalitis are limited. We aimed to describe the clinical features of VZV encephalitis in the ICU and to identify factors associated with a favorable neurologic outcome. We performed a multicenter cohort study of patients with VZV encephalitis admitted in 18 ICUs in France between 2000 and 2017. Factors associated with a favorable neurologic outcome, defined by a modified Rankin Score (mRS) of 0–2 1 year after ICU admission, were identified by multivariable regression analysis. Results Fifty-five patients (29 (53%) men, median age 53 (interquartile range 36–66)) were included, of whom 43 (78%) were immunocompromised. ICU admission occurred 1 (0–3) day after the onset of neurological symptoms. Median Glasgow Coma Score at ICU admission was 12 (7–14). Cerebrospinal fluid examination displayed a median leukocyte count of 68 (13–129)/mm3, and a median protein level of 1.37 (0.77–3.67) g/L. CT scan and MRI revealed brain lesions in 30% and 66% of the cases, respectively. Invasive mechanical ventilation was implemented in 46 (84%) patients for a median duration of 13 (3–30) days. Fourteen (25%) patients died in the ICU. One year after ICU admission, 20 (36%) patients had a favorable neurologic outcome (mRS 0–2), 12 (22%) had significant disability (mRS 3–5), and 18 (33%) were deceased (lost to follow-up n = 5, 9%). On multivariable analysis, age (OR 0.92 per year, (0.88–0.97), p = 0.01), and invasive mechanical ventilation (OR 0.09 CI 95% (0.01–0.84), p = 0.03) reduced the likelihood of favorable neurologic outcome. Conclusion One in every three critically ill patients with VZV encephalitis had a favorable neurologic outcome 1 year after ICU admission. Older age and invasive mechanical ventilation were associated with a higher risk of disability and death.

Abstract Background Severe acute respiratory syndrome coronavirus-2 (SARS–CoV-2)-induced acute respiratory distress syndrome (ARDS) causes high mortality. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) have potentially relevant immune-modulatory properties, whose place in ARDS treatment is not established. This phase 2b trial was undertaken to assess the efficacy of UC-MSCs in patients with SARS–CoV-2-induced ARDS. Methods This multicentre, double-blind, randomized, placebo-controlled trial (STROMA–CoV-2) recruited adults (≥ 18 years) with SARS–CoV-2-induced early (

Abstract Introduction Dyspnea is common and often severe symptom in mechanically ventilated patients. Proportional assist ventilation (PAV) is an assist ventilatory mode that adjusts the level of assistance to the activity of respiratory muscles. We hypothesized that PAV reduce dyspnea compared to pressure support ventilation (PSV). Patients and methods Mechanically ventilated patients with clinically significant dyspnea were included. Dyspnea intensity was assessed by the Dyspnea—Visual Analog Scale (D-VAS) and the Intensive Care-Respiratory Distress Observation Scale (IC-RDOS) at inclusion (PSV-Baseline), after personalization of ventilator settings in order to minimize dyspnea (PSV-Personalization), and after switch to PAV. Respiratory drive was assessed by record of electromyographic activity of inspiratory muscles, the proportion of asynchrony was analyzed. Results Thirty-four patients were included (73% males, median age of 66 [57–77] years). The D-VAS score was lower with PSV-Personalization (37 mm [20‒55]) and PAV (31 mm [14‒45]) than with PSV-Baseline (62 mm [28‒76]) (p

Abstract Background In acute respiratory distress syndrome (ARDS), extravascular lung water index (EVLWi) and pulmonary vascular permeability index (PVPI) measured by transpulmonary thermodilution reflect the degree of lung injury. Whether EVLWi and PVPI are different between non-COVID-19 ARDS and the ARDS due to COVID-19 has never been reported. We aimed at comparing EVLWi, PVPI, respiratory mechanics and hemodynamics in patients with COVID-19 ARDS vs. ARDS of other origin. Methods Between March and October 2020, in an observational study conducted in intensive care units from three university hospitals, 60 patients with COVID-19-related ARDS monitored by transpulmonary thermodilution were compared to the 60 consecutive non-COVID-19 ARDS admitted immediately before the COVID-19 outbreak between December 2018 and February 2020. Results Driving pressure was similar between patients with COVID-19 and non-COVID-19 ARDS, at baseline as well as during the study period. Compared to patients without COVID-19, those with COVID-19 exhibited higher EVLWi, both at the baseline (17 (14–21) vs. 15 (11–19) mL/kg, respectively, p = 0.03) and at the time of its maximal value (24 (18–27) vs. 21 (15–24) mL/kg, respectively, p = 0.01). Similar results were observed for PVPI. In COVID-19 patients, the worst ratio between arterial oxygen partial pressure over oxygen inspired fraction was lower (81 (70–109) vs. 100 (80–124) mmHg, respectively, p = 0.02) and prone positioning and extracorporeal membrane oxygenation (ECMO) were more frequently used than in patients without COVID-19. COVID-19 patients had lower maximal lactate level and maximal norepinephrine dose than patients without COVID-19. Day-60 mortality was similar between groups (57% vs. 65%, respectively, p = 0.45). The maximal value of EVLWi and PVPI remained independently associated with outcome in the whole cohort. Conclusion Compared to ARDS patients without COVID-19, patients with COVID-19 had similar lung mechanics, but higher EVLWi and PVPI values from the beginning of the disease. This was associated with worse oxygenation and with more requirement of prone positioning and ECMO. This is compatible with the specific lung inflammation and severe diffuse alveolar damage related to COVID-19. By contrast, patients with COVID-19 had fewer hemodynamic derangement. Eventually, mortality was similar between groups. Trial registration number and date of registration ClinicalTrials.gov (NCT04337983). Registered 30 March 2020—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04337983 .

Abstract Background Diaphragm dysfunction and weaning-induced pulmonary oedema are commonly involved during weaning failure, but their physiological interactions have been poorly reported. Our hypothesis was that diaphragm dysfunction is not particularly associated with weaning-induced pulmonary oedema. Methods It was a single-centre and physiological study conducted in patients who had failed a first spontaneous breathing trial and who underwent a second trial. The diaphragm function was evaluated by measuring the tracheal pressure generated in response to a bilateral magnetic phrenic nerves stimulations. Weaning-induced pulmonary oedema was diagnosed in case of failure of the spontaneous breathing trial if patients exhibited signs of plasma concentration or echocardiographic diagnosis of pulmonary artery occlusion pressure elevation. Results Fifty-three patients were included and 31/53 (58%) failed the spontaneous breathing trial, including 24/31 (77%) patients with weaning-induced pulmonary oedema. Diaphragm dysfunction was present in 33/53 (62%) patients. Diaphragm dysfunction or weaning-induced pulmonary oedema were present in 26/31 (84%) of the patients who failed the spontaneous breathing trial. Weaning-induced pulmonary oedema occurred in 20/33 (61%) patients with a diaphragm dysfunction and in 4/20 (20%) patients without (p = 0.005). Conclusion Weaning-induced pulmonary oedema was three times more frequent in case of diaphragm dysfunction. Even in case of diaphragm dysfunction, physicians might be encouraged to investigate the presence of weaning-induced pulmonary oedema during weaning failure.

Abstract Background Vascular access for renal replacement therapy (RRT) is routine question in the intensive care unit. Randomized trials comparing jugular and femoral sites have shown similar rate of nosocomial events and catheter dysfunction. However, recent prospective observational data on RRT catheters use are scarce. We aimed to assess the site of RRT catheter, the reasons for catheter replacement, and the complications according to site in a large population of critically ill patients with acute kidney injury. Patients and methods We performed an ancillary study of the AKIKI study, a pragmatic randomized controlled trial, in which patients with severe acute kidney injury (KDIGO 3 classification) with invasive mechanical ventilation, catecholamine infusion or both were randomly assigned to either an early or a delayed RRT initiation strategy. The present study involved all patients who underwent at least one RRT session. Number of RRT catheters, insertion sites, factors potentially associated with the choice of insertion site, duration of catheter use, reason for catheter replacement, and complications were prospectively collected. Results Among the 619 patients included in AKIKI, 462 received RRT and 459 were finally included, with 598 RRT catheters. Femoral site was chosen preferentially (n = 319, 53%), followed by jugular (n = 256, 43%) and subclavian (n = 23, 4%). In multivariate analysis, continuous RRT modality was significantly associated with femoral site (OR = 2.33 (95% CI (1.34–4.07), p = 0.003) and higher weight with jugular site [88.9 vs 83.2 kg, OR = 0.99 (95% CI 0.98–1.00), p = 0.03]. Investigator site was also significantly associated with the choice of insertion site (p = 0.03). Cumulative incidence of catheter replacement did not differ between jugular and femoral site [sHR 0.90 (95% CI 0.64—1.25), p = 0.67]. Catheter dysfunction was the main reason for replacement (n = 47), followed by suspected infection (n = 29) which was actually seldom proven (n = 4). No mechanical complication (pneumothorax or hemothorax) occurred. Conclusion Femoral site was preferentially used in this prospective study of RRT catheters in 31 French intensive care units. The choice of insertion site depended on investigating center habits, weight, RRT modality. A high incidence of catheter infection suspicion led to undue replacement.

The immunopathological pulmonary mechanisms leading to Coronavirus Disease (COVID-19)-related death in adults remain poorly understood. Bronchoalveolar lavage (BAL) and peripheral blood sampling were performed in 74 steroid and non-steroid-treated intensive care unit (ICU) patients (23–75 years; 44 survivors). Peripheral effector SARS-CoV-2-specific T cells were detected in 34/58 cases, mainly directed against the S1 portion of the spike protein. The BAL lymphocytosis consisted of T cells, while the mean CD4/CD8 ratio was 1.80 in non-steroid- treated patients and 1.14 in steroid-treated patients. Moreover, strong BAL SARS-CoV-2 specific T-cell responses were detected in 4/4 surviving and 3/3 non-surviving patients. Serum IFN-γ and IL-6 levels were decreased in steroid-treated patients when compared to non-steroid treated patients. In the lung samples from 3 (1 non-ICU and 2 ICU) additional deceased cases, a lymphocytic memory CD4 T-cell angiopathy colocalizing with SARS-CoV-2 was also observed. Taken together, these data show that disease severity occurs despite strong antiviral CD4 T cell-specific responses migrating to the lung, which could suggest a pathogenic role for perivascular memory CD4 T cells upon fatal COVID-19 pneumonia.

Abstract Background Mucormycosis is an emerging fungal infection that may lead to multi-organ failure, especially in patients with hematological malignancies (HM). We performed a retrospective, cohort study, in five intensive care units (ICU) to assess the outcome of critically ill patients with HM and mucormycosis between 2002 and 2018. The secondary objective was to identify prognostic factors in this setting. Results Twenty-six patients were included with a median age of 38 years [IQR, 26–57]). Acute leukemia was the most frequent underlying disease (50%). Nine patients (35%) underwent allogeneic stem cell transplantation (SCT). Nineteen patients (73%) had neutropenia and 16 (62%) had received steroids. The main reason for admission was acute respiratory failure (n = 14, 54%) followed by shock (n = 5 19%). The median SOFA score at admission was 7 [5–8]. According to EORTC/MSG criteria, mucormycosis was "proven" in 14 patients (54%), "probable" in 5 (19%) and “possible” in 7 (27%) in whom diagnosis was made by qPCR. Rhizopus and Mucor were the most frequent documented species. Seven patients (27%) had concurrent Aspergillus infection. Mucormycosis was diagnosed 1 day [−4 to + 6] after ICU admission. Sixteen patients (62%) had pulmonary involvement and ten (38%) rhino-cerebral involvement. Infection was disseminated in eight patients (31%). Twenty-two patients (85%) were treated with liposomal amphotericin B; 12 (46%) received antifungal combination including posaconazole in 7. Eight patients (31%) underwent curative surgery. Twenty-one patients (81%) required invasive mechanical ventilation (IMV), 18 (69%) vasopressors, and 9 (35%) renal replacement therapy. ICU and hospital mortality rates were 77% and 88%, respectively. The median overall survival was 9 days [3–22]. IMV was strongly associated with ICU mortality (p

Abstract Background Delayed intubation is associated with high mortality. There is a lack of objective criteria to decide the time of intubation. We assessed a recently described combined oxygenation index (ROX index) to predict intubation in immunocompromised patients. The study is a secondary analysis of randomized trials in immunocompromised patients, including all patients who received high-flow nasal cannula (HFNC). The first objective was to evaluate the accuracy of the ROX index to predict intubation for patients with acute respiratory failure. Results In the study, 302 patients received HFNC. Acute respiratory failure was mostly related to pneumonia (n = 150, 49.7%). Within 2 (1–3) days, 115 (38.1%) patients were intubated. The ICU mortality rate was 27.4% (n = 83). At 6 h, the ROX index was lower for patients who needed intubation compared with those who did not [4.79 (3.69–7.01) vs. 6.10 (4.48–8.68), p

The capacity of pre-existing immunity to human common coronaviruses (HCoV) to cross-protect against de novo COVID-19is yet unknown. In this work, we studied the sera of 175 COVID-19 patients, 76 healthy donors and 3 intravenous immunoglobulins (IVIG) batches. We found that most COVID-19 patients developed anti-SARS-CoV-2 IgG antibodies before IgM. Moreover, the capacity of their IgGs to react to beta-HCoV, was present in the early sera of most patients before the appearance of anti-SARS-CoV-2 IgG. This implied that a recall-type antibody response was generated. In comparison, the patients that mounted an anti-SARS-COV2 IgM response, prior to IgG responses had lower titres of anti-beta-HCoV IgG antibodies. This indicated that pre-existing immunity to beta-HCoV was conducive to the generation of memory type responses to SARS-COV-2. Finally, we also found that pre-COVID-19-era sera and IVIG cross-reacted with SARS-CoV-2 antigens without neutralising SARS-CoV-2 infectivity in vitro. Put together, these results indicate that whilst pre-existing immunity to HCoV is responsible for recall-type IgG responses to SARS-CoV-2, it does not lead to cross-protection against COVID-19.

Abstract Background The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak is spreading worldwide. To date, no specific treatment has convincingly demonstrated its efficacy. Hydroxychloroquine and lopinavir/ritonavir have potential interest, but virological and clinical data are scarce, especially in critically ill patients. Methods The present report took the opportunity of compassionate use and successive drug shortages to compare the effects of two therapeutic options, lopinavir/ritonavir and hydroxychloroquine, as compared to standard of care only. The primary outcomes were treatment escalation (intubation, extra-corporeal membrane oxygenation support, or renal replacement therapy) after day 1 until day 28. Secondary outcomes included ventilator-free days at day 28, mortality at day 14 and day 28, treatment safety issues and changes in respiratory tracts, and plasma viral load (as estimated by cycle threshold value) between admission and day 7. Results Eighty patients were treated during a 4-week period and included in the analysis: 22 (28%) received standard of care only, 20 (25%) patients received lopinavir/ritonavir associated to standard of care, and 38 (47%) patients received hydroxychloroquine and standard of care. Baseline characteristics were well balanced between the 3 groups. Treatment escalation occurred in 9 (41%), 10 (50%), and 15 (39%) patients who received standard of care only, standard of care and lopinavir/ritonavir, and standard of care and hydroxychloroquine, respectively (p = 0.567). There was no significant difference between groups regarding the number of ventilator-free days at day 28 and mortality at day 14 and day 28. Finally, there was no significant change between groups in viral respiratory or plasma load between admission and day 7. Conclusion In critically ill patients admitted for SARS-CoV-2-related pneumonia, no difference was found between hydroxychloroquine or lopinavir/ritonavir as compared to standard of care only on the proportion of patients who needed treatment escalation at day 28. Further randomized controlled trials are required to demonstrate whether these drugs may be useful in this context.

Abstract Background Diffuse alveolar hemorrhage (DAH) occurs during the course of autoimmune disease and may be life threatening. The objective was to assess characteristics and prognosis factors of DAH who required intensive care unit (ICU) admission in patients with autoimmune diseases. Methods French multicenter retrospective study including patients presenting DAH related to autoimmune diseases requiring ICU admission from 2000 to 2016. Results One hundred four patients (54% of men) with median age of 56 [32–68] years were included with 79 (76%) systemic vasculitis and 25 (24%) connective tissue disorders. All patients received steroids, and 72 (69%), 12 (11.5%), and 57 (55%) patients had cyclophosphamide, rituximab, and plasma exchanges, respectively. During ICU stay, 52 (50%), 36 (35%), and 55 (53%) patients required mechanical ventilation, vasopressor use, and renal replacement therapy, respectively. Factors associated with mechanical ventilation weaning were age (HR [95%CI] 0.97 [0.96–0.99] per 10 years, p

Abstract Background Intensive care unit (ICU)-acquired weakness and diaphragm dysfunction are frequent conditions, both associated with poor prognosis in critically ill patients. While it is well established that ICU-acquired weakness severely impairs long-term prognosis, the association of diaphragm dysfunction with this outcome has never been reported. This study investigated whether diaphragm dysfunction is associated with negative long-term outcomes and whether the coexistence of diaphragm dysfunction and ICU-acquired weakness has a particular association with 2-year survival and health-related quality of life (HRQOL). Methods This study is an ancillary study derived from an observational cohort study. Patients under mechanical ventilation were enrolled at the time of their first spontaneous breathing trial. Diaphragm dysfunction was defined by tracheal pressure generated by phrenic nerve stimulation

Abstract Background Noninvasive ventilation (NIV) is the application of mechanical ventilation through a mask. It is used to treat certain forms of acute respiratory failure in intensive care units (ICU). NIV has clinical benefits but can be anxiogenic for the patients. This study aimed at describing cognitive and affective attitudes toward NIV among patients experiencing NIV for the first time in the context of an ICU stay. Methods Semi-structured interviews were conducted in 10 patients during their ICU stay and soon after their first NIV experience. None of the patients had ever received NIV previously. Evaluative assertion analysis and thematic analysis were used to investigate cognitive and affective attitudes toward NIV before, during, and after the first NIV experience, as well as patient attitudes toward caregivers and relatives. Results Before their first NIV session, the cognitive attitudes of the patients were generally positive. They became less so and more ambiguous during and after NIV, as the patients discovered the actual barriers associated with NIV. Affective attitudes during NIV were more negative than affective attitudes before and after NIV, with reports of dyspnea, anxiety, fear, claustrophobic feelings, and reactivation of past traumatic experiences. The patients had more positive attitudes toward the presence of a caregiver during NIV, compared to the presence of a family member. Conclusion This study corroborates the possibly negative—or even traumatic—nature of the NIV experience, with emphasis on the role of affective attitudes. This is a rationale for evaluating the impact of NIV-targeted psychological interventions in ICU patients with acute respiratory failure.

Abstract Background The Artificial Kidney Initiation in Kidney Injury (AKIKI) trial showed that a delayed renal replacement therapy (RRT) strategy for severe acute kidney injury (AKI) in critically ill patients was safe and associated with major reduction in RRT initiation compared with an early strategy. The five criteria which mandated RRT initiation in the delayed arm were: severe hyperkalemia, severe acidosis, acute pulmonary edema due to fluid overload resulting in severe hypoxemia, serum urea concentration > 40 mmol/l and oliguria/anuria > 72 h. However, duration of anuria/oliguria and level of blood urea are still criteria open to debate. The objective of the study is to compare the delayed strategy used in AKIKI (now termed “standard”) with another in which RRT is further delayed for a longer period (termed “delayed strategy”). Methods/design This is a prospective, multicenter, open-label, two-arm randomized trial. The study is composed of two stages (observational and randomization stages). At any time, the occurrence of a potentially severe condition (severe hyperkalemia, severe metabolic or mixed acidosis, acute pulmonary edema due to fluid overload resulting in severe hypoxemia) suggests immediate RRT initiation. Patients receiving (or who have received) intravenously administered catecholamines and/or invasive mechanical ventilation and presenting with AKI stage 3 of the KDIGO classification and with no potentially severe condition are included in the observational stage. Patients presenting a serum urea concentration > 40 mmol/l and/or an oliguria/anuria for more than 72 h are randomly allocated to a standard (RRT is initiated within 12 h) or a delayed RRT strategy (RRT is initiated only if an above-mentioned potentially severe condition occurs or if the serum urea concentration reaches 50 mmol/l). The primary outcome will be the number of RRT-free days at day 28. One interim analysis is planned. It is expected to include 810 patients in the observational stage and to randomize 270 subjects. Discussion The AKIKI2 study should improve the knowledge of RRT initiation criteria in critically ill patients. The potential reduction in RRT use allowed by a delayed RRT strategy might be associated with less invasive care and decreased costs. Enrollment is ongoing. Inclusions are expected to be completed by November 2019. Trial registration ClinicalTrials.gov, ID: NCT03396757. Registered on 11 January 2018.

BackgroundLymphopenia and the neutrophil/lymphocyte ratio may have prognostic value in COVID-19 severity.ObjectiveWe investigated neutrophil subsets and functions in blood and bronchoalveolar lavage (BAL) of COVID-19 patients on the basis of patients’ clinical characteristics.MethodsWe used a multiparametric cytometry profiling based to mature and immature neutrophil markers in 146 critical or severe COVID-19 patients.ResultsThe Discovery study (38 patients, first pandemic wave) showed that 80% of Intensive Care Unit (ICU) patients develop strong myelemia with CD10−CD64+ immature neutrophils (ImNs). Cellular profiling revealed three distinct neutrophil subsets expressing either the lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1), the interleukin-3 receptor alpha (CD123), or programmed death-ligand 1 (PD-L1) overrepresented in ICU patients compared to non-ICU patients. The proportion of LOX-1- or CD123-expressing ImNs is positively correlated with clinical severity, cytokine storm (IL-1β, IL-6, IL-8, TNFα), acute respiratory distress syndrome (ARDS), and thrombosis. BALs of patients with ARDS were highly enriched in LOX-1-expressing ImN subsets and in antimicrobial neutrophil factors. A validation study (118 patients, second pandemic wave) confirmed and strengthened the association of the proportion of ImN subsets with disease severity, invasive ventilation, and death. Only high proportions of LOX-1-expressing ImNs remained strongly associated with a high risk of severe thrombosis independently of the plasma antimicrobial neutrophil factors, suggesting an independent association of ImN markers with their functions.ConclusionLOX-1-expressing ImNs may help identifying COVID-19 patients at high risk of severity and thrombosis complications.

Background Whereas first-line bronchial artery embolisation (BAE) is considered standard of care for the management of severe haemoptysis, it is unknown whether this approach is warranted for non-severe haemoptysis.Research question To assess the efficacy on bleeding control and the safety of first-line BAE in non-severe haemoptysis of mild abundance.Study design and methods This multicentre, randomised controlled open-label trial enrolled adult patients without major comorbid condition and having mild haemoptysis (onset

HighlightsInnate immune activation during Covid-19 infection is associated with pernicious clinical outcome.BackgroundCoronavirus disease 2019 (Covid-19) is a worldwide threat that has already caused more than 3 000 000 deaths. It is characterized by different patterns of disease evolution depending on host factors among which old-age and pre-existing comorbidities play a detrimental role. Previous coronavirus epidemics, notably SARS-CoV, were associated with increased serum neopterin levels, which can be interpreted as a sign of acute innate immunity in response to viral infection. Here we hypothesize that neopterin may serve as a biomarker of SARS-CoV-2 viral infection and Covid-19 disease severity.MethodsWe measured neopterin blood levels by ELISA. Seric concentration was quantified from 256 healthy donors and 374 Covid-19 patients at hospital admission. Enrolled Covid-19 patients were all symptomatic and displayed a large spectrum of comorbidities. Patients were followed until disease resolution or death.ResultsSevere and critically ill SARS-CoV-2 infected patients were characterized by a profound exacerbation of immune activation characterized by elevated neopterin blood levels. Systemic neopterin levels above 19nM stratified healthy individuals from Covid-19 patients with 87% specificity and 100% sensitivity. Moreover, systemic neopterin levels above 53nM differentiated non-survivors from survivors with 64% specificity and 100% sensitivity.ConclusionWe propose that neopterin concentration measured at arrival to hospital is a hallmark of severe Covid-19 and identifies a high-risk population of pernicious clinical outcome with a need for special medical care.

The SARS-CoV-2 variant of concern, α, spread worldwide at the beginning of 2021. It was suggested that this variant was associated with a higher risk of mortality than other variants. We aimed to characterize the genetic diversity of SARS-CoV-2 variants isolated from patients with severe COVID-19 and unravel the relationships between specific viral mutations/mutational patterns and clinical outcomes. This is a prospective multicenter observational cohort study. Patients aged ≥18 years admitted to 11 intensive care units (ICUs) in hospitals in the Greater Paris area for SARS-CoV-2 infection and acute respiratory failure between 1 October 2020 and 30 May 2021 were included. The primary clinical endpoint was day-28 mortality. Full-length SARS-CoV-2 genomes were sequenced by means of next-generation sequencing (Illumina COVIDSeq). In total, 413 patients were included, 183 (44.3%) were infected with pre-existing variants, 197 (47.7%) were infected with variant α, and 33 (8.0%) were infected with other variants. The patients infected with pre-existing variants were significantly older (64.9 ± 11.9 vs. 60.5 ± 11.8 years; p = 0.0005) and had more frequent COPD (11.5% vs. 4.1%; p = 0.009) and higher SOFA scores (4 [3–8] vs. 3 [2–4]; 0.0002). The day-28 mortality was no different between the patients infected with pre-existing, α, or other variants (31.1% vs. 26.2% vs. 30.3%; p = 0.550). There was no association between day-28 mortality and specific variants or the presence of specific mutations. At ICU admission, the patients infected with pre-existing variants had a different clinical presentation from those infected with variant α, but mortality did not differ between these groups. There was no association between specific variants or SARS-CoV-2 genome mutational pattern and day-28 mortality.

Abstract Background Immunocompromised critically ill patients constitute a population with the high risk of candidemia. This retrospective study aimed to assess the outcome of immunocompromised critically ill patients with candidemia. Secondary objectives were to describe clinical phenotypes of these patients, Candida ecology, and factors associated with mortality. Results Overall, 121 patients were included in this study. Median delay from candidemia to first antifungal therapy was 3 days, in line with the observed delay of blood culture positivity. Candia albicans was the main Candida specie identified (54%), and susceptibility of Candida to fluconazole and echinocandins was of, respectively, 70% and 92%. Hospital mortality was of 60%. After adjustment for confounders, severity as assessed by the need for vasopressors (HR 1.8, CI95% 1.1–3.1), need for mechanical ventilation (HR 2.0, CI95% 1.1–3.8) and allogenic stem cell transplantation (HR 2.5, CI95% 1.1–6.0) were independently associated with poor outcome. Candida specie, susceptibility and treatment strategies were not associated with outcome. Conclusions Candidemia in immunocompromised critically ill patients is associated with a grim outcome. Despite the high prevalence of Candida non-albicans species, neither C. species nor its susceptibility was associated with outcome. Conversely, severity and preexisting allogeneic stem cell transplantation were independently associated with poor outcome. Despite antifungal prophylaxis and use of preemptive antifungal therapy in neutropenic patients, antifungal therapy was initiated three days after symptoms onset suggesting needs for specific strategies aiming to reduce this delay.

Abstract Background Although outcomes of critically ill patients with haematological malignancies (HMs) have been fully investigated in terms of organ failure and mortality, data are scarce on health-related quality of life (HRQOL) in this population. We aim to assess post-intensive care unit (ICU) burden and HRQOL of critically ill patients with HMs and to identify risk factors for quality-of-life (QOL) impairment. Results In total, 1011 patients with HMs who required ICU admission in 17 ICUs in France and Belgium were included in the study; 278 and 117 patients were evaluated for QOL at 3 months and 1 year, respectively, after ICU discharge. HRQOL was determined by applying the interview form of the Short Form 36 (SF-36) questionnaire. Psychological distress symptoms were evaluated using the Hospital Anxiety Depression Score (HADS) and the Impact of Event Scale (IES). In-hospital mortality rates at 3 months and 1 year were, respectively, 39.1, 50.7 and 57.2%, respectively. At 3 months, median [IQR] physical and mental component summary scores (PCS and MCS) (SF-36) were 37 [28–46] and 51 [45–58], respectively. PCS was lower in ICU patients with HMs when compared to general ICU septic patients (52 [5–13], p = 0.00001). The median combined HAD score was 8 [5–13], and the median IES score was 8 [3–16]. However, recovery during the first year after ICU discharge was not consistent in all dimensions of HRQOL. Three months after ICU discharge, the maximum daily Sequential Organ Failure Assessment score and status of the underlying malignancy at ICU admission were significantly associated with MCS impairment (− 0.54 points [95% CI − 0.99; − 0.1], p = 0.018 and − 4.83 points [95% CI − 8.44; − 1.22], p = 0.009, respectively). Conclusion HRQOL is strongly impaired in critically ill patients with HMs at 3 months and 1 year after ICU discharge. Organ failure and disease status are strongly associated with QOL. The kinetic evaluation of QOL at 3 months and 1 year offers the opportunity to focus on QOL aspects that may be improved by therapeutic interventions during the first year after ICU discharge.

Whether severe COVID-19 is by itself a significant risk factor for the development of candidemia currently remains an open question as conflicting results have been published. We aim to assess the occurrence of candidemia in patients with severe COVID-19 admitted to the intensive care unit (ICU). We conducted a retrospective study on patients with severe SARS-CoV-2-related pneumonia admitted to 5 ICUs in France who were specifically screened for fungal complications between March 2020 and January 2021. The study population included a total of 264 patients; the median age was 56 years old and most of them were male (n = 186; 70.5%) and immunocompetent (n = 225; 87.5%), and 62.7% (n = 153/244) were on extracorporeal membrane oxygenation support. Microbiological analysis included 4864 blood culture samples and beta-glucan test performed on 975 sera. Candidemia was diagnosed in 13 (4.9%) patients. The species involved were mainly C. albicans (n = 6) and C. parapsilosis (n = 5). Almost all patients (12/13; 92.3%) had a colonization by yeasts. ICU mortality was not significantly impacted by the occurrence of candidemia. Unrelated positive beta-glucan tests were observed in 49 patients (23.4%), including 6 with mold infections and 43 with false positive results. In our series, patients with severe SARS-CoV-2-related pneumonia seemed at low risk of developing invasive candidiasis.

Background: The SARS-CoV-2 pandemic has resulted in a dramatic rise of the demand for medical devices and drugs. In this context, an important shortage of programmable syringe pumps, used to administrate different drugs in intensive care units, was seen. The opportunity of administrating combinations of five intensive care units selected drugs (Sufentanil, Clonidine, Loxapine, Midazolam, and Ketamine) was considered. Methods: The drug mixtures were studied in a pure form or diluted in NaCl 0.9% or G5%. Twenty-six possible combinations of the five drugs were produced in glass vials or polypropylene syringes and stored at 25 °C for 14 days. The LC method was implemented to study drugs combinations in the presence of the degradation products. The clearness and pH were also monitored. Results: All the 26 possible combinations displayed adequate physicochemical stability at 25 °C: at least 3 days and 7 days, respectively, for the dilution in 0.9% NaCl or glucose 5%, and the pure drug products mixtures. Conclusions: The study provided sufficient stability results, covering the medication administration period of at least three days. The combination of more than two drugs offers the advantage of minimizing the individual doses and reduces unwanted side-effects. Hence, this study opens up the possibility of combining the five drugs in one single syringe, which is useful especially under the current circumstances associated with an important shortage of programmable syringe pumps and pharmaceuticals.

BackgroundSince 1920, a decrease in serum cholesterol has been identified as a marker of severe pneumonia. We have assessed the performance of serum apolipoprotein-A1, the main transporter of HDL-cholesterol, to identify the early spread of coronavirus disease 2019 (Covid-19) in the general population and its diagnostic performance for the Covid-19.MethodsWe compared the daily mean serum apolipoprotein-A1 during the first 34 weeks of 2020 in a population that is routinely followed for a risk of liver fibrosis risk in the USA (212,297 serum) and in France (20,652 serum) in relation to a local increase in confirmed cases, and in comparison to the same period in 2019 (266,976 and 28,452 serum, respectively). We prospectively assessed the sensitivity of this marker in an observational study of 136 consecutive hospitalized cases and retrospectively evaluated its specificity in 7,481 controls representing the general population.ResultsThe mean serum apolipoprotein-A1 levels in the survey populations began decreasing in January 2020, compared to the same period in 2019. This decrease was highly correlated with the daily increase in confirmed Covid-19 cases in the following 34 weeks, both in France and USA, including the June and mid-July recovery periods in France. Apolipoprotein-A1 at the 1.25 g/L cutoff had a sensitivity of 90.6% (95%CI84.2-95.1) and a specificity of 96.1% (95.7-96.6%) for the diagnosis of Covid-19. The area under the characteristics curve was 0.978 (0.957-0.988), and outperformed haptoglobin and liver function tests. The adjusted risk ratio of apolipoprotein-A1 for survival without transfer to intensive care unit was 5.61 (95%CI 1.02-31.0; P = 0.04).ConclusionApolipoprotein-A1 could be a sentinel of the pandemic in existing routine surveillance of the general population. NCT01927133, CER-2020-14.

Abstract Background Tuberculous meningitis (TBM) is a devastating infection in tuberculosis endemic areas with limited access to intensive care. Functional outcomes of severe adult TBM patients admitted to the ICU in nonendemic areas are not known. Methods We conducted a retrospective multicenter cohort study (2004–2016) of consecutive TBM patients admitted to 12 ICUs in the Paris area, France. Clinical, biological, and brain magnetic resonance imaging (MRI) findings at admission associated with a poor functional outcome (i.e., a score of 3–6 on the modified Rankin scale (mRS) at 90 days) were identified by logistic regression. Factors associated with 1-year mortality were investigated by Cox proportional hazards modeling. Results We studied 90 patients, of whom 61 (68%) had a score on the Glasgow Coma Scale ≤ 10 at presentation and 63 (70%) required invasive mechanical ventilation. Brain MRI revealed infarction and hydrocephalus in 38/75 (51%) and 25/75 (33%) cases, respectively. A poor functional outcome was observed in 55 (61%) patients and was independently associated with older age (adjusted odds ratio (aOR) 1.03, 95% CI 1.0–1.07), cerebrospinal fluid protein level ≥ 2 g/L (aOR 5.31, 95% CI 1.67–16.85), and hydrocephalus on brain MRI (aOR 17.2, 95% CI 2.57–115.14). By contrast, adjunctive steroids were protective (aOR 0.13, 95% CI 0.03–0.56). The multivariable adjusted hazard ratio of adjunctive steroids for 1-year mortality (47%, 95% CI 37%–59%) was 0.23 (95% CI 0.11–0.44). Among survivors at 1 year, functional independence (mRS of 0–2) was observed in 27/37 (73%, 95% CI 59%–87%) cases. Conclusions A poor functional outcome in adult TBM patients admitted to the ICU in a nonendemic area is observed in 60% of cases and is independently associated with elevated cerebrospinal fluid protein level and hydrocephalus. Our data also suggest a protective effect of adjunctive steroids, with reduced disability and mortality, irrespective of immune status and severity of disease at presentation. One-year follow-up revealed functional independence in most survivors.

Abstract Background Diaphragm dysfunction is defined by a value of twitch tracheal pressure in response to magnetic phrenic stimulation (twitch pressure) amounting to less than 11 cmH2O. This study assessed whether this threshold or a lower one would predict accurately weaning failure from mechanical ventilation. Twitch pressure was compared to ultrasound measurement of diaphragm function. Methods In patients undergoing a first spontaneous breathing trial, diaphragm function was evaluated by twitch pressure and by diaphragm ultrasound (thickening fraction). Receiver operating characteristics curves were computed to determine the best thresholds predicting failure of spontaneous breathing trial. Results Seventy-six patients were evaluated, 48 (63%) succeeded and 28 (37%) failed the spontaneous breathing trial. The optimal thresholds of twitch pressure and thickening fraction to predict failure of the spontaneous breathing trial were, respectively, 7.2 cmH2O and 25.8%, respectively. The receiver operating characteristics curves were 0.80 (95% CI 0.70–0.89) for twitch pressure and 0.82 (95% CI 0.73–0.93) for thickening fraction. Both receiver operating characteristics curves were similar (p = 0.83). A twitch pressure value lower than 11 cmH2O (the traditional cutoff for diaphragm dysfunction) predicted failure of the spontaneous breathing trial with a sensitivity of 89% (95% CI 72–98%) and a specificity of 45% (95% CI 30–60%). Conclusions Failure of spontaneous breathing trial can be predicted with a lower value of twitch pressure than the value defining diaphragm dysfunction. Twitch pressure and thickening fraction had similar strong performance in the prediction of failure of the spontaneous breathing trial.

Abstract Tracheotomy is widely used in intensive care units, albeit with great disparities between medical teams in terms of frequency and modality. Indications and techniques are, however, associated with variable levels of evidence based on inhomogeneous or even contradictory literature. Our aim was to conduct a systematic analysis of the published data in order to provide guidelines. We present herein recommendations for the use of tracheotomy in adult critically ill patients developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. These guidelines were conducted by a group of experts from the French Intensive Care Society (Société de Réanimation de Langue Française) and the French Society of Anesthesia and Intensive Care Medicine (Société Francaise d’Anesthésie Réanimation) with the participation of the French Emergency Medicine Association (Société Française de Médecine d’Urgence), the French Society of Otorhinolaryngology. Sixteen experts and two coordinators agreed to consider questions concerning tracheotomy and its practical implementation. Five topics were defined: indications and contraindications for tracheotomy in intensive care, tracheotomy techniques in intensive care, modalities of tracheotomy in intensive care, management of patients undergoing tracheotomy in intensive care, and decannulation in intensive care. The summary made by the experts and the application of GRADE methodology led to the drawing up of 8 formal guidelines, 10 recommendations, and 3 treatment protocols. Among the 8 formal guidelines, 2 have a high level of proof (Grade 1+/−) and 6 a low level of proof (Grade 2+/−). For the 10 recommendations, GRADE methodology was not applicable and instead 10 expert opinions were produced.

Abstract Background Acute respiratory failure (ARF) is the leading reason for intensive care unit (ICU) admission in immunocompromised patients. High-flow nasal oxygen (HFNO) therapy is an alternative to standard oxygen. By providing warmed and humidified gas, HFNO allows the delivery of higher flow rates via nasal cannula devices, with FiO2 values of nearly 100%. Benefits include alleviation of dyspnea and discomfort, decreased respiratory distress and decreased mortality in unselected patients with acute hypoxemic respiratory failure. However, in preliminary reports, HFNO benefits are controversial in immunocompromised patients in whom it has never been properly evaluated. Methods/design This is a multicenter, open-label, randomized controlled superiority trial in 30 intensive care units, part of the Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique (GRRR-OH). Inclusion criteria will be: (1) adults, (2) known immunosuppression, (3) ARF, (4) oxygen therapy ≥ 6 L/min, (5) written informed consent from patient or proxy. Exclusion criteria will be: (1) imminent death (moribund patient), (2) no informed consent, (3) hypercapnia (PaCO2 ≥ 50 mmHg), (4) isolated cardiogenic pulmonary edema, (5) pregnancy or breastfeeding, (6) anatomical factors precluding insertion of a nasal cannula, (7) no coverage by the French statutory healthcare insurance system, and (8) post-surgical setting from day 1 to day 6 (patients with ARF occurring after day 6 of surgery can be included). The primary outcome measure is day-28 mortality. Secondary outcomes are intubation rate, comfort, dyspnea, respiratory rate, oxygenation, ICU length of stay, and ICU-acquired infections. Based on an expected 30% mortality rate in the standard oxygen group, and 20% in the HFNO group, error rate set at 5%, and a statistical power at 90%, 389 patients are required in each treatment group (778 patients overall). Recruitment period is estimated at 30 months, with 28 days of additional follow-up for the last included patient. Discussion The HIGH study will be the largest multicenter, randomized controlled trial seeking to demonstrate that survival benefits from HFNO reported in unselected patients also apply to a large immunocompromised population. Trial registration ClinicalTrials.gov, ID: NCT02739451. Registered on 15 April 2016.

Abstract Background Poor sleep is common in intensive care unit (ICU) patients, where environmental factors contribute to reduce and fragment sleep. The objective of this study was to evaluate the impact of earplugs and eye mask on sleep architecture in ICU patients. Methods A single-center randomized controlled trial of 64 ICU patients was conducted from July 2012 to December 2013. Patients were randomly assigned to sleep with or without earplugs and an eye mask from inclusion until ICU discharge. Polysomnography was performed on the first day and night following inclusion. The primary outcome was the proportion of stage N3 sleep over total sleep time. Secondary outcomes were other descriptors of sleep and major outcome variables. Results In the intervention group, nine (30%) patients did not wear earplugs all night long. The proportion of N3 sleep was 21 [7–28]% in the intervention group and 11 [3–23]% in the control group (p = 0.09). The duration of N3 sleep was higher among the patients in the intervention group who wore earplugs all night long than in the control group (74 [32–106] vs. 31 [7–76] minutes, p = 0.039). The number of prolonged awakenings was smaller in the intervention group (21 [19–26] vs. 31 [21–47] in the control group, p = 0.02). No significant difference was observed between the two groups in terms of clinical outcome variables. Conclusions Earplugs and eye mask reduce long awakenings and increase N3 duration when they are well tolerated. Trial registration ClinicalTrials.gov, NCT02292134. Registered on 21 Nov 2013.

Abstract Background Pneumonia is a dreaded complication of varicella-zoster virus (VZV) infection in adults; however, the data are limited. Our objective was to investigate the clinical features, management, and outcomes of critically ill patients with VZV-related community-acquired pneumonia (VZV-CAP). Methods This was an observational study of patients with VZV-CAP admitted to 29 intensive care units (ICUs) from January 1996 to January 2015. Results One hundred and two patients with VZV-CAP were included. Patients were young (age 39 years (interquartile range 32–51)) and 53 (52%) were immunocompromised. Time since respiratory symptom onset was 2 (1–3) days. There was a seasonal distribution of the disease, with more cases during spring and winter time. All but four patients presented with typical skin rash on ICU admission. Half the patients received mechanical ventilation within 1 (1–2) day following ICU admission (the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) = 150 (80–284), 80% with acute respiratory distress syndrome (ARDS)). Sequential Organ Failure Assessment (SOFA) score on day 1 (odds ratio (OR) 1.90 (1.33–2.70); p

Abstract Background Indications for red blood cell (RBC) transfusion in septic acute circulatory failure remain unclear. We addressed the practices and the prognostic impact of RBC transfusion in the early resuscitation of severe sepsis and septic shock in patients with hematological malignancies. Methods We performed a retrospective analysis of a prospectively collected database of patients with hematological malignancies who required intensive care unit (ICU) admission in 2010–2011. Patients with a main admission diagnosis of severe sepsis or septic shock were included in the present study. We assessed RBC transfusion during the first two days as part of initial resuscitation. Results Among the 1011 patients of the primary cohort, 631 (62.4%) were admitted to the ICU for severe sepsis (55%) or septic shock (45%). Among them, 210 (33.3%) patients received a median of 2 [interquartile 1–3] packed red cells during the first 48 h. Hemoglobin levels were lower in transfused patients at days 1 and 2 and became similar to those of non-transfused patients at day 3. Early RBC transfusion was more likely in patients with myeloid neoplasms and neutropenia. Transfused patients displayed more severe presentations as assessed by higher admission SOFA scores and blood lactate levels and the further requirements for organ failure supports. RBC transfusion within the first two days was associated with higher day 7 (20.5 vs. 13.3%, p = 0.02), in-ICU (39 vs. 25.2%, p