Ultra-low tidal volume ventilation for COVID-19-related ARDS in France (VT4COVID): a multicentre, open-label, parallel-group, randomised trial.

BACKGROUND: COVID-19-related acute respiratory distress syndrome (ARDS) is associated with a high mortality rate and longer mechanical ventilation. We aimed to assess the effectiveness of ventilation with ultra-low tidal volume (ULTV) compared with low tidal volume (LTV) in patients with COVID-19-related ARDS. METHODS: This study was a multicentre, open-label, parallel-group, randomised trial conducted in ten intensive care units in France. Eligible participants were aged 18 years or older, received invasive mechanical ventilation for COVID-19 (confirmed by RT-PCR), had ARDS according to the Berlin definition, a partial pressure of arterial oxygen to inspiratory oxygen fraction (PaO2/FiO2) ratio of 150 mm Hg or less, a tidal volume (VT) of 6·0 mL/kg predicted bodyweight or less, and received continuous intravenous sedation. Patients were randomly assigned (1:1) using randomisation blocks to receive ULTV (intervention group) aiming for VT of 4·0 mL/kg predicted bodyweight or LTV (control group) aiming for VT 6·0 mL/kg predicted bodyweight. Participants, investigators, and outcome assessors were not masked to group assignment. The primary outcome was a ranked composite score based on all-cause mortality at day 90 as the first criterion and ventilator-free days among patients alive at day 60 as the second criterion. Effect size was computed with the unmatched win ratio, on the basis of pairwise prioritised comparison of primary outcome components between every patient in the ULTV group and every patient in the LTV group. The unmatched win ratio was calculated as the ratio of the number of pairs with more favourable outcome in the ULTV group over the number of pairs with less favourable outcome in the ULTV group. Primary analysis was done in the modified intention-to-treat population, which included all participants who were randomly assigned and not lost to follow-up. This trial is registered with ClinicalTrials.gov, NCT04349618. FINDINGS: Between April 15, 2020, and April 13, 2021, 220 patients were included and five (2%) were excluded. 215 patients were randomly assigned (106 [49%] to the ULTV group and 109 [51%] to the LTV group). 58 (27%) patients were female and 157 (73%) were male. The median age was 68 years (IQR 60-74). 214 patients completed follow-up (one lost to follow-up in the ULTV group) and were included in the modified intention-to-treat analysis. The primary outcome was not significantly different between groups (unmatched win ratio in the ULTV group 0·85 [95% CI 0·60 to 1·19]; p=0·38). 46 (44%) of 105 patients in the ULTV group and 43 (39%) of 109 in the LTV group died by day 90 (absolute difference 4% [-9 to 18]; p=0·52). The rate of severe respiratory acidosis in the first 28 days was higher in the ULTV group than in the LTV group (35 [33%] vs 14 [13%]; absolute difference 20% [95% CI 9 to 31]; p=0·0004). INTERPRETATION: In patients with moderate-to-severe COVID-19-related ARDS, there was no significant difference with ULTV compared with LTV in the composite score based on mortality and ventilator-free days among patients alive at day 60. These findings do not support the systematic use of ULTV in patients with COVID-19-related ARDS. FUNDING: French Ministry of Solidarity and Health and Hospices Civils de Lyon.

Open-label randomized controlled trial of ultra-low tidal ventilation without extracorporeal circulation in patients with COVID-19 pneumonia and moderate to severe ARDS: study protocol for the VT4COVID trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe complication of COVID-19 pneumonia, with a mortality rate amounting to 34-50% in moderate and severe ARDS, and is associated with prolonged duration of invasive mechanical ventilation. Such as in non-COVID ARDS, harmful mechanical ventilation settings might be associated with worse outcomes. Reducing the tidal volume down to 4 mL kg-1 of predicted body weight (PBW) to provide ultra-low tidal volume ventilation (ULTV) is an appealing technique to minimize ventilator-inducted lung injury. Furthermore, in the context of a worldwide pandemic, it does not require any additional material and consumables and may be applied in low- to middle-income countries. We hypothesized that ULTV without extracorporeal circulation is a credible option to reduce COVID-19-related ARDS mortality and duration of mechanical ventilation. METHODS: The VT4COVID study is a randomized, multi-centric prospective open-labeled, controlled superiority trial. Adult patients admitted in the intensive care unit with COVID-19-related mild to severe ARDS defined by a PaO2/FiO2 ratio ≤ 150 mmHg under invasive mechanical ventilation for less than 48 h, and consent to participate to the study will be eligible. Patients will be randomized into two balanced parallels groups, at a 1:1 ratio. The control group will be ventilated with protective ventilation settings (tidal volume 6 mL kg-1 PBW), and the intervention group will be ventilated with ULTV (tidal volume 4 mL kg-1 PBW). The primary outcome is a composite score based on 90-day all-cause mortality as a prioritized criterion and the number of ventilator-free days at day 60 after inclusion. The randomization list will be stratified by site of recruitment and generated using random blocks of sizes 4 and 6. Data will be analyzed using intention-to-treat principles. DISCUSSION: The purpose of this manuscript is to provide primary publication of study protocol to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency. Enrollment of patients in the study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT04349618 . Registered on April 16, 2020.

Deterioration of vaccine-induced immune thrombotic thrombocytopenia treated by heparin and platelet transfusion: Insight from functional cytometry and serotonin release assay.

We report a case of a 62-year-old man who developed cerebral venous sinus thrombosis with subarachnoid hemorrhage and concomitant thrombocytopenia, which occurred 13 days after ChAdOx1 nCov-19 injection. The patient died in the intensive care unit after heparin infusion and platelet transfusion. The key clinical purpose of this case report is to better understand how to confirm vaccine-induced immune thrombotic thrombocytopenia (VITT). VITT diagnosis was made using 14C-serotonin release and flow cytometry evaluating activation and platelet microvesicles on washed platelets. Four control patients were examined: a patient with heparin-induced thrombocytopenia (HIT), two patients with thrombotic events without thrombocytopenia after ChAdOx1 nCov-19 or BNT162b2, and a patient with suspected HIT and an excluded diagnosis. We evidenced in the VITT case a high level of IgG anti-platelet factor 4-heparin antibodies associated with a high level of platelet activation in the absence of heparin. Conversely, the functional assays were negative in the patients with thrombosis without thrombocytopenia.

Role of ICU-acquired weakness on extubation outcome among patients at high risk of reintubation.

BACKGROUND: Whereas ICU-acquired weakness may delay extubation in mechanically ventilated patients, its influence on extubation failure is poorly known. This study aimed at assessing the role of ICU-acquired weakness on extubation failure and the relation between limb weakness and cough strength. METHODS: A secondary analysis of two previous prospective studies including patients at high risk of reintubation after a planned extubation, i.e., age greater than 65 years, with underlying cardiac or respiratory disease, or intubated for more than 7 days prior to extubation. Patients intubated less than 24 h and those with a do-not-reintubate order were not included. Limb and cough strength were assessed by a physiotherapist just before extubation. ICU-acquired weakness was clinically diagnosed as limb weakness defined as Medical Research Council (MRC) score < 48 points and severe weakness as MRC sum-score < 36. Cough strength was assessed using a semi-quantitative 5-Likert scale. Extubation failure was defined as reintubation or death within the first 7 days following extubation. RESULTS: Among 344 patients at high risk of reintubation, 16% experienced extubation failure (56/344). They had greater severity and lower MRC sum-score (41 ± 16 vs. 49 ± 13, p < 0.001) and were more likely to have ineffective cough than the others. The prevalence of ICU-acquired weakness at the time of extubation was 38% (130/244). The extubation failure rate was 12% (25/214) in patients with no limb weakness vs. 18% (12/65) and 29% (19/65) in those with moderate and severe limb weakness, respectively (p < 0.01). MRC sum-score and cough strength were weakly but significantly correlated (rho = 0.28, p < .001). After multivariate logistic regression analyses, the lower the MRC sum-score the greater the risk of reintubation; severe limb weakness was independently associated with extubation failure, even after adjustment on cough strength and severity at admission. CONCLUSION: ICU-acquired weakness was diagnosed in 38% in this population of patients at high risk at the time of extubation and was independently associated with extubation failure in the ICU.

Inability of Diaphragm Ultrasound to Predict Extubation Failure: A Multicenter Study.

BACKGROUND: Diaphragmatic dysfunction may promote weaning difficulties in patients who are mechanically ventilated. OBJECTIVE: The goal of this study was to assess whether diaphragm dysfunction detected by ultrasound prior to extubation could predict extubation failure in the ICU. METHODS: This multicenter prospective study included patients at high risk of reintubation: those aged > 65 years, with underlying cardiac or respiratory disease, or intubated > 7 days. All patients had successfully undergone a spontaneous breathing trial. Diaphragmatic function was assessed by ultrasound prior to extubation while breathing spontaneously on a T-piece. Bilateral diaphragmatic excursion and apposition thickening fraction were measured, and diaphragmatic dysfunction was defined as excursion < 10 mm or thickening < 30%. Cough strength was clinically assessed by physiotherapists. Extubation failure was defined as reintubation or death within the 7 days following extubation. RESULTS: Over a 20-month period, 191 at-risk patients were studied. Among them, 33 (17%) were considered extubation failures. The proportion of patients with diaphragmatic dysfunction was similar between those whose extubation succeeded and those whose extubation failed: 46% vs 51% using excursion (P = .55), and 71% vs 68% using thickening (P = .73), respectively. Values of excursion and thickening did not differ between the success and the failure groups: at right, excursion was 14 ± 7 mm vs 11 ± 8 (P = .13), and thickening was 29 ± 29% vs 38 ± 48% (P = .83), respectively. Extubation failure rates were 7%, 22%, and 46% in patients with effective, moderate, and ineffective cough (P < .01). Ineffective cough was the only variable independently associated with extubation failure. CONCLUSIONS: Diaphragmatic dysfunction assessed by ultrasound was not associated with an increased risk of extubation failure.

Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome.

Recently, dihydrotestosterone biosynthesis through the backdoor pathway has been implicated for the human testis in addition to the classic pathway for testosterone (T) synthesis. In the human ovary, androgen precursors are crucial for estrogen synthesis and hyperandrogenism in pathologies such as the polycystic ovary syndrome is partially due to ovarian overproduction. However, a role for the backdoor pathway is only established for the testis and the adrenal, but not for the human ovary. To investigate whether the backdoor pathway exists in normal and PCOS ovaries, we performed specific gene and protein expression studies on ovarian tissues. We found aldo-keto reductases (AKR1C1-1C4), 5α-reductases (SRD5A1/2) and retinol dehydrogenase (RoDH) expressed in the human ovary, indicating that the ovary might produce dihydrotestosterone via the backdoor pathway. Immunohistochemical studies showed specific localization of these proteins to the theca cells. PCOS ovaries show enhanced expression, what may account for the hyperandrogenism.

Return to Work after a Work Accident: Is Coordination between the Occupational Physician and the Insurance Physician Possible? / Retour à l'emploi après un accident de travail : une coordination entre médecin du travail et médecin-conseil d'assurance est-elle possible ?

Occupational physicians and insurance physicians each have their own roles in managing the consequences of work accidents and their interaction is pivotal in the administrative and clinical process of return to work. We wanted to analyse the barriers and facilitators of this collaboration in Belgium.A qualitative study was conducted based on individual interviews of a sample of insurance physicians and occupational physicians working in French-speaking Belgium. This sample was selected to represent all insurance companies and most prevention and protection services operating on the territory. The interview scheme was designed to explore the various dimensions of the RDIC model (Resource Dependence Institutional Collaboration) of collaboration between professionals.This study highlighted certain obstacles to collaboration, related to the mutual perception of the 2 professions, ignorance of the other profession's work context, lack of independent resources blocking the willingness to cooperate (sufficient time, fees). Some facilitating factors were also identified : occupational physicians' willingness to cooperate, a positive attitude towards the ability to cooperate, as well as proposals for immediate improvement of some factors. Collaboration between these 2 professions has rarely been studied and the results of the present study provide tracks for improvement that can be applied in the short or medium term to enable those two categories of physicians to be better organized and more efficient in managing disability consequences of work accidents.

Point-of-care ultrasound in intensive care units: assessment of 1073 procedures in a multicentric, prospective, observational study.

OBJECTIVE: To describe current use and diagnostic and therapeutic impacts of point-of-care ultrasound (POCUS) in the intensive care unit (ICU). BACKGROUND: POCUS is of growing importance in the ICU. Several guidelines recommend its use for procedural guidance and diagnostic assessment. Nevertheless, its current use and clinical impact remain unknown. METHODS: Prospective multicentric study in 142 ICUs in France, Belgium, and Switzerland. All the POCUS procedures performed during a 24-h period were prospectively analyzed. Data regarding patient condition and the POCUS procedures were collected. Factors associated with diagnostic and therapeutic impacts were identified. RESULTS: Among 1954 patients hospitalized during the study period, 1073 (55%) POCUS/day were performed in 709 (36%) patients. POCUS served for diagnostic assessment in 932 (87%) cases and procedural guidance in 141 (13%) cases. Transthoracic echocardiography, lung ultrasound, and transcranial Doppler accounted for 51, 17, and 16% of procedures, respectively. Diagnostic and therapeutic impacts of diagnostic POCUS examinations were 84 and 69%, respectively. Ultrasound guidance was used in 54 and 15% of cases for central venous line and arterial catheter placement, respectively. Hemodynamic instability, emergency conditions, transthoracic echocardiography, and ultrasounds performed by certified intensivists themselves were independent factors affecting diagnostic or therapeutic impacts. CONCLUSIONS: With regard to guidelines, POCUS utilization for procedural guidance remains insufficient. In contrast, POCUS for diagnostic assessment is of extensive use. Its impact on both diagnosis and treatment of ICU patients seems critical. This study identified factors associated with an improved clinical value of POCUS.

European bat Lyssavirus transmission among cats, Europe.

We identified 2 cases of European bat lyssavirus subtype 1 transmission to domestic carnivores (cats) in France. Bat-to-cat transmission is suspected. Low amounts of virus antigen in cat brain made diagnosis difficult.

[Workplace health promotion: models and practice]. / Promotion de la santé en milieu de travail: modèles et pratiques.

Acknowledging the synergies between occupational health and safety and health promotion, this paper aims to analyze the interactions between these two fields and their possible integration. It looks at the different health promotion concepts used in occupational health: creation of health-promoting settings, participation and community action, education and development of personal skills, re-orientating public policies, and inter-sectoral collaboration. Four models of action are defined and their characteristics are explored: occupational health and safety; use of health promotion principles, strategies and techniques for occupational health and safety management; general health education actions at the workplace, and integrated approaches (or settings-based ecological approaches).

Spectroscopic investigation of methylated amines by a cavity-ringdown-based spectrometer.

High-resolution absorption spectra of gas-phase monomethylamine (MMA, CH(3)NH(2)) and dimethylamine [DMA, (CH(3))(2)NH] in the region of the first overtone of the NH stretch vibration are reported. Measurements were performed with a near-infrared laser spectrometer based on the cavity-ringdown (CRD) detection technique. The minimum detectable absorption coefficient for the CRD detection setup is alpha(min)=1.55 x 10(-8) cm(-1) (for SNR = 1). This corresponds to detection limits of 350 parts in 10(9) (ppb) for MMA and 1.6 parts in 10(6) (ppm) for DMA in synthetic gas mixtures under interference-free conditions, or 10 ppm and 60 ppm for MMA and DMA, respectively, in the case of gas mixtures such as exhaled human breath containing H(2)O, CO(2), and other absorbing gases in this range.

Fiber-optic cavity sensing of hydrogen diffusion.

A novel type of fiber-optic cavity sensor for hydrogen diffusion into and out of fibers is presented. The sensor is an implementation of a cavity ringdown scheme in a silica-based single-mode fiber that has been exposed to gaseous hydrogen at normal pressure. The measured ringdown times during the H2 diffusion show good agreement with a theoretical diffusion model. This model allows the determination of the diffusion coefficient of hydrogen in silica, resulting in D = (3.02 +/- 0.07) x 10(-15) m2/s at 30 degrees C.

A method for the unambiguous identification of tryptophan in automated protein sequence analysis.

Some widely used standard protocols for the separation of phenylthiohydantoin amino acid derivatives by reverse-phase gradient HPLC do not provide separation of the phenylthiohydantoin derivative of tryptophan (PTH-Trp) from diphenylurea (DPU), a by-product generated during Edman degradation of proteins in variable amounts. Furthermore, PTH-Trp is usually recovered in low yield under typical experimental conditions used with automated sequencing equipment. These factors may compromise the unambiguous assignment of tryptophan residues in automated protein sequence analysis, especially when sequencing is performed at high sensitivity. We devised a reverse-phase HPLC method which allows the separation of DPU and PTH-Trp and therefore the correct assignment of PTH-Trp. The method is based on a modification of the HPLC gradient used to elute and separate all PTH amino acids of interest. With Applied Biosystems Model 477A protein sequencers with on-line PTH amino acid identification, the correct assignment of tryptophan was consistent and reproducible even when sequencing at very high sensitivity (5 pmol).