Quantitative analysis of early-stage EEG reactivity predicts awakening and recovery of consciousness in patients with severe brain injury.

BACKGROUND: Decisions of withdrawal of life-sustaining therapy for patients with severe brain injury are often based on prognostic evaluations such as analysis of electroencephalography (EEG) reactivity (EEG-R). However, EEG-R usually relies on visual assessment, which requires neurophysiological expertise and is prone to inter-rater variability. We hypothesised that quantitative analysis of EEG-R obtained 3 days after patient admission can identify new markers of subsequent awakening and consciousness recovery. METHODS: In this prospective observational study of patients with severe brain injury requiring mechanical ventilation, quantitative EEG-R was assessed using standard 11-lead EEG with frequency-based (power spectral density) and functional connectivity-based (phase-lag index) analyses. Associations between awakening in the intensive care unit (ICU) and reactivity to auditory and nociceptive stimulations were assessed with logistic regression. Secondary outcomes included in-ICU mortality and 3-month Coma Recovery Scale-Revised (CRS-R) score. RESULTS: Of 116 patients, 86 (74%) awoke in the ICU. Among quantitative EEG-R markers, variation in phase-lag index connectivity in the delta frequency band after noise stimulation was associated with awakening (adjusted odds ratio=0.89, 95% confidence interval: 0.81-0.97, P=0.02 corrected for multiple tests), independently of age, baseline severity, and sedation. This new marker was independently associated with improved 3-month CRS-R (adjusted ß=-0.16, standard error 0.075, P=0.048), but not with mortality (adjusted odds ratio=1.08, 95% CI: 0.99-1.18, P=0.10). CONCLUSIONS: An early-stage quantitative EEG-R marker was independently associated with awakening and 3-month level of consciousness in patients with severe brain injury. This promising marker based on functional connectivity will need external validation before potential integration into a multimodal prognostic model.

Clinical outcome of wild-type AmpC-producing Enterobacterales infection in critically ill patients treated with ß-lactams: a prospective multicenter study.

BACKGROUND: ß-lactams are the main antibiotics used against wild-type AmpC-producing Enterobacterales (wtAE). However, they may fail or select AmpC-overproducing mutants. Our aim was to assess factors associated with clinical failure of ß-lactams in the treatment of wtAE infection. METHODS: From September 2017 to December 2020, we prospectively included all consecutive patients treated by definitive ß-lactams therapy for wtAE infection in four university ICUs. Clinical failure was defined as inadequate response to antimicrobial therapy leading to death or to the switch for a broader-spectrum antibiotic. RESULTS: 177 patients were included and 29.4% progressed to clinical failure. E. cloacae was the most prevalent species (42.4%) and ventilator-associated pneumonia (VAP) was the most frequent wtAE infection (69.5%). Cefepime and cefotaxime were used as definitive antibiotic treatment in 42.9% and 27.7% of patients, respectively. Occurrence of AmpC-overproduction was documented in 5.6% of patients and was associated with clinical failure (p = 0.004). In multivariate analysis, VAP (p < 0.001, OR 11.58 [95% CI 3.11-43.02] and K. aerogenes (p = 0.030, OR 3.76 [95% CI 1.13-12.46]) were independently associated with clinical failure. Conversely, cefotaxime as definitive treatment was found inversely associated with the risk of clinical failure (p = 0.022, OR 0.25 [95% CI 0.08-0.82]). After inverse probability weighting, cefotaxime showed a 20% risk reduction of clinical failure (95% CI 5-35%, p = 0.007) whatever the location of infection, the SOFA score on the day of wtAE infection, or the bacterial species. CONCLUSIONS: Clinical failure in the treatment of wtAE infections is associated with the infection site and the causal microorganism. Additionally, cefotaxime use is probably protective against clinical failure in wtAE infection.

In vitro study of factors influencing the duration of antimicrobial protection of antimicrobial-impregnated external ventricular drains.

BACKGROUND: In vitro and clinical studies assessing the duration of the protective activity of antimicrobial-impregnated external ventricular drains (AI-EVDs) gave conflicting results. OBJECTIVES: To identify factors associated with decreased antimicrobial activity of AI-EVDs that were not taken into account in previous in vitro models. METHODS: We performed in vitro experiments with Bactiseal™ AI-EVDs, under different conditions. Tested parameters were chosen to mimic conditions in which AI-EVDs are used: perfusion by saline (at different flow rates) or not perfused, dwelling medium (air, saline, saline+protein, lipid) and temperature. Antimicrobial activity was assessed by measurement of inhibitory diameters of a 0.5 cm portion of an AI-EVD (cut every 2 days) placed onto agar plates covered by a standardized Staphylococcus spp. inoculum (three different isolates). MS was used to measure concentrations of rifampicin and clindamycin after 48 h of dwelling. RESULTS: In univariate analysis, most of the tested factors were associated with reduced antimicrobial activity: liquid media (as compared with ambient air), perfusion whatever the rate flow (as compared with no perfusion) and presence of protein in the media. In multivariate analysis, dwelling in media (lipid or saline) was the most constantly associated with a reduction of inhibition diameters (P < 0.01), as compared with ambient air. After 48 h of dwelling, the clindamycin concentration was higher than 100 and 450 mg/L in saline and saline+BSA, respectively. CONCLUSIONS: The medium in which an AI-EVD is dwelling plays a significant role in the duration of AI-EVD activity. These results may explain conflicting results between clinical and in vitro studies.

Intravenous immunoglobulins in patients with COVID-19-associated moderate-to-severe acute respiratory distress syndrome (ICAR): multicentre, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a major complication of COVID-19 and is associated with high mortality and morbidity. We aimed to assess whether intravenous immunoglobulins (IVIG) could improve outcomes by reducing inflammation-mediated lung injury. METHODS: In this multicentre, double-blind, placebo-controlled trial, done at 43 centres in France, we randomly assigned patients (1:1) receiving invasive mechanical ventilation for up to 72 h with PCR confirmed COVID-19 and associated moderate-to-severe ARDS to receive either IVIG (2 g/kg over 4 days) or placebo. Random assignment was done with a web-based system and was stratified according to the participating centre and the duration of invasive mechanical ventilation before inclusion in the trial (<12 h, 12-24 h, and >24-72 h), and treatment was administered within the first 96 h of invasive mechanical ventilation. To minimise the risk of adverse events, the IVIG administration was divided into four perfusions of 0·5 g/kg each administered over at least 8 hours. Patients in the placebo group received an equivalent volume of sodium chloride 0·9% (10 mL/kg) over the same period. The primary outcome was the number of ventilation-free days by day 28, assessed according to the intention-to-treat principle. This trial was registered on ClinicalTrials.gov, NCT04350580. FINDINGS: Between April 3, and October 20, 2020, 146 patients (43 [29%] women) were eligible for inclusion and randomly assigned: 69 (47%) patients to the IVIG group and 77 (53%) to the placebo group. The intention-to-treat analysis showed no statistical difference in the median number of ventilation-free days at day 28 between the IVIG group (0·0 [IQR 0·0-8·0]) and the placebo group (0·0 [0·0-6·0]; difference estimate 0·0 [0·0-0·0]; p=0·21). Serious adverse events were more frequent in the IVIG group (78 events in 22 [32%] patients) than in the placebo group (47 events in 15 [20%] patients; p=0·089). INTERPRETATION: In patients with COVID-19 who received invasive mechanical ventilation for moderate-to-severe ARDS, IVIG did not improve clinical outcomes at day 28 and tended to be associated with an increased frequency of serious adverse events, although not significant. The effect of IVIGs on earlier disease stages of COVID-19 should be assessed in future trials. FUNDING: Programme Hospitalier de Recherche Clinique.

Advance directives in France: do junior general practitioners want to improve their implementation and usage? A nationwide survey.

BACKGROUND: The doctor-patient relationship has evolved to respect "the autonomy and patients' rights". One of the cornerstones in such autonomy is the opportunity for patients to draw living wills, also known as advance directives (AD). However, information about AD available to patients remains scarce largely due to the lack of involvement of General practitioners for several reasons. The aim of our study was to evaluate current general practitioner residents' (GPR) behavior concerning their role in informing their patients about AD. METHOD: We built a French nationwide survey from GPR class of 2012 to 2014. RESULTS: Two thousand three hundred ten residents completed our survey (21.1% of the total population of GPR during the period). 89.8% declared their willingness to offer patients the opportunity of writing AD. When asked about the usefulness of AD, 73.6% of residents responded that these are a suitable help for patients, but 19.7% considered that AD are essentially geared towards frail patients. Among residents who want to inform patients about AD (n = 2075), 14.7% wanted to involve all patients. Only 20.5% thought that elderly people should be systematically informed about AD. When the question involves other frail people in various disease areas, information seems relevant for 60.1% of GPR considering patient with cancer or malignant hematologic disease and for 56.2% about patients affected by neurodegenerative disease. When considering the routine use of AD, 20.5% of GPR would take them into account only if they are in agreement with the patient's decision. CONCLUSIONS: The results of the survey indicate that GPR would rather choose to decide who should be informed about AD, and when to take AD into account for ethical concerns.

Ventilator-associated pneumonia: The central role of transcolonization.

Ventilator-associated pneumonia remain frequent and serious diseases since they are associated with considerable crude mortality. Pathophysiology is centered on modifications of regional bacterial flora, especially tracheobronchial tree and oropharyngeal sphere. Bacterial migration from an anatomical area to another seems to be the main explanation of these alterations which are called "transcolonization". The association of transcolonization and lack of tightness of the endotracheal tube cuff provides a direct pathway for bacteria from the upper to the subglottic airways, eventually leading to ventilator-associated pneumonia. Although modification of bacterial flora has been largely studied, the mechanism which underlays the ability of the implantation, growing and interactions with the local microbiome that leads to the observed transcolonization remains to be more clearly deciphered. The aim of our review is to emphasize the cornerstone importance of the "transcolonization" as a nosological entity playing a central role in ventilator-associated pneumonia.