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The article describes an initial experience of applying off-centre vv extracorporaeal membrane oxygenation (ECMO) by a mobile team employing a new bedside approach that uses echocardiography-guided, single-site cannulation with a bicaval, dual-lumen catheter. Topics discussed include the advantage of shortened procedural time inherent to an introduction procedure and reduction in the risks of catheter dislodgement during transport, bleeding and catheter-related infection.

Importance: A review of the study processes and protocols afterward by the researchers themselves is scarce., Objectives: The present study aimed to evaluate the study design and the process of data collection of the Maastricht Intensive Care COVID (MaastrICCht) cohort during the COVID-19 pandemic. This evaluation provides information about the quality of the predefined questions and contributes to transparency in science., Design, Setting, and Participants: Critical appraisal of studies using data from the MaastrICCht cohort., Main Outcomes and Measures: Evaluation of the process of study design and data collection during the COVID-19 pandemic, focusing on the research process and results., Results: From March 2020 to April 2023, all patients diagnosed with COVID-19 admitted to the ICU at Maastricht University Medical Center + (n = 544) were included in the MaastrICCht cohort. In total, 37 studies were carried out until April 2024. Fifteen studies addressed 11 of the 13 predetermined research questions, whereas 22 additional studies were performed based on the initial research questions described in the design. Furthermore, 10 studies were conducted with other researchers in national and international collaboration as a response to new arising questions based on evidence that appeared relevant during the pandemic., Conclusions and Relevance: Our critical appraisal indicated that using a study protocol enabled many publications and (inter)national collaborations, although formulating pertinent research questions in the context of a novel disease appeared daunting. Despite this, most questions were successfully addressed, whereas few were resolved by other researchers or lost importance due to the expanding body of knowledge., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2025 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

There is no universally accepted method for positive end expiratory pressure (PEEP) titration approach for patients on spontaneous mechanical ventilation (SMV). Electrical impedance tomography (EIT) guided PEEP-titration has shown promising results in controlled mechanical ventilation (CMV), current implemented algorithm for PEEP titration (based on regional compliance measurements) is not applicable in SMV. Regional peak flow (RPF, defined as the highest inspiratory flow rate based on EIT at a certain PEEP level) is a new method for quantifying regional lung mechanics designed for SMV. The objective is to study whether RPF by EIT is a feasible method for PEEP titration during SMV. Single EIT measurements were performed in COVID-19 ARDS patients on SMV. Clinical (i.e., tidal volume, airway occlusion pressure, end-tidal CO 2 ) and mechanical (cyclic alveolar recruitment, recruitment, cumulative overdistension (OD), cumulative collapse (CL), pendelluft, and PEEP) outcomes were determined by EIT at several pre-defined PEEP thresholds (1-10% CL and the intersection of the OD and CL curves) and outcomes at all thresholds were compared to the outcomes at baseline PEEP. In total, 25 patients were included. No significant and clinically relevant differences were found between thresholds for tidal volume, end-tidal CO 2 , and P0.1 compared to baseline PEEP; cyclic alveolar recruitment rates changed by -3.9% to -37.9% across thresholds; recruitment rates ranged from - 49.4% to + 79.2%; cumulative overdistension changed from - 75.9% to + 373.4% across thresholds; cumulative collapse changed from 0% to -94.3%; PEEP levels from 10 up to 14 cmH 2 O were observed across thresholds compared to baseline PEEP of 10 cmH 2 O. A threshold of approximately 5% cumulative collapse yields the optimum compromise between all clinical and mechanical outcomes. EIT-guided PEEP titration by the RPF approach is feasible and is linked to improved overall lung mechanics) during SMV using a threshold of approximately 5% CL. However, the long-term clinical safety and effect of this approach remain to be determined., Competing Interests: Declarations. Ethics approval and consent to participate: The study is approved by the ethical committee of the Maastricht University Medical Center + and University of Maastricht (METC: 2020 − 1565), registered in NTR with number NL8613, and conducted in accordance with the Declaration of Helsinki (as revised in 2013). During the pandemic, the board of directors of the Maastricht UMC + adopted a policy to inform patients or their legal representative and ask for their consent to use their data for COVID-19 research purposes. Consent for publication: Not applicable. Competing interests: SH, SdJ, DB have a patent on the algorithm (International Publication Number: WO 2024/003413 A1) used in the present manuscript to quantify regional and cumulative overdistension and collapse. The remaining authors do not have any other competing interests related to this study., (© 2024. The Author(s).)

Background: Lung ultrasound (LUS) in an emerging technique used in the intensive care unit (ICU). The derivative LUS aeration score has been shown to have associations with mortality in invasively ventilated patients. This study assessed the predictive value of baseline and early changes in LUS aeration scores in critically ill invasively ventilated patients with and without ARDS (Acute Respiratory Distress Syndrome) on 30- and 90-day mortality., Methods: This is a post hoc analysis of a multicenter prospective observational cohort study, which included patients admitted to the ICU with an expected duration of ventilation for at least 24 h. We restricted participation to patients who underwent a 12-region LUS exam at baseline and had the primary endpoint (30-day mortality) available. Logistic regression was used to analyze the primary and secondary endpoints. The analysis was performed for the complete patient cohort and for predefined subgroups (ARDS and no ARDS)., Results: A total of 442 patients were included, of whom 245 had a second LUS exam. The baseline LUS aeration score was not associated with mortality (1.02 (95% CI: 0.99 - 1.06), p = 0.143). This finding was not different in patients with and in patients without ARDS. Early deterioration of the LUS score was associated with mortality (2.09 (95% CI: 1.01 - 4.3), p = 0.046) in patients without ARDS, but not in patients with ARDS or in the complete patient cohort., Conclusion: In this cohort of critically ill invasively ventilated patients, the baseline LUS aeration score was not associated with 30- and 90-day mortality. An early change in the LUS aeration score was associated with mortality, but only in patients without ARDS., Trial Registration: ClinicalTrials.gov, ID NCT04482621., (© 2024. The Author(s).)

Purpose: To describe the effect of dexamethasone and tocilizumab on regional lung mechanics over admission in all mechanically ventilated COVID-19 patients., Materials and Methods: Dynamic compliance, alveolar overdistension and collapse were serially determined using electric impedance tomography (EIT). Patients were categorized into three groups; no anti-inflammatory therapy, dexamethasone therapy, dexamethasone + tocilizumab therapy. The EIT variables were (I) visualized using polynomial regression, (II) evaluated throughout admission using linear mixed-effects models, and (III) average respiratory variables were compared., Results: Visual inspection of EIT variables showed a pattern of decreasing dynamic compliance. Overall, optimal set PEEP was lower in the dexamethasone group (-1.4 cmH 2 O, -2.6; -0.2). Clinically applied PEEP was lower in the dexamethasone and dexamethasone + tocilizumab group (-1.5 cmH 2 O, -2.6; -0.2; -2.2 cmH 2 O, -5.1; 0.6). Dynamic compliance, alveolar overdistension, and alveolar collapse at optimal set PEEP did not significantly differ between the three groups., Conclusion: Optimal and clinically applied PEEP were lower in the dexamethasone and dexamethasone + tocilizumab groups. The results suggest that the potential beneficial effects of these therapies do not affect lung mechanics favorably. However, this study cannot fully rule out any beneficial effect of anti-inflammatory treatment on pulmonary function due to its observational nature., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Background: Acute respiratory distress syndrome (ARDS) poses challenges in early identification. Exhaled breath contains metabolites reflective of pulmonary inflammation., Aim: To evaluate the diagnostic accuracy of breath metabolites for ARDS in invasively ventilated intensive care unit (ICU) patients., Methods: This two-center observational study included critically ill patients receiving invasive ventilation. Gas chromatography and mass spectrometry (GC-MS) was used to quantify the exhaled metabolites. The Berlin definition of ARDS was assessed by three experts to categorize all patients into "certain ARDS", "certain no ARDS" and "uncertain ARDS" groups. The patients with "certain" labels from one hospital formed the derivation cohort used to train a classifier built based on the five most significant breath metabolites. The diagnostic accuracy of the classifier was assessed in all patients from the second hospital and combined with the lung injury prediction score (LIPS)., Results: A total of 499 patients were included in this study. Three hundred fifty-seven patients were included in the derivation cohort (60 with certain ARDS; 17%), and 142 patients in the validation cohort (47 with certain ARDS; 33%). The metabolites 1-methylpyrrole, 1,3,5-trifluorobenzene, methoxyacetic acid, 2-methylfuran and 2-methyl-1-propanol were included in the classifier. The classifier had an area under the receiver operating characteristics curve (AUROCC) of 0.71 (CI 0.63-0.78) in the derivation cohort and 0.63 (CI 0.52-0.74) in the validation cohort. Combining the breath test with the LIPS does not significantly enhance the diagnostic performance., Conclusion: An exhaled breath metabolomics-based classifier has moderate diagnostic accuracy for ARDS but was not sufficiently accurate for clinical use, even after combination with a clinical prediction score., (© 2024. The Author(s).)

Aims: The aim of this study is to evaluate whether agreement with autopsy-determined cause of death (COD) increases by use of postmortem CT (PMCT) or PMCT in combination with postmortem sampling (PMS), when compared with clinical assessment only., Methods: This prospective observational study included deceased patients from the intensive care unit and internal medicine wards between October 2013 and August 2017. The primary outcome was percentage agreement on COD between the reference standard (autopsy) and the alternative postmortem examinations (clinical assessment vs PMCT or PMCT+PMS). In addition, the COD of patient groups with and without conventional autopsy were compared with respect to involved organ systems and pathologies., Results: Of 730 eligible cases, 144 could be included for analysis: 63 underwent PCMT without autopsy and 81 underwent both PMCT and autopsy. Agreement with autopsy-determined COD was significantly higher for both PMCT with PMS (42/57, 74%), and PMCT alone (53/81, 65%) than for clinical assessment (40/81, 51%; p=0.007 and p=0.03, respectively). The difference in agreement between PMCT with PMS and PMCT alone was not significant (p=0.13). The group with autopsy had a significantly higher prevalence of circulatory system involvement and perfusion disorders, and a lower prevalence of pulmonary system involvement., Conclusion: PMCT and PMS confer additional diagnostic value in establishing the COD. Shortcomings in detecting vascular occlusions and perfusion disorders and susceptibility to pulmonary postmortem changes could in future be improved by additional techniques. Both PMCT and PMS are feasible in clinical practice and an alternative when autopsy cannot be performed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

We validated a Deep Embedded Clustering (DEC) model and its adaptation for integrating mixed datatypes (in this study, numerical and categorical variables). Deep Embedded Clustering (DEC) is a promising technique capable of managing extensive sets of variables and non-linear relationships. Nevertheless, DEC cannot adequately handle mixed datatypes. Therefore, we adapted DEC by replacing the autoencoder with an X-shaped variational autoencoder (XVAE) and optimising hyperparameters for cluster stability. We call this model "X-DEC". We compared DEC and X-DEC by reproducing a previous study that used DEC to identify clusters in a population of intensive care patients. We assessed internal validity based on cluster stability on the development dataset. Since generalisability of clustering models has insufficiently been validated on external populations, we assessed external validity by investigating cluster generalisability onto an external validation dataset. We concluded that both DEC and X-DEC resulted in clinically recognisable and generalisable clusters, but X-DEC produced much more stable clusters., (© 2024. The Author(s).)

Electrical Impedance Tomography (EIT) is a non-invasive bedside imaging technique that provides real-time lung ventilation information on critically ill patients. EIT can potentially become a valuable tool for optimising mechanical ventilation, especially in patients with acute respiratory distress syndrome (ARDS). In addition, EIT has been shown to improve the understanding of ventilation distribution and lung aeration, which can help tailor ventilatory strategies according to patient needs. Evidence from critically ill patients shows that EIT can reduce the duration of mechanical ventilation and prevent lung injury due to overdistension or collapse. EIT can also identify the presence of lung collapse or recruitment during a recruitment manoeuvre, which may guide further therapy. Despite its potential benefits, EIT has not yet been widely used in clinical practice. This may, in part, be due to the challenges associated with its implementation, including the need for specialised equipment and trained personnel and further validation of its usefulness in clinical settings. Nevertheless, ongoing research focuses on improving mechanical ventilation and clinical outcomes in critically ill patients.

Background: The concentration of exhaled octane has been postulated as a reliable biomarker for acute respiratory distress syndrome (ARDS) using metabolomics analysis with gas chromatography and mass spectrometry (GC-MS). A point-of-care (POC) breath test was developed in recent years to accurately measure octane at the bedside. The aim of the present study was to validate the diagnostic accuracy of exhaled octane for ARDS using a POC breath test in invasively ventilated intensive care unit (ICU) patients., Methods: This was an observational cohort study of consecutive patients receiving invasive ventilation for at least 24 h, recruited in two university ICUs. GC-MS and POC breath tests were used to quantify the exhaled octane concentration. ARDS was assessed by three experts following the Berlin definition and used as the reference standard. The area under the receiver operating characteristic curve (AUC) was used to assess diagnostic accuracy., Results: 519 patients were included and 190 (37%) fulfilled the criteria for ARDS. The median (interquartile range) concentration of octane using the POC breath test was not significantly different between patients with ARDS (0.14 (0.05-0.37) ppb) and without ARDS (0.11 (0.06-0.26) ppb; p=0.64). The AUC for ARDS based on the octane concentration in exhaled breath using the POC breath test was 0.52 (95% CI 0.46-0.57). Analysis of exhaled octane with GC-MS showed similar results., Conclusions: Octane in exhaled breath has insufficient diagnostic accuracy for ARDS. This disqualifies the use of octane as a biomarker in the diagnosis of ARDS and challenges most of the research performed up to now in the field of exhaled breath metabolomics., Competing Interests: Conflict of interest: L.D.J. Bos reports grants from the Dutch Lung Foundation (Young Investigator grant and Dirkje Postma Award), the Dutch Lung Foundation and Health Holland (public–private partnership grant), and the IMI COVID19 initiative, and an Amsterdam UMC fellowship, a ZonMW COVID-19 Urgency grant and the ERS Gold Metal for ARDS; he reports participating in advisory boards for Sobi, Exvastat, Santhera, Pfizer and AstraZeneca, all paid to his institution, and consultancy for Scailyte, Santhera and Janssen & Janssen, all paid to his institution, outside the submitted work. A.R.M. Verschueren, T.M.E. Nijsen, I. Geven, C.N. Presură and R. Rietman are employees of Philips Research. L.A. Hagens, N.F.L. Heijnen, M.R. Smit, D.W. Fenn, P. Brinkman, M.J. Schultz, D.C.J.J. Bergmans and R.M. Schnabel have no conflicts of interest to declare., (Copyright ©The authors 2023.)

Rationale: Lung ultrasound (LUS) is a promising tool for diagnosis of acute respiratory distress syndrome (ARDS), but adequately sized studies with external validation are lacking. Objectives: To develop and validate a data-driven LUS score for diagnosis of ARDS and compare its performance with that of chest radiography (CXR). Methods: This multicenter prospective observational study included invasively ventilated ICU patients who were divided into a derivation cohort and a validation cohort. Three raters scored ARDS according to the Berlin criteria, resulting in a classification of "certain no ARDS," or "certain ARDS" when experts agreed or "uncertain ARDS" when evaluations conflicted. Uncertain cases were classified in a consensus meeting. Results of a 12-region LUS exam were used in a logistic regression model to develop the LUS-ARDS score. Measurements and Main Results: Three hundred twenty-four (16% certain ARDS) and 129 (34% certain ARDS) patients were included in the derivation cohort and the validation cohort, respectively. With an ARDS diagnosis by the expert panel as the reference test, the LUS-ARDS score, including the left and right LUS aeration scores and anterolateral pleural line abnormalities, had an area under the receiver operating characteristic (ROC) curve of 0.90 (95% confidence interval [CI], 0.85-0.95) in certain patients of the derivation cohort and 0.80 (95% CI, 0.72-0.87) in all patients of the validation cohort. Within patients who had imaging-gold standard chest computed tomography available, diagnostic accuracy of eight independent CXR readers followed the ROC curve of the LUS-ARDS score. Conclusions: The LUS-ARDS score can be used to accurately diagnose ARDS also after external validation. The LUS-ARDS score may be a useful adjunct to a diagnosis of ARDS after further validation, as it showed performance comparable with that of the current practice with experienced CXR readers but more objectifiable diagnostic accuracy at each cutoff.

Background: Spontaneous breathing efforts during mechanical ventilation are a widely accepted weaning approach for acute respiratory distress syndrome (ARDS) patients. These efforts can be too vigorous, possibly inflicting lung and diaphragm damage. Higher positive end expiratory pressure (PEEP) levels can be used to lower the magnitude of vigorous breathing efforts. Nevertheless, PEEP titrating tools are lacking in spontaneous mechanical ventilation (SMV). Therefore, the aim is to develop an electrical impedance tomography (EIT) algorithm for quantifying regional lung mechanics independent from a stable plateau pressure phase based on regional peak flow (RPF) by EIT, which is hypothetically applicable in SMV and to validate this algorithm in patients on controlled mechanical ventilation (CMV)., Methods: The RPF algorithm quantifies a cumulative overdistension (OD RPF ) and collapse (CL RPF ) rate and is validated in a prospective cohort of mechanically ventilated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients on CMV. OD RPF and CL RPF are compared with compliance-based cumulative overdistension (OD P500 ) and collapse (CL P500 ) rates from the Pulmovista 500 EIT device at multiple PEEP levels (PEEP 10 cmH 2 O to PEEP 24 cmH 2 O) in EIT measurements from CMV patients by linear mixed models, Bland-Altman analysis and intraclass correlation coefficient (ICC)., Results: Seventy-eight patients were included. Linear mixed models revealed an association between OD RPF and OD P500 of 1.02 (0.98-1.07, P<0.001) and between CL RPF and CL P500 of 0.93 (0.80-1.05, P<0.001). ICC values ranged from 0.78 to 0.86 (P<0.001) for OD RPF and OD P500 and from 0.70 to 0.85 (P<0.001) for CL RPF and CL P500 (PEEP 10 to PEEP 24). The mean bias between OD RPF and OD P500 in these PEEP levels ranged from 0.80% to 4.19% and from -1.31% to 0.13% between CL RPF and CL P500 ., Conclusions: A RPF approach for quantifying regional lung mechanics showed a moderate to good agreement in coronavirus disease 2019 (COVID-19) related ARDS patients on CMV compared to the compliance-based approach. This, in addition to being independent of a plateau pressure phase, indicates that the RPF approach is a valid method to explore for quantifying regional lung mechanics in SMV., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (Available at https://atm.amegroups.com/article/view/10.21037/atm-22-3420/coif). SAMdJ, SJHH and DCJJB are awaiting decision from the European patent office with regard to the algorithm, as described in the present manuscript. FHCdJ serves as an unpaid Assessment Director of the European Respiratory Society. The other authors have no conflicts of interest to declare., (2023 Annals of Translational Medicine. All rights reserved.)

Background: Changes in exhaled volatile organic compounds (VOCs) can be used to discriminate between respiratory diseases, and increased concentrations of hydrocarbons are commonly linked to oxidative stress. However, the VOCs identified are inconsistent between studies, and translational studies are lacking., Methods: In this bench to bedside study, we captured VOCs in the headspace of A549 epithelial cells after exposure to hydrogen peroxide (H 2 O 2 ), to induce oxidative stress, using high-capacity polydimethylsiloxane sorbent fibres. Exposed and unexposed cells were compared using targeted and untargeted analysis. Breath samples of invasively ventilated intensive care unit patients (n=489) were collected on sorbent tubes and associated with the inspiratory oxygen fraction ( F IO 2 ) to reflect pulmonary oxidative stress. Headspace samples and breath samples were analysed using gas chromatography and mass spectrometry., Results: In the cell, headspace octane concentration was decreased after oxidative stress (p=0.0013), while the other VOCs were not affected. 2-ethyl-1-hexanol showed an increased concentration in the headspace of cells undergoing oxidative stress in untargeted analysis (p=0.00014 ) . None of the VOCs that were linked to oxidative stress showed a significant correlation with F IO 2 (R s range: -0.015 to -0.065) or discriminated between patients with F IO 2 ≥0.6 or below (area under the curve range: 0.48 to 0.55)., Conclusion: Despite a comprehensive translational approach, validation of known and novel volatile biomarkers of oxidative stress was not possible in patients at risk of pulmonary oxidative injury. The inconsistencies observed highlight the difficulties faced in VOC biomarker validation, and that caution is warranted in the interpretation of the pathophysiological origin of discovered exhaled breath biomarkers., Competing Interests: Conflict of interest: D. Fenn has nothing to disclose. Conflict of interest: T.A. Lilien has nothing to disclose. Conflict of interest: L.A. Hagens has nothing to disclose. Conflict of interest: M.R. Smit has nothing to disclose. Conflict of interest: N.F.L. Heijnen has nothing to disclose. Conflict of interest: A.M. Tuip-de Boer has nothing to disclose. Conflict of interest: A.H. Neerincx has nothing to disclose. Conflict of interest: K. Golebski has nothing to disclose. Conflict of interest: D.C.J.J. Bergmans has nothing to disclose. Conflict of interest: R.M. Schnabel has nothing to disclose. Conflict of interest: M.J. Schultz has nothing to disclose. Conflict of interest: A.H. Maitland-van der Zee has received research grants outside the submitted work from GSK, Boehringer Ingelheim and Vertex; she is the principal investigator of a P4O2 (Precision Medicine for more Oxygen) public–private partnership sponsored by Health Holland involving many private partners that contribute in cash and/or in kind (Boehringer Ingelheim, Breathomix, Fluidda, Ortec Logiqcare, Philips, Quantib-U, Roche, Smartfish, SODAQ, Thirona, TopMD and Novartis); and she has served in advisory boards for AstraZeneca, GSK and Boehringer Ingelheim, with money paid to her institution. Conflict of interest: P. Brinkman has nothing to disclose. Conflict of interest: L.D.J. Bos reports grants from the Dutch Lung Foundation (Young investigator grant), grants from the Dutch Lung Foundation and Health Holland (Public–Private Partnership grant), grants from the Dutch Lung Foundation (Dirkje Postma Award), grants from IMI COVID19 initiative, and grants from Amsterdam UMC fellowship, outside the submitted work; he has also served in advisory capacity for Santhera and Janssen with money paid to his institution., (Copyright ©The authors 2023.)

Introduction: The Radiographic Assessment of Lung Edema (RALE) score provides a semi-quantitative measure of pulmonary edema. In patients with acute respiratory distress syndrome (ARDS), the RALE score is associated with mortality. In mechanically ventilated patients in the intensive care unit (ICU) with respiratory failure not due to ARDS, a variable degree of lung edema is observed as well. We aimed to evaluate the prognostic value of RALE in mechanically ventilated ICU patients., Methods: Secondary analysis of patients enrolled in the 'Diagnosis of Acute Respiratory Distress Syndrome' (DARTS) project with an available chest X-ray (CXR) at baseline. Where present, additional CXRs at day 1 were analysed. The primary endpoint was 30-day mortality. Outcomes were also stratified for ARDS subgroups (no ARDS, non-COVID-ARDS and COVID-ARDS)., Results: 422 patients were included, of which 84 had an additional CXR the following day. Baseline RALE scores were not associated with 30-day mortality in the entire cohort (OR: 1.01, 95% CI: 0.98-1.03, p = 0.66), nor in subgroups of ARDS patients. Early changes in RALE score (baseline to day 1) were only associated with mortality in a subgroup of ARDS patients (OR: 1.21, 95% CI: 1.02-1.51, p = 0.04), after correcting for other known prognostic factors., Conclusions: The prognostic value of the RALE score cannot be extended to mechanically ventilated ICU patients in general. Only in ARDS patients, early changes in RALE score were associated with mortality.

Pulmonary edema is a central hallmark of acute respiratory distress syndrome (ARDS). Endothelial dysfunction and epithelial injury contribute to alveolar-capillary permeability but their differential contribution to pulmonary edema development remains understudied. Plasma levels of surfactant protein-D (SP-D), soluble receptor for advanced glycation end products (sRAGE), and angiopoietin-2 (Ang-2) were measured in a prospective, multicenter cohort of invasively ventilated patients. Pulmonary edema was quantified using the radiographic assessment of lung edema (RALE) and global lung ultrasound (LUS) score. Variables were collected within 48 h after intubation. Linear regression was used to examine the association of the biomarkers with pulmonary edema. In 362 patients, higher SP-D, sRAGE, and Ang-2 concentrations were significantly associated with higher RALE and global LUS scores. After stratification by ARDS subgroups (pulmonary, nonpulmonary, COVID, non-COVID), the positive association of SP-D levels with pulmonary edema remained, whereas sRAGE and Ang-2 showed less consistent associations throughout the subgroups. In a multivariable analysis, SP-D levels were most strongly associated with pulmonary edema when combined with sRAGE (RALE score: β SP-D = 6.79 units/log10 pg/mL, β sRAGE = 3.84 units/log10 pg/mL, R 2 = 0.23; global LUS score: β SP-D = 3.28 units/log10 pg/mL, β sRAGE = 2.06 units/log10 pg/mL, R 2 = 0.086), whereas Ang-2 did not further improve the model. Biomarkers of epithelial injury and endothelial dysfunction were associated with pulmonary edema in invasively ventilated patients. SP-D and sRAGE showed the strongest association, suggesting that epithelial injury may form a final common pathway in the alveolar-capillary barrier dysfunction underlying pulmonary edema.

Background: There is growing awareness that sex differences are associated with different patient outcomes in a variety of diseases. Studies investigating the effect of patient sex on sepsis-related mortality remain inconclusive and mainly focus on patients with severe sepsis and septic shock in the intensive care unit. We therefore investigated the association between patient sex and both clinical presentation and 30-day mortality in patients with the whole spectrum of sepsis severity presenting to the emergency department (ED) who were admitted to the hospital., Materials and Methods: In our multi-centre cohort study, we retrospectively investigated adult medical patients with sepsis in the ED. Multivariable analysis was used to evaluate the association between patient sex and all-cause 30-day mortality., Results: Of 2065 patients included, 47.6% were female. Female patients had significantly less comorbidities, lower Sequential Organ Failure Assessment score and abbreviated Mortality Emergency Department Sepsis score, and presented less frequently with thrombocytopenia and fever, compared to males. For both sexes, respiratory tract infections were predominant while female patients more often had urinary tract infections. Females showed lower 30-day mortality (10.1% vs. 13.6%; p  = .016), and in-hospital mortality (8.0% vs. 11.1%; p  = .02) compared to males. However, a multivariable logistic regression model showed that patient sex was not an independent predictor of 30-day mortality (OR 0.90; 95% CI 0.67-1.22; p  = .51)., Conclusions: Females with sepsis presenting to the ED had fewer comorbidities, lower disease severity, less often thrombocytopenia and fever and were more likely to have a urinary tract infection. Females had a lower in-hospital and 30-day mortality compared to males, but sex was not an independent predictor of 30-day mortality. The lower mortality in female patients may be explained by differences in comorbidity and clinical presentation compared to male patients.KEY MESSAGESOnly limited data exist on sex differences in sepsis patients presenting to the emergency department with the whole spectrum of sepsis severity.Female sepsis patients had a lower incidence of comorbidities, less disease severity and a different source of infection, which explains the lower 30-day mortality we found in female patients compared to male patients.We found that sex was not an independent predictor of 30-day mortality; however, the study was probably underpowered to evaluate this outcome definitively.

Objectives: Many prediction models for coronavirus disease 2019 (COVID-19) have been developed. External validation is mandatory before implementation in the intensive care unit (ICU). We selected and validated prognostic models in the Euregio Intensive Care COVID (EICC) cohort., Study Design and Setting: In this multinational cohort study, routine data from COVID-19 patients admitted to ICUs within the Euregio Meuse-Rhine were collected from March to August 2020. COVID-19 models were selected based on model type, predictors, outcomes, and reporting. Furthermore, general ICU scores were assessed. Discrimination was assessed by area under the receiver operating characteristic curves (AUCs) and calibration by calibration-in-the-large and calibration plots. A random-effects meta-analysis was used to pool results., Results: 551 patients were admitted. Mean age was 65.4 ± 11.2 years, 29% were female, and ICU mortality was 36%. Nine out of 238 published models were externally validated. Pooled AUCs were between 0.53 and 0.70 and calibration-in-the-large between -9% and 6%. Calibration plots showed generally poor but, for the 4C Mortality score and Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) score, moderate calibration., Conclusion: Of the nine prognostic models that were externally validated in the EICC cohort, only two showed reasonable discrimination and moderate calibration. For future pandemics, better models based on routine data are needed to support admission decision-making., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Acute respiratory distress syndrome (ARDS) often is not recognized in clinical practice, largely due to variation in the interpretation of chest x-ray (CXR) leading to poor interobserver reliability. We hypothesized that the agreement in the interpretation of chest imaging for the diagnosis of ARDS in invasively ventilated intensive care unit patients between experts improves when using an 8-grade confidence scale compared to using a dichotomous assessment and that the agreement increases after adding chest computed tomography (CT) or lung ultrasound (LUS) to CXR. Three experts scored ARDS according to the Berlin definition based on case records from an observational cohort study using a dichotomous assessment and an 8-grade confidence scale. The intraclass correlation (ICC), imaging modality, and the scoring method were calculated per day and compared using bootstrapping. A consensus judgement on the presence of ARDS was based on the combined confidence grades of the experts, followed by a consensus meeting for conflicting scores. In total, 401 patients were included in the analysis. The best ICC was found using an 8-grade confidence scale for LUS (ICC: 0.49; 95%-CI: 0.29-0.63) and CT evaluation (ICC: 0.49; 95%-CI: 0.34-0.61). The ICC of CXR increased by 0.022 and of CT by 0.065 when 8-grade scoring was used instead of the dichotomous assessment. Adding information from LUS or chest CT increased the ICC by 0.25 when using the 8-grade confidence assessment. An agreement on the diagnosis of ARDS can increase substantially by adapting the scoring system from a dichotomous assessment to an 8-grade confidence scale and by adding additional imaging modalities such as LUS or chest CT. This suggests that a simple assessment of the diagnosis of ARDS with a chart review by one assessor is insufficient to define ARDS in future studies., Clinical Trial Registration: Trialregister.nl (identifier NL8226)., Competing Interests: Author MJS was employed by Medical Affairs, Hamilton Medical AG. Author LB is a consultant for Sobi and Scailyte, which is paid to the institution, and received grants from Longfonds, Health Holland, IMI, and Amsterdam UMC, which is paid to the institution. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor DB declared a past co-authorship with the author MJS., (Copyright © 2022 Hagens, Van der Ven, Heijnen, Smit, Gietema, Gerretsen, Schultz, Bergmans, Schnabel and Bos.)

Patients with SARS-CoV-2 infection present with different lung compliance and progression of disease differs. Measures of lung mechanics in SARS-CoV-2 patients may unravel different pathophysiologic mechanisms during mechanical ventilation. The objective of this prospective observational study is to describe whether Electrical Impedance Tomography (EIT) guided positive end-expiratory pressure (PEEP) levels unravel changes in EIT-derived parameters over time and whether the changes differ between survivors and non-survivors. Serial EIT-measurements of alveolar overdistension, collapse, and compliance change in ventilated SARS-CoV-2 patients were analysed. In 80 out of 94 patients, we took 283 EIT measurements (93 from day 1-3 after intubation, 66 from day 4-6, and 124 from day 7 and beyond). Fifty-one patients (64%) survived the ICU. At admission mean PaO 2 /FiO 2 -ratio was 184.3 (SD 61.4) vs. 151.3 (SD 54.4) mmHg, (p = 0.017) and PEEP was 11.8 (SD 2.8) cmH 2 O vs. 11.3 (SD 3.4) cmH 2 O, (p = 0.475), for ICU survivors and non-survivors. At day 1-3, compliance was ~ 55 mL/cmH 2 O vs. ~ 45 mL/cmH 2 O in survivors vs. non-survivors. The intersection of overdistension and collapse curves appeared similar at a PEEP of ~ 12-13 cmH 2 O. At day 4-6 compliance changed to ~ 50 mL/cmH 2 O vs. ~ 38 mL/cmH 2 O. At day 7 and beyond, compliance was ~ 38 mL/cmH 2 O with the intersection at a PEEP of ~ 9 cmH 2 O vs. ~ 25 mL/cmH 2 O with overdistension intersecting at collapse curves at a PEEP of ~ 7 cmH 2 O. Surviving SARS-CoV-2 patients show more favourable EIT-derived parameters and a higher compliance compared to non-survivors over time. This knowledge is valuable for discovering the different groups., (© 2022. The Author(s).)

Background: Electrical impedance tomography (EIT) visualises alveolar overdistension and alveolar collapse and enables optimisation of ventilator settings by using the best balance between alveolar overdistension and collapse (ODCL). Besides, the global inhomogeneity index (GI), measured by EIT, may also be of added value in determining PEEP. Optimal PEEP is often determined based on the best dynamic compliance without EIT at the bedside. This study aimed to assess the effect of a PEEP trial on ODCL, GI and dynamic compliance in patients with and without ARDS. Secondly, PEEP levels from "optimal PEEP" approaches by ODCL, GI and dynamic compliance are compared., Methods: In 2015-2016, we included patients with ARDS using postoperative cardiothoracic surgery patients as a reference group. A PEEP trial was performed with four consecutive incremental followed by four decremental PEEP steps of 2 cmH 2 O. Primary outcomes at each step were GI, ODCL and best dynamic compliance. In addition, the agreement between ODCL, GI, and dynamic compliance was determined for the individual patient., Results: Twenty-eight ARDS and 17 postoperative cardiothoracic surgery patients were included. The mean optimal PEEP, according to best compliance, was 10.3 (±2.9) cmH 2 O in ARDS compared to 9.8 (±2.5) cmH 2 O in cardiothoracic surgery patients. Optimal PEEP according to ODCL was 10.9 (±2.5) in ARDS and 9.6 (±1.6) in cardiothoracic surgery patients. Optimal PEEP according to GI was 17.1 (±3.9) in ARDS compared to 14.2 (±3.4) in cardiothoracic surgery patients., Conclusions: Currently, no golden standard to titrate PEEP is available. We showed that when using the GI, PEEP requirements are higher compared to ODCL and best dynamic compliance during a PEEP trial in patients with and without ARDS., (© 2022. The Author(s).)

Objectives: Interhospital transports of critically ill patients are high-risk medical interventions. Well-established parameters to quantify the quality of transports are currently lacking. We aimed to develop and cross-validate a score for interhospital transports., Setting: An expert panel developed a score for interhospital transport by a Mobile Intensive Care Unit (MICU), the QUality of Interhospital Transportation in the Euregion Meuse-Rhine (QUIT-EMR) score. The QUIT-EMR score is an overall sum score that includes component scores of monitoring and intervention variables of the neurological (proxy for airway patency), respiratory and circulatory organ systems, ranging from -12 to +12. A score of 0 or higher defines an adequate transport. The QUIT-EMR score was tested to help to quantify the quality of transport., Participants: One hundred adult patients were randomly included and the transport charts were independently reviewed and classified as adequate or inadequate by four transport experts (ie, anaesthetists/intensivists)., Outcome Measures: Subsequently, the level of agreement between the QUIT-EMR score and expert classification was calculated using Gwet's AC 1 ., Results: From April 2012 to May 2014, a total of 100 MICU transports were studied. The median (IQR) QUIT-EMR score was 1 (0-2). Experts classified six transports as inadequate. The percentage agreement between the QUIT-EMR score and experts' classification for adequate/inadequate transport ranged from 84% to 92% (Gwet's AC 1 0.81-0.91). The interobserver agreement between experts was 87% to 94% (Gwet's AC 1 0.89-0.98)., Conclusion: The QUIT-EMR score is a novel validated tool to score MICU transportation adequacy in future studies contributing to quality control and improvement., Trial Registration Number: NTR 4937., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To determine the appropriateness of empiric antibiotic therapy and the possible benefit of adding short-course gentamicin in septic shock patients with abdominal, urogenital, or an unknown focus. Secondary objectives were the effect of gentamicin addition on shock reversal and the incidence of a fungal infection., Methods: Microbiological cultures, antibiotic treatment, and antibiotic resistance patterns of the cultured microorganisms were recorded during the first 5 days of admission. Inappropriate antibiotic therapy was defined as a prescription within the first 24 h that did not cover cultured bacteria during the first 5 days of admission and was determined in the overall group and in patients receiving adjunctive gentamicin (combination therapy) versus patients receiving monotherapy. Binomial logistic regression analysis was used to investigate the association of gentamicin addition with shock reversal., Results: Of 203 septic shock patients, with abdominal ( n  = 143), urogenital ( n  = 27) or unknown ( n  = 33) focus, 115 patients received monotherapy, and 88 patients received combination therapy. Inappropriate therapy occurred in 29 patients (14%), more frequently in monotherapy (17%) versus combination therapy (10%). Combination therapy would have been effective in 55% of patients with inappropriate monotherapy. We found no association between gentamicin addition and shock reversal ( p  = .223). A fungal infection was present in 22 patients (11%)., Conclusion: Inappropriate empirical antibiotic therapy occurs in 17% of septic shock patients receiving monotherapy. In 55% of these patients, additional gentamicin would have resulted in appropriate therapy. When clinical course is unfavourable, lowering the threshold for administering adjunctive aminoglycoside and antifungal therapy should be considered.

Background: Acute respiratory distress syndrome (ARDS) is currently diagnosed by the Berlin Definition. Diagnosis is subjective and often late. Untargeted metabolomics analysis of exhaled breath with gas chromatography and mass spectrometry (GC-MS) showed that the breath concentration of octane has a high diagnostic accuracy for ARDS. To facilitate rapid bedside measurement of this biomarker, a point-of-care (POC) breath test was developed. A prototype already showed good reproducibility and repeatability for the detection of octane. In this study we aim to measure octane in exhaled breath of invasively ventilated intensive care unit (ICU) patients and validate the diagnostic accuracy of the breath test for the early diagnosis of ARDS., Methods: This is a multicentre observational cohort study in patients admitted to the ICU receiving invasive ventilation for at least 24 hours. At least 500 patients in two academic hospitals in The Netherlands will be included. ARDS patients will be compared to patients without ARDS. ARDS diagnosis will be based on the Berlin Definition. Two diagnostic assessments will be performed during the first 72 hours of invasive ventilation, including breath sampling, arterial blood gas analysis and lung ultrasound (LUS). In patients fulfilling the criteria for ARDS, three additional breath samples will be taken to assess resolution. The primary endpoint is the diagnostic accuracy for ARDS, defined by the area under the receiver operating characteristics curve (AUROCC) of octane concentration in exhaled breath. Secondary endpoints are the association between exhaled breath octane and ARDS adjusted for confounders, and the added diagnostic accuracy of the breath test on top of the Lung Injury Prediction Score (LIPS)., Discussion: This is the first study that validates a metabolic biomarker of ARDS in an adequate sample size. The major novelty is the use of a POC breath test that has been specifically developed for the purpose of diagnosing ARDS. Strengths are; assessment in the early phase, in patients at risk for ARDS, longitudinal sampling and an expert panel to reliably diagnose ARDS. This study will provide a decisive answer on the question if exhaled breath metabolomics can be used to diagnose ARDS., Trial Registration: The trial is registered at trialregister.nl (ID: NL8226) with the tag "DARTS"., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-1384). ARMV, TMEN, and IG are employed by company Philips. RMS received grant for the research project, Lung fund, The Netherlands. LDJB received grants from Health Holland, Dutch Lung Foundation (longfonds), Innovative medicine initiative and Amsterdam UMC. The other authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: Hypoxia and inflammation are hallmarks of critical illness, related to multiple organ failure. A possible mechanism leading to multiple organ failure is hypoxia- or inflammation-induced down-regulation of the detoxifying glyoxalase system that clears dicarbonyl stress. The dicarbonyl methylglyoxal (MGO) is a highly reactive agent produced by metabolic pathways such as anaerobic glycolysis and gluconeogenesis. MGO leads to protein damage and ultimately multi-organ failure. Whether detoxification of MGO into D-lactate by glyoxalase functions appropriately under conditions of hypoxia and inflammation is largely unknown. We investigated the effect of inflammation and hypoxia on the MGO pathway in humans in vivo., Methods: After prehydration with glucose 2.5% solution, ten healthy males were exposed to hypoxia (arterial saturation 80-85%) for 3.5 h using an air-tight respiratory helmet, ten males to experimental endotoxemia (LPS 2 ng/kg i.v.), ten males to LPS+hypoxia and ten males to none of these interventions (control group). Serial blood samples were drawn, and glyoxalase-1 mRNA expression, MGO, methylglyoxal-derived hydroimidazolone-1 (MG-H1), D-lactate and L-lactate levels, were measured serially., Results: Glyoxalase-1 mRNA expression decreased in the LPS (β (95%CI); -0.87 (-1.24; -0.50) and the LPS+hypoxia groups; -0.78 (-1.07; -0.48) (P<0.001). MGO was equal between groups, whereas MG-H1 increased over time in the control group only (P=0.003). D-Lactate was increased in all four groups. L-Lactate was increased in all groups, except in the control group., Conclusion: Systemic inflammation downregulates glyoxalase-1 mRNA expression in humans. This is a possible mechanism leading to cell damage and multi-organ failure in critical illness with potential for intervention., (© 2021 The Author(s).)

Background: There is a demand for a non-invasive bedside method to diagnose Acute Respiratory Distress Syndrome (ARDS). Octane was discovered and validated as the most important breath biomarker for diagnosis of ARDS using gas-chromatography and mass-spectrometry (GC-MS). However, GC-MS is unsuitable as a point-of-care (POC) test in the intensive care unit (ICU). Therefore, we determined if a newly developed POC breath test can reliably detect octane in exhaled breath of invasively ventilated ICU patients., Methods: Two developmental steps were taken to design a POC breath test that relies on gas-chromatography using air as carrier gas with a photoionization detector. Calibration measurements were performed with a laboratory prototype in healthy subjects. Subsequently, invasively ventilated patients were included for validation and assessment of repeatability. After evolving to a POC breath test, this device was validated in a second group of invasively ventilated patients. Octane concentration was based on the area under the curve, which was extracted from the chromatogram and compared to known values from calibration measurements., Results: Five healthy subjects and 53 invasively ventilated patients were included. Calibration showed a linear relation (R2 = 1.0) between the octane concentration and the quantified octane peak in the low parts per billion (ppb) range. For the POC breath test the repeatability was excellent (R2 = 0.98, ICC = 0.97 (95% CI 0.94-0.99))., Conclusion: This is the first study to show that a POC breath test can rapidly and reliably detect octane, with excellent repeatability, at clinically relevant levels of low ppb in exhaled breath of ventilated ICU patients. This opens possibilities for targeted exhaled breath analysis to be used as a bedside test and makes it a potential diagnostic tool for the early detection of ARDS.

Rationale: Recent studies showed that biological subphenotypes in acute respiratory distress syndrome (ARDS) provide prognostic enrichment and show potential for predictive enrichment. Objectives: To determine whether these subphenotypes and their prognostic and potential for predictive enrichment could be extended to other patients in the ICU, irrespective of fulfilling the definition of ARDS. Methods: This is a secondary analysis of a prospective observational study of adult patients admitted to the ICU. We tested the prognostic enrichment of both cluster-derived and latent-class analysis (LCA)-derived biological ARDS subphenotypes by evaluating the association with clinical outcome (ICU-day, 30-day mortality, and ventilator-free days) using logistic regression and Cox regression analysis. We performed a principal component analysis to compare blood leukocyte gene expression profiles between subphenotypes and the presence of ARDS. Measurements and Main Results: We included 2,499 mechanically ventilated patients (674 with and 1,825 without ARDS). The cluster-derived "reactive" subphenotype was, independently of ARDS, significantly associated with a higher probability of ICU mortality, higher 30-day mortality, and a lower probability of successful extubation while alive compared with the "uninflamed" subphenotype. The blood leukocyte gene expression profiles of individual subphenotypes were similar for patients with and without ARDS. LCA-derived subphenotypes also showed similar profiles. Conclusions: The prognostic and potential for predictive enrichment of biological ARDS subphenotypes may be extended to mechanically ventilated critically ill patients without ARDS. Using the concept of biological subphenotypes for splitting cohorts of critically ill patients could add to improving future precision-based trial strategies and lead to identifying treatable traits for all critically ill patients.

An overview of the experiences with deployment of undergraduate medical students in a Dutch university center during the COVID-19 pandemic is provided from organisational and educational perspectives. Medical students' and specialists' experiences during the first peak of COVID-19 underscore the preliminary suggestion that students can be given more enhanced (yet supervised) responsibility for patient care early in their practicums., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: Influenza-associated pulmonary aspergillosis (IAPA) is a frequent complication in critically ill influenza patients, associated with significant mortality. We investigated whether antifungal prophylaxis reduces the incidence of IAPA., Methods: We compared 7 days of intravenous posaconazole (POS) prophylaxis with no prophylaxis (standard-of-care only, SOC) in a randomised, open-label, proof-of-concept trial in patients admitted to an intensive care unit (ICU) with respiratory failure due to influenza (ClinicalTrials.gov, NCT03378479). Adult patients with PCR-confirmed influenza were block randomised (1:1) within 10 days of symptoms onset and 48 h of ICU admission. The primary endpoint was the incidence of IAPA during ICU stay in patients who did not have IAPA within 48 h of ICU admission (modified intention-to-treat (MITT) population)., Results: Eighty-eight critically ill influenza patients were randomly allocated to POS or SOC. IAPA occurred in 21 cases (24%), the majority of which (71%, 15/21) were diagnosed within 48 h of ICU admission, excluding them from the MITT population. The incidence of IAPA was not significantly reduced in the POS arm (5.4%, 2/37) compared with SOC (11.1%, 4/36; between-group difference 5.7%; 95% CI - 10.8 to 21.7; p = 0.32). ICU mortality of early IAPA was high (53%), despite rapid antifungal treatment., Conclusion: The higher than expected incidence of early IAPA precludes any definite conclusion on POS prophylaxis. High mortality of early IAPA, despite timely antifungal therapy, indicates that alternative management strategies are required. After 48 h, still 11% of patients developed IAPA. As these could benefit from prophylaxis, differentiated strategies are likely needed to manage IAPA in the ICU.

Early death in sepsis occurs frequently; however, specific causes are largely unknown. An autopsy can contribute to ascertain causes of death. The objective of the study was to determine discrepancies in clinical diagnosis and postmortem findings in septic intensive care unit (ICU) patients deceased within 48 h after ICU admission. All septic ICU patients who deceased within 48 h after ICU admission were identified and included. Four intensivists determined the clinical cause of death by medical record review. An autopsy was performed within 24 h of death. Clinical diagnosis and postmortem findings were compared and classified as autopsy-identified missed clinical diagnoses and autopsy-refuted diagnoses. Class I and II missed major diagnoses using the Goldman criteria were scored. Between 2012 and 2017, 1107 septic patients were admitted to ICU. Of these, 344 patients (31%) died, of which 97 patients (28%) deceased within 48 h. In 32 (33%) early deceased patients, an autopsy was agreed. There were 26 autopsy-identified missed clinical diagnoses found, mostly myocardial infarction (n = 4) and pneumonia (n = 4). In four patients (13%), a class I discrepancy was found. In fourteen patients (42%), a class II discrepancy was found. In conclusion, an autopsy is an important diagnostic tool that can identify definite causes of death. These diagnoses deviate from diagnoses established during admission in early deceased sepsis patients.

Background: The majority of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are admitted to the Intensive Care Unit (ICU) for mechanical ventilation. The role of multi-organ failure during ICU admission as driver for outcome remains to be investigated yet., Design and Setting: Prospective cohort of mechanically ventilated critically ill with SARS-CoV-2 infection., Participants and Methods: 94 participants of the MaastrICCht cohort (21% women) had a median length of stay of 16 days (maximum of 77). After division into survivors (n = 59) and non-survivors (n = 35), we analysed 1555 serial SOFA scores using linear mixed-effects models., Results: Survivors improved one SOFA score point more per 5 days (95% CI: 4-8) than non-survivors. Adjustment for age, sex, and chronic lung, renal and liver disease, body-mass index, diabetes mellitus, cardiovascular risk factors, and Acute Physiology and Chronic Health Evaluation II score did not change this result. This association was stronger for women than men (P-interaction = 0.043)., Conclusions: The decrease in SOFA score associated with survival suggests multi-organ failure involvement during mechanical ventilation in patients with SARS-CoV-2. Surviving women appeared to improve faster than surviving men. Serial SOFA scores may unravel an unfavourable trajectory and guide decisions in mechanically ventilated patients with SARS-CoV-2., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Biological subphenotypes have been identified in acute respiratory distress syndrome (ARDS) based on two parsimonious models: the "uninflamed" and "reactive" subphenotype (cluster-model) and "hypo-inflammatory" and "hyper-inflammatory" (latent class analysis (LCA) model). The distinction between the subphenotypes is mainly driven by inflammatory and coagulation markers in plasma. However, systemic inflammation is not specific for ARDS and it is unknown whether these subphenotypes also reflect differences in the alveolar compartment. Alveolar inflammation and dysbiosis of the lung microbiome have shown to be important mediators in the development of lung injury. This study aimed to determine whether the "reactive" or "hyper-inflammatory" biological subphenotype also had higher concentrations of inflammatory mediators and enrichment of gut-associated bacteria in the lung. Levels of alveolar inflammatory mediators myeloperoxidase (MPO), surfactant protein D (SPD), interleukin (IL)-1b, IL-6, IL-10, IL-8, interferon gamma (IFN-ƴ), and tumor necrosis factor-alpha (TNFα) were determined in the mini-BAL fluid. Key features of the lung microbiome were measured: bacterial burden (16S rRNA gene copies/ml), community diversity (Shannon Diversity Index), and community composition. No statistically significant differences between the "uninflamed" and "reactive" ARDS subphenotypes were found in a selected set of alveolar inflammatory mediators and key features of the lung microbiome. LCA-derived subphenotypes and stratification based on cause of ARDS (direct vs. indirect) showed similar profiles, suggesting that current subphenotypes may not reflect the alveolar host response. It is important for future research to elucidate the pulmonary biology within each subphenotype properly, which is arguably a target for intervention., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Rationale: Acute respiratory distress syndrome (ARDS) is currently diagnosed by the Berlin definition, which does not include a direct measure of pulmonary oedema, endothelial permeability or pulmonary inflammation. We hypothesised that biomarkers of these processes have good diagnostic accuracy for ARDS., Methods: Medline and Scopus were searched for original diagnostic studies using minimally invasive testing. Primary outcome was the diagnostic accuracy per test and was categorised by control group. The methodological quality was assessed with QUADAS-2 tool. Biomarkers that had an area under the receiver operating characteristic curve (AUROCC) of >0.75 and were studied with minimal bias against an unselected control group were considered to be promising., Results: Forty-four articles were included. The median AUROCC for all evaluated tests was 0.80 (25th to 75th percentile: 0.72-0.88). The type of control group influenced the diagnostic accuracy (p=0.0095). Higher risk of bias was associated with higher diagnostic accuracy (AUROCC 0.75 for low-bias, 0.77 for intermediate-bias and 0.84 for high-bias studies; p=0.0023). Club cell protein 16 and soluble receptor for advanced glycation end-products in plasma and two panels with biomarkers of oxidative stress in breath showed good diagnostic accuracy in low-bias studies that compared ARDS patients to an unselected intensive care unit (ICU) population., Conclusion: This systematic review revealed only four diagnostic tests fulfilling stringent criteria for a promising biomarker in a low-bias setting. For implementation into the clinical setting, prospective studies in a general unselected ICU population with good methodological quality are needed., Competing Interests: Conflict of interest: L.A. Hagens has nothing to disclose. Conflict of interest: N.F.L. Heijnen has nothing to disclose. Conflict of interest: M.R. Smit has nothing to disclose. Conflict of interest: M.J. Schultz has nothing to disclose. Conflict of interest: D.C.J.J. Bergmans has nothing to disclose. Conflict of interest: R.M. Schnabel has nothing to disclose. Conflict of interest: L.D.J. Bos reports grants from the Dutch Lung Foundation (young investigator grant, public–private partnership grant and Dirkje Postma Award) outside the submitted work., (Copyright ©ERS 2021.)

Background: Sepsis is a global health care problem with a high mortality. Early death seems common; however, data are sparse. The objective of the present study was to report causes and influencing factors of early death in sepsis and septic shock., Methods: All septic ICU patients were included from 2012 to 2017. Early death was predefined as occurring within 48 h. Causes and factors leading up to death were reported by a panel of four intensivists, independently reviewing the medical files. Following factors were assessed: (1) delay in ICU admission; (2) futile ICU treatment; (3) missed diagnosis or inadequate treatment on the ICU. Fleiss kappa was used to assess inter-observer agreement., Results: 1107 septic patients (APACHE II score 25 ± 8) were included. 344 patients died of which 97 (28%) within 48 h. In 33% an autopsy was performed. Primary causes of early death were multiple organ failure, mesenteric ischaemia and death after cardio-pulmonary resuscitation (CPR). Delay in ICU admission was scored in 32% of early deaths with slight agreement (κ = 0.180), futile ICU treatment in 29% with moderate agreement (κ = 0.415) and missed diagnosis or treatment in 7% of cases with slight agreement (κ = 0.122)., Conclusions: Early death after ICU admission in sepsis is common and primarily caused by multiple organ failure, mesenteric ischaemia and death after unsuccessful CPR. Influencing factors were delay in ICU admission and futile ICU admission. Fleiss kappa indicates substantial variability in clinical judgement between intensivists, strengthening the necessity for shared decision making.

International guidelines do not recommend a specific probe for assessment of lung aeration using lung ultrasound (LUS). The aim of this study was to assess the concordance between linear and sector array probes of a handheld ultrasound device in assessment of lung aeration in invasively ventilated intensive care unit patients. This study included intensive care unit patients who were expected to be ventilated for longer than 24 h. A 12-region LUS exam was performed with a linear and a sector array probe. In each image, the LUS aeration score and number of B-lines were determined. Adding the LUS aeration scores of all regions resulted in a global LUS aeration score. Agreement between the two probes was calculated using intra-class correlation coefficients (ICCs). A total of 30 LUS exams were performed in 19 patients, resulting in a total of 328 pairs of images. Twenty-nine pairs of images were excluded from analysis because the images from the linear probe could not be scored. ICCs calculated for the remaining images revealed good concordance the LUS aeration scores for individual images (ICC = 0.73, 95% confidence interval 0.67-0.78), number of B-lines (ICC = 0.79, 95% confidence interval 0.72-0.83) and global LUS aeration score (ICC = 0.74, 95% confidence interval 0.52-0.87). In conclusion, there is good concordance between linear and sector array probes of a handheld ultrasound device in assessment of lung aeration patterns in mechanically ventilated intensive care unit patients. However, in roughly 10% of the images acquired using the linear probe, the aeration pattern could not be scored., (Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background: Many studies investigate the role of pharmacological treatments on disease course in Corona Virus Disease 2019 (COVID-19). Sex disparities in genetics, immunological responses, and hormonal mechanisms may underlie the substantially higher fatality rates reported in male COVID-19 patients. To optimise care for COVID-19 patients, prophylactic and therapeutic studies should include sex-specific design and analyses. Therefore, in this scoping review, we investigated whether studies on pharmacological treatment in COVID-19 were performed based on a priori sex-specific design or post-hoc sex-specific analyses., Methods: We systematically searched PubMed, EMBASE, UpToDate, clinical trial.org, and MedRxiv for studies on pharmacological treatment for COVID-19 until June 6th, 2020. We included case series, randomized controlled trials, and observational studies in humans (≥18 years) investigating antiviral, antimalarial, and immune system modulating drugs. Data were collected on 1) the proportion of included females, 2) whether sex stratification was performed (a priori by design or post-hoc), and 3) whether effect modification by sex was investigated., Findings: 30 studies were eligible for inclusion, investigating remdesivir ( n  = 2), lopinavir/ritonavir ( n  = 5), favipiravir ( n  = 1), umifenovir ( n  = 1), hydroxychloroquine/chloroquine ( n  = 8), convalescent plasma ( n  = 6), interleukin-6 (IL-6) pathway inhibitors ( n  = 5), interleukin-1 (IL-1) pathway inhibitors ( n  = 1) and corticosteroids ( n  = 3). Only one study stratified its data based on sex in a post-hoc analysis, whereas none did a priori by design. None of the studies investigated effect modification by sex. A quarter of the studies included twice as many males as females., Interpretation: Analyses assessing potential interference of sex with (side-)effects of pharmacological therapy for COVID-19 are rarely reported. Considering sex differences in case-fatality rates and genetic, immunological, and hormonal mechanisms, studies should include sex-specific analyses in their design to optimise COVID-19 care., Funding: None., Competing Interests: Dr. Marx reports grants and personal fees from Bbraun Melsungen AG, grants and personal fees from Sphingotec AG, grants and personal fees from 4TEEN4 Pharmaceuticals GmbH, outside the submitted work. In addition, Dr. Marx has a patent Modulation ofTLR4 signalling European Patent 2855519/US Patent: US9,745,369 B2 issued, and a patent Combination of C1-Inh and Lung surfactant for the treatment of respiratory disorders PatentÐo.: US 7053,176 B1 PCT/EP99/06845 issued. All other authors declare no interest. Furthermore, there are no known conflicts of interest associated with this publication, and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that all have approved the order of authors listed in the manuscript., (© 2020 The Authors.)

There is a restrained attitude toward the implementation and performance of resuscitative thoracotomy as a last resort procedure in patients with cardiac arrest after penetrating thoracic trauma. We present a case with a remarkable recovery and hope to boost morality in the use of this procedure in the prehospital setting. A disoriented 25-year-old woman stabbed multiple times was found next to the highway. Her clinical situation deteriorated swiftly upon arrival of the helicopter emergency medical services. They were able to perform a clamshell thoracotomy and fly the patient out to the nearest trauma center. She awoke with good neurologic function. Her hospital admission was complicated by mediastinitis. A routine cardiac ultrasound showed mitral valve insufficiency due to combined perforation of the anterior leaflet and ventricular septum. Both lesions were in the trajectory of the primary stab wound. Successful outcome in our case was due to the following: little delay between clinical deterioration and the arrival of the helicopter emergency medical services physician (signs of life on arrival of paramedics are an independent predictor of survival), young age and penetrating injury are associated with a good neurologic outcome in case of traumatic cardiac arrest, and extensive follow-up cardiac ultrasound as part of tertiary survey after resuscitative emergency thoracotomy is advised., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Over the last decade, there has been an increasing awareness for the potential harm of the administration of too much oxygen. We aimed to describe self-reported attitudes towards oxygen therapy by clinicians from a large representative sample of intensive care units (ICUs) in the Netherlands., Methods: In April 2019, 36 ICUs in the Netherlands were approached and asked to send out a questionnaire (59 questions) to their nursing and medical staff (ICU clinicians) eliciting self-reported behaviour and attitudes towards oxygen therapy in general and in specific ICU case scenarios., Results: In total, 1361 ICU clinicians (71% nurses, 24% physicians) from 28 ICUs returned the questionnaire. Of responding ICU clinicians, 64% considered oxygen-induced lung injury to be a major concern. The majority of respondents considered a partial pressure of oxygen (PaO2) of 6-10 kPa (45-75 mmHg) and an arterial saturation (SaO2) of 85-90% as acceptable for 15 minutes, and a PaO2 7-10 kPa (53-75 mmHg) and SaO2 90-95% as acceptable for 24-48 hours in an acute respiratory distress syndrome (ARDS) patient. In most case scenarios, respondents reported not to change the fraction of inspired oxygen (FiO2) if SaO2 was 90-95% or PaO2 was 12 kPa (90 mmHg)., Conclusion: A representative sample of ICU clinicians from the Netherlands were concerned about oxygen-induced lung injury, and reported that they preferred PaO2 and SaO2 targets in the lower physiological range and would adjust ventilation settings accordingly.

To report on our clinical experience using EIT in individualized PEEP titration in ARDS. Using EIT assessment, we optimized PEEP settings in 39 ARDS patients. The EIT PEEP settings were compared with the physicians' PEEP settings and the PEEP settings according to the ARDS network. We defined a PEEP difference equal to or greater than 4 cm H 2 O as clinically relevant. Changes in lung compliance and PaO 2 /FiO 2 -ratio were compared in patients with EIT-based PEEP adjustments and in patients with unaltered PEEP. In 28% of the patients, the difference in EIT-based PEEP and physician-PEEP was clinically relevant; in 36%, EIT-based PEEP and physician-PEEP were equal. The EIT-based PEEP disagreed with the PEEP settings according to the ARDS network. Adjusting PEEP based upon EIT led to a rapid increase in lung compliance and PaO 2 /FiO 2 -ratio. However, this increase was also observed in the group where the PEEP difference was less than 4 cm H 2 O. We hypothesize that this can be attributed to the alveolar recruitment during the PEEP trial. EIT based individual PEEP setting appears to be a promising method to optimize PEEP in ARDS patients. The clinical impact, however, remains to be established.

Background: Invasive pulmonary aspergillosis typically occurs in an immunocompromised host. For almost a century, influenza has been known to set up for bacterial superinfections, but recently patients with severe influenza were also reported to develop invasive pulmonary aspergillosis. We aimed to measure the incidence of invasive pulmonary aspergillosis over several seasons in patients with influenza pneumonia in the intensive care unit (ICU) and to assess whether influenza was an independent risk factor for invasive pulmonary aspergillosis., Methods: We did a retrospective multicentre cohort study. Data were collected from adult patients with severe influenza admitted to seven ICUs across Belgium and The Netherlands during seven influenza seasons. Patients were older than 18 years, were admitted to the ICU for more than 24 h with acute respiratory failure, had pulmonary infiltrates on imaging, and a confirmed influenza infection based on a positive airway PCR test (influenza cohort). We used logistic regression analyses to determine if influenza was independently associated with invasive pulmonary aspergillosis in non-immunocompromised (ie, no European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group [EORTC/MSG] host factor) influenza-positive patients (influenza case group) compared with non-immunocompromised patients with severe community-acquired pneumonia who had a negative airway influenza PCR test (control group)., Findings: Data were collected from patients admitted to the ICU between Jan 1, 2009, and June 30, 2016. Invasive pulmonary aspergillosis was diagnosed in 83 (19%) of 432 patients admitted with influenza (influenza cohort), a median of 3 days after admission to the ICU. The incidence was similar for influenza A and B. For patients with influenza who were immunocompromised, incidence of invasive pulmonary aspergillosis was as high as 32% (38 of 117 patients), whereas in the non-immunocompromised influenza case group, incidence was 14% (45 of 315 patients). Conversely, only 16 (5%) of 315 patients in the control group developed invasive pulmonary aspergillosis. The 90-day mortality was 51% in patients in the influenza cohort with invasive pulmonary aspergillosis and 28% in the influenza cohort without invasive pulmonary aspergillosis (p=0·0001). In this study, influenza was found to be independently associated with invasive pulmonary aspergillosis (adjusted odds ratio 5·19; 95% CI 2·63-10·26; p<0·0001), along with a higher APACHE II score, male sex, and use of corticosteroids., Interpretation: Influenza was identified as an independent risk factor for invasive pulmonary aspergillosis and is associated with high mortality. Future studies should assess whether a faster diagnosis or antifungal prophylaxis could improve the outcome of influenza-associated aspergillosis., Funding: None., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Diagnostic strategies currently used for pneumonia are time-consuming, lack accuracy and suffer from large inter-observer variability. Exhaled breath contains thousands of volatile organic compounds (VOCs), which include products of host and pathogen metabolism. In this systematic review we investigated the use of so-called 'breathomics' for diagnosing pneumonia. A Medline search yielded 18 manuscripts reporting on animal and human studies using organic and inorganic molecules in exhaled breath, that all could be used to answer whether analysis of VOC profiles could potentially improve the diagnostic process of pneumonia. Papers were categorised based on their specific aims; the exclusion of pneumonia; the detection of specific respiratory pathogens; and whether targeted or untargeted VOC analysis was used. Ten studies reported on the association between VOCs and presence of pneumonia. Eight studies demonstrated a difference in exhaled VOCs between pneumonia and controls; in the individual studies this discrimination was based on unique sets of VOCs. Eight studies reported on the accuracy of a breath test for a specific respiratory pathogen: five of these concerned pre-clinical studies in animals. All studies were valued as having a high risk of bias, except for one study that used an external validation cohort. The findings in the identified studies are promising. However, as yet no breath test has been shown to have sufficient diagnostic accuracy for pneumonia. We are in need of studies that further translate the knowledge from discovery studies to clinical practice.