Development and validation of a clinico-biological score to predict outcomes in patients with drowning-associated cardiac arrest.

BACKGROUND: While several scoring systems have been developed to predict short-term outcome in out-of-hospital cardiac arrest patients, there is currently no dedicated prognostic tool for drowning-associated cardiac arrest (DACA) patients. METHODS: Patients experiencing DACA from two retrospective multicenter cohorts of drowning patients were included in the present study. Among the patients from the development cohort, risk-factors for day-28 mortality were assessed by logistic regression. A prediction score was conceived and assessed in patients from the validation cohort. RESULTS: Among the 103 included patients from the development cohort, the day-28 mortality rate reached 51% (53/103). Identified independent early risk-factors for day-28 mortality included cardiopulmonary resuscitation duration longer than 20 min (OR 6.40 [95% CI 1.88-23.32]; p = 0.003), temperature at Intensive Care Unit admission <34 °C (OR 8.84 [95% CI 2.66-32.92]; p < 0.001), need for invasive mechanical ventilation (OR 6.83 [95% CI 1.47-40.87]; p = 0.02) and lactate concentration > 7 mmol/L (OR 3.56 [95% CI 1.01-13.07]; p = 0.04). The Area Under the ROC Curve (AUC) of the developed score based on those variables reached 0.91 (95% CI, 0.86-0.97). The optimal cut-off for predicting poor outcomes was 4 points with a sensitivity of 92% (95% CI, 82-98%), a specificity of 82% (95% CI, 67-91%), a positive predictive value (PPV) of 84% (95% CI, 72-95%) and a negative predictive value (NPV) of 91% (95% CI, 79-96%). The assessment of this score on the validation cohort of 81 patients exhibited an AUC of 0.82. Using the same 4 points threshold, sensitivity, specificity, PPV and NPV values of the validation cohort were: 81%, 67%, 72% and 77%, respectively. CONCLUSION: In patients suffering from drowning induced initial cardiac arrest admitted to ICU with a DACA score ≥ 4, the likelihood of survival at day-28 is significantly lower. Prospective validation of the DACA score and assessment of its usefulness are warranted in the future.

Invasive group A streptococcal infections requiring admission to ICU: a nationwide, multicenter, retrospective study (ISTRE study).

BACKGROUND: Group A Streptococcus is responsible for severe and potentially lethal invasive conditions requiring intensive care unit (ICU) admission, such as streptococcal toxic shock-like syndrome (STSS). A rebound of invasive group A streptococcal (iGAS) infection after COVID-19-associated barrier measures has been observed in children. Several intensivists of French adult ICUs have reported similar bedside impressions without objective data. We aimed to compare the incidence of iGAS infection before and after the COVID-19 pandemic, describe iGAS patients' characteristics, and determine ICU mortality associated factors. METHODS: We performed a retrospective multicenter cohort study in 37 French ICUs, including all patients admitted for iGAS infections for two periods: two years before period (October 2018 to March 2019 and October 2019 to March 2020) and a one-year after period (October 2022 to March 2023) COVID-19 pandemic. iGAS infection was defined by Group A Streptococcus isolation from a normally sterile site. iGAS infections were identified using the International Classification of Diseases and confirmed with each center's microbiology laboratory databases. The incidence of iGAS infections was expressed in case rate. RESULTS: Two hundred and twenty-two patients were admitted to ICU for iGAS infections: 73 before and 149 after COVID-19 pandemic. Their case rate during the period before and after COVID-19 pandemic was 205 and 949/100,000 ICU admissions, respectively (p < 0.001), with more frequent STSS after the COVID-19 pandemic (61% vs. 45%, p = 0.015). iGAS patients (n = 222) had a median SOFA score of 8 (5-13), invasive mechanical ventilation and norepinephrine in 61% and 74% of patients. ICU mortality in iGAS patients was 19% (14% before and 22% after COVID-19 pandemic; p = 0.135). In multivariate analysis, invasive mechanical ventilation (OR = 6.08 (1.71-21.60), p = 0.005), STSS (OR = 5.75 (1.71-19.22), p = 0.005), acute kidney injury (OR = 4.85 (1.05-22.42), p = 0.043), immunosuppression (OR = 4.02 (1.03-15.59), p = 0.044), and diabetes (OR = 3.92 (1.42-10.79), p = 0.008) were significantly associated with ICU mortality. CONCLUSION: The incidence of iGAS infections requiring ICU admission increased by 4 to 5 after the COVID-19 pandemic. After the COVID-19 pandemic, the rate of STSS was higher, with no significant increase in ICU mortality rate.

Covid-19-associated pulmonary aspergillosis in mechanically ventilated patients: incidence and outcome in a French multicenter observational cohort (APICOVID).

BACKGROUND: Recent studies identified coronavirus disease 2019 (COVID-19) as a risk factor for invasive pulmonary aspergillosis (IPA) but produced conflicting data on IPA incidence and impact on patient outcomes. We aimed to determine the incidence and outcomes of COVID-19-associated pulmonary aspergillosis (CAPA) in mechanically ventilated patients. METHODS: We performed a multicenter retrospective observational cohort study in consecutive adults admitted to 15 French intensive care units (ICUs) in 2020 for COVID-19 requiring mechanical ventilation. CAPA was diagnosed and graded according to 2020 ECMM/ISHAM consensus criteria. The primary objective was to determine the incidence of proven/probable CAPA, and the secondary objectives were to identify risk factors for proven/probable CAPA and to assess associations between proven/probable CAPA and patient outcomes. RESULTS: The 708 included patients (522 [73.7%] men) had a mean age of 65.2 ± 10.8 years, a median mechanical ventilation duration of 15.0 [8.0-27.0] days, and a day-90 mortality rate of 28.5%. Underlying immunosuppression was present in 113 (16.0%) patients. Corticosteroids were used in 348 (63.1%) patients. Criteria for probable CAPA were met by 18 (2.5%) patients; no patient had histologically proven CAPA. Older age was the only factor significantly associated with probable CAPA (hazard ratio [HR], 1.04; 95% CI 1.00-1.09; P = 0.04). Probable CAPA was associated with significantly higher day-90 mortality (HR, 2.07; 95% CI 1.32-3.25; P = 0.001) but not with longer mechanical ventilation or ICU length of stay. CONCLUSION: Probable CAPA is a rare but serious complication of severe COVID-19 requiring mechanical ventilation and is associated with higher day-90 mortality.

Antithrombin Levels and Heparin Responsiveness during Venoarterial Extracorporeal Membrane Oxygenation: A Prospective Single-center Cohort Study.

BACKGROUND: Unfractionated heparin, administered during venoarterial extracorporeal membrane oxygenation to prevent thromboembolic events, largely depends on plasma antithrombin for its antithrombotic effects. Decreased heparin responsiveness seems frequent on extracorporeal membrane oxygenation; however, its association with acquired antithrombin deficiency is poorly understood. The objective of this study was to describe longitudinal changes in plasma antithrombin levels during extracorporeal membrane oxygenation support and evaluate the association between antithrombin levels and heparin responsiveness. The hypothesis was that extracorporeal membrane oxygenation support would be associated with acquired antithrombin deficiency and related decreased heparin responsiveness. METHODS: Adults receiving venoarterial extracorporeal membrane oxygenation were prospectively included. All patients received continuous intravenous unfractionated heparin using a standardized protocol (target anti-Xa 0.3 to 0.5 IU/ml). For each patient, arterial blood was withdrawn into citrate-containing tubes at 11 time points (from hour 0 up to day 7). Anti-Xa (without dextran or antithrombin added) and antithrombin levels were measured. The primary outcome was the antithrombin plasma level. In the absence of consensus, antithrombin deficiency was defined as a time-weighted average of antithrombin less than or equal to 70%. Data regarding clinical management and heparin dosage were collected. RESULTS: Fifty patients, including 42% postcardiotomy, were included between April 2020 and May 2021, with a total of 447 samples. Median extracorporeal membrane oxygenation duration was 7 (interquartile range, 4 to 12) days. Median antithrombin level was 48% (37 to 60%) at baseline. Antithrombin levels significantly increased throughout the follow-up. Time-weighted average of antithrombin levels was 63% (57 to 73%) and was less than or equal to 70% in 32 (64%) of patients. Overall, 45 (90%) patients had at least one antithrombin value less than 70%, and 35 (70%) had at least one antithrombin value less than 50%. Antithrombin levels were not significantly associated with heparin responsiveness evaluated by anti-Xa assay or heparin dosage. CONCLUSIONS: Venoarterial extracorporeal membrane oxygenation support was associated with a moderate acquired antithrombin deficiency, mainly during the first 72 h, that did not correlate with heparin responsiveness.

Association between selective digestive decontamination and decreased rate of acquired candidemia in mechanically ventilated ICU patients: a multicenter nationwide study.

BACKGROUND: Candidemia is a high-risk complication among intensive care unit (ICU) patients. While selective digestive decontamination (SDD) has been shown to be effective in preventing ICU-acquired bacterial secondary infection, its effects on ICU-acquired candidemia (ICAC) remain poorly explored. Therefore, we sought to assess the effects of SDD on ICAC. METHOD: Using the REA-REZO network, we included adult patients receiving mechanical ventilation for at least 48 h from January 2017 to January 2023. Non-parsimonious propensity score matching with a 1:1 ratio was performed to investigate the association between SDD and the rate of ICAC. RESULTS: A total of 94 437 patients receiving at least 48 h of mechanical ventilation were included throughout the study period. Of those, 3 001 were treated with SDD and 651 patients developed ICAC. The propensity score matching included 2 931 patients in the SDD group and in the standard care group. In the matched cohort analysis as well as in the overall population, the rate of ICAC was lower in patients receiving SDD (0.8% versus 0.3%; p = 0.012 and 0.7% versus 0.3%; p = 0.006, respectively). Patients with ICAC had higher mortality rate (48.4% versus 29.8%; p < 0.001). Finally, mortality rates as well as ICU length of stay in the matched populations did not differ according to SDD (31.0% versus 31.1%; p = 0.910 and 9 days [5-18] versus 9 days [5-17]; p = 0.513, respectively). CONCLUSION: In this study with a low prevalence of ICAC, SDD was associated with a lower rate of ICAC that did not translate to higher survival.

Prediction of pulmonary aspergillosis in patients with ventilator-associated pneumonia.

BACKGROUND: Predictors of ICU-acquired pulmonary aspergillosis (IPA) are not well-established in critically ill patients with ventilator-associated pneumonia (VAP), making IPA commonly misdiagnosed and anti-fungal therapy delayed. We aimed to develop a clinical score for prediction of IPA among patients with VAP. METHODS: Mechanically ventilated patients who developed VAP in 4 ICUs in Bretagne, Western France, were included. The score was constructed in a learning cohort, based on predictors of IPA in logistic regression model, and validated in a validation cohort. RESULTS: Among 1636 mechanically ventilated patients, 215 developed VAP but only 39 developed IPA (4 possible and 35 probable/putative) (18%). Most cases (31/39) were documented through a positive broncho-alveolar sample culture. Independent predictors of IPA were immunodepression (including onco-hematological disorder, immunomodulatory treatment, solid organ transplant, neutropenia < 0.5G/L and high-dose steroids ≥ 1 mg/kg/day of prednisolone equivalent) (p = 0.001; score = 1 point) and lymphocyte count at admission < 0.8 G/L (p = 0.019; score = 1 point). Operational values of the predictive score in the learning/validation cohort were 50%/52% sensitivity and 90%/87% specificity, respectively, for high PiPa score (score = 2) and 94%/91% sensitivity and 44%/46% specificity, respectively, for moderate PiPa score (score = 1). Finally, the AUC for the prediction of IPA was 0.783 in the learning cohort and 0.770 in the validation cohort. CONCLUSIONS: We evaluated a clinical score with good predictive value which may help to predict IPA in patient with VAP. External validation will be needed to confirm our preliminary findings.

Early discontinuation of combination antibiotic therapy in severe community-acquired pneumonia: a retrospective cohort study.

BACKGROUND: Severe community-acquired pneumonia (SCAP) is commonly treated with an empiric combination therapy, including a macrolide, or a quinolone and a ß-lactam. However, the risk of Legionella pneumonia may lead to a prolonged combination therapy even after negative urinary antigen tests (UAT). METHODS: We conducted a retrospective cohort study in a French intensive care unit (ICU) over 6 years and included all the patients admitted with documented SCAP. All patients received an empirical combination therapy with a ß-lactam plus a macrolide or quinolone, and a Legionella UAT was performed. Macrolide or quinolone were discontinued when the UAT was confirmed negative. We examined the clinical and epidemiological features of SCAP and analysed the independent factors associated with ICU mortality. RESULTS: Among the 856 patients with documented SCAP, 26 patients had atypical pneumonia: 18 Legionella pneumophila (LP) serogroup 1, 3 Mycoplasma pneumonia (MP), and 5 Chlamydia psittaci (CP). UAT diagnosed 16 (89%) Legionella pneumonia and PCR confirmed the diagnosis for the other atypical pneumonia. No atypical pneumonia was found by culture only. Type of pathogen was not associated with a higher ICU mortality in the multivariate analysis. CONCLUSION: Legionella pneumophila UAT proved to be highly effective in detecting the majority of cases, with only a negligible percentage of patients being missed, but is not sufficient to diagnose atypical pneumonia, and culture did not provide any supplementary information. These results suggest that the discontinuation of macrolides or quinolones may be a safe option when Legionella UAT is negative in countries with a low incidence of Legionella pneumonia.

Prophylactic platelet transfusion response in critically ill patients: a prospective multicentre observational study.

BACKGROUND: Response to prophylactic platelet transfusion is suspected to be inconsistent in critically ill patients questioning how to optimize transfusion practices. This study aimed to describe prophylactic platelet transfusion response, to identify factors associated with a suboptimal response, to analyse the correlation between corrected count increment and platelet count increment and to determine the association between poor platelet transfusion response and clinical outcomes. METHODS: This prospective multicentre observational study recruited patients who received at least one prophylactic platelet transfusion in one of the nine participating intensive care units for a period up to 16 months. Poor platelet transfusion response was defined as a corrected count increment (CCI) that adjusts for platelet dose and body surface area, less than 7 at 18-24 h after platelet transfusion. Factors associated with poor platelet transfusion response were assessed in a mixed-effect model. Sensitivity analyses were conducted in patients with and without haematology malignancy and chemotherapy. RESULTS: Poor platelet transfusion response occurred in 349 of the 472 (73.9%) prophylactic platelet transfusions and in 141/181 (77.9%) patients. The mixed-effect model identified haemoglobin at ICU admission (odds ratio (OR): 0.79 [95% confidence interval (CI) 0.7-0.89]) and body mass index (BMI) (OR: 0.93 [0.89-0.98]) being positively and independently associated with platelet transfusion response, while a haematological malignancy (OR 1.93 [1.09-3.43]), sepsis as primary ICU admission diagnosis (OR: 2.81 [1.57-5.03]), SOFA score (OR 1.10 [1.03; 1.17]) and maximum storage duration of platelet (OR: 1.24 [1.02-1.52]) were independently associated with a suboptimal platelet increment. Clinical outcomes did not differ between groups, nor the requirement for red blood cells. Poor platelet transfusion response was found in 93.5% of patients with haematology malignancy and chemotherapy. CONCLUSIONS: In this study of critically ill patients, of whom more than half had bone marrow failure, almost three quarters of prophylactic platelet transfusions led to suboptimal platelet increment measured 18 to 24 h following platelet transfusion. Platelet storage duration was the only factor associated with poor platelet response that may be accessible to intervention. Trial registration in October 2017: ClinicalTrials.gov: NCT03325140.

Organizing and Sharing Medical Knowledge Among Anesthesiology and Intensive care Residents: Evaluating Existing Practices and the Feasibility of Implementing a Dedicated Multiplatform Application.

Treating patients with up-to-date medical knowledge is an ongoing goal for healthcare workers and implies efficient knowledge management at the point of care. Widely available mobile wireless technologies influence practices but a significant gap remains between technological possibilities and actual usage. The purpose of this study was to analyze residents' baseline practices in managing medical knowledge and to evaluate the use and impact of an innovative multiplatform application dedicated to anesthesiology and intensive care residents. This study took place in Rennes Teaching Hospital and comprised two distinct surveys. First, in April 2018, all residents received a ten-items online survey focusing on managing medical knowledge. Then, through a second online survey constituted of ten items, we sought to assess the use of a new multiplatform cloud-based application named "DansMaBlouse", dedicated to sharing and indexing medical knowledge, in anesthesiology and intensive care residents. Among 148 residents that answered the evaluation survey, the most sought out pieces of information in clinical setting were a phone or fax number (74%), drugs' characteristics (68%) and expert guidelines (57%). The main sources were senior staff (68%), medical databases (60%) and an Internet search engine (59%). Computers and smartphones were more frequently used than bound paper notebooks. After implementation of the multiplatform application DansMaBlouse, fifty-nine (82%) of the 72 residents that answered the evaluation survey reported using the application and 39% used it more than ten times. Among application users, 90% found it easy to use and 92% agreed that it improved point-of-care access to knowledge. Accessing appropriate medical knowledge at the point of care remains an issue for residents and can be improved by a multiplatform application combining personal and shared up-to-date resources.

Prevention of ICU-acquired infection with decontamination regimen in immunocompromised patients: a pre/post observational study.

PURPOSE: Although the proportion of immunocompromised patients admitted to the ICU is increasing, data regarding specific management, including acquired infection (ICU-AI) prophylaxis, in this setting are lacking. We aim to investigate the effect of multiple-site decontamination regimens (MSD) in immunocompromised patients. METHODS: We conducted a prospective pre-/post-observational study in 2 ICUs in Bretagne, western France. Adults who required mechanical ventilation for 24 h or more were eligible. During the study period, MSD was implemented in participating ICUs in addition to standard care. It consists of the administration of topical antibiotics (gentamicin, colistin sulfate, and amphotericin B), four times daily in the oropharynx and the gastric tube, 4% chlorhexidine bodywash once daily, and a 5-day nasal mupirocin course. RESULTS: Overall, 295 immunocompromised patients were available for analysis (151 in the post-implementation group vs 143 in the pre-implementation group). Solid organ cancer was present in 77/295 patients while immunomodulatory treatments were noticed in 135/295. They were 35 ICU-AI in 29/143 patients in the standard-care group as compared with 10 ICU-AI in 9/151 patients in the post-implementation group (p < 0.001). In a multivariable Poisson regression model, MSD was independently associated with a decreased incidence of ICU-AI (incidence rate ratio = 0.39; 95%CI [0.20-0.87] p = 0.008). There were 35/143 deaths in the standard-care group as compared with 22/151 in the post-implementation group (p = 0.046), this difference remained in a multivariable Cox model (HR = 0.58; 95CI [0.34-0.95] p = 0.048). CONCLUSION: In conclusion, MSD appeared to be associated with improved outcomes in critically ill immunocompromised patients.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome in the intensive care unit: a case report.

BACKGROUND: Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome is a newly discovered inflammatory disease affecting male subjects, for which few data exist in the literature. Here, we describe the case of a patient with known Sweet's syndrome admitted to the intensive care unit and for whom a vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome was diagnosed, allowing for appropriate treatment and the patient's discharge and recovery. CASE PRESENTATION: A 70-year-old male White patient was hospitalized in the intensive care unit following an intrahospital cardiac arrest. History started a year before with repeated deep vein thrombosis and episodes of skin eruption compatible with Sweet's syndrome. After a course of oral steroids, fever and inflammatory syndrome relapsed with onset of polychondritis, episcleritis along with neurological symptoms and pulmonary infiltrates. Intrahospital hypoxic cardiac arrest happened during patient's new investigations, and he was admitted in a critical state. During the intensive care unit stay, he presented with livedoid skin lesions on both feet. Vasculitis was not proven; however, cryoglobulinemia screening came back positive. Onset of pancytopenia was explored with a myelogram aspirate. It showed signs of dysmyelopoiesis and vacuoles in erythroid and myeloid precursors. Of note, new deep vein thrombosis developed, despite being treated with heparin leading to the diagnosis of heparin-induced thrombocytopenia. The course of symptoms were overlapping multiple entities, and so a multidisciplinary team discussion was implemented. Screening for UBA1-mutation in the blood came back positive, confirming the vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome. Corticosteroids and anti-IL1 infusion were started with satisfactory results supporting patient's discharge from intensive care unit to the internal medicine ward. CONCLUSIONS: Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome should be suspected in male patients presenting with inflammatory symptoms, such as fever, skin eruption, chondritis, venous thromboembolism, and vacuoles in bone marrow precursors. Patients with undiagnosed vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome may present with organ failure requiring hospitalization in intensive care unit, where screening for UBA1 mutation should be performed when medical history is evocative. Multidisciplinary team involvement is highly recommended for patient management, notably to start appropriate immunosuppressive treatments.

Clinical features and outcomes of patients admitted to the ICU for Cyclophosphamide-associated cardiac toxicity: a retrospective cohort.

PURPOSE: To describe the management and outcome of critically-ill patients with Cyclophosphamide (CY)-associated cardiac toxicity. METHODS: All patients admitted to the intensive care units (ICUs) of the Nantes and Rennes University Hospitals for a CY-associated cardiac toxicity between January 2015 and December 2020 were included. RESULTS: Of the thirty-four patients included in the study, twenty-four (70%) underwent allogeneic hematopoietic stem cell transplantation (HSCT), four (12%) autologous HSCT, and six (18%) chemotherapy for hematological malignancies. Acute pulmonary edema (65%), cardiac arrest (9%), and cardiac arrhythmia (6%) were the most common reasons for ICU admission. Patients were admitted to the ICU 6.5 (4-12) days after the intravenous administration of a median dose of CY of 100 [60-101] mg/Kg. Echocardiographic findings showed moderate to severe left ventricular systolic dysfunction (69%) and pericardial effusion (52%). Eighteen (53%) patients ultimately developed cardiogenic shock and required vasopressors (47%) and/or inotropes (18%). Invasive mechanical ventilation and renal replacement therapy were required in twenty (59%) and five (14%) patients, respectively. Sixteen (47%) patients died of whom 12 (35.3%) died from refractory cardiogenic shock. The left ventricular ejection fraction improved over time in most survivors with a median time until full recovery of 33 (12-62) days. Two (11%) patients had a persistent left ventricular dysfunction at 6 months. CONCLUSION: Refractory cardiogenic shock is the primary cause of death of patients with severe CY-related cardiotoxicity. Nonetheless, the cardiac function of most survivors recovered within a month.

Bacterial and fungal infections: a frequent and deadly complication among critically ill acute liver failure patients.

BACKGROUND: Acute liver failure (ALF) is a rare but life-threatening condition mostly requiring intensive care unit (ICU) admission. ALF induces immune disorders and may promote infection acquisition. However, the clinical spectrum and impact on patients' prognosis remain poorly explored. METHODS: We conducted a retrospective single-centre study on patients admitted for ALF to the ICU of a referral University Hospital from 2000 to 2021. Baseline characteristics and outcomes according to the presence of infection until day 28 were analysed. Risk factors for infection were determined using logistic regression. The impact of infection on 28-day survival was assessed using the proportional hazard Cox model. RESULTS: Of the 194 patients enrolled, 79 (40.7%) underwent infection: community-acquired, hospital-acquired before ICU and ICU-acquired before/without and after transplant in 26, 23, 23 and 14 patients, respectively. Most infections were pneumonia (41.4%) and bloodstream infection (38.8%). Of a total of 130 microorganisms identified, 55 were Gram-negative bacilli (42.3%), 48 Gram-positive cocci (36.9%) and 21 were fungi (16.2%). Obesity (OR 3.77 [95% CI 1.18-14.40]; p = .03) and initial mechanical ventilation (OR 2.26 [95% CI 1.25-4.12]; p = .007) were independent factors associated with overall infection. SAPSII > 37 (OR 3.67 [95% CI 1.82-7.76], p < .001) and paracetamol aetiology (OR 2.10 [95% CI 1.06-4.22], p = .03) were independently associated with infection at admission to ICU. On the opposite, paracetamol aetiology was associated with lower risk of ICU-acquired infection (OR 0.37 [95% CI 0.16-0.81], p = .02). Patients with any type of infection had lower day 28 survival rates (57% versus 73%; HR 1.65 [1.01-2.68], p = .04). The presence of infection at ICU admission (p = .04), but not ICU-acquired infection, was associated with decreased survival. CONCLUSIONS: The prevalence of infection is high in ALF patients which is associated with a higher risk of death. Further studies assessing the use of early antimicrobial therapy are needed.

Anticoagulation strategy and safety in critically ill COVID-19 patients: a French retrospective multicentre study.

BACKGROUND: Patients with critical illness due to COVID-19 exhibit increased coagulability associated with a high risk of venous thrombo-embolism (VTE). Data on prophylactic anticoagulation for these patients are limited and conflicting. The purpose of this study was to evaluate whether intermediate-dose prophylactic anticoagulation in patients with COVID-19 requiring ICU admission was associated with better outcomes compared to standard-dose prophylactic anticoagulation. METHODS: We retrospectively included adults admitted with severe COVID-19 to any of 15 ICUs, in 2020 or 2021. We compared the groups given intermediate-dose vs. standard-dose prophylactic anticoagulation. The primary outcome was all-cause day-90 mortality. Secondary outcomes were VTE (pulmonary embolism or deep vein thrombosis), ICU stay length, and adverse effects of anticoagulation. RESULTS: Of 1174 included patients (mean age, 63 years), 399 received standard-dose and 775 intermediate-dose prophylactic anticoagulation. Of the 211 patients who died within 90 days, 86 (21%) received intermediate and 125 (16%) standard doses. After adjustment on early corticosteroid therapy and critical illness severity, there were no significant between-group differences in day-90 mortality (hazard ratio [HR], 0.73; 95%CI, 0.52-1.04; p = 0.09) or ICU stay length (HR, 0.93; 95%CI, 0.79-1.10; p = 0.38). Intermediate-dose anticoagulation was significantly associated with fewer VTE events (HR, 0.55; 95%CI, 0.38-0.80; p < 0.001). Bleeding events occurred in similar proportions of patients in the two groups (odds ratio, 0.86; 95%CI, 0.50-1.47; p = 0.57). CONCLUSIONS: Mortality on day 90 did not differ between the groups given standard-dose and intermediate-dose prophylactic anticoagulation, despite a higher incidence of VTE in the standard-dose group.

COVID-19-Associated Pulmonary Aspergillosis Isolates Are Genomically Diverse but Similar to Each Other in Their Responses to Infection-Relevant Stresses.

Secondary infections caused by the pulmonary fungal pathogen Aspergillus fumigatus are a significant cause of mortality in patients with severe coronavirus disease 19 (COVID-19). Even though epithelial cell damage and aberrant cytokine responses have been linked to susceptibility to COVID-19-associated pulmonary aspergillosis (CAPA), little is known about the mechanisms underpinning copathogenicity. Here, we analyzed the genomes of 11 A. fumigatus isolates from patients with CAPA in three centers from different European countries. CAPA isolates did not cluster based on geographic origin in a genome-scale phylogeny of representative A. fumigatus isolates. Phenotypically, CAPA isolates were more similar to the A. fumigatus A1160 reference strain than to the Af293 strain when grown in infection-relevant stresses, except for interactions with human immune cells wherein macrophage responses were similar to those induced by the Af293 reference strain. Collectively, our data indicate that CAPA isolates are genomically diverse but are more similar to each other in their responses to infection-relevant stresses. A larger number of isolates from CAPA patients should be studied to better understand the molecular epidemiology of CAPA and to identify genetic drivers of copathogenicity and antifungal resistance in patients with COVID-19. IMPORTANCE Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) has been globally reported as a life-threatening complication in some patients with severe COVID-19. Most of these infections are caused by the environmental mold Aspergillus fumigatus, which ranks third in the fungal pathogen priority list of the WHO. However, little is known about the molecular epidemiology of Aspergillus fumigatus CAPA strains. Here, we analyzed the genomes of 11 A. fumigatus isolates from patients with CAPA in three centers from different European countries, and carried out phenotypic analyses with a view to understanding the pathophysiology of the disease. Our data indicate that A. fumigatus CAPA isolates are genomically diverse but are more similar to each other in their responses to infection-relevant stresses.

Impact of Arterial CO2 Retention in Patients With Moderate or Severe ARDS.

BACKGROUND: Lung-protective ventilation (reduced tidal volume and limited plateau pressure) may lead to CO2 retention. Data about the impact of hypercapnia in patients with ARDS are scarce and conflicting. METHODS: We performed a non-interventional cohort study with subjects with ARDS admitted from 2006 to 2021 and with PaO2 /FIO2 ≤ 150 mm Hg. We examined the association between severe hypercapnia (PaCO2 ≥ 50 mm Hg) on the first 5 days after the diagnosis of ARDS and death in ICU for 930 subjects. All the subjects received lung-protective ventilation. RESULTS: Severe hypercapnia was noted in 552 subjects (59%) on the first day of ARDS (day 1); 323/930 (34.7%) died in the ICU. Severe hypercapnia on day 1 was associated with mortality in the unadjusted (odds ratio 1.54, 95% CI 1.16-1.63; P = .003) and adjusted (odds ratio 1.47, 95% CI 1.08-2.43; P = .004) models. In the Bayesian analysis, the posterior probability that severe hypercapnia was associated with ICU death was > 90% in 4 different priors, including a septic prior for this association. Sustained severe hypercapnia on day 5, defined as severe hypercapnia present from day 1 to day 5, was noted in 93 subjects (12%). After propensity score matching, severe hypercapnia on day 5 remained associated with ICU mortality (odds ratio 1.73, 95% CI 1.02-2.97; P = .047). CONCLUSIONS: Severe hypercapnia was associated with mortality in subjects with ARDS who received lung-protective ventilation. Our results deserve further evaluation of the strategies and treatments that aim to control CO2 retention.

Low versus standard calorie and protein feeding in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3).

BACKGROUND: The optimal calorie and protein intakes at the acute phase of severe critical illness remain unknown. We hypothesised that early calorie and protein restriction improved outcomes in these patients, compared with standard calorie and protein targets. METHODS: The pragmatic, randomised, controlled, multicentre, open-label, parallel-group NUTRIREA-3 trial was performed in 61 French intensive care units (ICUs). Adults (≥18 years) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned to early nutrition (started within 24 h after intubation) with either low or standard calorie and protein targets (6 kcal/kg per day and 0·2-0·4 g/kg per day protein vs 25 kcal/kg per day and 1·0-1·3 g/kg per day protein) during the first 7 ICU days. The two primary endpoints were time to readiness for ICU discharge and day 90 all-cause mortality. Key secondary outcomes included secondary infections, gastrointestinal events, and liver dysfunction. The trial is registered on ClinicalTrials.gov, NCT03573739, and is completed. FINDINGS: Of 3044 patients randomly assigned between July 5, 2018, and 8 Dec 8, 2020, eight withdrew consent to participation. By day 90, 628 (41·3%) of 1521 patients in the low group and 648 (42·8%) of 1515 patients in the standard group had died (absolute difference -1·5%, 95% CI -5·0 to 2·0; p=0·41). Median time to readiness for ICU discharge was 8·0 days (IQR 5·0-14·0) in the low group and 9·0 days (5·0-17·0) in the standard group (hazard ratio [HR] 1·12, 95% CI 1·02 to 1·22; p=0·015). Proportions of patients with secondary infections did not differ between the groups (HR 0·85, 0·71 to 1·01; p=0·06). The low group had lower proportions of patients with vomiting (HR 0·77, 0·67 to 0·89; p<0·001), diarrhoea (0·83, 0·73 to 0·94; p=0·004), bowel ischaemia (0·50, 0·26 to 0·95; p=0·030), and liver dysfunction (0·92, 0·86-0·99; p=0·032). INTERPRETATION: Compared with standard calorie and protein targets, early calorie and protein restriction did not decrease mortality but was associated with faster recovery and fewer complications. FUNDING: French Ministry of Health.

Demultiplexing Ig repertoires by parallel mRNA/DNA sequencing shows major differential alterations in severe COVID-19.

To understand the fine differential elements that can lead to or prevent acute respiratory distress syndrome (ARDS) in COVID-19 patients, it is crucial to investigate the immune response architecture. We herein dissected the multiple layers of B cell responses by flow cytometry and Ig repertoire analysis from acute phase to recovery. Flow cytometry with FlowSOM analysis showed major changes associated with COVID-19 inflammation such as an increase of double-negative B-cells and ongoing plasma cell differentiation. This paralleled COVID-19-driven expansion of two disconnected B-cell repertoires. Demultiplexing successive DNA and RNA Ig repertoire patterns characterized an early expansion of IgG1 clonotypes with atypically long and uncharged CDR3, the abundance of this inflammatory repertoire being correlated with ARDS and likely pejorative. A superimposed convergent response included convergent anti-SARS-CoV-2 clonotypes. It featured progressively increasing somatic hypermutation together with normal-length or short CDR3 and it persisted until a quiescent memory B-cell stage after recovery.