Impact of intensive prone position therapy on outcomes in intubated patients with ARDS related to COVID-19.

BACKGROUND: Previous retrospective research has shown that maintaining prone positioning (PP) for an average of 40 h is associated with an increase of survival rates in intubated patients with COVID-19-related acute respiratory distress syndrome (ARDS). This study aims to determine whether a cumulative PP duration of more than 32 h during the first 2 days of intensive care unit (ICU) admission is associated with increased survival compared to a cumulative PP duration of 32 h or less. METHODS: This study is an ancillary analysis from a previous large international observational study involving intubated patients placed in PP in the first 48 h of ICU admission in 149 ICUs across France, Belgium and Switzerland. Given that PP is recommended for a 16-h daily duration, intensive PP was defined as a cumulated duration of more than 32 h during the first 48 h, whereas standard PP was defined as a duration equal to or less than 32 h. Patients were followed-up for 90 days. The primary outcome was mortality at day 60. An Inverse Probability Censoring Weighting (IPCW) Cox model including a target emulation trial method was used to analyze the data. RESULTS: Out of 2137 intubated patients, 753 were placed in PP during the first 48 h of ICU admission. The intensive PP group (n = 79) had a median PP duration of 36 h, while standard PP group (n = 674) had a median of 16 h during the first 48 h. Sixty-day mortality rate in the intensive PP group was 39.2% compared to 38.7% in the standard PP group (p = 0.93). Twenty-eight-day and 90-day mortality as well as the ventilator-free days until day 28 were similar in both groups. After IPCW, there was no significant difference in mortality at day 60 between the two-study groups (HR 0.95 [0.52-1.74], p = 0.87 and HR 1.1 [0.77-1.57], p = 0.61 in complete case analysis or in multiple imputation analysis, respectively). CONCLUSIONS: This secondary analysis of a large multicenter European cohort of intubated patients with ARDS due to COVID-19 found that intensive PP during the first 48 h did not provide a survival benefit compared to standard PP.

On variance estimation of the inverse probability-of-treatment weighting estimator: A tutorial for different types of propensity score weights.

Propensity score methods, such as inverse probability-of-treatment weighting (IPTW), have been increasingly used for covariate balancing in both observational studies and randomized trials, allowing the control of both systematic and chance imbalances. Approaches using IPTW are based on two steps: (i) estimation of the individual propensity scores (PS), and (ii) estimation of the treatment effect by applying PS weights. Thus, a variance estimator that accounts for both steps is crucial for correct inference. Using a variance estimator which ignores the first step leads to overestimated variance when the estimand is the average treatment effect (ATE), and to under or overestimated estimates when targeting the average treatment effect on the treated (ATT). In this article, we emphasize the importance of using an IPTW variance estimator that correctly considers the uncertainty in PS estimation. We present a comprehensive tutorial to obtain unbiased variance estimates, by proposing and applying a unifying formula for different types of PS weights (ATE, ATT, matching and overlap weights). This can be derived either via the linearization approach or M-estimation. Extensive R code is provided along with the corresponding large-sample theory. We perform simulation studies to illustrate the behavior of the estimators under different treatment and outcome prevalences and demonstrate appropriate behavior of the analytical variance estimator. We also use a reproducible analysis of observational lung cancer data as an illustrative example, estimating the effect of receiving a PET-CT scan on the receipt of surgery.

Renal replacement therapy initiation strategies in comatose patients with severe acute kidney injury: a secondary analysis of a multicenter randomized controlled trial.

PURPOSE: The effect of renal replacement therapy (RRT) in comatose patients with acute kidney injury (AKI) remains unclear. We compared two RRT initiation strategies on the probability of awakening in comatose patients with severe AKI. METHODS: We conducted a post hoc analysis of a trial comparing two delayed RRT initiation strategies in patients with severe AKI. Patients were monitored until they had oliguria for more than 72 h and/or blood urea nitrogen higher than 112 mg/dL and then randomized to a delayed strategy (RRT initiated after randomization) or a more-delayed one (RRT initiated if complication occurred or when blood urea nitrogen exceeded 140 mg/dL). We included only comatose patients (Richmond Agitation-Sedation scale [RASS] < - 3), irrespective of sedation, at randomization. A multi-state model was built, defining five mutually exclusive states: death, coma (RASS < - 3), incomplete awakening (RASS [- 3; - 2]), awakening (RASS [- 1; + 1] two consecutive days), and agitation (RASS > + 1). Primary outcome was the transition from coma to awakening during 28 days after randomization. RESULTS: A total of 168 comatose patients (90 delayed and 78 more-delayed) underwent randomization. The transition intensity from coma to awakening was lower in the more-delayed group (hazard ratio [HR] = 0.36 [0.17-0.78]; p = 0.010). Time spent awake was 10.11 days [8.11-12.15] and 7.63 days [5.57-9.64] in the delayed and the more-delayed groups, respectively. Two sensitivity analyses were performed based on sedation status and sedation practices across centers, yielding comparable results. CONCLUSION: In comatose patients with severe AKI, a more-delayed RRT initiation strategy resulted in a lower chance of transitioning from coma to awakening.

A methodological review of the high-dimensional propensity score in comparative-effectiveness and safety-of-interventions research finds incomplete reporting relative to algorithm development and robustness.

OBJECTIVES: The use of secondary databases has become popular for evaluating the effectiveness and safety of interventions in real-life settings. However, the absence of important confounders in these databases is challenging. To address this issue, the high-dimensional propensity score (hdPS) algorithm was developed in 2009. This algorithm uses proxy variables for mitigating confounding by combining information available across several healthcare dimensions. This study assessed the methodology and reporting of the hdPS in comparative effectiveness and safety research. STUDY DESIGN AND SETTING: In this methodological review, we searched PubMed and Google Scholar from July 2009 to May 2022 for studies that used the hdPS for evaluating the effectiveness or safety of healthcare interventions. Two reviewers independently extracted study characteristics and assessed how the hdPS was applied and reported. Risk of bias was evaluated with the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tool. RESULTS: In total, 136 studies met the inclusion criteria; the median publication year was 2018 (Q1-Q3 2016-2020). The studies included 192 datasets, mostly North American databases (n = 132, 69%). The hdPS was used in primary analysis in 120 studies (88%). Dimensions were defined in 101 studies (74%), with a median of 5 (Q1-Q3 4-6) dimensions included. A median of 500 (Q1-Q3 200-500) empirically identified covariates were selected. Regarding hdPS reporting, only 11 studies (8%) reported all recommended items. Most studies (n = 81, 60%) had a moderate overall risk of bias. CONCLUSION: There is room for improvement in the reporting of hdPS studies, especially regarding the transparency of methodological choices that underpin the construction of the hdPS.

High Airway Occlusion Pressure Is Associated with Dyspnea and Increased Mortality in Critically Ill Mechanically Ventilated Patients.

RATIONALE: 100 ms airway occlusion pressure (P0.1) reflects central respiratory drive. We aimed to assess factors associated with P0.1 and whether an abnormally low or high P0.1 value is associated with higher mortality and longer duration of mechanical ventilation (MV). METHODS: Secondary analysis of a prospective cohort study conducted in 10 intensive care units in France to evaluate dyspnea in communicative MV patients. In patients intubated for more than 24 hours, P0.1 was measured with dyspnea as soon as patients could communicate and the following day. RESULTS: 260 patients were assessed after a median time of ventilation of 4 days. P0.1 was 1.9 (1 - 3.5) cmH2O on enrollment, 24% had a P0.1 >3.5 cmH2O, 37% had a P0.1 between 1.5 and 3.5 cmH2O, and 39% had a P0.1 <1.5 cmH2O. In multivariable linear regression, independent factors associated with P0.1 level were presence of dyspnea (p=0.037), respiratory rate (p<0.001), and PaO2 (p=0.008). 90-day mortality was 33% in patients with P0.1 >3.5 cmH2O vs. 19% in those with a P0.1 between 1.5 and 3.5 cmH2O and 17% in patients with P0.1 <1.5 cmH2O (p=0.046). After adjustment for the main risk factors, P0.1 was associated with 90-day mortality (per cmH2O of P0.1, Hazard ratio 1.19, 95% Confidence interval 1.04 - 1.37, p=0.011). P0.1 was also independently associated with a longer duration of MV (per cmH2O of P0.1, Hazard ratio 1.10, 95% Confidence interval 1.02-1.19, p=0.016). CONCLUSIONS: In patients receiving invasive mechanical ventilation, abnormally high P0.1 values may suggest dyspnea and is associated with higher mortality and prolonged duration of MV.

Towards the Lowest Efficacious Dose: Results From a Multicenter Noninferiority Randomized Open-Label Controlled Trial Assessing Tocilizumab or Abatacept Injection Spacing in Rheumatoid Arthritis in Remission.

OBJECTIVE: We assess the clinical and structural impact at two years of progressively spacing tocilizumab (TCZ) or abatacept (ABA) injections versus maintenance at full dose in patients with rheumatoid arthritis in sustained remission. METHODS: This multicenter open-label noninferiority (NI) randomized clinical trial included patients with established rheumatoid arthritis in sustained remission receiving ABA or TCZ at a stable dose. Patients were randomized to treatment maintenance (M) at full dose (M-arm) or progressive injection spacing (S) driven by the Disease Activity Score in 28 joints every 3 months up to biologics discontinuation (S-arm). The primary end point was the evolution of disease activity according to the Disease Activity Score in 44 joints during the 2-year follow-up analyzed per protocol with a linear mixed-effects model, evaluated by an NI test based on the one-sided 95% confidence interval (95% CI) of the slope difference (NI margin 0.25). Other end points were flare incidence and structural damage progression. RESULTS: Overall, 202 of the 233 patients included were considered for per protocol analysis (90 in S-arm and 112 in M-arm). At the end of follow-up, 16.2% of the patients in the S-arm could discontinue their biologic disease-modifying antirheumatic drug, 46.9% tapered the dose and 36.9% returned to a full dose. NI was not demonstrated for the primary outcome, with a slope difference of 0.10 (95% CI 0.10-0.31) between the two arms. NI was not demonstrated for flare incidence (difference 42.6%, 95% CI 30.0-55.1) or rate of structural damage progression at two years (difference 13.9%, 95% CI -6.7 to 34.4). CONCLUSION: The Towards the Lowest Efficacious Dose trial failed to demonstrate NI for the proposed ABA or TCZ tapering strategy.

Prone Positioning During Extracorporeal Membrane Oxygenation in Patients With Severe ARDS: The PRONECMO Randomized Clinical Trial.

Importance: Prone positioning may improve outcomes in patients with severe acute respiratory distress syndrome (ARDS), but it is unknown whether prone positioning improves clinical outcomes among patients with ARDS who are undergoing venovenous extracorporeal membrane oxygenation (VV-ECMO) compared with supine positioning. Objective: To test whether prone positioning vs supine positioning decreases the time to successful ECMO weaning in patients with severe ARDS supported by VV-ECMO. Design, Setting, and Participants: Randomized clinical trial of patients with severe ARDS undergoing VV-ECMO for less than 48 hours at 14 intensive care units (ICUs) in France between March 3, 2021, and December 7, 2021. Interventions: Patients were randomized 1:1 to prone positioning (at least 4 sessions of 16 hours) (n = 86) or to supine positioning (n = 84). Main Outcomes and Measures: The primary outcome was time to successful ECMO weaning within 60 days following randomization. Secondary outcomes included ECMO and mechanical ventilation-free days, ICU and hospital length of stay, skin pressure injury, serious adverse events, and all-cause mortality at 90-day follow-up. Results: Among 170 randomized patients (median age, 51 [IQR, 43-59] years; n = 60 women [35%]), median respiratory system compliance was 15.0 (IQR, 10.7-20.6) mL/cm H2O; 159 patients (94%) had COVID-19-related ARDS; and 164 (96%) were in prone position before ECMO initiation. Within 60 days of enrollment, 38 of 86 patients (44%) had successful ECMO weaning in the prone ECMO group compared with 37 of 84 (44%) in the supine ECMO group (risk difference, 0.1% [95% CI, -14.9% to 15.2%]; subdistribution hazard ratio, 1.11 [95% CI, 0.71-1.75]; P = .64). Within 90 days, no significant difference was observed in ECMO duration (28 vs 32 days; difference, -4.9 [95% CI, -11.2 to 1.5] days; P = .13), ICU length of stay, or 90-day mortality (51% vs 48%; risk difference, 2.4% [95% CI, -13.9% to 18.6%]; P = .62). No serious adverse events were reported during the prone position procedure. Conclusions and Relevance: Among patients with severe ARDS supported by VV-ECMO, prone positioning compared with supine positioning did not significantly reduce time to successful weaning of ECMO. Trial Registration: ClinicalTrials.gov Identifier: NCT04607551.

A methodological review of population-adjusted indirect comparisons reveals inconsistent reporting and suggests publication bias.

OBJECTIVES: Population-adjusted indirect comparisons (PAICs) were developed in the 2010s to allow for comparisons between two treatments evaluated in different trials while accounting for differences in patient characteristics if individual patient data (IPD) are available for only one trial. Such comparisons are increasingly used in market access applications when a pharmaceutical company compares its new treatment (with IPD available) to another treatment developed by a competitor (with only aggregated data available). This study aimed to describe the characteristics of these PAICs, assess their methodology, and describe the reported results. STUDY DESIGN AND SETTING: Original articles reporting the use of at least one PAIC were searched on PubMed between January 1, 2010 and April 2, 2022. Two reviewers independently selected articles and extracted data. RESULTS: We included 133 publications reporting the results of 288 PAICs. Half of the articles were published on or after May 7, 2020, and 71 (53%) pertained to onco-hematology. The pharmaceutical industry was involved in 130 (98%) articles. Key methodological aspects were reported inconsistently, with only three articles adequately reporting all aspects. A total of 161 (56%) articles reported a statistically significant benefit for the treatment evaluated on IPD. Conversely, only one PAIC significantly favored the treatment evaluated on aggregated data. CONCLUSION: Although the number of published PAICs is increasing, the methodology and transparency need to be improved. Moreover, our study strongly suggests a reporting bias. This situation calls for strengthening guidelines to improve trust in PAIC results and thus their reliability in market access applications.

FX06 to rescue SARS-CoV-2-induced acute respiratory distress syndrome: a randomized clinical trial.

BACKGROUND: Vascular leakage is a major feature of acute respiratory distress syndrome (ARDS). We aimed to evaluate the efficacy of FX06, a drug under development that stabilizes interendothelial cell junctions, at reducing vascular leakage during SARS-CoV-2-induced ARDS. METHODS: This multicenter, double-blinded, randomized trial included adults with COVID-19-associated ARDS who had received invasive mechanical ventilation for < 5 days and were randomized to receive either intravenous FX06 (400 mg/d, for 5 days) or its vehicle as placebo. The primary endpoint was the lowering-from day 1 to day 7-of the transpulmonary thermodilution-derived extravascular lung-water index (EVLWi). RESULTS: Twenty-five patients were randomized to receive FX06 and 24 the placebo. Although EVLWi was elevated at baseline (median [IQR] 15.6 mL/kg [13.5; 18.5]), its declines from day 1 to day 7 were comparable for FX06 recipients and controls (respectively, - 1.9 [- 3.3; - 0.5] vs. - 0.8 [- 5.5; - 1.1] mL/kg; estimated effect - 0.8 [- 3.1; + 2.4], p = 0.51). Cardiac indexes, pulmonary vascular permeability indexes, and fluid balances were also comparable, as were PaO2/FiO2 ratios and durations of mechanical ventilation. Adverse event rates were similar for the 2 groups, although more FX06 recipients developed ventilator-associated pneumonia (16/25 (64%) vs. 6/24 (24%), p = 0.009). CONCLUSIONS: In this unique-dosing-regimen study, FX06 did not lower SARS-CoV-2-induced pulmonary vascular leakage. Future investigations will need to evaluate its efficacy at earlier times during the disease or using other regimens. Trial registration NCT04618042. Registered 5 November 2020.

Ability to predict rheumatoid arthritis relapse after tumour necrosis factor inhibitor tapering by the Multi-Biomarker Disease Activity Score: a post-hoc analysis of the STRASS trial.

OBJECTIVES: The aim was to evaluate the ability of baseline multi-biomarker disease activity (MBDA) score to discriminate between patients with rheumatoid arthritis (RA) in remission who are at high risk versus low risk of relapse after TNF-inhibitor (TNFi) tapering. METHODS: The study is a post-hoc analysis of patients who completed the Spacing of TNFi injections in Rheumatoid ArthritiS Study (STRASS), a multicentre 18-month equivalence randomised controlled study, of TNFi tapering in RA patients in remission, and had baseline serum samples available for MBDA testing. The primary endpoint of this study was the ability of the baseline MBDA score to predict relapse at any time during the 18 months following initiation of TNFi tapering. Secondary endpoints were the ability of baseline MBDA score to predict TNFi discontinuation at Month 18, and structural damage progression on x-rays assessed by the change in total van der Heijde-modified Sharp score from baseline to month 18. RESULTS: 64 and 73 patients were included in the spacing (S)-arm and maintenance (M)-arm, respectively. In the M-arm, the mean MBDA score at baseline was higher among patients who relapsed during the 18-month follow-up than those who did not relapse: 32.5 compared to 27.2 (p=0.053) whereas no difference in the MBDA score was observed in the S-arm between patients who relapsed or not 27 compared to 26.2 (p=0.57) 13 patients (21.3%) of the S-arm were able to discontinue TNFi, for which the predictive value of the MBDA score was low (AUC=0.560). Radiographic progression in both arms, although low (n=9) was not correlated with the MBDA score at baseline with a poor discriminative value in both arms (AUC=0.558). CONCLUSIONS: In our study MBDA score in baseline was not predictive of relapse, discontinuation of TNFi in patients with long-standing RA patients tapering TNFi.

Association Between Anti-CD20 Therapies and COVID-19 Severity Among Patients With Relapsing-Remitting and Progressive Multiple Sclerosis.

Importance: In patients with multiple sclerosis (MS), factors associated with severe COVID-19 include anti-CD20 therapies and neurologic disability, but it is still unclear whether these 2 variables are independently associated with severe COVID-19 or whether the association depends on MS clinical course. Objective: To assess the association between anti-CD20 therapies and COVID-19 severity in patients with relapsing-remitting MS (RRMS) and progressive MS (PMS). Design, Setting, and Participants: This multicenter, retrospective cohort study used data from the COVISEP study, which included patients with MS and COVID-19 from February 1, 2020, to June 30, 2022, at 46 French MS expert centers, general hospitals, and private neurology practices. Eligible patients with RRMS were those treated with high-efficacy MS therapy (ie, anti-CD20, fingolimod, or natalizumab), and eligible patients with PMS were those younger than 70 years with an Expanded Disability Status Scale (EDSS) score of 8 or lower. Patients were monitored from COVID-19 symptom onset until recovery or death. Exposures: Current anti-CD20 therapy (ocrelizumab or rituximab). Main Outcomes and Measures: The main outcome was severe COVID-19 (ie, hospitalization with any mode of oxygenation or death). All analyses were conducted separately in patients with RRMS and PMS using propensity score-weighted logistic regression. Subgroup analyses were performed according to COVID-19 vaccine status, sex, EDSS score, and age. Results: A total of 1400 patients, 971 with RRMS (median age, 39.14 years [IQR, 31.38-46.80 years]; 737 [76.1%] female) and 429 with PMS (median age, 54.21 years [IQR, 48.42-60.14 years]; 250 [58.3%] female) were included in the study. A total of 418 patients with RRMS (43.0%) and 226 with PMS (52.7%) were treated with anti-CD20 therapies. In weighted analysis, 13.4% and 2.9% of patients with RRMS treated and not treated with anti-CD20 had severe COVID-19, respectively, and anti-CD20 treatment was associated with increased risk of severe COVID-19 (odds ratio [OR], 5.20; 95% CI, 2.78-9.71); this association persisted among vaccinated patients (7.0% vs 0.9%; OR, 8.85; 95% CI, 1.26-62.12). Among patients with PMS, 19.0% and 15.5% of patients treated and not treated with anti-CD20 had severe COVID-19, respectively, and there was no association between anti-CD20 treatment and severe COVID-19 (OR, 1.28; 95% CI, 0.76-2.16). In PMS subgroup analysis, anti-CD20 exposure interacted negatively with EDSS score (P = .009 for interaction) and age (P = .03 for interaction); anti-CD20 therapies were associated with risk of severe COVID-19 only in patients with less neurologic disability and younger patients with PMS. Conclusions and Relevance: In this cohort study, risk of severe COVID-19 was higher in patients with PMS than in those with RRMS. Use of anti-CD20 therapies was associated with an increased risk of severe COVID-19 among patients with RRMS. In patients with PMS, there was no association between anti-CD20 therapies and risk of severe COVID-19.

COVID-19 trials were not more likely to report intent to share individual data than non-COVID-19 trials in ClinicalTrials.gov.

OBJECTIVES: To compare intent to share individual participant data (IPD) between COVID-19 and non-COVID-19 trials registered at ClinicalTrials.gov between 01/09/2020, and 01/03/2021. We also evaluated factors independently associated with intent to share IPD and whether intent to share IPD has improved as compared with the prepandemic period. METHODS: We searched ClinicalTrials.gov for all interventional phase 3 studies registered between 01/09/2020, and 01/03/2021. Then, we identified COVID-19 trials and selected a random sample of non-COVID-19 trials with a ratio 2:1. We compared the intent to share IPD between these trials and with 292 trials registered between 01/12/2019, and 01/03/2020 (prepandemic period). RESULTS: We included 148 COVID-19 trials and 296 non-COVID-19 trials. Intent to share IPD did not significantly differ between COVID-19 and non-COVID-19 trials (22.3% vs. 27.0%, P = 0.3). Intent to share IPD was independently associated with industry-sponsorship (odds ratio [OR] = 2.92; 95% confidence interval [CI]: 1.65-5.27) and location in the United States (OR = 2.93; 95% CI: 1.64-5.41) or the European Union (OR = 2.06; 95% CI: 1.03-4.19). The intent to share IPD has not significantly improved compared with the prepandemic period (P = 0.16). CONCLUSION: Data-sharing intent at registration does not seem better for COVID-19 trials.

Levosimendan in patients undergoing extracorporeal membrane oxygenation after cardiac surgery: an emulated target trial using observational data.

BACKGROUND: Retrospective cohorts have suggested that levosimendan may facilitate the weaning of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). We therefore studied this clinical question by emulating a randomized trial with observational data. METHODS: All patients with refractory postcardiotomy cardiogenic shock and assisted with VA-ECMO, admitted to a surgical intensive care unit at La Pitié-Salpêtrière Hospital between 2016 and 2019, were eligible. To avoid immortal-time bias, we emulated a target trial sequentially comparing levosimendan administration versus no levosimendan administration in patients treated with VA-ECMO. The primary outcome was time to successful ECMO weaning. The secondary outcomes were 30-day and 1-year mortality. We performed a multivariable analysis to adjust for confounding at baseline. RESULTS: Two hundred and thirty-nine patients were included in the study allowing building a nested trials cohort of 1434 copies of patients. No association of levosimendan treatment and VA-ECMO weaning was found (HR = 0.91, [0.57; 1.45], p = 0.659 in multivariable analysis), or 30-day mortality (OR = 1.03, [0.52; 2.03], p = 0.940) and 1-year mortality (OR = 1.00, [0.53; 1.89], p = 0.999). CONCLUSIONS: Using the emulated target trial framework, this study did not find any association of levosimendan treatment and ECMO weaning success after postcardiotomy cardiogenic shock. However, the population of interest remains heterogeneous and subgroups might benefit from levosimendan.

Impact of renal replacement therapy strategy on beta-lactam plasma concentrations: the BETAKIKI study-an ancillary study of a randomized controlled trial.

BACKGROUND: Sepsis prognosis correlates with antibiotic adequacy at the early phase. This adequacy is dependent on antibacterial spectrum, bacterial resistance profile and antibiotic dosage. Optimal efficacy of beta-lactams mandates concentrations above the minimal inhibitory concentration (MIC) of the targeted bacteria for the longest time possible over the day. Septic acute kidney injury (AKI) is the most common AKI syndrome in ICU and often mandates renal replacement therapy (RRT) initiation. Both severe AKI and RRT may increase outside target antibiotic concentrations and ultimately alter patient's prognosis. PATIENTS AND METHODS: This is a secondary analysis of a randomized controlled trial that compared an early RRT initiation strategy with a delayed one in 620 critically ill patients undergoing severe AKI (defined by KDIGO 3). We compared beta-lactam trough concentrations between the two RRT initiation strategies. The primary outcome was the proportion of patients with sufficient trough plasma concentration of beta-lactams defined by trough concentration above 4 times the MIC. We hypothesized that early initiation of RRT could be associated with an insufficient antibiotic plasma trough concentration compared to patients allocated to the delayed strategy. RESULTS: One hundred and twelve patients were included: 53 in the early group and 59 in the delayed group. Eighty-three patients (74%) had septic shock on inclusion. Trough beta-lactam plasma concentration was above 4 times the MIC breakpoint in 80.4% (n = 90) of patients of the whole population, without differences between the early and the delayed groups (79.2% vs. 81.4%, respectively, p = 0.78). On multivariate analysis, the presence of septic shock and a higher mean arterial pressure were significantly associated with a greater probability of adequate antibiotic trough concentration [OR 3.95 (1.14;13.64), p = 0.029 and OR 1.05 (1.01;1.10), p = 0.013, respectively). Evolution of procalcitonin level and catecholamine-free days as well as mortality did not differ whether beta-lactam trough concentration was above 4 times the MIC or not. CONCLUSIONS: In this secondary analysis of a randomized controlled trial, renal replacement therapy initiation strategy did not significantly influence plasma trough concentrations of beta-lactams in ICU patients with severe AKI. Presence of septic shock on inclusion was the main variable associated with a sufficient beta-lactam concentration. TRIAL REGISTRATION: The AKIKI trial was registered on ClinicalTrials.gov (Identifier: NCT01932190) before the inclusion of the first patient.

Comparative outcomes of extracorporeal membrane oxygenation for COVID-19 delivered in experienced European centres during successive SARS-CoV-2 variant outbreaks (ECMO-SURGES): an international, multicentre, retrospective cohort study.

BACKGROUND: To inform future research and practice, we aimed to investigate the outcomes of patients who received extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) due to different variants of SARS-CoV-2. METHODS: This retrospective study included consecutive adult patients with laboratory-confirmed SARS-CoV-2 infection who received ECMO for ARDS in 21 experienced ECMO centres in eight European countries (Austria, Belgium, England, France, Germany, Italy, Portugal, and Spain) between Jan 1, 2020, and Sept 30, 2021. We collected data on patient characteristics, clinical status, and management before and after the initiation of ECMO. Participants were grouped according to SARS-CoV-2 variant (wild type, alpha, delta, or other) and period of the pandemic (first [Jan 1-June 30] and second [July 1-Dec 31] semesters of 2020, and first [Jan 1-June 30] and second [July 1-Sept 30] semesters of 2021). Descriptive statistics and Kaplan-Meier survival curves were used to analyse evolving characteristics, management, and patient outcomes over the first 2 years of the pandemic, and independent risk factors of mortality were determined using multivariable Cox regression models. The primary outcome was mortality 90 days after the initiation of ECMO, with follow-up to Dec 30, 2021. FINDINGS: ECMO was initiated in 1345 patients. Patient characteristics and management were similar for the groups of patients infected with different variants, except that those with the delta variant had a younger median age and less hypertension and diabetes. 90-day mortality was 42% (569 of 1345 patients died) overall, and 43% (297/686) in patients infected with wild-type SARS-CoV-2, 39% (152/391) in those with the alpha variant, 40% (78/195) in those with the delta variant, and 58% (42/73) in patients infected with other variants (mainly beta and gamma). Mortality was 10% higher (50%) in the second semester of 2020, when the wild-type variant was still prevailing, than in other semesters (40%). Independent predictors of mortality were age, immunocompromised status, a longer time from intensive care unit admission to intubation, need for renal replacement therapy, and higher Sequential Organ Failure Assessment haemodynamic component score, partial pressure of arterial carbon dioxide, and lactate concentration before ECMO. After adjusting for these variables, mortality was significantly higher with the delta variant than with the other variants, the wild-type strain being the reference. INTERPRETATION: Although crude mortality did not differ between variants, adjusted risk of death was highest for patients treated with ECMO infected with the delta variant of SARS-CoV-2. The higher virulence and poorer outcomes associated with the delta strain might relate to higher viral load and increased inflammatory response syndrome in infected patients, reinforcing the need for a higher rate of vaccination in the population and updated selection criteria for ECMO, should a new and highly virulent strain of SARS-CoV-2 emerge in the future. Mortality was noticeably lower than in other large, multicentre series of patients who received ECMO for COVID-19, highlighting the need to concentrate resources at experienced centres. FUNDING: None.

Surgery for glioblastomas in the elderly: an Association des Neuro-oncologues d'Expression Française (ANOCEF) trial.

OBJECTIVE: The role of surgery in the treatment of malignant gliomas in the elderly is not settled. The authors conducted a randomized trial that compared tumor resection with biopsy only-both followed by standard therapy-in such patients. METHODS: Patients ≥ 70 years of age with a Karnofsky Performance Scale (KPS) score ≥ 50 and presenting with a radiological suspicion of operable glioblastoma (GBM) were randomly assigned between tumor resection and biopsy groups. Subsequently, they underwent standard radiotherapy during the first years of the trial (2008-2017), with the addition of adjunct therapy with temozolomide when this regimen became standard (2017-2019). The primary endpoint was survival, and secondary endpoints were progression-free survival (PFS), cognitive status (Mini-Mental State Examination), autonomy (KPS), quality of life (European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 and QLQ-BN20), and perioperative morbidity and mortality. RESULTS: Between 2008 and 2019, 107 patients from 9 centers were enrolled in the study; 101 were evaluable for analysis because a GBM was histologically confirmed (50 in the surgery arm and 51 in the biopsy arm). There was no statistically significant difference in median survival between the surgery (9.37 months) and the biopsy (8.96 months, p = 0.36) arms (adjusted HR 0.79, 95% CI 0.52-1.21, p = 0.28). However, the surgery group had an increased PFS (5.06 vs 4.02 months; p = 0.034) (adjusted HR 0.50, 95% CI 0.32-0.78, p = 0.002). Less deterioration of quality of life and KPS score evolution than in the biopsy group was observed. Surgery was not associated with increased mortality or morbidity. CONCLUSIONS: This study suggests that debulking surgery is safe, and-compared to biopsy-is associated with a less severe deterioration of quality of life and autonomy, as well as a significant although modest improvement of PFS in elderly patients suffering from newly diagnosed malignant glioma. Although resection does not provide a significant survival benefit in the elderly, the authors believe that the risk/benefit analysis favors an attempt at optimal tumor resection in this population, provided there is careful preoperative geriatric evaluation. Clinical trial registration no.: NCT02892708 (ClinicalTrials.gov).