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.

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.

Setting positive end-expiratory pressure: using the pressure-volume curve.

PURPOSE OF REVIEW: To discuss the role of pressure-volume curve (PV curve) in exploring elastic properties of the respiratory system and setting mechanical ventilator to reduce ventilator-induced lung injury. RECENT FINDINGS: Nowadays, quasi-static PV curves and loops can be easily obtained and analyzed at the bedside without disconnection of the patient from the ventilator. It is shown that this tool can provide useful information to optimize ventilator setting. For example, PV curves can assess for patient's individual potential for lung recruitability and also evaluate the risk for lung injury of the ongoing mechanical ventilation setting. SUMMARY: In conclusion, PV curve is an easily available bedside tool: its correct interpretation can be extremely valuable to enlighten potential for lung recruitability and select a high or low positive end-expiratory pressure (PEEP) strategy. Furthermore, recent studies have shown that PV curve can play a significant role in PEEP and driving pressure fine tuning: clinical studies are needed to prove whether this technique will improve outcome.

Ventilation during extracorporeal gas exchange in acute respiratory distress syndrome.

PURPOSE OF REVIEW: Accumulating evidence ascribes the benefit of extracorporeal gas exchange, at least in most severe cases, to the provision of a lung healing environment through the mitigation of ventilator-induced lung injury (VILI) risk. In spite of pretty homogeneous criteria for extracorporeal gas exchange application (according to the degree of hypoxemia/hypercapnia), ventilatory management during extracorporeal membrane oxygenation (ECMO)/carbon dioxide removal (ECCO 2 R) varies across centers. Here we summarize the recent evidence regarding the management of mechanical ventilation during extracorporeal gas exchange for respiratory support. RECENT FINDINGS: At present, the most common approach to protect the native lung against VILI following ECMO initiation involves lowering tidal volume and driving pressure, making modest reductions in respiratory rate, while typically maintaining positive end-expiratory pressure levels unchanged.Regarding ECCO 2 R treatment, higher efficiency devices are required in order to reduce significantly respiratory rate and/or tidal volume. SUMMARY: The best compromise between reduction of native lung ventilatory load, extracorporeal gas exchange efficiency, and strategies to preserve lung aeration deserves further investigation.

Airway pressure release ventilation for lung protection in acute respiratory distress syndrome: an alternative way to recruit the lungs.

PURPOSE OF REVIEW: Airway pressure release ventilation (APRV) is a modality of ventilation in which high inspiratory continuous positive airway pressure (CPAP) alternates with brief releases. In this review, we will discuss the rationale for APRV as a lung protective strategy and then provide a practical introduction to initiating APRV using the time-controlled adaptive ventilation (TCAV) method. RECENT FINDINGS: APRV using the TCAV method uses an extended inspiratory time and brief expiratory release to first stabilize and then gradually recruit collapsed lung (over hours/days), by progressively 'ratcheting' open a small volume of collapsed tissue with each breath. The brief expiratory release acts as a 'brake' preventing newly recruited units from re-collapsing, reversing the main drivers of ventilator-induced lung injury (VILI). The precise timing of each release is based on analysis of expiratory flow and is set to achieve termination of expiratory flow at 75% of the peak expiratory flow. Optimization of the release time reflects the changes in elastance and, therefore, is personalized (i.e. conforms to individual patient pathophysiology), and adaptive (i.e. responds to changes in elastance over time). SUMMARY: APRV using the TCAV method is a paradigm shift in protective lung ventilation, which primarily aims to stabilize the lung and gradually reopen collapsed tissue to achieve lung homogeneity eliminating the main mechanistic drivers of VILI.

The place of positive end expiratory pressure in ventilator-induced lung injury generation.

PURPOSE OF REVIEW: Describe the rationale for concern and accumulating pathophysiologic evidence regarding the adverse effects of high-level positive end expiratory pressure (PEEP) on excessive mechanical stress and ventilator-induced lung injury (VILI). RECENT FINDINGS: Although the inclusion of PEEP in numerical estimates of mechanical power may be theoretically debated, its potential to increase stress, strain, and mean airway pressure are not. Recent laboratory data in a variety of animal models demonstrate that higher levels of PEEP coupled with additional fluids needed to offset its impediment of hemodynamic function are associated with increased VILI. Moreover, counteracting end-tidal hyperinflation by external chest wall pressure may paradoxically improve respiratory mechanics, indicating that lower PEEP helps protect the small 'baby lung' of advanced acute respiratory distress syndrome (ARDS). SUMMARY: The potentially adverse effects of PEEP on VILI can be considered in three broad categories. First, the contribution of PEEP to total mechanical energy expressed through mechanical power, raised mean airway pressure, and end-tidal hyperinflation; second, the hemodynamic consequences of altered cardiac loading, heightened pulmonary vascular stress and total lung water; and third, the ventilatory consequences of compromised carbon dioxide eliminating efficiency. Minimizing ventilation demands, optimized body positioning and care to avoid unnecessary PEEP are central to lung protection in all stages of ARDS.

Electroacupuncture Attenuates Ventilator-Induced Lung Injury by Modulating the Nrf2/HO-1 Pathway.

INTRODUCTION: Ventilator-induced lung injury (VILI) is the most common complication associated with mechanical ventilation. Electroacupuncture (EA) has shown potent anti-inflammatory effects. This study aimed to investigate the effects of EA on VILI and explore the underlying mechanisms. METHODS: Male C57BL/6 mice were subjected to high tidal volume ventilation to induce VILI. Prior to mechanical ventilation, mice received treatment with EA, nonacupoint EA, or EA combined with zinc protoporphyrin. RESULTS: EA treatment significantly improved oxygenation, as indicated by increased PaO2 levels in VILI mice. Moreover, EA reduced lung injury score, lung wet/dry weight ratio, and protein concentration in bronchoalveolar lavage fluid. EA also decreased the expression of pro-inflammatory cytokines including interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, IL-18, chemokine keratinocyte chemoattractant, macrophage inflammatory protein 2, and malondialdehyde. Furthermore, EA increased the activities of antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase in VILI mice. At the molecular level, EA upregulated the expression of Nrf2 (nucleus) and heme oxygenase -1, while down-regulating the expression of p-NF-κB p65, NLR Family Pyrin Domain Containing 3, Cleaved Caspase-1, and ASC in VILI mice. Notably, the effects of EA were reversed by zinc protoporphyrin treatment, nonacupoint EA did not affect the aforementioned indicators of VILI. CONCLUSIONS: EA alleviates VILI by inhibiting the NLR Family Pyrin Domain Containing three inflammasome through activation of the Nrf2/HO-1 pathway.

Mechanical Power of Ventilation: From Computer to Clinical Implications.

Mechanical ventilation is a lifesaving intervention that may also induce further lung injury by exerting excessive mechanical forces on susceptible lung tissue, a phenomenon termed ventilator-induced lung injury (VILI). The concept of mechanical power (MP) aims to unify in one single variable the contribution of the different ventilatory parameters that could induce VILI by measuring the energy transfer to the lung over time. Despite an increasing amount of evidence demonstrating that high MP values can be associated with VILI development in experimental studies, the evidence regarding the association of MP and clinical outcomes remains controversial. In the present review, we describe the different determinants of VILI, the concept and computation of MP, and discuss the experimental and clinical studies related to MP. Currently, due to different limitations, the clinical application of MP is debatable. Further clinical studies are required to enhance our understanding of the relationship between MP and the development of VILI, as well as its potential impact on clinical outcomes.

[A new type of artificial airway sealer used between artificial airway and ventilator pipeline].

The need for mechanical ventilation due to severe hypoxemia and acute respiratory distress syndrome has increased dramatically in the global pandemic of severe respiratory infectious diseases. In clinical scenarios, it is sometimes necessary to briefly disconnect the ventilator pipeline from the artificial airway. Still, this operation can lead to a sharp drop in airway pressure, which is contrary to the protective lung ventilation strategy and increases the risk of environmental exposure to bioaerosol, posing a serious threat to patients and medical workers. At present, there is yet to be a practical solution. A new artificial airway device was designed by the medical staff from the department of critical care medicine of Beijing Tiantan Hospital, Capital Medical University, based on many years of research experience in respiratory support therapy, and recently obtained the National Utility Model Patent of China (ZL 2019 2 0379605.4). The device comprises two connecting pipes, the sealing device body, and the globe valve represented by the iridescent optical ring. It has a simple structure, convenient operation, and low production cost. The device is installed between the artificial airway and the ventilator pipeline and realizes the instantaneous sealing of the artificial airway by adjusting the shut-off valve. Using this device to treat mechanically ventilated patients can minimize the ventilator-induced lung injury caused by the repeated disconnection of pipelines, avoid iatrogenic transmission of bioaerosols, and realize dual protection for patients and medical workers. It has extensive clinical application prospects and high health and economic value.

Dynamic lung aeration and strain with positive end-expiratory pressure individualized to maximal compliance versus ARDSNet low-stretch strategy: a study in a surfactant depletion model of lung injury.

BACKGROUND: Positive end-expiratory pressure (PEEP) individualized to a maximal respiratory system compliance directly implies minimal driving pressures with potential outcome benefits, yet, raises concerns on static and dynamic overinflation, strain and cyclic recruitment. Detailed accurate assessment and understanding of these has been hampered by methodological limitations. We aimed to investigate the effects of a maximal compliance-guided PEEP strategy on dynamic lung aeration, strain and tidal recruitment using current four-dimensional computed tomography (CT) techniques and analytical methods of tissue deformation in a surfactant depletion experimental model of acute respiratory distress syndrome (ARDS). METHODS: ARDS was induced by saline lung lavage in anesthetized and mechanically ventilated healthy sheep (n = 6). Animals were ventilated in a random sequence with: (1) ARDSNet low-stretch protocol; (2) maximal compliance PEEP strategy. Lung aeration, strain and tidal recruitment were acquired with whole-lung respiratory-gated high-resolution CT and quantified using registration-based techniques. RESULTS: Relative to the ARDSNet low-stretch protocol, the maximal compliance PEEP strategy resulted in: (1) improved dynamic whole-lung aeration at end-expiration (0.456 ± 0.064 vs. 0.377 ± 0.101, P = 0.019) and end-inspiration (0.514 ± 0.079 vs. 0.446 ± 0.083, P = 0.012) with reduced non-aerated and increased normally-aerated lung mass without associated hyperinflation; (2) decreased aeration heterogeneity at end-expiration (coefficient of variation: 0.498 ± 0.078 vs. 0.711 ± 0.207, P = 0.025) and end-inspiration (0.419 ± 0.135 vs. 0.580 ± 0.108, P = 0.014) with higher aeration in dorsal regions; (3) tidal aeration with larger inspiratory increases in normally-aerated and decreases in poorly-aerated areas, and negligible in hyperinflated lung (Aeration × Strategy: P = 0.026); (4) reduced tidal strains in lung regions with normal-aeration (Aeration × Strategy: P = 0.047) and improved regional distributions with lower tidal strains in middle and ventral lung (Region-of-interest [ROI] × Strategy: P < 0.001); and (5) less tidal recruitment in middle and dorsal lung (ROI × Strategy: P = 0.044) directly related to whole-lung tidal strain (r = 0.751, P = 0.007). CONCLUSIONS: In well-recruitable ARDS models, a maximal compliance PEEP strategy improved end-expiratory/inspiratory whole-lung aeration and its homogeneity without overinflation. It further reduced dynamic strain in middle-ventral regions and tidal recruitment in middle-dorsal areas. These findings suggest the maximal compliance strategy minimizing whole-lung dynamically quantified mechanisms of ventilator-induced lung injury with less cyclic recruitment and no additional overinflation in large heterogeneously expanded and recruitable lungs.

Mechanical ventilation during pediatric extracorporeal life support.

PURPOSE OF REVIEW: To discuss the role of ventilator induced lung injury (VILI) and patient self-inflicted lung injury in ventilated children supported on extracorporeal membrane oxygenation (ECMO). RECENT FINDINGS: While extracorporeal life support is used routinely used every day around the globe to support neonatal, pediatric, and adult patients with refractory cardiac and/or respiratory failure, the optimal approach to mechanical ventilation, especially for those with acute respiratory distress syndrome (ARDS), remains unknown and controversial. Given the lack of definitive data in this population, one must rely on available evidence in those with ARDS not supported with ECMO and extrapolate adult observations. Ventilatory management should include, as a minimum standard, limiting inspiratory and driving pressures, providing a sufficient level of positive end-expiratory pressure, and setting a low rate to reduce mechanical power. Allowing for spontaneous breathing and use of pulmonary specific ancillary treatment modalities must be individualized, while balancing the risk and benefits. Future studies delineating the best strategies for optimizing MV during pediatric extracorporeal life support are much needed. SUMMARY: Future investigations will hopefully provide the needed evidence and better understanding of the overall goal of reducing mechanical ventilation intensity to decrease risk for VILI and promote lung recovery for those supported with ECMO.

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

BACKGROUND: Ventilator-induced lung injury (VILI) is a common complication of mechanical ventilation under general anesthesia. Regular aerobic exercise before surgery improves postoperative recovery and reduces postoperative pulmonary complications, but the mechanism driving this protective effect is unclear. METHODS: To determine how aerobic exercise prevents VILI, we investigated the effects of exercise and mechanical ventilation on the lungs of male mice and the effects of AMPK stimulation (simulating exercise) and cyclic stretching on human lung microvascular endothelial cells (HLMVEC). Sirtuin 1 (Sirt1) knockdown male mice were generated to explore the regulating mechanisms of sirt1 on mitochondrial function in male mice after mechanical ventilation was explored. Western blot, flow cytometry, live cell imaging, and mitochondrial function evaluations were used to determine the protective effects of aerobic exercise in preventing mitochondrial damage in VILI. RESULTS: Mitochondrial function and cell junctions were destroyed by mechanical ventilation in male mice or cyclic stretching in HLMVEC, a model of VILI. However, mitochondrial function and cell junction dysfunction were improved by exercise before mechanical ventilation (male mice) or treatment with AMPK before cyclic stretching (HLMVEC). p66shc, a marker of oxidative stress, was increased, and PINK1, a marker of mitochondrial autophagy, was decreased by mechanical ventilation or cyclic stretching. Sirt1 knockdown increased p66shc and decreased PINK1. Increased sirt1 expression was observed in the exercise and exercise + ventilation groups, suggesting that sirt1 inhibits mitochondrial damage in VILI. CONCLUSIONS: Mechanical ventilation induces mitochondrial damage in lung cells and leads to VILI. Regular aerobic exercise before ventilation may prevent VILI by improving mitochondrial function.

Fibroblast growth factor 21 attenuates ventilator-induced lung injury by inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathway.

BACKGROUND: Ventilator-induced lung injury (VILI) is caused by overdistension of the alveoli by the repetitive recruitment and derecruitment of alveolar units. This study aims to investigate the potential role and mechanism of fibroblast growth factor 21 (FGF21), a metabolic regulator secreted by the liver, in VILI development. METHODS: Serum FGF21 concentrations were determined in patients undergoing mechanical ventilation during general anesthesia and in a mouse VILI model. Lung injury was compared between FGF21-knockout (KO) mice and wild-type (WT) mice. Recombinant FGF21 was administrated in vivo and in vitro to determine its therapeutic effect. RESULTS: Serum FGF21 levels in patients and mice with VILI were significantly higher than in those without VILI. Additionally, the increment of serum FGF21 in anesthesia patients was positively correlated with the duration of ventilation. VILI was aggravated in FGF21-KO mice compared with WT mice. Conversely, the administration of FGF21 alleviated VILI in both mouse and cell models. FGF21 reduced Caspase-1 activity, suppressed the mRNA levels of Nlrp3, Asc, Il-1ß, Il-18, Hmgb1 and Nf-κb, and decreased the protein levels of NLRP3, ASC, IL-1ß, IL-18, HMGB1 and the cleaved form of GSDMD. CONCLUSIONS: Our findings reveal that endogenous FGF21 signaling is triggered in response to VILI, which protects against VILI by inhibiting the NLRP3/Caspase-1/GSDMD pyroptosis pathway. These results suggest that boosting endogenous FGF21 or the administration of recombinant FGF21 could be promising therapeutic strategies for the treatment of VILI during anesthesia or critical care.

Practical assessment of risk of VILI from ventilating power: a conceptual model.

At the bedside, assessing the risk of ventilator-induced lung injury (VILI) requires parameters readily measured by the clinician. For this purpose, driving pressure (DP) and end-inspiratory static 'plateau' pressure ([Formula: see text]) of the tidal cycle are unquestionably useful but lack key information relating to associated volume changes and cumulative strain. 'Mechanical power', a clinical term which incorporates all dissipated ('non-elastic') and conserved ('elastic') energy components of inflation, has drawn considerable interest as a comprehensive 'umbrella' variable that accounts for the influence of ventilating frequency per minute as well as the energy cost per tidal cycle. Yet, like the raw values of DP and [Formula: see text], the absolute levels of energy and power by themselves may not carry sufficiently precise information to guide safe ventilatory practice. In previous work we introduced the concept of 'damaging energy per cycle'. Here we describe how-if only in concept-the bedside clinician might gauge the theoretical hazard of delivered energy using easily observed static circuit pressures ([Formula: see text] and positive end expiratory pressure) and an estimate of the maximally tolerated (threshold) non-dissipated ('elastic') airway pressure that reflects the pressure component applied to the alveolar tissues. Because its core inputs are already in use and familiar in daily practice, the simplified mathematical model we propose here for damaging energy and power may promote deeper comprehension of the key factors in play to improve lung protective ventilation.

[Research progress on mechanism of biotrauma caused by ventilation-induced lung injury].

Mechanical ventilation is an advanced life support treatment for patients with acute respiratory failure. While stabilizing respiratory function, it also acts as an injury factor to exacerbate or lead to lung injury, that is, ventilation-induced lung injury (VILI). There may be a more subtle form of damage to VILI known as "biotrauma". However, the mechanism of biotrauma in VILI is still unclear. This article intends to review the mechanism of biotrauma of VILI from the aspects of inflammatory response, oxidative stress and complement activation, in order to provide a new strategy for clinical prevention and treatment of biotrauma caused by VILI.

Respiratory Monitoring During Mechanical Ventilation: The Present and the Future.

The increased application of mechanical ventilation, the recognition of its harms and the interest in individualization raised the need for an effective monitoring. An increasing number of monitoring tools and modalities were introduced over the past 2 decades with growing insight into asynchrony, lung and chest wall mechanics, respiratory effort and drive. They should be used in a complementary rather than a standalone way. A sound strategy can guide a reduction in adverse effects like ventilator-induced lung injury, ventilator-induced diaphragm dysfunction, patient-ventilator asynchrony and helps early weaning from the ventilator. However, the diversity, complexity, lack of expertise, and associated cost make formulating the appropriate monitoring strategy a challenge for clinicians. Most often, a big amount of data is fed to the clinicians making interpretation difficult. Therefore, it is fundamental for intensivists to be aware of the principle, advantages, and limits of each tool. This analytic review includes a simplified narrative of the commonly used basic and advanced respiratory monitors along with their limits and future prospective.

S1P lyase inhibition prevents lung injury following high pressure-controlled mechanical ventilation in aging mice.

Ventilator-induced Lung Injury (VILI) is characterized by hypoxia, inflammatory cytokine influx, loss of alveolar barrier integrity, and decreased lung compliance. Aging influences lung structure and function and is a predictive factor in the severity of VILI; however, the mechanisms of aging that influence the progression or increased susceptibility remain unknown. Aging impacts immune system function and may increase inflammation in healthy individuals. Recent studies suggest that the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P) and the enzyme that degrades it S1P lyase (SPL) may be involved in lung pathologies including acute lung injury. It is unknown whether aging influences S1P and SPL expression that have been implicated in lung inflammation, injury, and cell apoptosis. We hypothesized that aging and injurious mechanical ventilation synergistically impair S1P levels and enhance S1P lyase (SPL) expression that amplifies alveolar barrier damage and diminishes pulmonary function. Young (2-3 mo) and old (20-25 mo) C57BL/6 mice were mechanically ventilated for 2 h using pressure-controlled mechanical ventilation (PCMV) at 45 cmH2O and 35 cmH2O, respectively. We assessed the impact of aging and PCMV on several indications of acute lung injury, immune cell recruitment, S1P levels and SPL activity. Furthermore, we evaluated the protective effects of inhibiting SPL by tetrahydroxybutylimidazol (THI) administration on the negative outcomes associated with aging and mechanical injury. PCMV exacerbated lung injury in old mice and increased neutrophil influx that was further exacerbated due to aging. SPL expression increased in the young and old ventilated mice and the old nonventilated group. THI treatment reduced several of the indicators of lung injury and resulted in elevated S1P levels in lung tissue and plasma from mice that were injured from mechanical ventilation. CD80 and CD206 activation markers of alveolar and interstitial macrophages were also influenced by THI. SPL inhibition may be a viable therapeutic approach for patients requiring mechanical ventilation by preventing or regulating the exaggerated inflammatory response and reducing lung injury.

The Practice Change and Clinical Impact of Lung-Protective Ventilation Initiated in the Emergency Department: A Secondary Analysis of Individual Patient-Level Data From Prior Clinical Trials and Cohort Studies.

OBJECTIVES: Mechanically ventilated emergency department (ED) patients experience high morbidity and mortality. In a prior trial at our center, ED-based lung-protective ventilation was associated with improved care delivery and outcomes. Whether this strategy has persisted in the years after the trial remains unclear. The objective was to assess practice change and clinical outcomes associated with ED lung-protective ventilation. DESIGN: Secondary analysis of individual patient-level data from prior clinical trials and cohort studies. SETTING: ED and ICUs of a single academic center. PATIENTS: Mechanically ventilated adults. INTERVENTIONS: A lung-protective ventilator protocol used as the default approach in the ED. MEASUREMENTS AND MAIN RESULTS: The primary ventilator-related outcome was tidal volume, and the primary clinical outcome was hospital mortality. Secondary outcomes included ventilator-, hospital-, and ICU-free days. Multivariable logistic regression, propensity score (PS)-adjustment, and multiple a priori subgroup analyses were used to evaluate outcome as a function of the intervention. A total of 1,796 patients in the preintervention period and 1,403 patients in the intervention period were included. In the intervention period, tidal volume was reduced from 8.2 mL/kg predicted body weight (PBW) (7.3-9.1) to 6.5 mL/kg PBW (6.1-7.1), and low tidal volume ventilation increased from 46.8% to 96.2% ( p < 0.01). The intervention period was associated with lower mortality (35.9% vs 19.1%), remaining significant after multivariable logistic regression analysis (adjusted odds ratio [aOR], 0.43; 95% CI, 0.35-0.53; p < 0.01). Similar results were seen after PS adjustment and in subgroups. The intervention group had more ventilator- (18.8 [10.1] vs 14.1 [11.9]; p < 0.01), hospital- (12.2 [9.6] vs 9.4 [9.5]; p < 0.01), and ICU-free days (16.6 [10.1] vs 13.1 [11.1]; p < 0.01). CONCLUSIONS: ED lung-protective ventilation has persisted in the years since implementation and was associated with improved outcomes. These data suggest the use of ED-based lung-protective ventilation as a means to improve outcome.