Effects of elastoviscoplastic properties of mucus on airway closure in healthy and pathological conditions

Airway mucus is a complex material with both viscoelastic and viscoplastic properties that vary with healthy and pathological conditions of the lung. In this study, the effects of these conditions on airway closure are examined in a model problem, where an elastoviscoplastic (EVP) single liquid layer lines the inner wall of a rigid pipe and surrounds the air core. The EVP liquid layer is modelled using the Saramito-HB model. The parameters for the model are obtained for the mucus in healthy, asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) conditions by fitting the rheological model to the experimental data. Then the liquid plug formation is studied by varying the Laplace number and undisturbed liquid film thickness. Airway closure is a surface-tension-driven phenomenon that occurs when the ratio of the pulmonary liquid layer thickness to the airway radius exceeds a certain threshold. In previous studies, it has been found that airway epithelial cells can be lethally or sublethally damaged due to the high peak of the wall stresses and stress gradients during the liquid plug formation. Here we demonstrate that these stresses are also related to the EVP features of the liquid layer. Yielded zones of the liquid layer are investigated for the different mucus conditions, and it is found that the liquid layer is in a chiefly unyielded state before the closure, which indicates that this phase is dominated by the elastic behavior and solvent viscosity. This is further confirmed by showing that the elastic coefficient is one of the most critical parameters determining whether the closure occurs. This parameter also largely affects the closure time. The wall stresses are also investigated for the pathological and healthy cases. Their peaks for COPD and CF are found to be the highest due to the viscoelastic extra stress contribution. Contrary to the Newtonian case, the wall stresses for COPD and CF do not smoothly relax after closure, as they rather remain effectively almost as high as the Newtonian peak. Moreover, the local normal wall stress gradients are smaller for the COPD and CF liquid layer due to their higher stiffness causing a smaller curvature at the capillary wave. The local tangential wall stress gradients are also shown to be smaller for these cases because of the slower accumulation of the liquid at the bulge

Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults with nonhypoxic ischaemic acute brain injuries and conditions in the intensive care unit (Mega-ROX Brains)

Background: The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults who have nonhypoxic ischaemic encephalopathy acute brain injuries and conditions and are receiving invasive mechanical ventilation in the intensive care unit (ICU) is uncertain. Objective: The objective of this study was to summarise the protocol and statistical analysis plan for the Mega-ROX Brains trial. Design, setting, and participants: Mega-ROX Brains is an international randomised clinical trial, which will be conducted within an overarching 40,000-participant, registry-embedded clinical trial comparing conservative and liberal ICU oxygen therapy regimens. We expect to enrol between 7500 and 9500 participants with nonhypoxic ischaemic encephalopathy acute brain injuries and conditions who are receiving unplanned invasive mechanical ventilation in the ICU. Main outcome measures: The primary outcome is in-hospital all-cause mortality up to 90 d from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and the proportion of participants discharged home. Results and conclusions: Mega-ROX Brains will compare the effect of conservative vs. liberal oxygen therapy regimens on 90-day in-hospital mortality in adults in the ICU with acute brain injuries and conditions. The protocol and planned analyses are reported here to mitigate analysis bias. Trial Registration: Australian and New Zealand Clinical Trials Registry (ACTRN 12620000391976)