Introduction: Besides dyspnoea and cough, patients with idiopathic pulmonary fibrosis (IPF) or sarcoidosis may experience distressing non-respiratory symptoms, such as fatigue or muscle weakness. However, whether and to what extent symptom burden differs between patients with IPF or sarcoidosis and individuals without respiratory disease remains currently unknown. Objectives: To study the respiratory and non-respiratory burden of multiple symptoms in patients with IPF or sarcoidosis and to compare the symptom burden with individuals without impaired spirometric values, FVC and FEV1 (controls). Methods: Demographics and symptoms were assessed in 59 patients with IPF, 60 patients with sarcoidosis and 118 controls (age ≥18 years). Patients with either condition were matched to controls by sex and age. Severity of 14 symptoms was assessed using a Visual Analogue Scale. Results: 44 patients with IPF (77.3% male; age 70.6±5.5 years) and 44 matched controls, and 45 patients with sarcoidosis (48.9% male; age 58.1±8.6 year) and 45 matched controls were analyzed. Patients with IPF scored higher on 11 symptoms compared to controls (p<0.05), with the largest differences for dyspnoea, cough, fatigue, muscle weakness and insomnia. Patients with sarcoidosis scored higher on all 14 symptoms (p<0.05), with the largest differences for dyspnoea, fatigue, cough, muscle weakness, insomnia, pain, itch, thirst, micturition (night, day). Conclusions: Generally, respiratory and non-respiratory symptom burden is significantly higher in patients with IPF or sarcoidosis compared to controls. This emphasizes the importance of awareness for respiratory and non-respiratory symptom burden in IPF or sarcoidosis and the need for additional research to study the underlying mechanisms and subsequent interventions.
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INTRODUCTION: Patients with COVID-19-related acute respiratory distress syndrome (ARDS) have been postulated to present with distinct respiratory subphenotypes. However, most phenotyping schema have been limited by sample size, disregard for temporal dynamics, and insufficient validation. We aimed to identify respiratory subphenotypes of COVID-19-related ARDS using unbiased data-driven approaches.METHODS: PRoVENT-COVID was an investigator-initiated, national, multicentre, prospective, observational cohort study at 22 intensive care units (ICUs) in the Netherlands. Consecutive patients who had received invasive mechanical ventilation for COVID-19 (aged 18 years or older) served as the derivation cohort, and similar patients from two ICUs in the USA served as the replication cohorts. COVID-19 was confirmed by positive RT-PCR. We used latent class analysis to identify subphenotypes using clinically available respiratory data cross-sectionally at baseline, and longitudinally using 8-hourly data from the first 4 days of invasive ventilation. We used group-based trajectory modelling to evaluate trajectories of individual variables and to facilitate potential clinical translation. The PRoVENT-COVID study is registered with ClinicalTrials.gov, NCT04346342.FINDINGS: Between March 1, 2020, and May 15, 2020, 1007 patients were admitted to participating ICUs in the Netherlands, and included in the derivation cohort. Data for 288 patients were included in replication cohort 1 and 326 in replication cohort 2. Cross-sectional latent class analysis did not identify any underlying subphenotypes. Longitudinal latent class analysis identified two distinct subphenotypes. Subphenotype 2 was characterised by higher mechanical power, minute ventilation, and ventilatory ratio over the first 4 days of invasive mechanical ventilation than subphenotype 1, but PaO2/FiO2, pH, and compliance of the respiratory system did not differ between the two subphenotypes. 185 (28%) of 671 patients with subphenotype 1 and 109 (32%) of 336 patients with subphenotype 2 had died at day 28 (p=0·10). However, patients with subphenotype 2 had fewer ventilator-free days at day 28 (median 0, IQR 0-15 vs 5, 0-17; p=0·016) and more frequent venous thrombotic events (109 [32%] of 336 patients vs 176 [26%] of 671 patients; p=0·048) compared with subphenotype 1. Group-based trajectory modelling revealed trajectories of ventilatory ratio and mechanical power with similar dynamics to those observed in latent class analysis-derived trajectory subphenotypes. The two trajectories were: a stable value for ventilatory ratio or mechanical power over the first 4 days of invasive mechanical ventilation (trajectory A) or an upward trajectory (trajectory B). However, upward trajectories were better independent prognosticators for 28-day mortality (OR 1·64, 95% CI 1·17-2·29 for ventilatory ratio; 1·82, 1·24-2·66 for mechanical power). The association between upward ventilatory ratio trajectories (trajectory B) and 28-day mortality was confirmed in the replication cohorts (OR 4·65, 95% CI 1·87-11·6 for ventilatory ratio in replication cohort 1; 1·89, 1·05-3·37 for ventilatory ratio in replication cohort 2).INTERPRETATION: At baseline, COVID-19-related ARDS has no consistent respiratory subphenotype. Patients diverged from a fairly homogenous to a more heterogeneous population, with trajectories of ventilatory ratio and mechanical power being the most discriminatory. Modelling these parameters alone provided prognostic value for duration of mechanical ventilation and mortality.
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BACKGROUND: The intensity of ventilation, reflected by driving pressure (ΔP) and mechanical power (MP), has an association with outcome in invasively ventilated patients with or without acute respiratory distress syndrome (ARDS). It is uncertain if a similar association exists in coronavirus disease 2019 (COVID-19) patients with acute respiratory failure.METHODS: We aimed to investigate the impact of intensity of ventilation on patient outcome. The PRoVENT-COVID study is a national multicenter observational study in COVID-19 patients receiving invasive ventilation. Ventilator parameters were collected a fixed time points on the first calendar day of invasive ventilation. Mean dynamic ΔP and MP were calculated for individual patients at time points without evidence of spontaneous breathing. A Cox proportional hazard model, and a double stratification analysis adjusted for confounders were used to estimate the independent associations of ΔP and MP with outcome. The primary endpoint was 28-day mortality.RESULTS: In 825 patients included in this analysis, 28-day mortality was 27.5%. ΔP was not independently associated with mortality (HR 1.02 [95% confidence interval 0.88-1.18]; P = 0.750). MP, however, was independently associated with 28-day mortality (HR 1.17 [95% CI 1.01-1.36]; P = 0.031), and increasing quartiles of MP, stratified on comparable levels of ΔP, had higher risks of 28-day mortality (HR 1.15 [95% CI 1.01-1.30]; P = 0.028).CONCLUSIONS: In this cohort of critically ill invasively ventilated COVID-19 patients with acute respiratory failure, we show an independent association of MP, but not ΔP with 28-day mortality. MP could serve as one prognostic biomarker in addition to ΔP in these patients. Efforts aiming at limiting both ΔP and MP could translate in a better outcome. Trial registration Clinicaltrials.gov (study identifier NCT04346342).
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BACKGROUND The mechanical power of ventilation (MP) has an association with outcome in invasively ventilated patients with the acute respiratory distress syndrome (ARDS). Whether a similar association exists in invasively ventilated patients without ARDS is less certain.OBJECTIVE To investigate the association of mechanical power with mortality in ICU patients without ARDS.DESIGN This was an individual patient data analysis that uses the data of three multicentre randomised trials.SETTING This study was performed in academic and nonacademic ICUs in the Netherlands.PATIENTS One thousand nine hundred and sixty-two invasively ventilated patients without ARDS were included in this analysis. The median [IQR] age was 67 [57 to 75] years, 706 (36%) were women.MAIN OUTCOME MEASURES The primary outcome was the all-cause mortality at day 28. Secondary outcomes were the all-cause mortality at day 90, and length of stay in ICU and hospital.RESULTS At day 28, 644 patients (33%) had died. Hazard ratios for mortality at day 28 were higher with an increasing MP, even when stratified for its individual components (driving pressure (P < 0.001), tidal volume (P < 0.001), respiratory rate (P < 0.001) and maximum airway pressure (P = 0.001). Similar associations of mechanical power (MP) were found with mortality at day 90, lengths of stay in ICU and hospital. Hazard ratios for mortality at day 28 were not significantly different if patients were stratified for MP, with increasing levels of each individual component.CONCLUSION In ICU patients receiving invasive ventilation for reasons other than ARDS, MP had an independent association with mortality. This finding suggests that MP holds an added predictive value over its individual components, making MP an attractive measure to monitor and possibly target in these patients.TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02159196, ClinicalTrials.gov Identifier: NCT02153294, ClinicalTrials.gov Identifier: NCT03167580.
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BackgroundMechanical ventilation affects the respiratory muscles, but little is known about long-term recovery of respiratory muscle weakness (RMW) and potential associations with physical functioning in survivors of critical illness. The aim of this study was to investigate the course of recovery of RMW and its association with functional outcomes in patients who received mechanical ventilation.MethodsWe conducted a prospective cohort study with 6-month follow-up among survivors of critical illness who received ≥ 48 hours of invasive mechanical ventilation. Primary outcomes, measured at 3 timepoints, were maximal inspiratory and expiratory pressures (MIP/MEP). Secondary outcomes were functional exercise capacity (FEC) and handgrip strength (HGS). Longitudinal changes in outcomes and potential associations between MIP/MEP, predictor variables, and secondary outcomes were investigated through linear mixed model analysis.ResultsA total of 59 participants (male: 64%, median age [IQR]: 62 [53–66]) were included in this study with a median (IQR) ICU and hospital length of stay of 11 (8–21) and 35 (21–52) days respectively. While all measures were well below predicted values at hospital discharge (MIP: 68.4%, MEP 76.0%, HGS 73.3% of predicted and FEC 54.8 steps/2m), significant 6-month recovery was seen for all outcomes. Multivariate analyses showed longitudinal associations between older age and decreased MIP and FEC, and longer hospital length of stay and decreased MIP and HGS outcomes. In crude models, significant, longitudinal associations were found between MIP/MEP and FEC and HGS outcomes. While these associations remained in most adjusted models, an interaction effect was observed for sex.ConclusionRMW was observed directly after hospital discharge while 6-month recovery to predicted values was noted for all outcomes. Longitudinal associations were found between MIP and MEP and more commonly used measures for physical functioning, highlighting the need for continued assessment of respiratory muscle strength in deconditioned patients who are discharged from ICU. The potential of targeted training extending beyond ICU and hospital discharge should be further explored.
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Background: Estimates for dead space ventilation have been shown to be independently associated with an increased risk of mortality in the acute respiratory distress syndrome and small case series of COVID-19-related ARDS. Methods: Secondary analysis from the PRoVENT-COVID study. The PRoVENT-COVID is a national, multicenter, retrospective observational study done at 22 intensive care units in the Netherlands. Consecutive patients aged at least 18 years were eligible for participation if they had received invasive ventilation for COVID-19 at a participating ICU during the first month of the national outbreak in the Netherlands. The aim was to quantify the dynamics and determine the prognostic value of surrogate markers of wasted ventilation in patients with COVID-19-related ARDS. Results: A total of 927 consecutive patients admitted with COVID-19-related ARDS were included in this study. Estimations of wasted ventilation such as the estimated dead space fraction (by Harris–Benedict and direct method) and ventilatory ratio were significantly higher in non-survivors than survivors at baseline and during the following days of mechanical ventilation (p < 0.001). The end-tidal-to-arterial PCO2 ratio was lower in non-survivors than in survivors (p < 0.001). As ARDS severity increased, mortality increased with successive tertiles of dead space fraction by Harris–Benedict and by direct estimation, and with an increase in the VR. The same trend was observed with decreased levels in the tertiles for the end-tidal-to-arterial PCO2 ratio. After adjustment for a base risk model that included chronic comorbidities and ventilation- and oxygenation-parameters, none of the dead space estimates measured at the start of ventilation or the following days were significantly associated with 28-day mortality. Conclusions: There is significant impairment of ventilation in the early course of COVID-19-related ARDS but quantification of this impairment does not add prognostic information when added to a baseline risk model. Trial registration: ISRCTN04346342. Registered 15 April 2020. Retrospectively registered.
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Background: Preoperative inspiratory muscle training (IMT) is frequently used in patients waiting for major surgery to improve respiratory muscle function and to reduce the risk of postoperative pulmonary complications (PPCs). Currently, the mechanism of action of IMT in reducing PPCs is still unclear. Therefore, we investigated the associations between preoperative IMT variables and the occurrence of PPCs in patients with esophageal cancer. Methods: A multi-center cohort study was conducted in subjects scheduled for esophagectomy, who followed IMT as part of a prehabilitation program. IMT variables included maximum inspiratory pressure (PImax) before and after IMT and IMT intensity variables including training load, frequency, and duration. Associations between PImax and IMT intensity variables and PPCs were analyzed using independent samples t tests and logistic regression analyses, corrected for age and pulmonary comorbidities and stratified for the occurrence of anastomotic leakages. Results: Eighty-seven subjects were included (69 males; mean age 66.7 ± 7.3 y). A higher PImax (odds ratio 1.016, P = .07) or increase in PImax during IMT (odds ratio 1.020, P = .066) was not associated with a reduced risk of PPCs after esophagectomy. Intensity variables of IMT were also not associated (P ranging from .16 to .95) with PPCs after esophagectomy. Analyses stratified for the occurrence of anastomotic leakages showed no associations between IMT variables and PPCs. Conclusions: This study shows that an improvement in preoperative inspiratory muscle strength during IMT and training intensity of IMT were not associated with a reduced risk on PPCs after esophagectomy. Further research is needed to investigate other possible factors explaining the mechanism of action of preoperative IMT in patients undergoing major surgery, such as the awareness of patients related to respiratory muscle function and a diaphragmatic breathing pattern.
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Patients who are critically ill and receiving invasivemechanical ventilation are at increased risk for accumula-tion of secretions in the lower airways. Such accumula-tion of airway mucus can induce atelectasis and contributeto ventilator-associated pneumonia. Preventive airwaycare interventions, including humidification, endotrachealsuctioning, and pharmacologic interventions, are thereforefrequently initiated during invasive ventilation. However,evidence for the efficacy of these interventions is scarce,and the absence of guidelines enhances variation in indica-tions for their use. Currently, the choice and timing of interventions aremainly driven by clinical assessment of mucus viscosity based on a mucus classification scale or preference by thetreating physician. Alternatively, airway mucus proper-ties can be measured through rheology, a more objectiveparameter, which characterizes its biophysical properties(eg, viscoelasticity). Previously, studies reported that rhe-ology of airway secretions may help classify chronic muco-obstructive respiratory diseases and serve as a marker ofdisease progression. In this study, we tested the hypoth-esis that airway mucus viscoelastic properties, as measuredby rheology in patients who are critically ill and receivinginvasive mechanical ventilation, correlates with its clinicalmucus classification score.
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BACKGROUND: Estimates for dead space ventilation have been shown to be independently associated with an increased risk of mortality in the acute respiratory distress syndrome and small case series of COVID-19-related ARDS.METHODS: Secondary analysis from the PRoVENT-COVID study. The PRoVENT-COVID is a national, multicenter, retrospective observational study done at 22 intensive care units in the Netherlands. Consecutive patients aged at least 18 years were eligible for participation if they had received invasive ventilation for COVID-19 at a participating ICU during the first month of the national outbreak in the Netherlands. The aim was to quantify the dynamics and determine the prognostic value of surrogate markers of wasted ventilation in patients with COVID-19-related ARDS.RESULTS: A total of 927 consecutive patients admitted with COVID-19-related ARDS were included in this study. Estimations of wasted ventilation such as the estimated dead space fraction (by Harris-Benedict and direct method) and ventilatory ratio were significantly higher in non-survivors than survivors at baseline and during the following days of mechanical ventilation (p < 0.001). The end-tidal-to-arterial PCO2 ratio was lower in non-survivors than in survivors (p < 0.001). As ARDS severity increased, mortality increased with successive tertiles of dead space fraction by Harris-Benedict and by direct estimation, and with an increase in the VR. The same trend was observed with decreased levels in the tertiles for the end-tidal-to-arterial PCO2 ratio. After adjustment for a base risk model that included chronic comorbidities and ventilation- and oxygenation-parameters, none of the dead space estimates measured at the start of ventilation or the following days were significantly associated with 28-day mortality.CONCLUSIONS: There is significant impairment of ventilation in the early course of COVID-19-related ARDS but quantification of this impairment does not add prognostic information when added to a baseline risk model.TRIAL REGISTRATION: ISRCTN04346342. Registered 15 April 2020. Retrospectively registered.
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From the publisher: "Background: The introduction of whole new foods in a population may lead to sensitization and food allergy. This constitutes a potential public health problem and a challenge to risk assessors and managers as the existing understanding of the pathophysiological processes and the currently available biological tools for prediction of the risk for food allergy development and the severity of the reaction are not sufficient. There is a substantial body of in vivo and in vitro data describing molecular and cellular events potentially involved in food sensitization. However, these events have not been organized in a sequence of related events that is plausible to result in sensitization, and useful to challenge current hypotheses. The aim of this manuscript was to collect and structure the current mechanistic understanding of sensitization induction to food proteins by applying the concept of adverse outcome pathway (AOP). Main body: The proposed AOP for food sensitization is based on information on molecular and cellular mechanisms and pathways evidenced to be involved in sensitization by food and food proteins and uses the AOPs for chemical skin sensitization and respiratory sensitization induction as templates. Available mechanistic data on protein respiratory sensitization were included to fill out gaps in the understanding of how proteins may affect cells, cell-cell interactions and tissue homeostasis. Analysis revealed several key events (KE) and biomarkers that may have potential use in testing and assessment of proteins for their sensitizing potential. Conclusion: The application of the AOP concept to structure mechanistic in vivo and in vitro knowledge has made it possible to identify a number of methods, each addressing a specific KE, that provide information about the food allergenic potential of new proteins. When applied in the context of an integrated strategy these methods may reduce, if not replace, current animal testing approaches. The proposed AOP will be shared at the www.aopwiki.org platform to expand the mechanistic data, improve the confidence in each of the proposed KE and key event relations (KERs), and allow for the identification of new, or refinement of established KE and KERs." Authors: Jolanda H. M. van BilsenEmail author, Edyta Sienkiewicz-Szłapka, Daniel Lozano-Ojalvo, Linette E. M. Willemsen, Celia M. Antunes, Elena Molina, Joost J. Smit, Barbara Wróblewska, Harry J. Wichers, Edward F. Knol, Gregory S. Ladics, Raymond H. H. Pieters, Sandra Denery-Papini, Yvonne M. Vissers, Simona L. Bavaro, Colette Larré, Kitty C. M. Verhoeckx and Erwin L. Roggen
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