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.

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.

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.

Preemptive Mechanical Ventilation Based on Dynamic Physiology in the Alveolar Microenvironment: Novel Considerations of Time-Dependent Properties of the Respiratory System.

The acute respiratory distress syndrome (ARDS) remains a serious clinical problem with the current treatment being supportive in the form of mechanical ventilation. However, mechanical ventilation can be a double-edged sword; if set properly, it can significantly reduce ARDS associated mortality but if set improperly it can have unintended consequences causing a secondary ventilator induced lung injury (VILI). The hallmark of ARDS pathology is a heterogeneous lung injury, which predisposes the lung to a secondary VILI. The current standard of care approach is to wait until ARDS is well established and then apply a low tidal volume (LVt) strategy to avoid over-distending the remaining normal lung. However, even with the use of LVt strategy, the mortality of ARDS remains unacceptably high at ~40%. In this review, we analyze the lung pathophysiology associated with ARDS that renders the lung highly vulnerable to a secondary VILI. The current standard of care LVt strategy is critiqued as well as new strategies used in combination with LVt to protect the lung. Using the current understanding of alveolar mechanics (i.e. the dynamic change in alveolar size and shape with tidal ventilation) we provide a rationale for why the current protective ventilation strategies have not further reduced ARDS mortality. New strategies of protective ventilation based on dynamic physiology in the micro-environment (i.e. alveoli and alveolar ducts) are discussed. Current evidence suggests that alveolar inflation and deflation is viscoelastic in nature, with a fast and slow phase in both alveolar recruitment and collapse. Using this knowledge, a ventilation strategy with a prolonged time at inspiration would recruit alveoli and a brief release time at expiration would prevent alveolar collapse, converting heterogeneous to homogeneous lung inflation significantly reducing ARDS incidence and mortality.

Enteral administration of bacteria fermented formula in newborn piglets: A high fidelity model for necrotizing enterocolitis (NEC).

OBJECTIVE: To develop an animal model which replicates neonatal NEC and characterizes the importance of bacterial fermentation of formula and short chain fatty acids (SCFAs) in its pathogenesis. BACKGROUND: NEC is a severe form of intestinal inflammation in preterm neonates and current models do not reproduce the human condition. METHODS: Three groups of newborn piglets: Formula alone (FO), Bacteria alone (E.coli: BO) and E.coli-fermented formula (FF) were anesthetized, instrumented and underwent post-pyloric injection of formula, bacteria or fermented-formula. SCFA levels were measured by gas chromatography-mass spectrometry. At 6 h bowel appearance was assessed, histologic and molecular analysis of intestine were performed. Gut inflammation (p65 NF-κB, TLR4, TNF-α, IL-1ß), apoptosis (cleaved caspase-3, BAX, apoptosis) and tight junction proteins (claudin-2, occludin) were measured. RESULTS: SCFAs were increased in FF. Small bowel from FF piglet's demonstrated inflammation, coagulative necrosis and pneumatosis resembling human NEC. Histologic gut injury (injury score, mast cell activation) were increased by Bacteria, but more severe in FF piglets. Intestinal expression of p65 NF-κB, NF-κB activation, TNF-α and IL-1ß were increased in BO and markedly increased in the FF group (P<0.05 vs. FO). Intestine from Bacteria piglets demonstrated increased apoptotic index, pro-apoptotic protein expression and decreased tight junction proteins. These changes were more severe in FF piglets. CONCLUSIONS: Our piglet model demonstrates the findings of NEC in human neonates: systemic acidosis, intestinal inflammation, pneumatosis and portal venous gas. Bacteria alone can initiate intestinal inflammation, injury and apoptosis, but bacterial fermentation of formula generates SCFAs which contribute to the pathogenesis of NEC.

Excessive Extracellular ATP Desensitizes P2Y2 and P2X4 ATP Receptors Provoking Surfactant Impairment Ending in Ventilation-Induced Lung Injury.

Stretching the alveolar epithelial type I (AT I) cells controls the intercellular signaling for the exocytosis of surfactant by the AT II cells through the extracellular release of adenosine triphosphate (ATP) (purinergic signaling). Extracellular ATP is cleared by extracellular ATPases, maintaining its homeostasis and enabling the lung to adapt the exocytosis of surfactant to the demand. Vigorous deformation of the AT I cells by high mechanical power ventilation causes a massive release of extracellular ATP beyond the clearance capacity of the extracellular ATPases. When extracellular ATP reaches levels >100 μM, the ATP receptors of the AT II cells become desensitized and surfactant impairment is initiated. The resulting alteration in viscoelastic properties and in alveolar opening and collapse time-constants leads to alveolar collapse and the redistribution of inspired air from the alveoli to the alveolar ducts, which become pathologically dilated. The collapsed alveoli connected to these dilated alveolar ducts are subject to a massive strain, exacerbating the ATP release. After reaching concentrations >300 μM extracellular ATP acts as a danger-associated molecular pattern, causing capillary leakage, alveolar space edema, and further deactivation of surfactant by serum proteins. Decreasing the tidal volume to 6 mL/kg or less at this stage cannot prevent further lung injury.

Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury.

Severe pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high ATP levels despite the conversion to adenosine. Above a certain level, extracellular ATP molecules act as danger-associated molecular patterns (DAMPs) and activate the pro-inflammatory response of the innate immunity through purinergic receptors on the surface of the immune cells. This results in lung tissue inflammation, capillary leakage, interstitial and alveolar oedema and lung injury reducing the production of surfactant by the damaged AT II cells and deactivating the surfactant function by the concomitant extravasated serum proteins through capillary leakage followed by a substantial increase in alveolar surface tension and alveolar collapse. The resulting inhomogeneous ventilation of the lungs is an important mechanism in the development of ventilation-induced lung injury. The high levels of extracellular ATP and the upregulation of ecto-enzymes and soluble enzymes that hydrolyse ATP to adenosine (CD39 and CD73) increase the extracellular adenosine levels that inhibit the innate and adaptive immune responses rendering the host susceptible to infection by invading microorganisms. Moreover, high levels of extracellular adenosine increase the expression, the production and the activation of pro-fibrotic proteins (such as TGF-ß, α-SMA, etc.) followed by the establishment of lung fibrosis.

Limiting ventilator-associated lung injury in a preterm porcine neonatal model.

PURPOSE: Preterm infants are prone to respiratory distress syndrome (RDS), with severe cases requiring mechanical ventilation for support. However, there are no clear guidelines regarding the optimal ventilation strategy. We hypothesized that airway pressure release ventilation (APRV) would mitigate lung injury in a preterm porcine neonatal model. METHODS: Preterm piglets were delivered on gestational day 98 (85% of 115day term), instrumented, and randomized to volume guarantee (VG; n=10) with low tidal volumes (5.5cm3kg-1) and PEEP 4cmH2O or APRV (n=10) with initial ventilator settings: PHigh 18cmH2O, PLow 0cmH2O, THigh 1.30s, TLow 0.15s. Ventilator setting changes were made in response to clinical parameters in both groups. Animals were monitored continuously for 24hours. RESULTS: The mortality rates between the two groups were not significantly different (p>0.05). The VG group had relatively increased oxygen requirements (FiO2 50%±9%) compared with the APRV group (FiO2 28%±5%; p>0.05) and a decrease in PaO2/FiO2 ratio (VG 162±33mmHg; APRV 251±45mmHg; p<0.05). The compliance of the VG group (0.51±0.07L·cmH2O-1) was significantly less than the APRV group (0.90±0.06L·cmH2O-1; p<0.05). CONCLUSION: This study demonstrates that APRV improves oxygenation and compliance as compared with VG. This preliminary work suggests further study into the clinical uses of APRV in the neonate is warranted. LEVEL OF EVIDENCE: Not Applicable (Basic Science Animal Study).

DIFFERENTIAL SUSCEPTIBILITY OF HUMAN SP-B GENETIC VARIANTS ON LUNG INJURY CAUSED BY BACTERIAL PNEUMONIA AND THE EFFECT OF A CHEMICALLY MODIFIED CURCUMIN.

Staphylococcus aureus is a common cause of nosocomial pneumonia frequently resulting in acute respiratory distress syndrome (ARDS). Surfactant protein B (SP-B) gene expresses two proteins involved in lowering surface tension and host defense. Genotyping studies demonstrate a significant association between human SP-B genetic variants and ARDS. Curcumins have been shown to attenuate host inflammation in many sepsis models. Our hypothesis is that functional differences of SP-B variants and treatment with curcumin (CMC2.24) modulate lung injury in bacterial pneumonia. Humanized transgenic mice, expressing either SP-B T or C allele without mouse SP-B gene, were used. Bioluminescent labeled S. aureus Xen 36 (50 µL) was injected intratracheally to cause pneumonia. Infected mice received daily CMC2.24 (40 mg/kg) or vehicle alone by oral gavage. Dynamic changes of bacteria were monitored using in vivo imaging system. Histological, cellular, and molecular indices of lung injury were studied in infected mice 48 h after infection. In vivo imaging analysis revealed total flux (bacterial number) was higher in the lung of infected SP-B-C mice compared with infected SP-B-T mice (P < 0.05). Infected SP-B-C mice demonstrated increased mortality, lung injury, apoptosis, and NF-κB expression compared with infected SP-B-T mice. Compared with controls, CMC2.24 treatment significantly reduced the following: mortality, total bacterial flux and lung tissue apoptosis, inflammatory cells, NF-κB expression (P < 0.05), and MMPs-2, -9, -12 activities (P < 0.05). We conclude that mice with SP-B-C allele are more susceptible to S. aureus pneumonia than mice with SP-B-T allele, and that CMC2.24 attenuates lung injury thus reducing mortality.

Effect of Airway Pressure Release Ventilation on Dynamic Alveolar Heterogeneity.

IMPORTANCE: Ventilator-induced lung injury may arise from heterogeneous lung microanatomy, whereby some alveoli remain collapsed throughout the breath cycle while their more compliant or surfactant-replete neighbors become overdistended, and this is called dynamic alveolar heterogeneity. OBJECTIVE: To determine how dynamic alveolar heterogeneity is influenced by 2 modes of mechanical ventilation: low tidal-volume ventilation (LTVV) and airway pressure release ventilation (APRV), using in vivo microscopy to directly measure alveolar size distributions. DESIGN, SETTING, AND PARTICIPANTS: In a randomized, nonblinded laboratory animal study conducted between January 2013 and December 2014, 14 rats (450-500 g in size) were randomized to a control group with uninjured lungs (n = 4) and 2 experimental groups with surfactant deactivation induced by polysorbate lavage: the LTVV group (n = 5) and the APRV group (n = 5). For all groups, a thoracotomy and in vivo microscopy were performed. Following lung injury induced by polysorbate lavage, the LTVV group was ventilated with a tidal volume of 6 mL/kg and progressively higher positive end-expiratory pressure (PEEP) (5, 10, 16, 20, and 24 cm H2O). Following lung injury induced by polysorbate lavage, the APRV group was ventilated with a progressively shorter time at low pressure, which increased the ratio of the end-expiratory flow rate (EEFR) to the peak expiratory flow rate (PEFR; from 10% to 25% to 50% to 75%). MAIN OUTCOMES AND MEASURES: Alveolar areas were quantified (using PEEP and EEFR to PEFR ratio) to determine dynamic heterogeneity. RESULTS: Following lung injury induced by polysorbate lavage, a higher PEEP (20-24 cm H2O) with LTVV resulted in alveolar occupancy (reported as percentage of total frame area) at inspiration (39.9%-42.2%) and expiration (35.9%-38.7%) similar to that in the control group (inspiration 53.3%; expiration 50.3%; P > .01). Likewise, APRV with an increased EEFR to PEFR ratio (50%-75%) resulted in alveolar occupancy at inspiration (46.7%-47.9%) and expiration (40.2%-46.6%) similar to that in the control group (P > .01). At inspiration, the distribution of the alveolar area of the control group was similar to that of the APRV group (P > .01) (but not to that of the LTVV group [P < .01]). A lower PEEP (5-10 cm H2O) and a decreased EEFR to PEFR ratio (≤50%) demonstrated dynamic heterogeneity between inspiration and expiration (P < .01 for both) with a greater percentage of large alveoli at expiration. Dynamic alveolar homogeneity between inspiration and expiration occurred with higher PEEP (16-24 cm H2O) (P > .01) and an increased EEFR to PEFR ratio (75%) (P > .01). CONCLUSIONS AND RELEVANCE: Increasing PEEP during LTVV increased alveolar recruitment and dynamic homogeneity but had a significantly different alveolar size distribution compared with the control group. By comparison, reducing the time at low pressure (EEFR to PEFR ratio of 75%) in the APRV group provided dynamic homogeneity and a closer approximation of the dynamics observed in the control group.

Trauma in silico: Individual-specific mathematical models and virtual clinical populations.

Trauma-induced critical illness is driven by acute inflammation, and elevated systemic interleukin-6 (IL-6) after trauma is a biomarker of adverse outcomes. We constructed a multicompartment, ordinary differential equation model that represents a virtual trauma patient. Individual-specific variants of this model reproduced both systemic inflammation and outcomes of 33 blunt trauma survivors, from which a cohort of 10,000 virtual trauma patients was generated. Model-predicted length of stay in the intensive care unit, degree of multiple organ dysfunction, and IL-6 area under the curve as a function of injury severity were in concordance with the results from a validation cohort of 147 blunt trauma patients. In a subcohort of 98 trauma patients, those with high-IL-6 single-nucleotide polymorphisms (SNPs) exhibited higher plasma IL-6 levels than those with low IL-6 SNPs, matching model predictions. Although IL-6 could drive mortality in individual virtual patients, simulated outcomes in the overall cohort were independent of the propensity to produce IL-6, a prediction verified in the 98-patient subcohort. In silico randomized clinical trials suggested a small survival benefit of IL-6 inhibition, little benefit of IL-1ß inhibition, and worse survival after tumor necrosis factor-α inhibition. This study demonstrates the limitations of extrapolating from reductionist mechanisms to outcomes in individuals and populations and demonstrates the use of mechanistic simulation in complex diseases.

Predicting the response of the injured lung to the mechanical breath profile.

Mechanical ventilation is a crucial component of the supportive care provided to patients with acute respiratory distress syndrome. Current practice stipulates the use of a low tidal volume (VT) of 6 ml/kg ideal body weight, the presumptive notion being that this limits overdistension of the tissues and thus reduces volutrauma. We have recently found, however, that airway pressure release ventilation (APRV) is efficacious at preventing ventilator-induced lung injury, yet APRV has a very different mechanical breath profile compared with conventional low-VT ventilation. To gain insight into the relative merits of these two ventilation modes, we measured lung mechanics and derecruitability in rats before and following Tween lavage. We fit to these lung mechanics measurements a computational model of the lung that accounts for both the degree of tissue distension of the open lung and the amount of lung derecruitment that takes place as a function of time. Using this model, we predicted how tissue distension, open lung fraction, and intratidal recruitment vary as a function of ventilator settings both for conventional low-VT ventilation and for APRV. Our predictions indicate that APRV is more effective at recruiting the lung than low-VT ventilation, but without causing more overdistension of the tissues. On the other hand, low-VT ventilation generally produces less intratidal recruitment than APRV. Predictions such as these may be useful for deciding on the relative benefits of different ventilation modes and thus may serve as a means for determining how to ventilate a given lung in the least injurious fashion.

Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation.

Cessation of blood flow represents a physical event that is sensed by the pulmonary endothelium leading to a signaling cascade that has been termed "mechanotransduction." This paradigm has clinical relevance for conditions such as pulmonary embolism, lung bypass surgery, and organ procurement and storage during lung transplantation. On the basis of our findings with stop of flow, we postulate that normal blood flow is "sensed" by the endothelium by virtue of its location at the interface of the blood and vessel wall and that this signal is necessary to maintain the endothelial cell membrane potential. Stop of flow is sensed by a "mechanosome" consisting of PECAM-VEGF receptor-VE cadherin that is located in the endothelial cell caveolae. Activation of the mechanosome results in endothelial cell membrane depolarization that in turn leads to activation of NADPH oxidase (NOX2) to generate reactive oxygen species (ROS). Endothelial depolarization additionally results in opening of T-type voltage-gated Ca(2+) channels, increased intracellular Ca(2+), and activation of nitric oxide (NO) synthase with resultant generation of NO. Increased NO causes vasodilatation whereas ROS provide a signal for neovascularization; however, with lung transplantation overproduction of ROS and NO can cause oxidative injury and/or activation of proteins that drive inflammation and cell death. Understanding the key events in the mechanosignaling cascade has important lessons for the design of strategies or interventions that may reduce injury during storage of donor lungs with the goal to increase the availability of lungs suitable for donation and thus improving access to lung transplantation.

Mechanical breath profile of airway pressure release ventilation: the effect on alveolar recruitment and microstrain in acute lung injury.

IMPORTANCE: Improper mechanical ventilation settings can exacerbate acute lung injury by causing a secondary ventilator-induced lung injury. It is therefore important to establish the mechanism by which the ventilator induces lung injury to develop protective ventilation strategies. It has been postulated that the mechanism of ventilator-induced lung injury is the result of heterogeneous, elevated strain on the pulmonary parenchyma. Acute lung injury has been associated with increases in whole-lung macrostrain, which is correlated with increased pathology. However, the effect of mechanical ventilation on alveolar microstrain remains unknown. OBJECTIVE: To examine whether the mechanical breath profile of airway pressure release ventilation (APRV), consisting of a prolonged pressure-time profile and brief expiratory release phase, reduces microstrain. DESIGN, SETTING, AND PARTICIPANTS: In a randomized, nonblinded laboratory animal study, rats were randomized into a controlled mandatory ventilation group (n = 3) and an APRV group (n = 3). Lung injury was induced by polysorbate lavage. A thoracotomy was performed and an in vivo microscope was placed on the lungs to measure alveolar mechanics. MAIN OUTCOMES AND MEASURES: In the controlled mandatory ventilation group, multiple levels of positive end-expiratory pressure (PEEP; 5, 10, 16, 20, and 24 cm H2O) were tested. In the APRV group, decreasing durations of expiratory release (time at low pressure [T(low)]) were tested. The T(low) was set to achieve ratios of termination of peak expiratory flow rate (T-PEFR) to peak expiratory flow rate (PEFR) of 10%, 25%, 50%, and 75% (the smaller this ratio is [ie, 10%], the more time the lung is exposed to low pressure during the release phase, which decreases end-expiratory lung volume and potentiates derecruitment). Alveolar perimeters were measured at peak inspiration and end expiration using digital image analysis, and strain was calculated by normalizing the change in alveolar perimeter length to the original length. Macrostrain was measured by volume displacement. RESULTS: Higher PEEP (16-24 cm H2O) and a brief T(low) (APRV T-PEFR to PEFR ratio of 75%) reduced microstrain. Microstrain was minimized with an APRV T-PEFR to PEFR ratio of 75% (mean [SEM], 0.05 [0.03]) and PEEP of 16 cm H2O (mean [SEM], 0.09 [0.08]), but an APRV T-PEFR to PEFR ratio of 75% also promoted alveolar recruitment compared with PEEP of 16 cm H2O (mean [SEM] total inspiratory area, 52.0% [2.9%] vs 29.4% [4.3%], respectively; P < .05). Whole-lung strain was correlated with alveolar microstrain in tested settings (P < .05) except PEEP of 16 cm H2O (P > .05). CONCLUSIONS AND RELEVANCE: Increased positive-end expiratory pressure and reduced time at low pressure (decreased T(low)) reduced alveolar microstrain. Reduced microstrain and improved alveolar recruitment using an APRV T-PEFR to PEFR ratio of 75% may be the mechanism of lung protection seen in previous clinical and animal studies.

Early application of airway pressure release ventilation may reduce mortality in high-risk trauma patients: a systematic review of observational trauma ARDS literature.

BACKGROUND: Adult respiratory distress syndrome is often refractory to treatment and develops after entering the health care system. This suggests an opportunity to prevent this syndrome before it develops. The objective of this study was to demonstrate that early application of airway pressure release ventilation in high-risk trauma patients reduces hospital mortality as compared with similarly injured patients on conventional ventilation. METHODS: Systematic review of observational data in patients who received conventional ventilation in other trauma centers were compared with patients treated with early airway pressure release ventilation in our trauma center. Relevant studies were identified in a PubMed and MEDLINE search from 1995 to 2012 and included prospective and retrospective observational and cohort studies enrolling 100 or more adult trauma patients with reported adult respiratory distress syndrome incidence and mortality data. RESULTS: Early airway pressure release ventilation as compared with the other trauma centers represented lower mean adult respiratory distress syndrome incidence (14.0% vs. 1.3%) and in-hospital mortality (14.1% vs. 3.9%). CONCLUSION: These data suggest that early airway pressure release ventilation may prevent progression of acute lung injury in high-risk trauma patients, reducing trauma-related adult respiratory distress syndrome mortality. LEVEL OF EVIDENCE: Systematic review, level IV.

Airway pressure release ventilation prevents ventilator-induced lung injury in normal lungs.

IMPORTANCE: Up to 25% of patients with normal lungs develop acute lung injury (ALI) secondary to mechanical ventilation, with 60% to 80% progressing to acute respiratory distress syndrome (ARDS). Once established, ARDS is treated with mechanical ventilation that can paradoxically elevate mortality. A ventilation strategy that reduces the incidence of ARDS could change the clinical paradigm from treatment to prevention. OBJECTIVES: To demonstrate that (1) mechanical ventilation with tidal volume (VT) and positive end-expiratory pressure (PEEP) settings used routinely on surgery patients causes ALI/ARDS in normal rats and (2) preemptive application of airway pressure release ventilation (APRV) blocks drivers of lung injury (ie, surfactant deactivation and alveolar edema) and prevents ARDS. DESIGN, SETTING, AND SUBJECTS: Rats were anesthetized and tracheostomy was performed at State University of New York Upstate Medical University. Arterial and venous lines, a peritoneal catheter, and a rectal temperature probe were inserted. Animals were randomized into 3 groups and followed up for 6 hours: spontaneous breathing ventilation (SBV, n = 5), continuous mandatory ventilation (CMV, n = 6), and APRV (n = 5). Rats in the CMV group were ventilated with Vt of 10 cc/kg and PEEP of 0.5 cm H2O. Airway pressure release ventilation was set with a P(High) of 15 to 20 cm H2O; P(Low) was set at 0 cm H2O. Time at P(High) (T(High)) was 1.3 to 1.5 seconds and a T(Low) was set to terminate at 75% of the peak expiratory flow rate (0.11-0.14 seconds), creating a minimum 90% cycle time spent at P(High). Bronchoalveolar lavage fluid and lungs were harvested for histopathologic analysis at necropsy. RESULTS: Acute lung injury/ARDS developed in the CMV group (mean [SE] PaO2/FiO2 ratio, 242.96 [24.82]) and was prevented with preemptive APRV (mean [SE] PaO2/FIO2 ratio, 478.00 [41.38]; P < .05). Airway pressure release ventilation also significantly reduced histopathologic changes and bronchoalveolar lavage fluid total protein (endothelial permeability) and preserved surfactant proteins A and B concentrations as compared with the CMV group. CONCLUSIONS AND RELEVANCE: Continuous mandatory ventilation in normal rats for 6 hours with Vt and PEEP settings similar to those of surgery patients caused ALI. Preemptive application of APRV blocked early drivers of lung injury, preventing ARDS. Our data suggest that APRV applied early could reduce the incidence of ARDS in patients at risk.

Early airway pressure release ventilation prevents ARDS-a novel preventive approach to lung injury.

Acute respiratory distress syndrome (ARDS) afflicts 200,000 patients annually with a mortality rate of 30% to 60% despite wide use of low tidal volume (LTV) ventilation, the present standard of care. High-permeability alveolar edema and instability occur early in the development of ARDS, before clinical signs of lung injury, and represent potential targets for therapy. We hypothesize that early application of a protective ventilation strategy (airway pressure release ventilation [APRV]) will stabilize alveoli and reduce alveolar edema, preventing the development of ARDS. Yorkshire pigs (30-40 kg) were anesthetized and subjected to two-hit injury: (a) intestinal ischemia-reperfusion, (b) peritoneal sepsis, or sham surgery. Following surgery, pigs were randomized into APRV (n = 4), according to current published guidelines for APRV; LTV ventilation (n = 3), using the current published ARDS Network guidelines (6 mL/kg); or sham (n = 5). The clinical care of all pigs was administered per the Surviving Sepsis Campaign guidelines. Animals were killed, and necropsy performed at 48 h. Arterial blood gases were measured to assess for the development of clinical lung injury. Lung tissue epithelial cadherin (E-cadherin) was measured to assess alveolar permeability. Bronchoalveolar lavage fluid (BALF) surfactant protein A was measured to assess alveolar stability. Lung edema content and histopathology were analyzed at 48 h. Airway pressure release ventilation pigs did not develop ARDS. In contrast, pigs in the LTV ventilation met ARDS criteria (PaO2/FIO2 ratio) (APRV: baseline = 471 ± 16; 48 h = 392 ± 8; vs. LTV ventilation: baseline = 551 ± 28; 48 h = 138 ± 88; P < 0.001). Airway pressure release ventilation preserved alveolar epithelial integrity demonstrated by higher levels of E-cadherin in lung tissue as compared with LTV ventilation (P < 0.05). Surfactant protein A levels were higher in BALF from the APRV group, suggesting APRV preserved alveolar stability. Quantitative histologic scoring showed improvements in all stigmata of ARDS in the APRV group versus the LTV ventilation (P < 0.05). Airway pressure release ventilation had significantly lower lung edema (wet-dry weight) than LTV ventilation (P < 0.05). Protective ventilation with APRV immediately following injury prevents development of ARDS. Reduction in lung edema, preservation of lung E-cadherin, and surfactant protein A abundance in BALF suggest that APRV attenuates lung permeability, edema, and surfactant degradation. Protective ventilation could change the clinical paradigm from supportive care for ARDS with LTV ventilation to preventing development of ARDS with APRV.