Ventilator-induced Lung Injury Research Articles

Low volume ventilation of pre-injured 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 hours at PEEP=1cmH2O and compared to bleomycin treated group ventilated protectively with PEEP=5cmH2O to minimize microatelectases. Lung mechanics were measured during ventilation. Afterwards lungs were fixed at end-inspiration or end-expiration for design-based stereology. Prior to 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 up to 56 µm. After PEEP=5cmH2O ventilation for 6 hours, N(alvair,par) remained stable while PEEP=1cmH2O 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, quasi-static 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 by stress concentration-induced local vascular leak and surfactant dysfunction.

Inconsistent Methods Used to Set Airway Pressure Release Ventilation in Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Regression Analysis.

Airway pressure release ventilation (APRV) is a protective mechanical ventilation mode for patients with acute respiratory distress syndrome (ARDS) that theoretically may reduce ventilator-induced lung injury (VILI) and ARDS-related mortality. However, there is no standard method to set and adjust the APRV mode shown to be optimal. Therefore, we performed a meta-regression analysis to evaluate how the four individual APRV settings impacted the outcome in these patients. Methods: Studies investigating the use of the APRV mode for ARDS patients were searched from electronic databases. We tested individual settings, including (1) high airway pressure (PHigh); (2) low airway pressure (PLow); (3) time at high airway pressure (THigh); and (4) time at low pressure (TLow) for association with PaO2/FiO2 ratio and ICU length of stay. Results: There was no significant difference in PaO2/FiO2 ratio between the groups in any of the four settings (PHigh difference -12.0 [95% CI -100.4, 86.4]; PLow difference 54.3 [95% CI -52.6, 161.1]; TLow difference -27.19 [95% CI -127.0, 72.6]; THigh difference -51.4 [95% CI -170.3, 67.5]). There was high heterogeneity across all parameters (PhHgh I2 = 99.46%, PLow I2 = 99.16%, TLow I2 = 99.31%, THigh I2 = 99.29%). Conclusions: None of the four individual APRV settings independently were associated with differences in outcome. A holistic approach, analyzing all settings in combination, may improve APRV efficacy since it is known that small differences in ventilator settings can significantly alter mortality. Future clinical trials should set and adjust APRV based on the best current scientific evidence available.

Electrical Impedance Tomography: A Monitoring Tool for Ventilation Induced Lung Injury.

Electrical Impedance Tomography: A Monitoring Tool for Ventilation Induced Lung Injury.

A scale-free model of acute and ventilator-induced lung injury: a network theory approach inspired by seismology

IntroductionAcute respiratory distress syndrome (ARDS) presents a significant clinical challenge, with ventilator-induced lung injury (VILI) being a critical complication arising from life-saving mechanical ventilation. Understanding the spatial and temporal dynamics of VILI can inform therapeutic strategies to mitigate lung damage and improve outcomes.MethodsHistological sections from initially healthy mice and pulmonary lavage-injured mice subjected to a second hit of VILI were segmented with Ilastik to define regions of lung injury. A scale-free network approach was applied to assess the correlation between injury regions, with regions of injury represented as ‘nodes’ in the network and ‘edges’ quantifying the degree of correlation between nodes. A simulated time series analysis was conducted to emulate the temporal sequence of injury events.ResultsAutomated segmentation identified different lung regions in good agreement with manual scoring, achieving a sensitivity of 78% and a specificity of 85% across ‘injury’ pixels. Overall accuracy across ‘injury’, ‘air’, and ‘other’ pixels was 81%. The size of injured regions followed a power-law distribution, suggesting a ‘rich-get-richer’ phenomenon in the distribution of lung injury. Network analysis revealed a scale-free distribution of injury correlations, highlighting hubs of injury that could serve as focal points for therapeutic intervention. Simulated time series analysis further supported the concept of secondary injury events following an initial insult, with patterns resembling those observed in seismological studies of aftershocks.ConclusionThe size distribution of injured regions underscores the spatially heterogeneous nature of acute and ventilator-induced lung injury. The application of network theory demonstrates the emergence of injury ‘hubs’ that are consistent with a ‘rich-get-richer’ dynamic. Simulated time series analysis demonstrates that the progression of injury events in the lung could follow spatiotemporal patterns similar to the progression of aftershocks in seismology, providing new insights into the mechanisms of injury distribution and propagation. Both phenomena suggest a potential for interventions targeting these injury ‘hubs’ to reduce the impact of VILI in ARDS management.

Clinical validation of a capnodynamic method for measuring end-expiratory lung volume in critically ill patients

RationaleEnd-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.ObjectiveValidation of a novel continuous capnodynamic method based on expired carbon dioxide (CO2) kinetics for measuring EELV in mechanically ventilated critically-ill patients.MethodsProspective study of mechanically ventilated patients scheduled for a diagnostic computed tomography exploration. Comparisons were made between absolute and corrected EELVCO2 values, the latter accounting for the amount of CO2 dissolved in lung tissue, with the reference EELV measured by computed tomography (EELVCT). Uncorrected and corrected EELVCO2 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 resultsOf the 46 patients included in the final analysis, 25 had a diagnosis of ARDS (24 of which COVID-19). Both EELVCT and EELVCO2 were significantly reduced (39 and 40% respectively) when compared with theoretical values of functional residual capacity (p < 0.0001). Uncorrected EELVCO2 tended to overestimate EELVCT with a correlation r2 0.58; Bias − 285 and limits of agreement (LoA) (+ 513 to − 1083; 95% CI) ml. Agreement improved for the corrected EELVCO2 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 EELVCO2 with functional EELVCT with a r2 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.ConclusionIn this first validation in critically ill patients, the capnodynamic method provided good estimates of both total and functional EELV. Bias improved after correcting EELVCO2 for extra-alveolar CO2 content when compared with CT estimated volume. If confirmed in further validations EELVCO2 may become an attractive monitoring option for continuously monitor EELV in critically ill mechanically ventilated patients.Trial registration: clinicaltrials.gov (NCT04045262).

Rutin targets AKT to inhibit ferroptosis in ventilator-induced lung injury.

Our previous research confirmed that rutin reduced ventilator-induced lung injury (VILI) in mice. Ferroptosis has been reported to participate in the pathogenic process of VILI. We will explore whether rutin inhibits ferroptosis to alleviate VILI. A mouse model of VILI was constructed with or without rutin pretreatment to perform a multiomics analysis. Hematoxylin-eosin (HE) staining and transmission electron microscopy were used to evaluate lung injury in VILI mice. Dihydroethidium (DHE) staining and the malondialdehyde (MDA) and superoxide dismutase (SOD) levels were detected. Molecular docking was performed to determine the binding affinity between rutin and ferroptosis-related proteins. Western blot analysis, real-time PCR (RT-PCR) and immunohistochemical (IHC) staining were conducted to detect the expression levels of GPX4, XCT, ACSL4, FTH1, AKT and p-AKT in lung tissues. Microscale thermophoresis (MST) was used to evaluate the binding between rutin and AKT1. Transcriptomic and proteomic analyses showed that ferroptosis may play a key role in VILI mice. Metabolomic analysis demonstrated that rutin may affect ferroptosis via the AKT pathway. Molecular docking analysis indicated that rutin may regulate the expression of ferroptosis-related proteins. Moreover, rutin upregulated GPX4 expression and downregulated the expression of XCT, ACSL4 and FTH1 in the lung tissues. Rutin also increased the ratio of p-AKT/AKT and p-AKT expression. MST analysis showed that rutin binds to AKT1. Rutin binds to AKT to activate the AKT signaling pathway, contributing to inhibit ferroptosis, thus preventing VILI in mice. Our study elucidated a possible novel strategy of involving the use of rutin for preventing VILI.

Negative pressure ventilation, an umbrella against ventilator induced lung injury.

Negative pressure ventilation, an umbrella against ventilator induced lung injury.

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 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 Wwox knockout (EC Wwox KO) mice were subjected to cyclic stretch (18% elongation, 0.5 Hz, 4 hours). 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 histologic 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-1β, and MCP-1) relative to controls. This was associated with increased ERK and JNK phosphorylation but decreased p38 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. 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 to be dependent on upregulation of zyxin.

Aerobic Exercise in Male Mice Prevents Ventilator-Induced Lung Injury by Inhibiting Mitochondrial Damage from sirt1 Dysregulation - Retraction.

Aerobic Exercise in Male Mice Prevents Ventilator-Induced Lung Injury by Inhibiting Mitochondrial Damage from sirt1 Dysregulation - Retraction.

Rationale and study design for an Individualized PeriopeRative Open lung VEntilatory approach in Emergency Abdominal Laparotomy/scopy: study protocol for a prospective international randomized controlled trial

BackgroundPostoperative pulmonary complications (PPC) are the most frequent postoperative complications, with an estimated prevalence in elective surgery ranging from 20% in observational cohort studies to 40% in randomized clinical trials. However, the prevalence of PPCs in patients undergoing emergency abdominal surgery is not well defined. Lung-protective ventilation aims to minimize ventilator-induced lung injury and reduce PPCs. The open lung approach (OLA), which combines recruitment manoeuvres (RM) and positive end-expiratory pressure (PEEP) titration, aims to minimize areas of atelectasis and the development of PPCs; however, there is no conclusive evidence in the literature that OLA can prevent PPCs. The purpose of this study is to compare an individualized perioperative OLA with conventional standardized lung-protective ventilation in patients undergoing emergency abdominal surgery with clinical signs of intraoperative lung collapse. MethodsRandomized international clinical trial to compare an individualized perioperative OLA (RM plus individualized PEEP and individualized postoperative respiratory support) with conventional lung-protective ventilation (standard PEEP of 5 cmH2O and conventional postoperative oxygen therapy) in patients undergoing emergency abdominal surgery with clinical signs of lung collapse. Patients will be randomised to open-label parallel groups. The primary outcome is any severe PPC during the first 7 postoperative days, including: acute respiratory failure, pneumothorax, weaning failure, acute respiratory distress syndrome, and pulmonary infection. The estimated sample size is 732 patients (366 per group). The final sample size will be readjusted during the interim analysis. DiscussionThe Individualized Perioperative Open-lung Ventilatory Strategy in emergency abdominal laparotomy (iPROVE-EAL) is the first multicentre, randomized, controlled trial to investigate whether an individualized perioperative approach prevents PPCs in patients undergoing emergency surgery.

Flow-controlled ventilation decreases mechanical power in postoperative ICU patients

BackgroundMechanical power (MP) is the energy delivered by the ventilator to the respiratory system and combines factors related to the development of ventilator-induced lung injury (VILI). Flow-controlled ventilation (FCV) is a new ventilation mode using a constant low flow during both inspiration and expiration, which is hypothesized to lower the MP and to improve ventilation homogeneity. Data demonstrating these effects are scarce, since previous studies comparing FCV with conventional controlled ventilation modes in ICU patients suffer from important methodological concerns.ObjectivesThis study aims to assess the difference in MP between FCV and pressure-controlled ventilation (PCV). Secondary aims were to explore the effect of FCV in terms of minute volume, ventilation distribution and homogeneity, and gas exchange.MethodsThis is a physiological study in post-cardiothoracic surgery patients requiring mechanical ventilation in the ICU. During PCV at baseline and 90 min of FCV, intratracheal pressure, airway flow and electrical impedance tomography (EIT) were measured continuously, and hemodynamics and venous and arterial blood gases were obtained repeatedly. Pressure–volume loops were constructed for the calculation of the MP.ResultsIn 10 patients, optimized FCV versus PCV resulted in a lower MP (7.7 vs. 11.0 J/min; p = 0.004). Although FCV did not increase overall ventilation homogeneity, it did lead to an improved ventilation of the dependent lung regions. A stable gas exchange at lower minute volumes was obtained.ConclusionsFCV resulted in a lower MP and improved ventilation of the dependent lung regions in post-cardiothoracic surgery patients on the ICU.Trial registration Clinicaltrials.gov identifier: NCT05644418. Registered 1 December 2022, retrospectively registered.

Cyclic energy: the transcendental relevance of respiratory rate. A retrospective observational study with Bayesian analysis

Introduction The calculation of energy transfer in patients with acute respiratory distress syndrome (ARDS), has multiple interpretations and proposals. The parameters described as safe to minimize mechanical ventilator-associated lung injury (VALI) include only static values in their conception, and dynamic variables have been relegated to a secondary role. Subjects and Methods Analytical, observational, retrospective study of patients hospitalized in a respiratory intensive care unit, with a diagnosis of severe ARDS due to SARS-CoV-2 in whom mechanical ventilator management was guided by the use of esophageal catheter for the calculation of ventilatory variables. Thirty-four patients were included in this study, 23.5 % were women and the mean body mass index was 34.9 kg/m2. The primary objective was to quantify the amount of energy (Mechanical Power MP) transmitted by using multiple known equations and the secondary objective was to find the variables best associated with such energy transfer and with the severity of ARDS using Bayesian analysis. Results A mean of 22.2 days on invasive mechanical ventilation was recorded. Baseline MPGattinoni averaged 21.4 J/min, which did not change significantly at 30 minutes (7.5%) or 24 hours (- 0.4%) from baseline, despite esophageal catheter-guided management. The Bayesian analyses used to calculate the a posteriori inclusion probability showed that respiratory rate was the only variable consistently related to energy transfer, regardless of the equation used for its calculation and the chronological time at which these equations were measured [baseline MPGattinoni: (mean, 0.89; 95% Cred Interval: 0.75 to 1.02), at 30 minutes: (mean, 1.09; 95% Cred Interval: 0.68 to 1.49), at 24 hours: (mean, 0.65; 95% Cred Interval: 0.01 to 1.03)] or [baseline MPModesto: (mean, 0.1; 95% Cred Interval: 0.09 to 0.1), at 30 minutes: (mean, 0.1; 95% Cred Interval: 0.09 to 0.1), at 24 hours: (mean, 0.1; 95% Cred Interval: 0.09 to 0.1)]. Conclusions In severe ARDS, it is essential to minimize VALI. The calculation of energy transfer, regardless of the equation used, should always be a dynamic objective to be measured. Respiratory rate is probably the most relevant dynamic variable in the genesis of VALI. Keywords: mechanical power, elastic power, respiratory rate, ARDS, COVID-19

Effects of prone positioning on lung mechanical power components in patients with acute respiratory distress syndrome: a physiologic study

BackgroundProne positioning (PP) homogenizes ventilation distribution and may limit ventilator-induced lung injury (VILI) in patients with moderate to severe acute respiratory distress syndrome (ARDS). The static and dynamic components of ventilation that may cause VILI have been aggregated in mechanical power, considered a unifying driver of VILI. PP may affect mechanical power components differently due to changes in respiratory mechanics; however, the effects of PP on lung mechanical power components are unclear. This study aimed to compare the following parameters during supine positioning (SP) and PP: lung total elastic power and its components (elastic static power and elastic dynamic power) and these variables normalized to end-expiratory lung volume (EELV).MethodsThis prospective physiologic study included 55 patients with moderate to severe ARDS. Lung total elastic power and its static and dynamic components were compared during SP and PP using an esophageal pressure-guided ventilation strategy. In SP, the esophageal pressure-guided ventilation strategy was further compared with an oxygenation-guided ventilation strategy defined as baseline SP. The primary endpoint was the effect of PP on lung total elastic power non-normalized and normalized to EELV. Secondary endpoints were the effects of PP and ventilation strategies on lung elastic static and dynamic power components non-normalized and normalized to EELV, respiratory mechanics, gas exchange, and hemodynamic parameters.ResultsLung total elastic power (median [interquartile range]) was lower during PP compared with SP (6.7 [4.9–10.6] versus 11.0 [6.6–14.8] J/min; P < 0.001) non-normalized and normalized to EELV (3.2 [2.1–5.0] versus 5.3 [3.3–7.5] J/min/L; P < 0.001). Comparing PP with SP, transpulmonary pressures and EELV did not significantly differ despite lower positive end-expiratory pressure and plateau airway pressure, thereby reducing non-normalized and normalized lung elastic static power in PP. PP improved gas exchange, cardiac output, and increased oxygen delivery compared with SP.ConclusionsIn patients with moderate to severe ARDS, PP reduced lung total elastic and elastic static power compared with SP regardless of EELV normalization because comparable transpulmonary pressures and EELV were achieved at lower airway pressures. This resulted in improved gas exchange, hemodynamics, and oxygen delivery.Trial registration: German Clinical Trials Register (DRKS00017449). Registered June 27, 2019. https://drks.de/search/en/trial/DRKS00017449

Effect of additional dead space using end-tidal CO2 measurement on ventilating preterm infants: An experimental study.

Dead space is the part of the airway where no gas exchange takes place. Any increase in dead space volume has a proportional effect on the required tidal volume and thus on the risk of ventilation-induced lung injury. Inserts that increase dead space are therefore not used in small preterm infants. This includes end-tidal CO2 measurement. The aim of this study was to investigate the effect of the end-tidal CO2 measurement adapter on ventilation. In an experimental setup, an end-tidal CO2 measurement adapter, three different pneumotachographs (PNT-A, PNT-B, PNT-Neo), and a closed suction adapter were combined in varying set-ups. The time required for CO2 elimination by a CO2-flooded preterm infant test lung was measured. PNT-A prolonged CO2 elimination time by 0.9 s (+3.3%), Neo-PNT by 3.2 s (+11.6%) and PNT-B by 9.0s (+32.7%). The end-tidal CO2 measurement adapter prolonged the elimination time by an additional second without the pneumotachograph (+3.6%) and in combination with PNT-A (+3.1%) and PNT-Neo (+3.1%). In conjunction with PNT-B, the end-tidal CO2 measurement adapter reduced the elimination time by 0.3 seconds (-1%). The use of a closed suction adaptor increased the CO2 elimination time by a further second with PNT-Neo (+3.1%) and by an additional two seconds with no flow sensor (+6.9%), with PNT-A (+6.4%) and with PNT-B (+5.5%). The flow sensor had the greatest influence on ventilatory effort, while end-tidal CO2 measurement had only a moderate effect. The increased ventilatory effort levied by the CO2 measurement was dependent on the flow sensor selected. The use of closed suctioning more negatively impacted ventilatory effort than did end-tidal CO2 measurement.

21st century critical care medicine: An overview.

Critical care medicine in the 21st century has witnessed remarkable advancements that have significantly improved patient outcomes in intensive care units (ICUs). This abstract provides a concise summary of the latest developments in critical care, highlighting key areas of innovation. Recent advancements in critical care include Precision Medicine: Tailoring treatments based on individual patient characteristics, genomics, and biomarkers to enhance the effectiveness of therapies. The objective is to describe the recent advancements in Critical Care Medicine. Telemedicine: The integration of telehealth technologies for remote patient monitoring and consultation, facilitating timely interventions. Artificial intelligence (AI): AI-driven tools for early disease detection, predictive analytics, and treatment optimization, enhancing clinical decision-making. Organ Support: Advanced life support systems, such as Extracorporeal Membrane Oxygenation and Continuous Renal Replacement Therapy provide better organ support. Infection Control: Innovative infection control measures to combat emerging pathogens and reduce healthcare-associated infections. Ventilation Strategies: Precision ventilation modes and lung-protective strategies to minimize ventilator-induced lung injury. Sepsis Management: Early recognition and aggressive management of sepsis with tailored interventions. Patient-Centered Care: A shift towards patient-centered care focusing on psychological and emotional well-being in addition to medical needs. We conducted a thorough literature search on PubMed, EMBASE, and Scopus using our tailored strategy, incorporating keywords such as critical care, telemedicine, and sepsis management. A total of 125 articles meeting our criteria were included for qualitative synthesis. To ensure reliability, we focused only on articles published in the English language within the last two decades, excluding animal studies, in vitro/molecular studies, and non-original data like editorials, letters, protocols, and conference abstracts. These advancements reflect a dynamic landscape in critical care medicine, where technology, research, and patient-centered approaches converge to improve the quality of care and save lives in ICUs. The future of critical care promises even more innovative solutions to meet the evolving challenges of modern medicine.

Intraoperative mechanical power and postoperative pulmonary complications in low-risk surgical patients: a prospective observational cohort study

BackgroundInadequate intraoperative mechanical ventilation (MV) can lead to ventilator-induced lung injury and increased risk for postoperative pulmonary complications (PPCs). Mechanical power (MP) was shown to be a valuable indicator for MV outcomes in critical care patients. The aim of this study is to assess the association between intraoperative MP in low-risk surgical patients undergoing general anesthesia and PPCs.MethodsTwo-hundred eighteen low-risk surgical patients undergoing general anesthesia for elective surgery were included in the study. Intraoperative mechanical ventilatory support parameters were collected for all patients. Postoperatively, patients were followed throughout their hospital stay and up to seven days post discharge for the occurrence of any PPCs.ResultsOut of 218 patients, 35% exhibited PPCs. The average body mass index, tidal volume per ideal body weight, peak inspiratory pressure, and MP were significantly higher in the patients with PPCs than in the patients without PPCs (30.3 ± 8.1 kg/m2 vs. 26.8 ± 4.9 kg.m2, p < 0.001; 9.1 ± 1.9 ml/kg vs. 8.6 ± 1.4 ml/kg, p = 0.02; 20 ± 4.9 cmH2O vs. 18 ± 3.7 cmH2O, p = 0.001; 12.9 ± 4.5 J/min vs. 11.1 ± 3.7 J/min, p = 0.002). A multivariable regression analysis revealed MP as the sole significant predictor for the risk of postoperative pulmonary complications [OR 1.1 (95% CI 1.0–1.2, p = 0.036].ConclusionsHigh intraoperative mechanical power is a risk factor for developing postoperative pulmonary complications. Furthermore, intraoperative mechanical power is superior to other traditional mechanical ventilation variables in identifying surgical patients who are at risk for developing postoperative pulmonary complications.Clinical trial registration NCT03551899; 24/02/2017.

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.

Mathematical modeling of lung mechanics and pressure‐controlled ventilation design for barotrauma minimization: A numerical simulation study

SummaryMechanical ventilation represents a fundamental mode of therapy for severely ill patients who cannot breathe autonomously. At the same time, it has the potential of determining Ventilator‐Induced Lung Injury (VILI) and further damaging the patient's respiratory system. In this work we present a model‐based approach for pressure delivery optimization in the context of pressure‐control mechanical ventilation, with the aim of maintaining oxygenation while minimizing barotrauma. A simple compartmental model of respiration describes both mechanical ventilation, alveolar oxygen exchange and blood oxygen transport. Model Predictive Control is used to optimize delivered air pressure at the mouth at each inspiration, optimizing a trade‐off between oxygenation and barotrauma. Numerical simulations with different values of the trade‐off parameter and in two emblematic pulmonary disease scenarios (ARDS and COPD) show the effectiveness of the proposed approach.

Pulmonary inflammation decreases with ultra-protective ventilation in experimental ARDS under VV-ECMO: a positron emission tomography study.

Experimentally, ultra-protective ventilation (UPV, tidal volumes [VT] < 4 mL.kg-1) strategies in conjunction with veno-venous extracorporeal membrane oxygenation (VV-ECMO) are associated with lesser ventilator-induced lung injuries (VILI) during acute respiratory distress syndrome (ARDS). However, whether these strategies reduce lung inflammation more effectively than protective ventilation (PV) remains unclear. We aimed to demonstrate that a UPV strategy decreases acute lung inflammation in comparison with PV in an experimental swine model of ARDS. ARDS was induced by tracheal instillation of chlorhydric acid in sedated and paralyzed animals under mechanical ventilation. Animals were randomized to receive either UPV (VT 1 mL.kg-1, positive end-expiration pressure [PEEP] set to obtain plateau pressure between 20 and 25 cmH2O and respiratory rate [RR] at 5 min-1 under VV-ECMO) or PV (VT 6 mL.kg-1, PEEP set to obtain plateau pressure between 28 and 30 cmH2O and RR at 25 min-1) during 4 h. After 4 h, a positron emission tomography with [11C](R)-PK11195 (ligand to TSPO-bearing macrophages) injection was realized, coupled with quantitative computerized tomography (CT). Pharmacokinetic multicompartment models were used to quantify regional [11C](R)-PK11195 lung uptake. [11C](R)-PK11195 lung uptake and CT-derived respiratory variables were studied regionally across eight lung regions distributed along the antero-posterior axis. Five pigs were randomized to each study group. Arterial O2 partial pressure to inspired O2 fraction were not significantly different between study groups after experimental ARDS induction (75 [68-80] mmHg in a PV group vs. 87 [69-133] mmHg in a UPV group, p = 0.20). Compared to PV animals, UPV animals exhibited a significant decrease in the regional non-aerated compartment in the posterior lung levels, in mechanical power, and in regional dynamic strain and no statistical difference in tidal hyperinflation after 4 h. UPV animals had a significantly lower [11C](R)-PK11195 uptake, compared to PV animals (non-displaceable binding potential 0.35 [IQR, 0.20-0.59] in UPV animals and 1.01 [IQR, 0.75-1.59] in PV animals, p = 0.01). Regional [11C](R)-PK11195 uptake was independently associated with the interaction of regional tidal hyperinflation and regional lung compliance. In an experimental model of ARDS, 4 h of UPV strategy significantly decreased lung inflammation, in relation to the control of VT-derived determinants of VILI.

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.