Patients with acute exacerbation of lung fibrosis with usual interstitial pneumonia (EUIP) pattern are at increased risk for ventilator-induced lung injury (VILI) and mortality when exposed to mechanical ventilation (MV). Yet, lack of a mechanical model describing UIP-lung deformation during MV represents a research gap. Aim of this study was to develop a constitutive mathematical model for UIP-lung deformation during lung protective MV based on the stress-strain behavior and the specific elastance of patients with EUIP as compared to that of acute respiratory distress syndrome (ARDS) and healthy lung. Partitioned lung and chest wall mechanics were assessed for patients with EUIP and primary ARDS (1:1 matched based on body mass index and PaO2/FiO2 ratio) during a PEEP trial performed within 24 h from intubation. Patient\'s stress-strain curve and the lung specific elastance were computed and compared with those of healthy lungs, derived from literature. Respiratory mechanics were used to fit a novel mathematical model of the lung describing mechanical-inflation-induced lung parenchyma deformation, differentiating the contributions of elastin and collagen, the main components of lung extracellular matrix. Five patients with EUIP and 5 matched with primary ARDS were included and analyzed. Global strain was not different at low PEEP between the groups. Overall specific elastance was significantly higher in EUIP as compared to ARDS (28.9 [22.8-33.2] cmH2O versus 11.4 [10.3-14.6] cmH2O, respectively). Compared to ARDS and healthy lung, the stress/strain curve of EUIP showed a steeper increase, crossing the VILI threshold stress risk for strain values greater than 0.55. The contribution of elastin was prevalent at lower strains, while the contribution of collagen was prevalent at large strains. The stress/strain curve for collagen showed an upward shift passing from ARDS and healthy lungs to EUIP lungs. During MV, patients with EUIP showed different respiratory mechanics, stress-strain curve and specific elastance as compared to ARDS patients and healthy subjects and may experience VILI even when protective MV is applied. According to our mathematical model of lung deformation during mechanical inflation, the elastic response of UIP-lung is peculiar and different from ARDS. Our data suggest that patients with EUIP experience VILI with ventilatory setting that are lung-protective for patients with ARDS.

Although patients with interstitial pneumonia pattern (ILD-UIP) and acute exacerbation (AE) leading to severe acute respiratory failure may require invasive mechanical ventilation (MV), physiological data on lung mechanics during MV are lacking. We aimed at describing the physiological effect of lung-protective ventilation in patients with AE-ILD-UIP compared with primary ARDS.
Partitioned lung and chest wall mechanics were assessed in a series of AE-ILD-UIP patients matched 1:1 with primary ARDS as controls (based on BMI and PaO2/FiO2 ratio). Three PEEP levels (zero = ZEEP, 4-8 cmH2O = PEEPLOW, and titrated to achieve positive end-expiratory transpulmonary pressure PL,EE = PEEPTITRATED) were used for measurements.
Ten AE-ILD-UIP patients and 10 matched ARDS were included. In AE-ILD-UIP median PL,EE at ZEEP was - 4.3 [- 7.6- - 2.3] cmH2O and lung elastance (EL) 44 [40-51] cmH2O/L. At PEEPLOW, PL,EE remained negative and EL did not change (p = 0.995) versus ZEEP. At PEEPTITRATED, PL,EE increased to 0.8 [0.3-1.5] cmH2O and EL to 49 [43-59] (p = 0.004 and p < 0.001 compared to ZEEP and PEEPLOW, respectively). ΔPL decreased at PEEPLOW (p = 0.018) and increased at PEEPTITRATED (p = 0.003). In matched ARDS control PEEP titration to obtain a positive PL,EE did not result in significant changes in EL and ΔPL.
In mechanically ventilated AE-ILD-UIP patients, differently than in patients with primary ARDS, PEEP titrated to obtain a positive PL,EE significantly worsened lung mechanics.

BACKGROUND: Studies investigating the effect of trunk inclination on respiratory mechanics in mechanically ventilated patients with ARDS have reported postural differences in partition respiratory mechanics. Compared with more upright positions, the supine-flat position provided lower lung and chest wall elastance, allowing reduced driving pressures and end-inspiratory transpulmonary pressure. However, the effect of trunk inclination on respiratory mechanics in patients with obesity and ARDS is uncertain.
OBJECTIVE: Does the effect of change in posture on partition respiratory mechanics differ between patients with ARDS with and without obesity?
METHODS: In this single-center study, patients with ARDS with and without obesity were randomized into two 15-minute steps in which trunk inclination was changed from semi-recumbent (40° head up) to supine-flat (0°), or vice versa. At the end of each step partition respiratory mechanics, airway opening pressure and arterial blood gases were measured. Paired t test was used to examine respiratory mechanics and blood gas variables in each group.
RESULTS: Forty consecutive patients were enrolled. Twenty were obese (BMI, 38.4 [34.5-42.3]), and 20 were non-obese (BMI, 26.6 [25.2-28.5]). In the patients with obesity, lung and chest wall elastance, driving pressure, inspiratory transpulmonary pressure, Paco2, and ventilatory ratio were lower supine than semi-recumbent (P < .001). Airways resistance was greater supine (P = .006). In the patients without obesity, only chest wall elastance was lower in supine vs semi-recumbent (P < .001).
CONCLUSIONS: In mechanically ventilated patients with ARDS and obesity, supine posture provided lower lung and chest wall elastance, and better CO2 clearance, than the semi-recumbent posture.
BACKGROUND: This study was registered with Australian New Zealand Clinical Trials Registry (ACTRN12623000794606).

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Respiratory system modelling can assist clinicians in making clinical decisions during mechanical ventilation (MV) management in intensive care. However, there are some cases where the MV patients produce asynchronous breathing (asynchrony events) due to the spontaneous breathing (SB) effort even though they are fully sedated. Currently, most of the developed models are only suitable for fully sedated patients, which means they cannot be implemented for patients who produce asynchrony in their breathing. This leads to an incorrect measurement of the actual underlying mechanics in these patients. As a result, there is a need to develop a model that can detect asynchrony in real-time and at the bedside throughout the ventilated days. This paper demonstrates the asynchronous event detection of MV patients in the ICU of a hospital by applying a developed extended time-varying elastance model. Data from 10 mechanically ventilated respiratory failure patients admitted at the International Islamic University Malaysia (IIUM) Hospital were collected. The results showed that the model-based technique precisely detected asynchrony events (AEs) throughout the ventilation days. The patients showed an increase in AEs during the ventilation period within the same ventilation mode. SIMV mode produced much higher asynchrony compared to SPONT mode (p < 0.05). The link between AEs and the lung elastance (AUC Edrs) was also investigated. It was found that when the AEs increased, the AUC Edrs decreased and vice versa based on the results obtained in this research. The information of AEs and AUC Edrs provides the true underlying lung mechanics of the MV patients. Hence, this model-based method is capable of detecting the AEs in fully sedated MV patients and providing information that can potentially guide clinicians in selecting the optimal ventilation mode of MV, allowing for precise monitoring of respiratory mechanics in MV patients.

UNASSIGNED: What is the central question of this study? Does endogenous testosterone modulate the consequences of intermittent hypoxia (IH) in the lungs of male mice? What is the main finding and its importance? Orchiectomized mice exposed to IH develop a pattern that is similar to emphysema or obstructive lung disease with elevated lung volumes, low pulmonary elastance during a methacholine challenge test and high counts of lymphocytes in bronchoalveolar lavages. Since low testosterone levels and other respiratory diseases are common in sleep apnoea, there is a clear clinical relevance to these results.
UNASSIGNED: We tested the hypothesis that low testosterone levels modulate the pulmonary responses to intermittent hypoxia (IH; used as a model of sleep apnoea (SA)) in male mice. We used intact (SHAM) or orchiectomized (ORX) mice exposed to IH for 14 days (12 h/day, 10 cycles/h, 6% oxygen) or to normoxia (Nx). We first measured ventilation and metabolic rates in freely behaving mice (whole-body plethysmography) and then respiratory mechanics in tracheotomized mice (flexiVent). We assessed the respiratory system resistance and elastance (Ers ), Newtonian resistance (resistance of the large airways), tissue damping and tissue elastance (H) under baseline conditions and during a methacholine challenge test. We also measured the quasi-static compliance and inspiratory capacity with partial pressure-volume loops. Finally, inflammatory cells were counted in the broncho-alveolar lavage (BAL) and we measured lung volume by water displacement. ORX-IH mice had higher tidal volume, inspiratory capacity and lung volume compared to the other groups, but showed signs of low efficiency of O2 exchange rate relative to minute ventilation. During the methacholine challenge, orchiectomy decreased the values of most mechanical parameters and IH reduced Ers and H leading to very low values in ORX-IH mice. Finally, the total number of cells and the number of lymphocytes in BAL were both increased by IH in ORX mice. Since reduced lung elasticity, low O2 extraction, increased lung volumes and inflammation are signs of emphysematous lung disease, we conclude that testosterone might prevent lung emphysema during IH exposures.

Deep inspiration (DI)-induced bronchodilation is the first line of defense against bronchoconstriction in healthy subjects. A hallmark of asthma is the lack of this beneficial effect of DI. The mechanism underlying the bronchodilatory effect of DI is not clear. Understanding the mechanism will help us unravel the mystery of asthma pathophysiology. It has been postulated that straining airway smooth muscle (ASM) during a DI could lead to bronchodilation and bronchoprotection. The hypothesis is currently under debate, and a central question is whether ASM is sufficiently stretched during a DI for its contractility to be compromised. Besides bronchoconstriction, another contributor to lung resistance is airway heterogeneity. The present study examines changes in airway diameter and heterogeneity at different lung volumes. Freshly explanted sheep lungs were used in plethysmographic measurements of lung resistance and elastance at different lung volumes, whereas the airway dimensions were measured by computed tomography (CT). The change in airway diameter informed by CT measurements was applied to isolated airway ring preparations to determine the strain-induced loss of ASM contractility. We found that changing the transpulmonary pressure from 5 to 30 cmH2O led to a 51% increase in lung volume, accompanied by a 46% increase in the airway diameter with no change in airway heterogeneity. When comparable airway strains measured in the whole lung were applied to isolated airway rings in either relaxed or contracted state, a significant loss of ASM contractility was observed, suggesting that DI-induced bronchodilation and bronchoprotection can result from strain-induced loss of ASM contractility.

Lung fibrosis results from the synergic interplay between regenerative deficits of the alveolar epithelium and dysregulated mechanisms of repair in response to alveolar and vascular damage, which is followed by progressive fibroblast and myofibroblast proliferation and excessive deposition of the extracellular matrix. The increased parenchymal stiffness of fibrotic lungs significantly affects respiratory mechanics, making the lung more fragile and prone to non-physiological stress during spontaneous breathing and mechanical ventilation. Given their parenchymal inhomogeneity, fibrotic lungs may display an anisotropic response to mechanical stresses with different regional deformations (micro-strain). This behavior is not described by the standard stress-strain curve but follows the mechano-elastic models of \"squishy balls\", where the elastic limit can be reached due to the excessive deformation of parenchymal areas with normal elasticity that are surrounded by inelastic fibrous tissue or collapsed induration areas, which tend to protrude outside the fibrous ring. Increasing evidence has shown that non-physiological mechanical forces applied to fibrotic lungs with associated abnormal mechanotransduction could favor the progression of pulmonary fibrosis. With this review, we aim to summarize the state of the art on the relation between mechanical forces acting on the lung and biological response in pulmonary fibrosis, with a focus on the progression of damage in the fibrotic lung during spontaneous breathing and assisted ventilatory support.

OBJECTIVE: Elucidate how the degree of ventilator-induced lung injury due to atelectrauma that is produced in the injured lung during mechanical ventilation is determined by both the timing and magnitude of the airway pressure profile.
METHODS: A computational model of the injured lung provides a platform for exploring how mechanical ventilation parameters potentially modulate atelectrauma and volutrauma. This model incorporates the time dependence of lung recruitment and derecruitment, and the time-constant of lung emptying during expiration as determined by overall compliance and resistance of the respiratory system.
METHODS: Computational model.
METHODS: Simulated scenarios representing patients with both normal and acutely injured lungs.
RESULTS: Protective low-tidal volume ventilation (Low-Vt) of the simulated injured lung avoided atelectrauma through the elevation of positive end-expiratory pressure while maintaining fixed tidal volume and driving pressure. In contrast, airway pressure release ventilation avoided atelectrauma by incorporating a very brief expiratory duration () that both prevents enough time for derecruitment and limits the minimum alveolar pressure prior to inspiration. Model simulations demonstrated that has an effective threshold value below which airway pressure release ventilation is safe from atelectrauma while maintaining a tidal volume and driving pressure comparable with those of Low-Vt. This threshold is strongly influenced by the time-constant of lung-emptying.
CONCLUSIONS: Low-Vt and airway pressure release ventilation represent markedly different strategies for the avoidance of ventilator-induced lung injury, primarily involving the manipulation of positive end-expiratory pressure and , respectively. can be based on exhalation flow values, which may provide a patient-specific approach to protective ventilation.

Ventilator-induced lung injury (VILI) is driven by the processes of volutrauma and atelectrauma, which can act synergistically to compromise the blood-gas barrier. We have postulated that this synergy arises through a rich-get-richer mechanism whereby atelectrauma causes holes to form in the blood-gas barrier while concomitant volutrauma causes susceptible holes to progressively enlarge as VILI worsens. We previously developed an analytical model based on this idea that accurately predicts the progressive increases in lung elastance seen immediately following a recruitment maneuver as VILI progresses over the course of hours. In the present study we extend this model to account for the rate of change of elastance, due to closure of lung units, in the minutes following a recruitment maneuver. We found that the distribution of unit closing velocities throughout the lung can be described by a power law with an exponent of -2 that matches previously published power laws associated with the dynamics of lung recruitment. Our model thus reveals lung collapse as an example of emergent complex behavior and links the dynamics of altered function in the injured lung to structural damage in a way that explains the mechanisms of injury progression arising from the ongoing stresses and strains applied by mechanical ventilation.