We describe the incidence and practice of prone positioning and determined the association of use of prone positioning with outcomes in invasively ventilated patients with acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) in a national, multicenter observational study, performed at 22 intensive care units in the Netherlands. Patients were categorized into 4 groups, based on indication for and actual use of prone positioning. The primary outcome was 28-day mortality. Secondary endpoints were 90-day mortality, and ICU and hospital length of stay. In 734 patients, prone positioning was indicated in 60%—the incidence of prone positioning was higher in patients with an indication than in patients without an indication for prone positioning (77 vs. 48%, p = 0.001). Patients were left in the prone position for median 15.0 (10.5–21.0) hours per full calendar day—the duration was longer in patients with an indication than in patients without an indication for prone positioning (16.0 (11.0–23.0) vs. 14.0 (10.0–19.0) hours, p < 0.001). Ventilator settings and ventilation parameters were not different between the four groups, except for FiO₂ which was higher in patients having an indication for and actually receiving prone positioning. Our data showed no difference in mortality at day 28 between the 4 groups (HR no indication, no prone vs. no indication, prone vs. indication, no prone vs. indication, prone: 1.05 (0.76–1.45) vs. 0.88 (0.62–1.26) vs. 1.15 (0.80–1.54) vs. 0.96 (0.73–1.26) (p = 0.08)). Factors associated with the use of prone positioning were ARDS severity and FiO₂. The findings of this study are that prone positioning is often used in COVID-19 patients, even in patients that have no indication for this intervention. Sessions of prone positioning lasted long. Use of prone positioning may affect outcomes.

Non-intubated patients with acute respiratory failure due to COVID-19 could benefit from awake proning. Awake proning is an attractive intervention in settings with limited resources, as it comes with no additional costs. However, awake proning remains poorly used probably because of unfamiliarity and uncertainties regarding potential benefits and practical application. To summarize evidence for benefit and to develop a set of pragmatic recommendations for awake proning in patients with COVID-19 pneumonia, focusing on settings where resources are limited, international healthcare professionals from high and low- and middle-income countries (LMICs) with known expertise in awake proning were invited to contribute expert advice. A growing number of observational studies describe the effects of awake proning in patients with COVID-19 pneumonia in whom hypoxemia is refractory to simple measures of supplementary oxygen. Awake proning improves oxygenation in most patients, usually within minutes, and reduces dyspnea and work of breathing. The effects are maintained for up to 1 hour after turning back to supine, and mostly disappear after 6–12 hours. In available studies, awake proning was not associated with a reduction in the rate of intubation for invasive ventilation. Awake proning comes with little complications if properly implemented and monitored. Pragmatic recommendations including indications and contraindications were formulated and adjusted for resource-limited settings. Awake proning, an adjunctive treatment for hypoxemia refractory to supplemental oxygen, seems safe in non-intubated patients with COVID-19 acute respiratory failure. We provide pragmatic recommendations including indications and contraindications for the use of awake proning in LMICs.

Airway care interventions may prevent accumulation of airway secretions and promote their evacuation, but evidence is scarce. Interventions include heated humidification, nebulization of mucolytics and/or bronchodilators, manual hyperinflation and use of mechanical insufflation-exsufflation (MI-E). Our aim is to identify current airway care practices for invasively ventilated patients in intensive care units (ICU) in the Netherlands. A self–administered web-based survey was sent to a single pre–appointed representative of all ICUs in the Netherlands. Response rate was 85% (72 ICUs). We found substantial heterogeneity in the intensity and combinations of airway care interventions used. Most (81%) ICUs reported using heated humidification as a routine prophylactic intervention. All (100%) responding ICUs used nebulized mucolytics and/or bronchodilators; however, only 43% ICUs reported nebulization as a routine prophylactic intervention. Most (81%) ICUs used manual hyperinflation, although only initiated with a clinical indication like difficult oxygenation. Few (22%) ICUs used MI-E for invasively ventilated patients. Use was always based on the indication of insufficient cough strength or as a continuation of home use. In the Netherlands, use of routine prophylactic airway care interventions is common despite evidence of no benefit. There is an urgent need for evidence of the benefit of these interventions to inform evidence-based guidelines.

Alterations in platelet function have been implicated in the pathophysiology of COVID-19 since the beginning of the pandemic. While early reports linked hyperactivated platelets to thromboembolic events in COVID-19, subsequent investigations demonstrated hyporeactive platelets with a procoagulant phenotype. Mitochondria are important for energy metabolism and the function of platelets. Here, we sought to map the energy metabolism of platelets in a cohort of noncritically ill COVID-19 patients and assess platelet mitochondrial function, activation status, and responsiveness to external stimuli. We enrolled hospitalized COVID-19 patients and controls between October 2020 and December 2021. Platelets function and metabolism was analyzed by flow cytometry, metabolomics, glucose fluxomics, electron and fluorescence microscopy and western blot. Platelets from COVID-19 patients showed increased phosphatidylserine externalization indicating a procoagulant phenotype and hyporeactivity to ex vivo stimuli, associated with profound mitochondrial dysfunction characterized by mitochondrial depolarization, lower mitochondrial DNA–encoded transcript levels, an altered mitochondrial morphology consistent with increased mitochondrial fission, and increased pyruvate/lactate ratios in platelet supernatants. Metabolic profiling by untargeted metabolomics revealed NADH, NAD⁺, and ATP among the top decreased metabolites in patients’ platelets, suggestive of energy metabolism failure. Consistently, platelet fluxomics analyses showed a strongly reduced utilization of ¹³C-glucose in all major energy pathways together with a rerouting of glucose to de novo generation of purine metabolites. Patients’ platelets further showed evidence of oxidative stress, together with increased glutathione oxidation and synthesis. Addition of plasma from COVID-19 patients to normal platelets partially reproduced the phenotype of patients’ platelets and disclosed a temporal relationship between mitochondrial decay and (subsequent) phosphatidylserine exposure and hyporeactivity. These data link energy metabolism failure in platelets from COVID-19 patients with a prothrombotic platelet phenotype with features matching cell death.

Preventive nebulization of mucolytic agents and bronchodilating drugs is a strategy aimed at the prevention of sputum plugging, and therefore atelectasis and pneumonia, in intubated and ventilated intensive care unit (ICU) patients. The present trial aims to compare a strategy using the preventive nebulization of acetylcysteine and salbutamol with nebulization on indication in intubated and ventilated ICU patients. The preventive nebulization of mucolytic agents and bronchodilating drugs in invasively ventilated intensive care unit patients (NEBULAE) trial is a national multicenter open-label, two-armed, randomized controlled non-inferiority trial in the Netherlands. Nine hundred and fifty intubated and ventilated ICU patients with an anticipated duration of invasive ventilation of more than 24 hours will be randomly assigned to receive either a strategy consisting of preventive nebulization of acetylcysteine and salbutamol or a strategy consisting of nebulization of acetylcysteine and/or salbutamol on indication. The primary endpoint is the number of ventilator-free days and surviving on day 28. Secondary endpoints include ICU and hospital length of stay, ICU and hospital mortality, the occurrence of predefined pulmonary complications (acute respiratory distress syndrome, pneumonia, large atelectasis and pneumothorax), and the occurrence of predefined side effects of the intervention. Related healthcare costs will be estimated in a cost-benefit and budget-impact analysis. The NEBULAE trial is the first randomized controlled trial powered to investigate whether preventive nebulization of acetylcysteine and salbutamol shortens the duration of ventilation in critically ill patients. NCT02159196 , registered on 6 June 2014.

Background: Critically ill patients receiving invasive ventilation are at risk of sputum retention. Mechanical insufflation-exsufflation (MI-E) is a technique used to mobilise sputum and optimise airway clearance. Recently, interest has increased in the use of mechanical insufflation-exsufflation for invasively ventilated critically ill adults, but evidence for the feasibility, safety and efficacy of this treatment is sparse. The aim of this scoping review is to map current and emerging evidence on the feasibility, safety and efficacy of MI-E for invasively ventilated adult patients with the aim of highlighting knowledge gaps and identifying areas for future research. Specific research questions aim to identify information informing indications and contraindications to the use of MI-E in the invasively ventilated adult, MI-E settings used, outcome measures reported within studies, adverse effects reported and perceived barriers and facilitators to using MI-E reported. Methods: We will search electronic databases MEDLINE, EMBASE, CINAHL using the OVID platform, PROSPERO, The Cochrane Library, ISI Web of Science and the International Clinical Trials Registry Platform. Two authors will independently screen citations, extract data and evaluate risk of bias using the Mixed Methods Appraisal Tool. Studies included will present original data and describe MI-E in invasively ventilated adult patients from 1990 onwards. Our exclusion criteria are studies in a paediatric population, editorial pieces or letters and animal or bench studies. Search results will be presented in a PRISMA study flow diagram. Descriptive statistics will be used to summarise quantitative data. For qualitative data relating to barriers and facilitators, we will use content analysis and the Theoretical Domains Framework (TDF) as a conceptual framework. Additional tables and relevant figures will present data addressing our research questions. Discussion: Our findings will enable us to map current and emerging evidence on the feasibility, safety and efficacy of MI-E for invasively ventilated critically ill adult patients. These data will provide description of how the technique is currently used, support healthcare professionals in their clinical decision making and highlight areas for future research in this important clinical area. Systematic review registration: Open Science Framework submitted on 9 July 2020. https://osf.io/mpksq/.