Spontaneous breathing trial with pressure support on positive end-expiratory pressure and extensive use of non-invasive ventilation versus T-piece in difficult-to-wean patients from mechanical ventilation: a randomized controlled trial.

BACKGROUND: The aim of this study is to assess whether a strategy combining spontaneous breathing trial (SBT) with both pressure support (PS) and positive end-expiratory pressure (PEEP) and extended use of post-extubation non-invasive ventilation (NIV) (extensively-assisted weaning) would shorten the time until successful extubation as compared with SBT with T-piece (TP) and post-extubation NIV performed in selected patients as advocated by guidelines (standard weaning), in difficult-to-wean patients from mechanical ventilation. METHODS: The study is a single-center prospective open label, randomized controlled superiority trial with two parallel groups and balanced randomization with a 1:1 ratio. Eligible patients were intubated patients mechanically ventilated for more than 24 h who failed their first SBT using TP. In the extensively-assisted weaning group, SBT was performed with PS (7 cmH2O) and PEEP (5 cmH2O). In case of SBT success, an additional SBT with TP was performed. Failure of this SBT-TP was an additional criterion for post-extubation NIV in this group in addition to other recommended criteria. In the standard weaning group, SBT was performed with TP, and NIV was performed according to international guidelines. The primary outcome criterion was the time between inclusion and successful extubation evaluated with a Cox model with adjustment on randomization strata. RESULTS: From May 2019 to March 2023, 98 patients were included and randomized in the study (49 in each group). Four patients were excluded from the intention-to-treat population (2 in both groups); therefore, 47 patients were analyzed in each group. The extensively-assisted weaning group had a higher median age (68 [58-73] vs. 62 [55-71] yrs.) and similar sex ratio (62% male vs. 57%). Time until successful extubation was not significantly different between extensively-assisted and standard weaning groups (median, 172 [50-436] vs. 95 [47-232] hours, Cox hazard ratio for successful extubation, 0.88 [95% confidence interval: 0.55-1.42] using the standard weaning group as a reference; p = 0.60). All secondary outcomes were not significantly different between groups. CONCLUSION: An extensively-assisted weaning strategy did not lead to a shorter time to successful extubation than a standard weaning strategy. Trial registration The trial was registered on ClinicalTrials.gov (NCT03861117), on March 1, 2019, before the inclusion of the first patient. https://clinicaltrials.gov/study/NCT03861117 .

Pharmacokinetics, efficacy and tolerance of cefoxitin in the treatment of cefoxitin-susceptible extended-spectrum beta-lactamase producing Enterobacterales infections in critically ill patients: a retrospective single-center study.

BACKGROUND: Cefoxitin is active against some extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-PE), but has not been evaluated so far in the intensive care unit (ICU) settings. Data upon its pharmacokinetics (PK), tolerance and efficacy in critical conditions are scanty. We performed a retrospective single-center study in a university hospital medical ICU, in subjects presenting with cefoxitin-susceptible ESBL-PE infection and treated with cefoxitin. The primary aim was to determine cefoxitin PK. Secondary endpoints were efficacy, tolerance, and emergence of cephamycin-resistance. RESULTS: Forty-one patients were included in this study, mainly with ESBL-PE pneumonia (35 patients, 85%). Cefoxitin was administered during a median [interquartile range (IQR)] duration of 5 [4-7] days. Cefoxitin serum concentrations strongly depended on renal function. Target serum concentration (> 5 × minimum inhibitory concentration (MIC) 24 h after cefoxitin onset was obtained in 34 patients (83%), using a median [IQR] daily dose of 6 [6-6] g with continuous administration. The standard dosage of 6 g/24 h was not sufficient to achieve the PK/PD target serum concentration for MIC up to 4-8 mg/L, except in patients with severe renal impairment and those treated with renal replacement therapy. Treatment failure occurred in 26 cases (63%), among whom 12 patients (29%) died, 13 patients (32%) were switched to alternative antibiotic therapy and 11 patients (27%) presented with relapse of infection with the same ESBL-PE. Serious adverse events attributed to cefoxitin occurred in 7 patients (17%). Acquisition of cephamycin-resistance with the same Enterobacterales was identified in 13 patients (32%), and was associated with underdosage. CONCLUSION: Continuous administration of large doses of cefoxitin appears necessary to achieve the PK/PD target in patients with normal renal function. Renal status, MIC determination and therapeutic drug monitoring may be useful for treatment individualization in this setting. The treatment failure rate was 63%. The cefoxitin safety profile was favorable, but we observed a high rate of cephamycin-resistance emergence.

Necrotizing external otitis: analysis of relapse risk factors in 66 patients managed during a 12 year period.

BACKGROUND: Necrotizing external otitis (NEO) is a severe infection of the skull base that occurs generally in the elderly and/or in diabetic recipients. There are few data in the literature about the therapeutic management of this complex bone infection. OBJECTIVES: To analyse relapses after NEO treatment completion, and to describe the clinical features of NEO. METHODS: We performed a retrospective cohort study in the Lyon regional reference centre for the management of complex bone and joint infections. Consecutive cases of NEO from 1 January 2006 to 31 December 2018 were included. The primary outcome was the relapse of NEO. Variables were analysed using Cox regression survival analysis with adjusted hazard ratio (aHR) and Kaplan-Meier curve. RESULTS: Sixty-six patients were included. Median age was 75 (IQR 69-81) years and 46 (70%) patients were diabetic. Eleven patients (17%) had temporomandibular arthritis, 10 (15%) cranial nerve paralysis, 2 (3%) cerebral thrombophlebitis, and 2 (3%) contiguous abscess. Microbiological documentation was obtained in 56 patients and revealed Pseudomonas aeruginosa in 44/56 patients (79%). Nine (14%) cases had no microbiological documentation. Antibiotic therapy was dual for 63 (95%) patients. During a median follow-up of 27 (IQR 12-40) months, 16 out of 63 (25%) patients experienced a relapse. Fungal infection was significantly associated with relapse [aHR 4.1 (95% CI 1.1-15); P = 0.03]. CONCLUSIONS: NEO is a severe bone infection, mainly (but not exclusively) caused by P. aeruginosa, which occurs in elderly and diabetic recipients. Fungal infections at baseline significantly impact the outcome.

Short- and long-term prognosis of acute critically ill patients with systemic rheumatic diseases: A retrospective multicentre study.

ABSTRACT: Patients with systemic rheumatic disease (SRD) share the risks of multi-organ flare-up, cardiovascular diseases, and immunosuppression. Such situations can lead to an acute critical illness. The present study describes the clinical features of SRD patients admitted to the intensive care unit (ICU) and their short- and long- term mortality.We performed a multicentre retrospective study in 10 French ICU in Lyon, France. Inclusion criteria were SRD diagnosis and admission for an acute organ failure. The primary endpoint was ICU mortality.A total of 271 patients were included. SRD included systemic lupus erythematosus (23.2% of included patients), vasculitis (10.7%), systemic sclerosis (10.7%), idiopathic inflammatory myopathy (6.3%), and other connective tissue disorders (rheumatoid arthritis, Sjögren and Sharp syndromes; 50.9%). Initial organ failure(s) were shock (43.5% of included patients), acute kidney injury (30.5%), and acute respiratory failure (23.2%). The cause(s) of ICU admission included sepsis (61.6%), cardiovascular events (33.9%), SRD-flare up (32.8%), and decompensations related to comorbidities (28%). The ICU mortality reached 14.3%. The factors associated with ICU mortality were chronic cardiac failure, invasive ventilation and admission in ICU for another reason than sepsis or SRD flare-up. The median follow-up after ICU discharge was 33.6 months. During follow-up, 109 patients died. The factors associated with long-term mortality included age, Charlson comorbidity index, and ICU admission for sepsis or SRD flare-up.The ICU mortality of patients with SRD was low. Sepsis was the first cause of admission. Cardiovascular events and comorbidities negatively impacted ICU mortality. Admission for sepsis or SRD flare-up exerted a negative effect on the long-term outcome.

Prevalence and risk factors of hemodynamic instability associated with preload-dependence during continuous renal replacement therapy in a prospective observational cohort of critically ill patients.

BACKGROUND: Hemodynamic instability is a frequent complication of continuous renal replacement therapy (CRRT). Postural tests (i.e., passive leg raising in the supine position or Trendelenburg maneuver in the prone position) combined with measurement of cardiac output are highly reliable to identify preload-dependence and may provide new insights into the mechanisms involved in hemodynamic instability related to CRRT (HIRRT). We aimed to assess the prevalence and risk factors of HIRRT associated with preload-dependence in ICU patients. We conducted a single-center prospective observational cohort study in ICU patients with acute kidney injury KDIGO 3, started on CRRT in the last 24 h, and monitored with a PiCCO® device. The primary endpoint was the rate of HIRRT episodes associated with preload-dependence during the first 7 days after inclusion. HIRRT was defined as the occurrence of a mean arterial pressure below 65 mmHg requiring therapeutic intervention. Preload-dependence was assessed by postural tests every 4 h, and during each HIRRT episode. Data are expressed in median [1st quartile-3rd quartile], unless stated otherwise. RESULTS: 42 patients (62% male, age 69 [59-77] year, SAPS-2 65 [49-76]) were included 6 [1-16] h after CRRT initiation and studied continuously for 121 [60-147] h. A median of 5 [3-8] HIRRT episodes occurred per patient, for a pooled total of 243 episodes. 131 episodes (54% [CI95% 48-60%]) were associated with preload-dependence, 108 (44%, [CI95% 38-51%]) without preload-dependence, and 4 were unclassified. Multivariate analysis (using variables collected prior to HIRRT) identified the following variables as risk factors for the occurrence of HIRRT associated with preload-dependence: preload-dependence before HIRRT [odds ratio (OR) = 3.82, p < 0.001], delay since last HIRRT episode > 8 h (OR = 0.56, p < 0.05), lactate (OR = 1.21 per 1-mmol L-1 increase, p < 0.05), cardiac index (OR = 0.47 per 1-L min-1 m-2 increase, p < 0.001) and SOFA at ICU admission (OR = 0.91 per 1-point increase, p < 0.001). None of the CRRT settings was identified as risk factor for HIRRT. CONCLUSIONS: In this single-center study, HIRRT associated with preload-dependence was slightly more frequent than HIRRT without preload-dependence in ICU patients undergoing CRRT. Testing for preload-dependence could help avoiding unnecessary decrease of fluid removal in preload-independent HIRRT during CRRT.

Ventilation Management and Outcomes for Subjects With Neuromuscular Disorders Admitted to ICUs With Acute Respiratory Failure.

BACKGROUND: Patients with neuromuscular disorders (NMD) share the risk of acute respiratory failure (ARF) leading to ICU admissions. Noninvasive ventilation (NIV) is often proposed as an alternative to invasive ventilation. This study describes clinical features, ventilation management, and outcomes of subjects with NMD admitted to ICU and managed for ARF. METHODS: We performed a multicenter retrospective study in 7 adult ICUs in the Auvergne-Rhone-Alpes area in France involving subjects with NMD admitted to the ICU for ARF. The primary end point was ICU mortality. Secondary end points were NIV failure, weaning from invasive ventilation, and long-term mortality. We hypothesized a poorer outcome in the case of bulbar musculature involvement. RESULTS: A total of 242 subjects were included; 142 subjects had nonhereditary NMD (58.7%), and 100 had hereditary NMD (41.3%). Eleven subjects had home ventilation through a tracheostomy. While 112 were intubated at admission, 119 initially underwent NIV. NIV was successful in avoiding orotracheal intubation in 78 subjects (65.5%). ICU mortality was 13.6%. Factors associated with ICU mortality were nonhereditary NMD and requirement for invasive ventilation. The involvement of bulbar musculature in ARF and hereditary NMD were associated with NIV failure. After a median follow-up of 1.2 y, 53 of 209 subjects had died. CONCLUSIONS: The ICU mortality of NMD subjects with ARF was low, with no impact of bulbar muscles involvement. NIV was proposed for approximately half of the subjects, and it was more effective when ARF was not attributed to bulbar musculature involvement. The long-term outcome was good.

Simultaneous Presentation of Parvovirus B19 Infection and Systemic Lupus Erythematosus in a Patient: Description and Review of the Literature.

We present the case of a 25-year-old woman without medical history, presenting with acute respiratory failure needing mechanical ventilation. Aetiologic screening showed PVB19 primary infection and concomitant SLE flare-up. We discuss the causative interactions between PVB19 and SLE in the pathogenesis of the disease. Difficulty diagnosing inaugural SLE flare-up concomitant with PVB19 infection can lead to delayed diagnosis and treatment. Inversely, overtreating a SLE-mimicking PVB19 infection with immunosuppressive agents can be highly detrimental. LEARNING POINTS: The differential diagnosis between parvovirus B19 primary infection and systemic lupus erythematosus flare-up can be difficult.Parvovirus B19 primary infection can elicit authentic severe systemic lupus erythematosus flare-up that requires urgent immunosuppressive therapy.Parvovirus B19 primary infection can also mimic systemic lupus erythematosus.

Transpulmonary pressures in obese and non-obese COVID-19 ARDS.

BACKGROUND: Data on respiratory mechanics of COVID-19 ARDS patients are scarce. Respiratory mechanics and response to positive expiratory pressure (PEEP) may be different in obese and non-obese patients. METHODS: We investigated esophageal pressure allowing determination of transpulmonary pressures (PL ) and elastances (EL) during a decremental PEEP trial from 20 to 6 cm H2O in a cohort of COVID-19 ARDS patients. RESULTS: Fifteen patients were investigated, 8 obese and 7 non-obese patients. PEEP ≥ 16 cm H2O for obese patients and PEEP ≥10 cm H2O for non-obese patients were necessary to obtain positive expiratory PL. Change of PEEP did not alter significantly ΔPL or elastances in obese patients. However, in non-obese patients lung EL  and ΔPL increased significantly with PEEP increase. Chest wall EL was not affected by PEEP variations in both groups.

Quantitative-analysis of computed tomography in COVID-19 and non COVID-19 ARDS patients: A case-control study.

PURPOSE: The aim of this study was to assess whether the computed tomography (CT) features of COVID-19 (COVID+) ARDS differ from those of non-COVID-19 (COVID-) ARDS patients. MATERIALS AND METHODS: The study is a single-center prospective observational study performed on adults with ARDS onset ≤72 h and a PaO2/FiO2 ≤ 200 mmHg. CT scans were acquired at PEEP set using a PEEP-FiO2 table with VT adjusted to 6 ml/kg predicted body weight. RESULTS: 22 patients were included, of whom 13 presented with COVID-19 ARDS. Lung weight was significantly higher in COVID- patients, but all COVID+ patients presented supranormal lung weight values. Noninflated lung tissue was significantly higher in COVID- patients (36 ± 14% vs. 26 ± 15% of total lung weight at end-expiration, p < 0.01). Tidal recruitment was significantly higher in COVID- patients (20 ± 12 vs. 9 ± 11% of VT, p < 0.05). Lung density histograms of 5 COVID+ patients with high elastance (type H) were similar to those of COVID- patients, while those of the 8 COVID+ patients with normal elastance (type L) displayed higher aerated lung fraction.

Antimony to Cure Visceral Leishmaniasis Unresponsive to Liposomal Amphotericin B.

We report on 4 patients (1 immunocompetent, 3 immunosuppressed) in whom visceral leishmaniasis had become unresponsive to (or had relapsed after) treatment with appropriate doses of liposomal amphotericin B. Under close follow-up, full courses of pentavalent antimony were administered without life-threatening adverse events and resulted in rapid and sustained clinical and parasitological cure.

An unusual cause of cardiothyreosis.

Severe hyperthyroidism can cause cardiac complications, such as severe rhythm disturbances, heart failure and angina. Gestational trophoblastic disease (GTD) is a rare complication of pregnancy, ranging from benign hydatidiform mole to malignant form. Clinical hyperthyroidism may occur in GTD, as human chorionic gonadotropin (hCG) secreted by molar tissue is structurally similar to thyroid-stimulating hormone. Cardiothyreosis in this context is exceptional. We report the case of a nulligravida 42-year-old woman without thyroid or cardiac history who presented to the emergency department for dyspnoea. Examinations revealed an acute pulmonary oedema and sinus tachycardia. Serum hCG concentration was abnormally high (762 878 UI/l, N < 5). CT scan showed a voluminous uterine mass and eliminated pulmonary embolism. Cardiac output was increased in echocardiography. Complementary blood tests showed a peripheral hyperthyroidism. GTD was evoked in the context of uterine mass and high hCG concentration, which was responsible for inducing clinical hyperthyroidism and cardiothyreosis. A total hysterectomy was performed and histopathological examinations concluded to a non-invasive complete hydatidiform mole (begnin form). hCG fell to normal within 12 weeks, cardiac and thyroid functions normalized after mole evacuation.

An intracellular wave of cytochrome c propagates and precedes Bax redistribution during apoptosis.

Bax is considered to be pivotal in inducing cytochrome c release (CCR) from mitochondria during apoptosis. Indeed, Bax redistributes to the mitochondrial outer membrane (MOM) upon activation and forms homo-multimers that are capable of permeabilizing the MOM. Our attempts to image this sequence of events in single live cells resulted in unexpected observations. Bax redistribution exhibited two distinct components: an early minor redistribution that was silent in terms of homo-multimerization and a major late redistribution that was synchronous with the formation of Bax multimers, but that proceeded belatedly, i.e. only after caspase 3/7 (C3/7) had already been activated. Intriguingly, neither of these two components of redistribution correlated with CCR, which turned out to be spatially organized, propagating as a traveling wave at constant velocity. Strikingly, propagation of the CCR wave (1) preceded signs of in situ Bax conformational activation; (2) appeared to be independent of autocatalytic loops involving a positive feedback of either C3/7, Ca(2+) mobilization or mitochondrial permeability transition; and (3) was triggered by diffuse stimulation with the synthetic Bak activator BH3I-1 but then proceeded independently of Bak activation. Thus, the CCR wave not only questions the exact role of Bax redistribution in cell death, but also indicates the existence of yet unidentified positive-feedback loops that ensure a spatiotemporal control of apoptosis at the subcellular scale.