Stress-strain curve and elastic behavior of the fibrotic lung with usual interstitial pneumonia pattern during protective mechanical ventilation.

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.

Ventilator-induced Lung Injury Promotes Inflammation within the Pleural Cavity.

Mechanical ventilation contributes to the morbidity and mortality of patients in intensive care, likely through the exacerbation and dissemination of inflammation. Despite the proximity of the pleural cavity to the lungs and exposure to physical forces, little attention has been paid to its potential as an inflammatory source during ventilation. Here, we investigate the pleural cavity as a novel site of inflammation during ventilator-induced lung injury. Mice were subjected to low or high tidal volume ventilation strategies for up to 3 hours. Ventilation with a high tidal volume significantly increased cytokine and total protein levels in BAL and pleural lavage fluid. In contrast, acid aspiration, explored as an alternative model of injury, only promoted intraalveolar inflammation, with no effect on the pleural space. Resident pleural macrophages demonstrated enhanced activation after injurious ventilation, including upregulated ICAM-1 and IL-1ß expression, and the release of extracellular vesicles. In vivo ventilation and in vitro stretch of pleural mesothelial cells promoted ATP secretion, whereas purinergic receptor inhibition substantially attenuated extracellular vesicles and cytokine levels in the pleural space. Finally, labeled protein rapidly translocated from the pleural cavity into the circulation during high tidal volume ventilation, to a significantly greater extent than that of protein translocation from the alveolar space. Overall, we conclude that injurious ventilation induces pleural cavity inflammation mediated through purinergic pathway signaling and likely enhances the dissemination of mediators into the vasculature. This previously unidentified consequence of mechanical ventilation potentially implicates the pleural space as a focus of research and novel avenue for intervention in critical care.

Low-volume ventilation of preinjured lungs degrades lung function via stress concentration and progressive alveolar collapse.

Mechanical ventilation can cause ventilation-induced lung injury (VILI). The concept of stress concentrations suggests that surfactant dysfunction-induced microatelectases might impose injurious stresses on adjacent, open alveoli and function as germinal centers for injury propagation. The aim of the present study was to quantify the histopathological pattern of VILI progression and to test the hypothesis that injury progresses at the interface between microatelectases and ventilated lung parenchyma during low-positive end-expiratory pressure (PEEP) ventilation. Bleomycin was used to induce lung injury with microatelectases in rats. Lungs were then mechanically ventilated for up to 6 h at PEEP = 1 cmH2O and compared with bleomycin-treated group ventilated protectively with PEEP = 5 cmH2O to minimize microatelectases. Lung mechanics were measured during ventilation. Afterward, lungs were fixed at end-inspiration or end-expiration for design-based stereology. Before VILI, bleomycin challenge reduced the number of open alveoli [N(alvair,par)] by 29%. No differences between end-inspiration and end-expiration were observed. Collapsed alveoli clustered in areas with a radius of up to 56 µm. After PEEP = 5 cmH2O ventilation for 6 h, N(alvair,par) remained stable while PEEP = 1 cmH2O ventilation led to an additional loss of aerated alveoli by 26%, mainly due to collapse, with a small fraction partly edema filled. Alveolar loss strongly correlated to worsening of tissue elastance, quasistatic compliance, and inspiratory capacity. The radius of areas of collapsed alveoli increased to 94 µm, suggesting growth of the microatelectases. These data provide evidence that alveoli become unstable in neighborhood of microatelectases, which most likely occurs due to stress concentration-induced local vascular leak and surfactant dysfunction.NEW & NOTEWORTHY Low-volume mechanical ventilation in the presence of high surface tension-induced microatelectases leads to the degradation of lung mechanical function via the progressive loss of alveoli. Microatelectases grow at the interfaces of collapsed and open alveoli. Here, stress concentrations might cause injury and alveolar instability. Accumulation of small amounts of alveolar edema can be found in a fraction of partly collapsed alveoli but, in this model, alveolar flooding is not a major driver for degradation of lung mechanics.

Comparison of limited driving pressure ventilation and low tidal volume strategies in adults with acute respiratory failure on mechanical ventilation: a randomized controlled trial.

BACKGROUND: Ventilator-induced lung injury (VILI) presents a grave risk to acute respiratory failure patients undergoing mechanical ventilation. Low tidal volume (LTV) ventilation has been advocated as a protective strategy against VILI. However, the effectiveness of limited driving pressure (plateau pressure minus positive end-expiratory pressure) remains unclear. OBJECTIVES: This study evaluated the efficacy of LTV against limited driving pressure in preventing VILI in adults with respiratory failure. DESIGN: A single-centre, prospective, open-labelled, randomized controlled trial. METHODS: This study was executed in medical intensive care units at Siriraj Hospital, Mahidol University, Bangkok, Thailand. We enrolled acute respiratory failure patients undergoing intubation and mechanical ventilation. They were randomized in a 1:1 allocation to limited driving pressure (LDP; ⩽15 cmH2O) or LTV (⩽8 mL/kg of predicted body weight). The primary outcome was the acute lung injury (ALI) score 7 days post-enrolment. RESULTS: From July 2019 to December 2020, 126 patients participated, with 63 each in the LDP and LTV groups. The cohorts had the mean (standard deviation) ages of 60.5 (17.6) and 60.9 (17.9) years, respectively, and they exhibited comparable baseline characteristics. The primary reasons for intubation were acute hypoxic respiratory failure (LDP 49.2%, LTV 63.5%) and shock-related respiratory failure (LDP 39.7%, LTV 30.2%). No significant difference emerged in the primary outcome: the median (interquartile range) ALI scores for LDP and LTV were 1.75 (1.00-2.67) and 1.75 (1.25-2.25), respectively (p = 0.713). Twenty-eight-day mortality rates were comparable: LDP 34.9% (22/63), LTV 31.7% (20/63), relative risk (RR) 1.08, 95% confidence interval (CI) 0.74-1.57, p = 0.705. Incidences of newly developed acute respiratory distress syndrome also aligned: LDP 14.3% (9/63), LTV 20.6% (13/63), RR 0.81, 95% CI 0.55-1.22, p = 0.348. CONCLUSIONS: In adults with acute respiratory failure, the efficacy of LDP and LTV in averting lung injury 7 days post-mechanical ventilation was indistinguishable. CLINICAL TRIAL REGISTRATION: The study was registered with the ClinicalTrials.gov database (identification number NCT04035915).

Limited breathing pressure or low amount of air given to the lung; which one is better for adults who need breathing help by ventilator machineWe conducted this research at Siriraj Hospital in Bangkok, Thailand, aiming to compare two ways of helping patients with breathing problems. We studied 126 patients who were randomly put into two groups. One group received a method where the pressure during breathing was limited (limited driving pressure: LDP), and the other group got a method where the amount of air given to the lungs was kept low (low tidal volume: LTV). We checked how bad the lung injury was at seven days later. The results showed that there was no difference between the two methods. Both ways of helping patients breathe had similar outcomes, and neither was significantly better than the other in preventing lung problems. The study suggests that both approaches work about the same for patients who need help with breathing using a machine.

Effect of antibody-mediated connective tissue growth factor neutralization on lung edema in ventilator-induced lung injury in rats.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is characterized by alveolar edema that can progress to septal fibrosis. Mechanical ventilation can augment lung injury, termed ventilator-induced lung injury (VILI). Connective tissue growth factor (CTGF), a mediator of fibrosis, is increased in ARDS patients. Blocking CTGF inhibits fibrosis and possibly vascular leakage. This study investigated whether neutralizing CTGF reduces pulmonary edema in VILI. METHODS: Following LPS administration, rats were mechanically ventilated for 6 h with low (6 mL/kg; low VT) or moderate (10 mL/kg; mod VT) tidal volume and treated with a neutralizing CTGF antibody (FG-3154) or placebo lgG (vehicle). Control rats without LPS were ventilated for 6 h with low VT. Lung wet-to-dry weight ratio, FITC-labeled dextran permeability, histopathology, and soluble RAGE were determined. RESULTS: VILI was characterized by reduced PaO2/FiO2 ratio (low VT: 540 [381-661] vs. control: 693 [620-754], p < 0.05), increased wet-to-dry weight ratio (low VT: 4.8 [4.6-4.9] vs. control: 4.5 [4.4-4.6], p < 0.05), pneumonia (low VT: 30 [0-58] vs. control: 0 [0-0]%, p < 0.05) and interstitial inflammation (low VT: 2 [1-3] vs. control: 1 [0-1], p < 0.05). FG-3154 did not affect wet-to-dry weight ratio (mod VT + FG-3154: 4.8 [4.7-5.0] vs. mod VT + vehicle: 4.8 [4.8-5.0], p > 0.99), extravasated dextrans (mod VT + FG-3154: 0.06 [0.04-0.09] vs. mod VT + vehicle: 0.04 [0.03-0.09] µg/mg tissue, p > 0.99), sRAGE (mod VT + FG-3154: 1865 [1628-2252] vs. mod VT + vehicle: 1885 [1695-2159] pg/mL, p > 0.99) or histopathology. CONCLUSIONS: 'Double hit' VILI was characterized by inflammation, impaired oxygenation, pulmonary edema and histopathological lung injury. Blocking CTGF does not improve oxygenation nor reduce pulmonary edema in rats with VILI.

Effects of mechanical ventilation on the interstitial extracellular matrix in healthy lungs and lungs affected by acute respiratory distress syndrome: a narrative review.

BACKGROUND: Mechanical ventilation, a lifesaving intervention in critical care, can lead to damage in the extracellular matrix (ECM), triggering inflammation and ventilator-induced lung injury (VILI), particularly in conditions such as acute respiratory distress syndrome (ARDS). This review discusses the detailed structure of the ECM in healthy and ARDS-affected lungs under mechanical ventilation, aiming to bridge the gap between experimental insights and clinical practice by offering a thorough understanding of lung ECM organization and the dynamics of its alteration during mechanical ventilation. MAIN TEXT: Focusing on the clinical implications, we explore the potential of precise interventions targeting the ECM and cellular signaling pathways to mitigate lung damage, reduce inflammation, and ultimately improve outcomes for critically ill patients. By analyzing a range of experimental studies and clinical papers, particular attention is paid to the roles of matrix metalloproteinases (MMPs), integrins, and other molecules in ECM damage and VILI. This synthesis not only sheds light on the structural changes induced by mechanical stress but also underscores the importance of cellular responses such as inflammation, fibrosis, and excessive activation of MMPs. CONCLUSIONS: This review emphasizes the significance of mechanical cues transduced by integrins and their impact on cellular behavior during ventilation, offering insights into the complex interactions between mechanical ventilation, ECM damage, and cellular signaling. By understanding these mechanisms, healthcare professionals in critical care can anticipate the consequences of mechanical ventilation and use targeted strategies to prevent or minimize ECM damage, ultimately leading to better patient management and outcomes in critical care settings.

Endothelial knockdown of the tumor suppressor, WWOX, increases inflammation in ventilator-induced lung injury.

Chronic cigarette smoke exposure decreases lung expression of WWOX which is known to protect the endothelial barrier during infectious models of acute respiratory distress syndrome (ARDS). Proteomic analysis of WWOX-silenced endothelial cells (ECs) was done using tandem mass tag mass spectrometry (TMT-MS). WWOX-silenced ECs as well as those isolated from endothelial cell Wwox knockout (EC Wwox KO) mice were subjected to cyclic stretch (18% elongation, 0.5 Hz, 4 h). Cellular lysates and media supernatant were harvested for assays of cellular signaling, protein expression, and cytokine release. These were repeated with dual silencing of WWOX and zyxin. Control and EC Wwox KO mice were subjected to high tidal volume ventilation. Bronchoalveolar lavage fluid and mouse lung tissue were harvested for cellular signaling, cytokine secretion, and histological assays. TMT-MS revealed upregulation of zyxin expression during WWOX knockdown which predicted a heightened inflammatory response to mechanical stretch. WWOX-silenced ECs and ECs isolated from EC Wwox mice displayed significantly increased cyclic stretch-mediated secretion of various cytokines (IL-6, KC/IL-8, IL-1ß, and MCP-1) relative to controls. This was associated with increased ERK and JNK phosphorylation but decreased p38 mitogen-activated kinases (MAPK) phosphorylation. EC Wwox KO mice subjected to VILI sustained a greater degree of injury than corresponding controls. Silencing of zyxin during WWOX knockdown abrogated stretch-induced increases in IL-8 secretion but not in IL-6. Loss of WWOX function in ECs is associated with a heightened inflammatory response during mechanical stretch that is associated with increased MAPK phosphorylation and appears, in part, to be dependent on the upregulation of zyxin.NEW & NOTEWORTHY Prior tobacco smoke exposure is associated with an increased risk of acute respiratory distress syndrome (ARDS) during critical illness. Our laboratory is investigating one of the gene expression changes that occurs in the lung following smoke exposure: WWOX downregulation. Here we describe changes in protein expression associated with WWOX knockdown and its influence on ventilator-induced ARDS in a mouse model.

Electrical impedance tomography-guided positive end-expiratory pressure titration in ARDS: a systematic review and meta-analysis.

PURPOSE: Assessing efficacy of electrical impedance tomography (EIT) in optimizing positive end-expiratory pressure (PEEP) for acute respiratory distress syndrome (ARDS) patients to enhance respiratory system mechanics and prevent ventilator-induced lung injury (VILI), compared to traditional methods. METHODS: We carried out a systematic review and meta-analysis, spanning literature from January 2012 to May 2023, sourced from Scopus, PubMed, MEDLINE (Ovid), Cochrane, and LILACS, evaluated EIT-guided PEEP strategies in ARDS versus conventional methods. Thirteen studies (3 randomized, 10 non-randomized) involving 623 ARDS patients were analyzed using random-effects models for primary outcomes (respiratory mechanics and mechanical power) and secondary outcomes (PaO2/FiO2 ratio, mortality, stays in intensive care unit (ICU), ventilator-free days). RESULTS: EIT-guided PEEP significantly improved lung compliance (n = 941 cases, mean difference (MD) = 4.33, 95% confidence interval (CI) [2.94, 5.71]), reduced mechanical power (n = 148, MD = - 1.99, 95% CI [- 3.51, - 0.47]), and lowered driving pressure (n = 903, MD = - 1.20, 95% CI [- 2.33, - 0.07]) compared to traditional methods. Sensitivity analysis showed consistent positive effect of EIT-guided PEEP on lung compliance in randomized clinical trials vs. non-randomized studies pooled (MD) = 2.43 (95% CI - 0.39 to 5.26), indicating a trend towards improvement. A reduction in mortality rate (259 patients, relative risk (RR) = 0.64, 95% CI [0.45, 0.91]) was associated with modest improvements in compliance and driving pressure in three studies. CONCLUSIONS: EIT facilitates real-time, individualized PEEP adjustments, improving respiratory system mechanics. Integration of EIT as a guiding tool in mechanical ventilation holds potential benefits in preventing ventilator-induced lung injury. Larger-scale studies are essential to validate and optimize EIT's clinical utility in ARDS management.

Electrical impedance tomography: Usefulness for respiratory physiotherapy in critical illnesses.

Respiratory physiotherapy, including the management of invasive mechanical ventilation (MV) and noninvasive mechanical ventilation (NIV), is a key supportive intervention for critically ill patients. MV has potential for inducing ventilator-induced lung injury (VILI) as well as long-term complications related to prolonged bed rest, such as post-intensive care syndrome and intensive care unit acquired weakness. Physical and respiratory therapy, developed by the critical care team, in a timely manner, has been shown to prevent these complications. In this pathway, real-time bedside monitoring of changes in pulmonary aeration and alveolar gas distribution associated with postural positioning, respiratory physiotherapy techniques and changes in MV strategies can be crucial in guiding these procedures, providing safe therapy and prevention of potential harm to the patient. Along this path, electrical impedance tomography (EIT) has emerged as a new key non-invasive bedside strategy free of radiation, to allow visualization of lung recruitment. This review article presents the main and potential applications of EIT in relation to physiotherapy techniques in the ICU setting.

Guide to Lung-Protective Ventilation in Cardiac Patients.

The incidence of acute respiratory insufficiency has continued to increase among patients admitted to modern-day cardiovascular intensive care units. Positive pressure ventilation (PPV) remains the mainstay of treatment for these patients. Alterations in intrathoracic pressure during PPV has distinct effects on both the right and left ventricles, affecting cardiovascular performance. Lung-protective ventilation (LPV) minimizes the risk of further lung injury through ventilator-induced lung injury and, hence, an understanding of LPV and its cardiopulmonary interactions is beneficial for cardiologists.

Imp7 siRNA nanoparticles protect against mechanical ventilation-associated liver injury by inhibiting HMGB1 production and NETs formation.

Mechanical ventilation (MV) has the potential to induce extra-pulmonary organ damage by adversely affecting the lungs and promoting the secretion of inflammatory cytokines. High-mobility group box 1 protein (HMGB1) is a pro-inflammatory mediator in ventilator-induced lung injury (VILI), but its effect on MV-associated liver injury and the mechanisms are poorly understood. In the present study, mice were subjected to high-volume MV (20 ml/kg) to induce VILI. MV-induced HMGB1 prompted neutrophil extracellular traps (NETs) formation and PANoptosis within the liver. Inhibiting NETs formation by DNase I or PAD4 inhibitor, or by HMGB1 neutralizing ameliorated the liver injury. HMGB1 activated neutrophils to form NETs through TLR4/MyD88/TRAF6 pathway. Importantly, Importin7 siRNA nanoparticles inhibited HMGB1 release and protected against MV-associated liver injury. These data provide evidence of MV-induced HMGB1 prompted NETs formation and PANoptosis in the liver via the TLR4/MyD88/TRAF6 pathway. HMGB1 is a potential therapeutic target for MV-associated liver injury.

Age-dependent ventilator-induced lung injury: Mathematical modeling, experimental data, and statistical analysis.

A variety of pulmonary insults can prompt the need for life-saving mechanical ventilation; however, misuse, prolonged use, or an excessive inflammatory response, can result in ventilator-induced lung injury. Past research has observed an increased instance of respiratory distress in older patients and differences in the inflammatory response. To address this, we performed high pressure ventilation on young (2-3 months) and old (20-25 months) mice for 2 hours and collected data for macrophage phenotypes and lung tissue integrity. Large differences in macrophage activation at baseline and airspace enlargement after ventilation were observed in the old mice. The experimental data was used to determine plausible trajectories for a mathematical model of the inflammatory response to lung injury which includes variables for the innate inflammatory cells and mediators, epithelial cells in varying states, and repair mediators. Classification methods were used to identify influential parameters separating the parameter sets associated with the young or old data and separating the response to ventilation, which was measured by changes in the epithelial state variables. Classification methods ranked parameters involved in repair and damage to the epithelial cells and those associated with classically activated macrophages to be influential. Sensitivity results were used to determine candidate in-silico interventions and these interventions were most impact for transients associated with the old data, specifically those with poorer lung health prior to ventilation. Model results identified dynamics involved in M1 macrophages as a focus for further research, potentially driving the age-dependent differences in all macrophage phenotypes. The model also supported the pro-inflammatory response as a potential indicator of age-dependent differences in response to ventilation. This mathematical model can serve as a baseline model for incorporating other pulmonary injuries.

Time-Controlled Adaptive Ventilation (TCAV): a personalized strategy for lung protection.

Acute respiratory distress syndrome (ARDS) alters the dynamics of lung inflation during mechanical ventilation. Repetitive alveolar collapse and expansion (RACE) predisposes the lung to ventilator-induced lung injury (VILI). Two broad approaches are currently used to minimize VILI: (1) low tidal volume (LVT) with low-moderate positive end-expiratory pressure (PEEP); and (2) open lung approach (OLA). The LVT approach attempts to protect already open lung tissue from overdistension, while simultaneously resting collapsed tissue by excluding it from the cycle of mechanical ventilation. By contrast, the OLA attempts to reinflate potentially recruitable lung, usually over a period of seconds to minutes using higher PEEP used to prevent progressive loss of end-expiratory lung volume (EELV) and RACE. However, even with these protective strategies, clinical studies have shown that ARDS-related mortality remains unacceptably high with a scarcity of effective interventions over the last two decades. One of the main limitations these varied interventions demonstrate to benefit is the observed clinical and pathologic heterogeneity in ARDS. We have developed an alternative ventilation strategy known as the Time Controlled Adaptive Ventilation (TCAV) method of applying the Airway Pressure Release Ventilation (APRV) mode, which takes advantage of the heterogeneous time- and pressure-dependent collapse and reopening of lung units. The TCAV method is a closed-loop system where the expiratory duration personalizes VT and EELV. Personalization of TCAV is informed and tuned with changes in respiratory system compliance (CRS) measured by the slope of the expiratory flow curve during passive exhalation. Two potentially beneficial features of TCAV are: (i) the expiratory duration is personalized to a given patient's lung physiology, which promotes alveolar stabilization by halting the progressive collapse of alveoli, thereby minimizing the time for the reopened lung to collapse again in the next expiration, and (ii) an extended inspiratory phase at a fixed inflation pressure after alveolar stabilization gradually reopens a small amount of tissue with each breath. Subsequently, densely collapsed regions are slowly ratcheted open over a period of hours, or even days. Thus, TCAV has the potential to minimize VILI, reducing ARDS-related morbidity and mortality.