Regional peak flow as a novel approach to assess regional pulmonary mechanics by electrical impedance tomography: an observational validation study.

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 (ODRPF) and collapse (CLRPF) rate and is validated in a prospective cohort of mechanically ventilated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients on CMV. ODRPF and CLRPF are compared with compliance-based cumulative overdistension (ODP500) and collapse (CLP500) rates from the Pulmovista 500 EIT device at multiple PEEP levels (PEEP 10 cmH2O to PEEP 24 cmH2O) 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 ODRPF and ODP500 of 1.02 (0.98-1.07, P<0.001) and between CLRPF and CLP500 of 0.93 (0.80-1.05, P<0.001). ICC values ranged from 0.78 to 0.86 (P<0.001) for ODRPF and ODP500 and from 0.70 to 0.85 (P<0.001) for CLRPF and CLP500 (PEEP 10 to PEEP 24). The mean bias between ODRPF and ODP500 in these PEEP levels ranged from 0.80% to 4.19% and from -1.31% to 0.13% between CLRPF and CLP500. 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.

Biomarkers of alveolar epithelial injury and endothelial dysfunction are associated with scores of pulmonary edema in invasively ventilated patients.

BACKGROUND: Pulmonary edema is a central hallmark of Acute Respiratory Distress Syndrome (ARDS). Endothelial dysfunction and epithelial injury contribute to permeability but their differential contribution to pulmonary edema development remains understudied. METHODS: 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 hours after intubation. Linear regression was used to examine the association of the biomarkers with pulmonary edema. RESULTS: 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, non-pulmonary, COVID, non-COVID), the positive association of SP-D levels with pulmonary edema remained, while 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: ßSP-D = 6.79 units/log10 pg/mL, ßsRAGE = 3.84 units/log10 pg/mL, R2 = 0.23; global LUS score: ßSP-D = 3.28 units/log10 pg/mL, ßsRAGE = 2.06 units/log10 pg/mL, R2 = 0.086), while Ang-2 did not further improve the model. CONCLUSION: 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.

Prognostic Value of the Radiographic Assessment of Lung Edema Score in Mechanically Ventilated ICU Patients.

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.

Predicting COVID-19 prognosis in the ICU remained challenging: external validation in a multinational regional cohort.

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.

Pulmonary pathophysiology development of COVID-19 assessed by serial Electrical Impedance Tomography in the MaastrICCht cohort.

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 PaO2/FiO2-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) cmH2O vs. 11.3 (SD 3.4) cmH2O, (p = 0.475), for ICU survivors and non-survivors. At day 1-3, compliance was ~ 55 mL/cmH2O vs. ~ 45 mL/cmH2O in survivors vs. non-survivors. The intersection of overdistension and collapse curves appeared similar at a PEEP of ~ 12-13 cmH2O. At day 4-6 compliance changed to ~ 50 mL/cmH2O vs. ~ 38 mL/cmH2O. At day 7 and beyond, compliance was ~ 38 mL/cmH2O with the intersection at a PEEP of ~ 9 cmH2O vs. ~ 25 mL/cmH2O with overdistension intersecting at collapse curves at a PEEP of ~ 7 cmH2O. 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.

Virtual patients for mechanical ventilation in the intensive care unit.

BACKGROUND: Mechanical ventilation (MV) is a core intensive care unit (ICU) therapy. Significant inter- and intra- patient variability in lung mechanics and condition makes managing MV difficult. Accurate prediction of patient-specific response to changes in MV settings would enable optimised, personalised, and more productive care, improving outcomes and reducing cost. This study develops a generalised digital clone model, or in-silico virtual patient, to accurately predict lung mechanics in response to changes in MV. METHODS: An identifiable, nonlinear hysteresis loop model (HLM) captures patient-specific lung dynamics identified from measured ventilator data. Identification and creation of the virtual patient model is fully automated using the hysteresis loop analysis (HLA) method to identify lung elastances from clinical data. Performance is evaluated using clinical data from 18 volume-control (VC) and 14 pressure-control (PC) ventilated patients who underwent step-wise recruitment maneuvers. RESULTS: Patient-specific virtual patient models accurately predict lung response for changes in PEEP up to 12 cmH2O for both volume and pressure control cohorts. R2 values for predicting peak inspiration pressure (PIP) and additional retained lung volume, Vfrc in VC, are R2=0.86 and R2=0.90 for 106 predictions over 18 patients. For 14 PC patients and 84 predictions, predicting peak inspiratory volume (PIV) and Vfrc yield R2=0.86 and R2=0.83. Absolute PIP, PIV and Vfrc errors are relatively small. CONCLUSIONS: Overall results validate the accuracy and versatility of the virtual patient model for capturing and predicting nonlinear changes in patient-specific lung mechanics. Accurate response prediction enables mechanically and physiologically relevant virtual patients to guide personalised and optimised MV therapy.

The "sex gap" in COVID-19 trials: a scoping review.

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.

Decreased serial scores of severe organ failure assessments are associated with survival in mechanically ventilated patients; the prospective Maastricht Intensive Care COVID cohort.

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.

Lessons learned: Contribution to healthcare by medical students during COVID-19.

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.