Effects of Lung Injury and Abdominal Insufflation on Respiratory Mechanics and Lung Volume During Time-Controlled Adaptive Ventilation.

BACKGROUND: Lung volume measurements are important for monitoring functional aeration and recruitment, and may help guide adjustments in ventilator settings. The expiratory phase of APRV may provide physiologic information about lung volume based on the expiratory flow-time slope, angle, and time to approach a no-flow state (TExp). We hypothesized that expiratory flow rate would correlate with estimated lung volume (ELV), as measured using a modified nitrogen washout/washin technique in a large animal lung injury model. METHODS: Eight pigs (35.2±1.0kg) were mechanically ventilated using an Engström Carescape R860 on the APRV mode. All settings were held constant except the expiratory duration (TLow), which was adjusted based on the expiratory flow curve. Abdominal pressure was increased to 15mmHg in normal and Tween-injured lungs to replicate a combination of pulmonary and extrapulmonary lung injury. ELV was estimated using the Carescape FRC InView Tool. The expiratory flow-time slope and TExp were measured from the expiratory flow profile. RESULTS: Lung elastance increased with Tween-induced lung injury from 29.3±7.3cmH2O/L to 39.9±15.1cmH2O/L and chest wall elastance increased with increasing intra-abdominal pressures from 15.3±4.1cmH2O/L to 25.7±10.0cmH2O/L in the normal lung and 15.8±6.0cmH2O/L to 33.0±6.2cmH2O/L in the Tween-injured lung (p=0.39). ELV decreased from 1.90±0.83L in the Tween-Injured lung to 0.67±0.1L by increasing intra-abdominal pressures to 15mmHg. This had a significant correlation with a TExp decrease from 2.3±0.8s to 1.0±0.1s in the Tween-injured group with increasing insufflation pressures (ρ = 0.95) and with the expiratory flow-time slope, which increased from 0.29±0.06L/s2 to 0.63±0.05L/s2 (ρ = 0.78). CONCLUSIONS: Changes in ELV over time, and the TExp and flow-time slope, can be used to demonstrate evolving lung injury during APRV. Using the slope to infer changes in functional lung volume represents a unique, reproducible, real-time, bedside technique that does not interrupt ventilation and may be used for clinical interpretation.

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.

The use of protective mechanical ventilation during extracorporeal membrane oxygenation for the treatment of acute respiratory failure.

Acute respiratory failure (ARF) strikes an estimated two million people in the United States each year, with care exceeding US$50 billion. The hallmark of ARF is a heterogeneous injury, with normal tissue intermingled with a large volume of low compliance and collapsed tissue. Mechanical ventilation is necessary to oxygenate and ventilate patients with ARF, but if set inappropriately, it can cause an unintended ventilator-induced lung injury (VILI). The mechanism of VILI is believed to be overdistension of the remaining normal tissue known as the 'baby' lung, causing volutrauma, repetitive collapse and reopening of lung tissue with each breath, causing atelectrauma, and inflammation secondary to this mechanical damage, causing biotrauma. To avoid VILI, extracorporeal membrane oxygenation (ECMO) can temporally replace the pulmonary function of gas exchange without requiring high tidal volumes (VT) or airway pressures. In theory, the lower VT and airway pressure will minimize all three VILI mechanisms, allowing the lung to 'rest' and heal in the collapsed state. The optimal method of mechanical ventilation for the patient on ECMO is unknown. The ARDSNetwork Acute Respiratory Management Approach (ARMA) is a Rest Lung Approach (RLA) that attempts to reduce the excessive stress and strain on the remaining normal lung tissue and buys time for the lung to heal in the collapsed state. Theoretically, excessive tissue stress and strain can also be avoided if the lung is fully open, as long as the alveolar re-collapse is prevented during expiration, an approach known as the Open Lung Approach (OLA). A third lung-protective strategy is the Stabilize Lung Approach (SLA), in which the lung is initially stabilized and gradually reopened over time. This review will analyze the physiologic efficacy and pathophysiologic potential of the above lung-protective approaches.

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.

Sustained vs. Intratidal Recruitment in the Injured Lung During Airway Pressure Release Ventilation: A Computational Modeling Perspective.

INTRODUCTION: During mechanical ventilation, cyclic recruitment and derecruitment (R/D) of alveoli result in focal points of heterogeneous stress throughout the lung. In the acutely injured lung, the rates at which alveoli can be recruited or derecruited may also be altered, requiring longer times at higher pressure levels to be recruited during inspiration, but shorter times at lower pressure levels to minimize collapse during exhalation. In this study, we used a computational model to simulate the effects of airway pressure release ventilation (APRV) on acinar recruitment, with varying inspiratory pressure levels and durations of exhalation. MATERIALS AND METHODS: The computational model consisted of a ventilator pressure source, a distensible breathing circuit, an endotracheal tube, and a porcine lung consisting of recruited and derecruited zones, as well as a transitional zone capable of intratidal R/D. Lung injury was simulated by modifying each acinus with an inflation-dependent surface tension. APRV was simulated for an inhalation duration (Thigh) of 4.0 seconds, inspiratory pressures (Phigh) of 28 and 40 cmH2O, and exhalation durations (Tlow) ranging from 0.2 to 1.5 seconds. RESULTS: Both sustained acinar recruitment and intratidal R/D within the subtree were consistently higher for Phigh of 40 cmH2O vs. 28 cmH2O, regardless of Tlow. Increasing Tlow was associated with decreasing sustained acinar recruitment, but increasing intratidal R/D, within the subtree. Increasing Tlow was associated with decreasing elastance of both the total respiratory system and transitional subtree of the model. CONCLUSIONS: Our computational model demonstrates the confounding effects of cyclic R/D, sustained recruitment, and parenchymal strain stiffening on estimates of total lung elastance during APRV. Increasing inspiratory pressures leads to not only more sustained recruitment of unstable acini but also more intratidal R/D. Our model indicates that higher inspiratory pressures should be used in conjunction with shorter exhalation times, to avoid increasing intratidal R/D.

Ratchet recruitment in the acute respiratory distress syndrome: lessons from the newborn cry.

Patients with acute respiratory distress syndrome (ARDS) have few treatment options other than supportive mechanical ventilation. The mortality associated with ARDS remains unacceptably high, and mechanical ventilation itself has the potential to increase mortality further by unintended ventilator-induced lung injury (VILI). Thus, there is motivation to improve management of ventilation in patients with ARDS. The immediate goal of mechanical ventilation in ARDS should be to prevent atelectrauma resulting from repetitive alveolar collapse and reopening. However, a long-term goal should be to re-open collapsed and edematous regions of the lung and reduce regions of high mechanical stress that lead to regional volutrauma. In this paper, we consider the proposed strategy used by the full-term newborn to open the fluid-filled lung during the initial breaths of life, by ratcheting tissues opened over a series of initial breaths with brief expirations. The newborn's cry after birth shares key similarities with the Airway Pressure Release Ventilation (APRV) modality, in which the expiratory duration is sufficiently short to minimize end-expiratory derecruitment. Using a simple computational model of the injured lung, we demonstrate that APRV can slowly open even the most recalcitrant alveoli with extended periods of high inspiratory pressure, while reducing alveolar re-collapse with brief expirations. These processes together comprise a ratchet mechanism by which the lung is progressively recruited, similar to the manner in which the newborn lung is aerated during a series of cries, albeit over longer time scales.

First Stabilize and then Gradually Recruit: A Paradigm Shift in Protective Mechanical Ventilation for Acute Lung Injury.

Acute respiratory distress syndrome (ARDS) is associated with a heterogeneous pattern of injury throughout the lung parenchyma that alters regional alveolar opening and collapse time constants. Such heterogeneity leads to atelectasis and repetitive alveolar collapse and expansion (RACE). The net effect is a progressive loss of lung volume with secondary ventilator-induced lung injury (VILI). Previous concepts of ARDS pathophysiology envisioned a two-compartment system: a small amount of normally aerated lung tissue in the non-dependent regions (termed "baby lung"); and a collapsed and edematous tissue in dependent regions. Based on such compartmentalization, two protective ventilation strategies have been developed: (1) a "protective lung approach" (PLA), designed to reduce overdistension in the remaining aerated compartment using a low tidal volume; and (2) an "open lung approach" (OLA), which first attempts to open the collapsed lung tissue over a short time frame (seconds or minutes) with an initial recruitment maneuver, and then stabilize newly recruited tissue using titrated positive end-expiratory pressure (PEEP). A more recent understanding of ARDS pathophysiology identifies regional alveolar instability and collapse (i.e., hidden micro-atelectasis) in both lung compartments as a primary VILI mechanism. Based on this understanding, we propose an alternative strategy to ventilating the injured lung, which we term a "stabilize lung approach" (SLA). The SLA is designed to immediately stabilize the lung and reduce RACE while gradually reopening collapsed tissue over hours or days. At the core of SLA is time-controlled adaptive ventilation (TCAV), a method to adjust the parameters of the airway pressure release ventilation (APRV) modality. Since the acutely injured lung at any given airway pressure requires more time for alveolar recruitment and less time for alveolar collapse, SLA adjusts inspiratory and expiratory durations and inflation pressure levels. The TCAV method SLA reverses the open first and stabilize second OLA method by: (i) immediately stabilizing lung tissue using a very brief exhalation time (≤0.5 s), so that alveoli simply do not have sufficient time to collapse. The exhalation duration is personalized and adaptive to individual respiratory mechanical properties (i.e., elastic recoil); and (ii) gradually recruiting collapsed lung tissue using an inflate and brake ratchet combined with an extended inspiratory duration (4-6 s) method. Translational animal studies, clinical statistical analysis, and case reports support the use of TCAV as an efficacious lung protective strategy.

Ventilator-Induced Lung Injury as a Dynamic Balance Between Epithelial Cell Damage and Recovery.

Acute respiratory distress syndrome (ARDS) has a high mortality rate that is due in part to ventilator-induced lung injury (VILI). Nevertheless, the majority of patients eventually recover, which means that their innate reparative capacities eventually prevail. Since there are currently no medical therapies for ARDS, minimizing its mortality thus amounts to achieving an optimal balance between spontaneous tissue repair versus the generation of VILI. In order to understand this balance better, we developed a mathematical model of the onset and recovery of VILI that incorporates two hypotheses: (1) a novel multi-hit hypothesis of epithelial barrier failure, and (2) a previously articulated rich-get-richer hypothesis of the interaction between atelectrauma and volutrauma. Together, these concepts explain why VILI appears in a normal lung only after an initial latent period of injurious mechanical ventilation. In addition, they provide a mechanistic explanation for the observed synergy between atelectrauma and volutrauma. The model recapitulates the key features of previously published in vitro measurements of barrier function in an epithelial monolayer and in vivo measurements of lung function in mice subjected to injurious mechanical ventilation. This provides a framework for understanding the dynamic balance between factors responsible for the generation of and recovery from VILI.

Protective ventilation in a pig model of acute lung injury: timing is as important as pressure.

Ventilator-induced lung injury (VILI) is a significant risk for patients with acute respiratory distress syndrome (ARDS). Management of the patient with ARDS is currently dominated by the use of low tidal volume mechanical ventilation, the presumption being that this mitigates overdistension (OD) injury to the remaining normal lung tissue. Evidence exists, however, that it may be more important to avoid cyclic recruitment and derecruitment (RD) of lung units, although the relative roles of OD and RD in VILI remain unclear. Forty pigs had a heterogeneous lung injury induced by Tween instillation and were randomized into four groups (n = 10 each) with higher (↑) or lower (↓) levels of OD and/or RD imposed using airway pressure release ventilation (APRV). OD was increased by setting inspiratory airway pressure to 40 cmH2O and lessened with 28 cmH2O. RD was attenuated using a short duration of expiration (∼0.45 s) and increased with a longer duration (∼1.0 s). All groups developed mild ARDS following injury. RD ↑ OD↑ caused the greatest degree of lung injury as determined by [Formula: see text]/[Formula: see text] ratio (226.1 ± 41.4 mmHg). RD ↑ OD↓ ([Formula: see text]/[Formula: see text]= 333.9 ± 33.1 mmHg) and RD ↓ OD↑ ([Formula: see text]/[Formula: see text] = 377.4 ± 43.2 mmHg) were both moderately injurious, whereas RD ↓ OD↓ ([Formula: see text]/[Formula: see text] = 472.3 ± 22.2 mmHg; P < 0.05) was least injurious. Both tidal volume and driving pressure were essentially identical in the RD ↑ OD↓ and RD ↓ OD↑ groups. We, therefore, conclude that considerations of expiratory time may be at least as important as pressure for safely ventilating the injured lung.NEW & NOTEWORTHY In a large animal model of ARDS, recruitment/derecruitment caused greater VILI than overdistension, whereas both mechanisms together caused severe lung damage. These findings suggest that eliminating cyclic recruitment and derecruitment during mechanical ventilation should be a preeminent management goal for the patient with ARDS. The airway pressure release ventilation (APRV) mode of mechanical ventilation can achieve this if delivered with an expiratory duration (TLow) that is brief enough to prevent derecruitment at end expiration.

Unshrinking the baby lung to calm the VILI vortex.

A hallmark of ARDS is progressive shrinking of the 'baby lung,' now referred to as the ventilator-induced lung injury (VILI) 'vortex.' Reducing the risk of the VILI vortex is the goal of current ventilation strategies; unfortunately, this goal has not been achieved nor has mortality been reduced. However, the temporal aspects of a mechanical breath have not been considered. A brief expiration prevents alveolar collapse, and an extended inspiration can recruit the atelectatic lung over hours. Time-controlled adaptive ventilation (TCAV) is a novel ventilator approach to achieve these goals, since it considers many of the temporal aspects of dynamic lung mechanics.

Myths and Misconceptions of Airway Pressure Release Ventilation: Getting Past the Noise and on to the Signal.

In the pursuit of science, competitive ideas and debate are necessary means to attain knowledge and expose our ignorance. To quote Murray Gell-Mann (1969 Nobel Prize laureate in Physics): "Scientific orthodoxy kills truth". In mechanical ventilation, the goal is to provide the best approach to support patients with respiratory failure until the underlying disease resolves, while minimizing iatrogenic damage. This compromise characterizes the philosophy behind the concept of "lung protective" ventilation. Unfortunately, inadequacies of the current conceptual model-that focuses exclusively on a nominal value of low tidal volume and promotes shrinking of the "baby lung" - is reflected in the high mortality rate of patients with moderate and severe acute respiratory distress syndrome. These data call for exploration and investigation of competitive models evaluated thoroughly through a scientific process. Airway Pressure Release Ventilation (APRV) is one of the most studied yet controversial modes of mechanical ventilation that shows promise in experimental and clinical data. Over the last 3 decades APRV has evolved from a rescue strategy to a preemptive lung injury prevention approach with potential to stabilize the lung and restore alveolar homogeneity. However, several obstacles have so far impeded the evaluation of APRV's clinical efficacy in large, randomized trials. For instance, there is no universally accepted standardized method of setting APRV and thus, it is not established whether its effects on clinical outcomes are due to the ventilator mode per se or the method applied. In addition, one distinctive issue that hinders proper scientific evaluation of APRV is the ubiquitous presence of myths and misconceptions repeatedly presented in the literature. In this review we discuss some of these misleading notions and present data to advance scientific discourse around the uses and misuses of APRV in the current literature.

Effect of low dose acetylsalicylic acid and anticoagulant on clinical outcomes in COVID-19, analytical cross-sectional study.

Background and aims: The therapeutic strategy for the treatment of known sequelae of COVID-19 has shifted from reactive to preventative. In this study, we aim to evaluate the effects of acetylsalicylic acid (ASA), and anticoagulants on COVID-19 related morbidity and mortality. Methods: This record-based analytical cross-sectional study targeted 539 COVID-19 patients in a single United States medical center between March and December 2020. Through a random stratified sample, we recruited outpatient (n = 206) and inpatient (n = 333) cases from three management protocols, including standard care (SC) (n = 399), low-dose ASA only (ASA) (n = 112), and anticoagulation only (AC) (n = 28). Collected data included demographics, comorbidities, and clinical outcomes. The primary outcome measure was inpatient admission. Exploratory secondary outcome measures included length of stay, 30-day readmission rates, medical intensive care unit (MICU) admission, need for mechanical ventilation, the occurrence of acute respiratory distress syndrome (ARDS), bleeding events, clotting events, and mortality. The collected data were coded and analyzed using standard tests. Results: Age, mean number of comorbidities, and all individual comorbidities except for asthma, and malignancy were significantly lower in the SC compared to ASA and AC. After adjusting for age and comorbidity via binary logistic regression models, no statistical differences were found between groups for the studied outcomes. When compared to the SC group, ASA had lower 30-day readmission rates (odds ration [OR] 0.81 95% confidence interval [CI] 0.35-1.88, p = 0.63), MICU admission (OR 0.63 95% CI 0.34-1.17, p = 0.32), ARDS (OR 0.71 95% CI 0.33-1.52, p = 0.38), and death (OR 0.85 95% CI 0.36-1.99, p = 0.71). Conclusion: Low-dose ASA has a nonsignificant but potentially protective role in reducing the risk of COVID-19 related morbidity and mortality. Our data suggests a trend toward reduced 30-day readmission rates, ARDS, MICU admissions, need for mechanical ventilation, and mortality compared to the standard management protocol. Further randomized control trials are needed to establish causal effects.

Assessment of Heterogeneity in Lung Structure and Function During Mechanical Ventilation: A Review of Methodologies.

The mammalian lung is characterized by heterogeneity in both its structure and function, by incorporating an asymmetric branching airway tree optimized for maintenance of efficient ventilation, perfusion, and gas exchange. Despite potential benefits of naturally occurring heterogeneity in the lungs, there may also be detrimental effects arising from pathologic processes, which may result in deficiencies in gas transport and exchange. Regardless of etiology, pathologic heterogeneity results in the maldistribution of regional ventilation and perfusion, impairments in gas exchange, and increased work of breathing. In extreme situations, heterogeneity may result in respiratory failure, necessitating support with a mechanical ventilator. This review will present a summary of measurement techniques for assessing and quantifying heterogeneity in respiratory system structure and function during mechanical ventilation. These methods have been grouped according to four broad categories: (1) inverse modeling of heterogeneous mechanical function; (2) capnography and washout techniques to measure heterogeneity of gas transport; (3) measurements of heterogeneous deformation on the surface of the lung; and finally (4) imaging techniques used to observe spatially-distributed ventilation or regional deformation. Each technique varies with regard to spatial and temporal resolution, degrees of invasiveness, risks posed to patients, as well as suitability for clinical implementation. Nonetheless, each technique provides a unique perspective on the manifestations and consequences of mechanical heterogeneity in the diseased lung.

Electric Cell-Substrate Impedance Sensing (ECIS) as a Platform for Evaluating Barrier-Function Susceptibility and Damage from Pulmonary Atelectrauma.

Biophysical insults that either reduce barrier function (COVID-19, smoke inhalation, aspiration, and inflammation) or increase mechanical stress (surfactant dysfunction) make the lung more susceptible to atelectrauma. We investigate the susceptibility and time-dependent disruption of barrier function associated with pulmonary atelectrauma of epithelial cells that occurs in acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI). This in vitro study was performed using Electric Cell-substrate Impedance Sensing (ECIS) as a noninvasive evaluating technique for repetitive stress stimulus/response on monolayers of the human lung epithelial cell line NCI-H441. Atelectrauma was mimicked through recruitment/derecruitment (RD) of a semi-infinite air bubble to the fluid-occluded micro-channel. We show that a confluent monolayer with a high level of barrier function is nearly impervious to atelectrauma for hundreds of RD events. Nevertheless, barrier function is eventually diminished, and after a critical number of RD insults, the monolayer disintegrates exponentially. Confluent layers with lower initial barrier function are less resilient. These results indicate that the first line of defense from atelectrauma resides with intercellular binding. After disruption, the epithelial layer community protection is diminished and atelectrauma ensues. ECIS may provide a platform for identifying damaging stimuli, ventilation scenarios, or pharmaceuticals that can reduce susceptibility or enhance barrier-function recovery.

Nano-chemically Modified Tetracycline-3 (nCMT-3) Attenuates Acute Lung Injury via Blocking sTREM-1 Release and NLRP3 Inflammasome Activation.

BACKGROUND: Intratracheal (IT) lipopolysaccharide (LPS) causes severe acute lung injury (ALI) and systemic inflammation. CMT-3 has pleiotropic anti-inflammatory effects including matrix metalloproteinase (MMP) inhibition, attenuation of neutrophil (PMN) activation, and elastase release. CMT-3's poor water solubility limits its bioavailability when administered orally for treating ALI. We developed a nano-formulation of CMT-3 (nCMT-3) to test the hypothesis that the pleiotropic anti-inflammatory activities of IT nCMT-3 can attenuate LPS-induced ALI. METHODS: C57BL/6 mice were treated with aerosolized IT nCMT-3 or saline, then had IT LPS or saline administered 2 h later. Tissues were harvested at 24 h. The effects of LPS and nCMT-3 on ALI were assessed by lung histology, MMP level/activity (zymography), NLRP3 protein, and activated caspase-1 levels. Blood and bronchoalveolar lavage fluid (BALF) cell counts, PMN elastase, and soluble triggering receptor expressed on myelocytes-1 (sTREM-1) levels, TNF-α, IL-1ß, IL-6, IL-18, and BALF protein levels were also measured. RESULTS: LPS-induced ALI was characterized by histologic lung injury (PMN infiltration, alveolar thickening, edema, and consolidation) elevated proMMP-2, -9 levels and activity, increased NLRP-3 protein and activated caspase-1 levels in lung tissue. LPS-induced increases in plasma and BALF levels of sTREM-1, TNF-α, IL-1ß, IL-6, IL-18, PMN elastase and BALF protein levels demonstrate significant lung/systemic inflammation and capillary leak. nCMT-3 significantly ameliorated all of these LPS-induced inflammatory markers to control levels, and decreased the incidence of ALI. CONCLUSIONS: Pre-treatment with nCMT3 significantly attenuates LPS-induced lung injury/inflammation by multiple mechanisms including: MMP activation, PMN elastase, sTREM-1 release, and NLRP3 inflammasome/caspase-1 activation.

Effects of time-controlled adaptive ventilation on cardiorespiratory parameters and inflammatory response in experimental emphysema.

The time-controlled adaptive ventilation (TCAV) method attenuates lung damage in acute respiratory distress syndrome. However, so far, no study has evaluated the impact of the TCAV method on ventilator-induced lung injury (VILI) and cardiac function in emphysema. We hypothesized that the use of the TCAV method to achieve an expiratory flow termination/expiratory peak flow (EFT/EPF) of 25% could reduce VILI and improve right ventricular function in elastase-induced lung emphysema in rats. Five weeks after the last intratracheal instillation of elastase, animals were anesthetized and mechanically ventilated for 1 h using TCAV adjusted to either EFT/EPF 25% or EFT/EPF 75%, the latter often applied in acute respiratory distress syndrome (ARDS). Pressure-controlled ventilation (PCV) groups with positive end-expiratory pressure levels similar to positive end-release pressure in TCAV with EFT/EPF 25% and EFT/EPF 75% were also analyzed. Echocardiography and lung ultrasonography were monitored. Lung morphometry, alveolar heterogeneity, and biological markers related to inflammation [interleukin 6 (IL-6), CINC-1], alveolar pulmonary stretch (amphiregulin), lung matrix damage [metalloproteinase 9 (MMP-9)] were assessed. EFT/EPF 25% reduced respiratory system peak pressure, mean linear intercept, B lines at lung ultrasonography, and increased pulmonary acceleration time/pulmonary ejection time ratio compared with EFT/EPF 75%. The volume fraction of mononuclear cells, neutrophils, and expression of IL-6, CINC-1, amphiregulin, and MMP-9 were lower with EFT/EPF 25% than with EFT/EPF 75%. In conclusion, TCAV with EFT/EPF 25%, compared with EFT/EPF 75%, led to less lung inflammation, hyperinflation, and pulmonary arterial hypertension, which may be a promising strategy for patients with emphysema.NEW & NOTEWORTHY The TCAV method reduces lung damage in ARDS. However, so far, no study has evaluated the impact of the TCAV method on ventilator-induced lung injury and cardiac function in experimental emphysema. The TCAV method at EFT/EPF ratio of 25%, compared with EFT/EPF of 75% (frequently used in ARDS), reduced lung inflammation, alveolar heterogeneity and hyperinflation, and pulmonary arterial hypertension in elastase-induced emphysema. TCAV may be a promising and personalized ventilation strategy for patients with emphysema.