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Abstract Rationale Unphysiologic strain (the ratio between tidal volume and functional residual capacity) and stress (the transpulmonary pressure) can cause ventilator-induced lung damage. Objectives To identify a strain–stress threshold (if any) above which ventilator-induced lung damage can occur. Methods Twenty-nine healthy pigs were mechanically ventilated for 54 hours with a tidal volume producing a strain between 0.45 and 3.30. Ventilator-induced lung damage was defined as net increase in lung weight. Measurements and Main Results Initial lung weight and functional residual capacity were measured with computed tomography. Final lung weight was measured using a balance. After setting tidal volume, data collection included respiratory system mechanics, gas exchange and hemodynamics (every 6 h); cytokine levels in serum (every 12 h) and bronchoalveolar lavage fluid (end of the experiment); and blood laboratory examination (start and end of the experiment). Two clusters of animals could be clearly identified: animals that increased their lung weight (n = 14) and those that did not (n = 15). Tidal volume was 38 ± 9 ml/kg in the former and 22 ± 8 ml/kg in the latter group, corresponding to a strain of 2.16 ± 0.58 and 1.29 ± 0.57 and a stress of 13 ± 5 and 8 ± 3 cm H2O, respectively. Lung weight gain was associated with deterioration in respiratory system mechanics, gas exchange, and hemodynamics, pulmonary and systemic inflammation and multiple organ dysfunction. Conclusions In healthy pigs, ventilator-induced lung damage develops only when a strain greater than 1.5–2 is reached or overcome. Because of differences in intrinsic lung properties, caution is warranted in translating these findings to humans.

Deterioration of lung function during the first week of COVID-19 has been observed when patients remain with insufficient respiratory support. Patient self-inflicted lung injury (P-SILI) is theorized as the responsible, but there is not robust experimental and clinical data to support it. Given the limited understanding of P-SILI, we describe the physiological basis of P-SILI and we show experimental data to comprehend the role of regional strain and heterogeneity in lung injury due to increased work of breathing. In addition, we discuss the current approach to respiratory support for COVID-19 under this point of view.

Rationale End-expiratory lung volume (EELV) is reduced in mechanically ventilated patients, especially in pathologic conditions. The resulting heterogeneous distribution of ventilation increases the risk for ventilation induced lung injury. Clinical measurement of EELV however, remains difficult. Objective Validation of a novel continuous capnodynamic method based on expired carbon dioxide (CO 2 ) kinetics for measuring EELV in mechanically ventilated critically-ill patients. Methods Prospective study of mechanically ventilated patients scheduled for a diagnostic computed tomography exploration. Comparisons were made between absolute and corrected EELVCO 2 values, the latter accounting for the amount of CO 2 dissolved in lung tissue, with the reference EELV measured by computed tomography (EELVCT). Uncorrected and corrected EELVCO 2 was compared with total CT volume (density compartments between − 1000 and 0 Hounsfield units (HU) and functional CT volume, including density compartments of − 1000 to − 200HU eliminating regions of increased shunt. We used comparative statistics including correlations and measurement of accuracy and precision by the Bland Altman method. Measurements and main results Of the 46 patients included in the final analysis, 25 had a diagnosis of ARDS (24 of which COVID-19). Both EELVCT and EELVCO 2 were significantly reduced (39 and 40% respectively) when compared with theoretical values of functional residual capacity ( p  < 0.0001). Uncorrected EELVCO 2 tended to overestimate EELVCT with a correlation r 2 0.58; Bias − 285 and limits of agreement (LoA) (+ 513 to − 1083; 95% CI) ml. Agreement improved for the corrected EELVCO 2 to a Bias of − 23 and LoA of (+ 763 to − 716; 95% CI) ml. The best agreement of the method was obtained by comparison of corrected EELVCO 2 with functional EELVCT with a r 2 of 0.59; Bias − 2.75 (+ 755 to − 761; 95% CI) ml. We did not observe major differences in the performance of the method between ARDS (most of them COVID related) and non-ARDS patients. Conclusion In this first validation in critically ill patients, the capnodynamic method provided good estimates of both total and functional EELV. Bias improved after correcting EELVCO 2 for extra-alveolar CO 2 content when compared with CT estimated volume. If confirmed in further validations EELVCO 2 may become an attractive monitoring option for continuously monitor EELV in critically ill mechanically ventilated patients. Trial registration : clinicaltrials.gov (NCT04045262).

Clinicians currently monitor pressure and volume at the airway opening, assuming that these observations relate closely to stresses and strains at the micro level. Indeed, this assumption forms the basis of current approaches to lung protective ventilation. Nonetheless, although the airway pressure applied under static conditions may be the same everywhere in healthy lungs, the stresses within a mechanically non-uniform ARDS lung are not. Estimating actual tissue stresses and strains that occur in a mechanically non-uniform environment must account for factors beyond the measurements from the ventilator circuit of airway pressures, tidal volume, and total mechanical power. A first conceptual step for the clinician to better define the VILI hazard requires consideration of lung unit tension, stress focusing, and intracycle power concentration. With reasonable approximations, better understanding of the value and limitations of presently used general guidelines for lung protection may eventually be developed from clinical inputs measured by the caregiver. The primary purpose of the present thought exercise is to extend our published model of a uniform, spherical lung unit to characterize the amplifications of stress (tension) and strain (area change) that occur under static conditions at interface boundaries between a sphere’s surface segments having differing compliances. Together with measurable ventilating power, these are incorporated into our perspective of VILI risk. This conceptual exercise brings to light how variables that are seldom considered by the clinician but are both recognizable and measurable might help gauge the hazard for VILI of applied pressure and power.

Background The effect of alterations in tidal volume on mortality of acute respiratory distress syndrome (ARDS) is determined by respiratory system compliance. We aimed to investigate the effects of different tidal volumes on lung strain in ARDS patients who had various levels of respiratory system compliance. Methods Nineteen patients were divided into high (C high group) and low (C low group) respiratory system compliance groups based on their respiratory system compliance values. We defined compliance ≥0.6 ml/(cmH 2 O/kg) as C high and compliance <0.6 ml/(cmH 2 O/kg) as C low . End-expiratory lung volumes (EELV) at various tidal volumes were measured by nitrogen wash-in/washout. Lung strain was calculated as the ratio between tidal volume and EELV. The primary outcome was that lung strain is a function of tidal volume in patients with various levels of respiratory system compliance. Results The mean baseline EELV, strain and respiratory system compliance values were 1873 ml, 0.31 and 0.65 ml/(cmH 2 O/kg), respectively; differences in all of these parameters were statistically significant between the two groups. For all participants, a positive correlation was found between the respiratory system compliance and EELV (R = 0.488, p  = 0.034). Driving pressure and strain increased together as the tidal volume increased from 6 ml/kg predicted body weight (PBW) to 12 ml/kg PBW. Compared to the C high ARDS patients, the driving pressure was significantly higher in the C low patients at each tidal volume. Similar effects of lung strain were found for tidal volumes of 6 and 8 ml/kg PBW. The “lung injury” limits for driving pressure and lung strain were much easier to exceed with increases in the tidal volume in C low patients. Conclusions Respiratory system compliance affected the relationships between tidal volume and driving pressure and lung strain in ARDS patients. These results showed that increasing tidal volume induced lung injury more easily in patients with low respiratory system compliance. Trial registration Clinicaltrials.gov identifier NCT01864668 , Registered 21 May 2013.

In patients with acute respiratory distress syndrome, mechanical ventilation often leads to ventilation-induced lung injury (VILI), which is attributed to unphysiological lung strain (UPLS) in respiratory dynamics. Platelet endothelial cell adhesion molecule-1 (PECAM-1), a transmembrane receptor, senses mechanical signals. The Src/STAT3 pathway plays a crucial role in the mechanotransduction network, concurrently triggering pyroptosis related inflammatory responses. We hypothesized that the mechanical stretch caused by UPLS can be sensed by PECAM-1 in the lungs, leading to VILI via the Src/STAT3 and pyroptosis pathway. A VILI model was established in rats through UPLS. The link between lung strain and VILI as well as the change in the activation of PECAM-1, Src/STAT3, and pyroptosis was firstly being explored. Then, the inhibitors of PECAM-1, Src, STAT3 were adopted respectively, the effect on VILI, inflammation, the Src/STAT3 pathway, and pyroptosis was evaluated. , human umbilical vein endothelial cells (HUVECs) were used to validate the findings . UPLS activated PECAM-1, Src/STAT3 signaling pathway, inflammation, and pyroptosis in the VILI model with rats, whereas inhibition of PECAM-1 or the Src/STAT3 signaling pathway decreased lung injury, inflammatory responses, and pyroptosis. Inhibition of PECAM-1 also reduced activation of the Src/STAT3 signaling pathway. The mechanism was validated with HUVECs exposed to overload mechanical cyclic stretch. This study suggests that UPLS contributes to VILI by activating the PECAM-1/Src/STAT3 pathway and inducing inflammatory responses as well aspyroptosis.

Mechanical ventilation is a fundamental intervention in intensive care medicine, providing vital support for patients with severe respiratory failure. However, this life-sustaining therapy also carries the risk of harm. Ventilator-induced lung injury (VILI) is now predominantly understood in terms of lung overdistension, characterized by excessive stress and strain on pulmonary tissue. In recent years, a variety of novel monitoring strategies have emerged, from refined measurements of respiratory mechanics to advanced imaging and physiologic modeling, to help in bedside detection of excessive lung stress and strain. Electrical impedance tomography is a non-invasive tool providing real-time imaging of regional ventilation and assisting in the diagnosis of overdistension and its minimization through positive end-expiratory pressure titration, also during partial support ventilation. Pleural and lung ultrasound might also suggest the occurrence of overdistension, although clinical data are still preliminary. Bedside maneuvers, such as changing patient positioning or applying abdominal weights, can help identify overdistension by observing change in respiratory mechanics. Ventilator-based methods like the recruitment-to-inflation ratio and the overdistension index help assess the risk of overdistension, despite requiring careful interpretation and validation. Biomarkers such as Clara cell secretory protein-16 and stretch-induced gene signatures represent a promising avenue for real-time monitoring of lung injury, though further validation is needed. These tools aim to help clinicians individualize ventilator settings, balancing adequate gas exchange with lung protection. Despite this progress, most techniques remain in the realm of research. Few have undergone the rigorous physiological and clinical validation necessary for routine bedside use. As the critical care community moves toward more personalized ventilation strategies, establishing reliable, real-time methods to assess lung stress and strain at the bedside will be key to translating innovation into improved patient outcomes.

Purpose To investigate ventilator-induced lung injury (VILI), several experimental models were designed including different mammalian species and ventilator settings, leading to a large variability in the observed time-course and injury severity. We hypothesized that the time-course of VILI may be fully explained from a single perspective when considering the insult actually applied, i.e. lung stress and strain. Methods Studies in which healthy animals were aggressively ventilated until preterminal VILI were selected via a Medline search. Data on morphometry, ventilator settings, respiratory function and duration of ventilation were derived. For each animal group, lung stress (transpulmonary pressure) and strain (end-inspiratory lung inflation/lung resting volume ratio) were estimated. Results From the Medline search 20 studies including five mammalian species (sheep, pigs, rabbits, rats, mice) were selected. Time to achieve preterminal VILI varied widely (18–2,784 min), did not correlate with either tidal volume (expressed in relation to body weight) or airway pressure applied, but was weakly associated with lung stress ( r 2  = 0.25, p  = 0.008). In contrast, the duration of mechanical ventilation was closely correlated with both lung strain ( r 2  = 0.85, p  < 0.0001) and lung strain weighted for the actual time of application during each breath ( r 2  = 0.83, p  < 0.0001), according to exponential decay functions. When it was normalized for the lung strain applied, larger species showed a greater resistance to VILI than smaller species (medians, 25th–75th percentiles: 690, 460–2,001 min vs. 16, 4–59 min, respectively; p  < 0.001). Conclusion Lung strain may play a critical role as a unifying rule describing the development of VILI among mammals with healthy lungs.

Although mechanical ventilation (MV) is a life-saving intervention for patients with acute respiratory distress syndrome (ARDS), it can aggravate or cause lung injury, known as ventilator-induced lung injury (VILI). The biophysical characteristics of heterogeneously injured ARDS lungs increase the parenchymal stress associated with breathing, which is further aggravated by MV. Cells, in particular those lining the capillaries, airways and alveoli, transform this strain into chemical signals (mechanotransduction). The interaction of reparative and injurious mechanotransductive pathways leads to VILI. Several attempts have been made to identify clinical surrogate measures of lung stress/strain (e.g., density changes in chest computed tomography, lower and upper inflection points of the pressure-volume curve, plateau pressure and inflammatory cytokine levels) that could be used to titrate MV. However, uncertainty about the topographical distribution of stress relative to that of the susceptibility of the cells and tissues to injury makes the existence of a single 'global stress/strain injury threshold doubtful.

Background Data on the lung respiratory mechanics and gas exchange in the time course of COVID-19-associated respiratory failure is limited. This study aimed to explore respiratory mechanics and gas exchange, the lung recruitability and risk of overdistension during the time course of mechanical ventilation. Methods This was a prospective observational study in critically ill mechanically ventilated patients ( n  = 116) with COVID-19 admitted into Intensive Care Units of Sechenov University. The primary endpoints were: «optimum» positive end-expiratory pressure (PEEP) level balanced between the lowest driving pressure and the highest SpO 2 and number of patients with recruitable lung on Days 1 and 7 of mechanical ventilation. We measured driving pressure at different levels of PEEP (14, 12, 10 and 8 cmH 2 O) with preset tidal volume, and with the increase of tidal volume by 100 ml and 200 ml at preset PEEP level, and calculated static respiratory system compliance (C RS ), PaO 2 /FiO 2 , alveolar dead space and ventilatory ratio on Days 1, 3, 5, 7, 10, 14 and 21. Results The «optimum» PEEP levels on Day 1 were 11.0 (10.0–12.8) cmH 2 O and 10.0 (9.0–12.0) cmH 2 O on Day 7. Positive response to recruitment was observed on Day 1 in 27.6% and on Day 7 in 9.2% of patients. PEEP increase from 10 to 14 cmH 2 O and VT increase by 100 and 200 ml led to a significant decrease in C RS from Day 1 to Day 14 ( p  < 0.05). Ventilatory ratio was 2.2 (1.7–2,7) in non-survivors and in 1.9 (1.6–2.6) survivors on Day 1 and decreased on Day 7 in survivors only ( p  < 0.01). PaO 2 /FiO 2 was 105.5 (76.2–141.7) mmHg in non-survivors on Day 1 and 136.6 (106.7–160.8) in survivors ( p  = 0.002). In survivors, PaO 2 /FiO 2 rose on Day 3 ( p  = 0.008) and then between Days 7 and 10 ( p  = 0.046). Conclusion Lung recruitability was low in COVID-19 and decreased during the course of the disease, but lung overdistension occurred at «intermediate» PEEP and VT levels. In survivors gas exchange improvements after Day 7 mismatched C RS . Trial registration ClinicalTrials.gov, NCT04445961 . Registered 24 June 2020—Retrospectively registered.