Duration of Invasive Mechanical Ventilation before Veno-Venous ExtraCorporeal Membrane Oxygenation for Covid-19 related Acute Respiratory Distress Syndrome: The experience of a tertiary care center.

Background: Veno-Venous Extracorporeal Membrane Oxygenation (VV-ECMO) is an efficient ventilatory support in patients with refractory Covid-19-related Acute Respiratory Distress Syndrome (ARDS), however the duration of invasive mechanical ventilation (IMV) before ECMO initiation as a contraindication is still controversial. The aim of this study was to investigate the impact of prolonged IMV prior to VV-ECMO in patients suffering from refractory Covid-19-related ARDS. Methods: This single-center retrospective study included all patients treated with VV-ECMO for refractory Covid-19-related ARDS between January 1, 2020 and May 31, 2022. The impact of IMV duration was investigated by comparing patients on VV-ECMO during the 7 days (and 10 days) following IMV with those assisted after 7 days (and 10 days). The primary endpoint was in-hospital mortality. Results: Sixty-four patients were hospitalized in the ICU for Covid-19-related refractory ARDS requiring VV-ECMO. Global in-hospital mortality was 55 %. Median duration of IMV was 4 [2; 8] days before VV-ECMO initiation. There was no significant difference in in-hospital mortality between patients assisted with IMV pre-VV-ECMO for a duration of ≤7 days (≤10 days) and those assisted after 7 days (and 10 days) ((p = 0.59 and p = 0.45). Conclusion: This study suggests that patients assisted with VV-ECMO after prolonged IMV had the same prognosis than those assisted earlier in refractory Covid-19-related ARDS. Therefore, prolonged mechanical ventilation of more than 7-10 days should not contraindicate VV-ECMO support. An individual approach is necessary to balance the risks and benefits of ECMO in this population.

Bacterial and viral co-infections in patients with severe SARS-CoV-2 pneumonia admitted to a French ICU.

BACKGROUND: Data on the prevalence of bacterial and viral co-infections among patients admitted to the ICU for acute respiratory failure related to SARS-CoV-2 pneumonia are lacking. We aimed to assess the rate of bacterial and viral co-infections, as well as to report the most common micro-organisms involved in patients admitted to the ICU for severe SARS-CoV-2 pneumonia. PATIENTS AND METHODS: In this monocenter retrospective study, we reviewed all the respiratory microbiological investigations performed within the first 48 h of ICU admission of COVID-19 patients (RT-PCR positive for SARS-CoV-2) admitted for acute respiratory failure. RESULTS: From March 13th to April 16th 2020, a total of 92 adult patients (median age: 61 years, 1st-3rd quartiles [55-70]; males: n = 73/92, 79%; baseline SOFA: 4 [3-7] and SAPS II: 31 [21-40]; invasive mechanical ventilation: n = 83/92, 90%; ICU mortality: n = 45/92, 49%) were admitted to our 40-bed ICU for acute respiratory failure due to SARS-CoV-2 pneumonia. Among them, 26 (28%) were considered as co-infected with a pathogenic bacterium at ICU admission with no co-infection related to atypical bacteria or viruses. The distribution of the 32 bacteria isolated from culture and/or respiratory PCRs was as follows: methicillin-sensitive Staphylococcus aureus (n = 10/32, 31%), Haemophilus influenzae (n = 7/32, 22%), Streptococcus pneumoniae (n = 6/32, 19%), Enterobacteriaceae (n = 5/32, 16%), Pseudomonas aeruginosa (n = 2/32, 6%), Moraxella catarrhalis (n = 1/32, 3%) and Acinetobacter baumannii (n = 1/32, 3%). Among the 24 pathogenic bacteria isolated from culture, 2 (8%) and 5 (21%) were resistant to 3rd generation cephalosporin and to amoxicillin-clavulanate combination, respectively. CONCLUSIONS: We report on a 28% rate of bacterial co-infection at ICU admission of patients with severe SARSCoV-2 pneumonia, mostly related to Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae and Enterobacteriaceae. In French patients with confirmed severe SARSCoV-2 pneumonia requiring ICU admission, our results encourage the systematic administration of an empiric antibiotic monotherapy with a 3rd generation cephalosporin, with a prompt de-escalation as soon as possible. Further larger studies are needed to assess the real prevalence and the predictors of co-infection together with its prognostic impact on critically ill patients with severe SARS-CoV-2 pneumonia.

Pulmonary embolism or thrombosis in ARDS COVID-19 patients: A French monocenter retrospective study.

Hypercoagulability and endotheliopathy reported in patients with coronavirus disease 2019 (COVID-19) combined with strict and prolonged immobilization inherent to deep sedation and administration of neuromuscular blockers for Acute Respiratory Distress Syndrome (ARDS) may expose critically ill COVID-19 patients to an increased risk of venous thrombosis and pulmonary embolism (PE). We aimed to assess the rate and to describe the clinical features and the outcomes of ARDS COVID-19 patients diagnosed with PE during ICU stay. From March 13th to April 24th 2020, a total of 92 patients (median age: 61 years, 1st-3rd quartiles [55-70]; males: n = 73/92, 79%; baseline SOFA: 4 [3-7] and SAPS II: 31 [21-40]; invasive mechanical ventilation: n = 83/92, 90%; ICU mortality: n = 45/92, 49%) were admitted to our 41-bed COVID-19 ICU for ARDS due to COVID-19. Among them, 26 patients (n = 26/92, 28%) underwent a Computed Tomography Pulmonary Angiography which revealed PE in 16 (n = 16/26, 62%) of them, accounting for 17% (n = 16/92) of the whole cohort. PE was bilateral in 3 (19%) patients and unilateral in 13 (81%) patients. The most proximal thrombus was localized in main (n = 4, 25%), lobar (n = 2, 12%) or segmental (n = 10, 63%) pulmonary artery. Most of the thrombi (n = 13/16, 81%) were located in a parenchymatous condensation. Only three of the 16 patients (19%) had lower limb venous thrombosis on Doppler ultrasound. Three patients were treated with alteplase and anticoagulation (n = 3/16, 19%) while the 13 others (n = 13/16, 81%) were treated with anticoagulation alone. ICU mortality was higher in patients with PE compared to that of patients without PE (n = 11/16, 69% vs. n = 2/10, 20%; p = 0.04). The low rate of lower limb venous thrombosis together with the high rate of distal pulmonary thrombus argue for a local immuno-thrombotic process associated with the classic embolic process. Further larger studies are needed to assess the real prevalence and the risk factors of pulmonary embolism/thrombosis together with its prognostic impact on critically ill patients with COVID-19.

Factors associated with major adverse kidney events in patients who underwent veno-arterial extracorporeal membrane oxygenation.

OBJECTIVE: To describe acute kidney injury (AKI) natural history and to identify predictors of major adverse kidney events (MAKE) within 1 year in patients supported by veno-arterial extracorporeal membrane oxygenation (VA-ECMO). DESIGN: Retrospective observational study. SETTING: Medical French intensive care unit between January 2014 and December 2016. PATIENTS: Consecutive patients implanted with VA-ECMO ≥ 16 years, VA-ECMO for at least ≥ 48 h, and without end-stage chronic kidney disease (CKD). INTERVENTION: None. MEASUREMENTS: Multivariate logistic regression of factors associated with MAKE at 1 year defined as one of the following criteria within day 360: death and receipt of renal replacement therapy (RRT) or persistent renal dysfunction, i.e., CKD ≥ stage 3 corresponding to an estimated glomerular filtration rate (eGFR) ≤ 60 ml/min/1.73 m2 and MAKE at day 30 and day 90 defined as one of the following criteria within day 30 or day 90: death, receipt of renal replacement therapy and serum creatinine ≥ threefold increase. MAIN RESULTS: 158 consecutive patients were included (male sex: 75.9%; median and interquartile range: age: 59 [47-66], Simplified Acute Physiology Score II: 55 [39-66], Sepsis-related Organ Failure Assessment Score: 9 [7-12], time on VA-ECMO: 7.5 [4-12] days). Among them 145 (91.8%) developed an AKI during the intensive care unit (ICU) stay and 85 (53.8%) needed renal replacement therapy (RRT). 59.9% (91/152), 60.5% (89/147) and 85.1% (120/141) evaluable patients had a MAKE-30, MAKE-90 and MAKE-360, respectively. Factors significantly associated with MAKE-360 were eGFR at baseline (odds ratio (OR) 0.98, confidence interval 95% (CI) [0.97;1.00], p 0.02), Kidney Disease Improving Global Outcome (KDIGO) stage at cannulation (p = 0.03), e.g., stage 3 vs. reference stage 0 OR 10.20 [1.77-58.87], and number of red blood cell (RBC) packs received while under ECMO (OR 1.14, CI 95% [1.01;1.28], p = 0.03). At 1 year among the 51 survivors, almost half of the alive patients (n = 20/51) had a decline of estimated glomerular filtration (eGFR) > 30% mL/min/1.73 m2. Their median eGFR decline was - 26.3% [- 46.6;- 10.7]. CONCLUSION: Patients undergoing VA-ECMO had a high risk of AKI during the ICU stay. Factors associated with MAKE 360 were mainly eGFR at baseline, KDIGO stage at cannulation and, number of RBC packs received while under ECMO. Among survivors at 1 year, almost half of the alive patients (n = 20/51) had a decline eGFR > 30%.

Fine-tuning nucleophosmin in macrophage differentiation and activation.

M-CSF-driven differentiation of peripheral blood monocytes is one of the sources of tissue macrophages. In humans and mice, the differentiation process involves the activation of caspases that cleave a limited number of proteins. One of these proteins is nucleophosmin (NPM1), a multifunctional and ubiquitous protein. Here, we show that caspases activated in monocytes exposed to M-CSF cleave NPM1 at D213 to generate a 30-kDa N-terminal fragment. The protein is further cleaved into a 20-kDa fragment, which involves cathepsin B. NPM1 fragments contribute to the limited motility, migration, and phagocytosis capabilities of resting macrophages. Their activation with lipopolysaccharides inhibits proteolytic processes and restores expression of the full-length protein that negatively regulates the transcription of genes encoding inflammatory cytokines (eg, NPM1 is recruited with NF-κB on the MCP1 gene promoter to decrease its transcription). In mice with heterozygous npm gene deletion, cytokine production in response to lipopolysaccharides, including CXCL1 (KC), MCP1, and MIP2, is dramatically enhanced. These results indicate a dual function of NPM1 in M-CSF-differentiated macrophages. Proteolysis of the protein participates in the establishment of a mature macrophage phenotype. In response to inflammatory stimuli, the full-length protein negatively regulates inflammatory cytokine production.