A long-lasting porcine model of ARDS caused by pneumonia and ventilator-induced lung injury.

BACKGROUND: Animal models of acute respiratory distress syndrome (ARDS) do not completely resemble human ARDS, struggling translational research. We aimed to characterize a porcine model of ARDS induced by pneumonia-the most common risk factor in humans-and analyze the additional effect of ventilator-induced lung injury (VILI). METHODS: Bronchoscopy-guided instillation of a multidrug-resistant Pseudomonas aeruginosa strain was performed in ten healthy pigs. In six animals (pneumonia-with-VILI group), pulmonary damage was further increased by VILI applied 3 h before instillation and until ARDS was diagnosed by PaO2/FiO2 < 150 mmHg. Four animals (pneumonia-without-VILI group) were protectively ventilated 3 h before inoculum and thereafter. Gas exchange, respiratory mechanics, hemodynamics, microbiological studies and inflammatory markers were analyzed during the 96-h experiment. During necropsy, lobar samples were also analyzed. RESULTS: All animals from pneumonia-with-VILI group reached Berlin criteria for ARDS diagnosis until the end of experiment. The mean duration under ARDS diagnosis was 46.8 ± 7.7 h; the lowest PaO2/FiO2 was 83 ± 5.45 mmHg. The group of pigs that were not subjected to VILI did not meet ARDS criteria, even when presenting with bilateral pneumonia. Animals developing ARDS presented hemodynamic instability as well as severe hypercapnia despite high-minute ventilation. Unlike the pneumonia-without-VILI group, the ARDS animals presented lower static compliance (p = 0.011) and increased pulmonary permeability (p = 0.013). The highest burden of P. aeruginosa was found at pneumonia diagnosis in all animals, as well as a high inflammatory response shown by a release of interleukin (IL)-6 and IL-8. At histological examination, only animals comprising the pneumonia-with-VILI group presented signs consistent with diffuse alveolar damage. CONCLUSIONS: In conclusion, we established an accurate pulmonary sepsis-induced ARDS model.

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.

Obesity Attenuates Ventilator-Induced Lung Injury by Modulating the STAT3-SOCS3 Pathway.

Background: Ventilator-induced lung injury (VILI) is characterized by vascular barrier dysfunction and suppression of alveolar fluid clearance (AFC). Obesity itself leads to chronic inflammation, which may initiate an injurious cascade to the lungs and simultaneously induce a protective feedback. In this study, we investigated the protective mechanism of obesity on VILI in a mouse model. Methods: The VILI model was set up via 6-h mechanical ventilation with a high tidal volume. Parameters including lung injury score, STAT3/NFκB pathway, and AFC were assessed. Mice with diet-induced obesity were obtained by allowing free access to a high-fat diet since the age of 3 weeks. After a 9-week diet intervention, these mice were sacrificed at the age of 12 weeks. The manipulation of SOCS3 protein was achieved by siRNA knockdown and pharmaceutical stimulation using hesperetin. WNK4 knockin and knockout obese mice were used to clarify the pathway of AFC modulation. Results: Obesity itself attenuated VILI. Knockdown of SOCS3 in obese mice offset the protection against VILI afforded by obesity. Hesperetin stimulated SOCS3 upregulation in nonobese mice and provided protection against VILI. In obese mice, the WNK4 axis was upregulated at the baseline, but was significantly attenuated after VILI compared with nonobese mice. At the baseline, the manipulation of SOCS3 by siRNA and hesperetin also led to the corresponding alteration of WNK4, albeit to a lesser extent. After VILI, WNK4 expression correlated with STAT3/NFκB activation, regardless of SOCS3 status. Obese mice carrying WNK4 knockout had VILI with a severity similar to that of wild-type obese mice. The severity of VILI in WNK4-knockin obese mice was counteracted by obesity, similar to that of wild-type nonobese mice only. Conclusions: Obesity protects lungs from VILI by upregulating SOCS3, thus suppressing the STAT3/NFκB inflammatory pathway and enhancing WNK4-related AFC. However, WNK4 activation is mainly from direct NFκB downstreaming, and less from SOCS3 upregulation. Moreover, JAK2-STAT3/NFκB signaling predominates the pathogenesis of VILI. Nevertheless, the interaction between SOCS3 and WNK4 in modulating VILI in obesity warrants further investigation.

Innovative in vitro method to study ventilator induced lung injury.

Mechanical ventilation (MV) is a life-saving therapy for critically ill patients, alleviating the work of breathing and supporting adequate gas exchange. However, MV can cause ventilator induced lung injury (VILI) by baro/volu- and atelectrauma, even lead to acute respiratory distress syndrome (ARDS), and substantially augment mortality. There is a need for specific biomarkers and novel research platforms for VILI/ARDS research to study these detrimental disorders and seek ways to avoid or prevent them. Previous in vitro studies on bronchial epithelium, cultured in air-liquid interface (ALI) conditions, have generally utilized static or constant pressure.  We have developed a Cyclical Pressure ALI Device (CPAD) that enables cyclical stress on ALI cultured human bronchial cells, with the aim of mimicking the effects of MV. Using CPAD we were able to analyze differentially expressed VILI/ARDS and innate immunity associated genes along with increased expression of associated proteins. CPAD provides an easy and accessible way to analyze functional and phenotypic changes that occur during VILI and may provide a platform for future drug testing.

Acute respiratory distress syndrome.

The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients and is defined by the acute onset of noncardiogenic pulmonary oedema, hypoxaemia and the need for mechanical ventilation. ARDS occurs most often in the setting of pneumonia, sepsis, aspiration of gastric contents or severe trauma and is present in ~10% of all patients in intensive care units worldwide. Despite some improvements, mortality remains high at 30-40% in most studies. Pathological specimens from patients with ARDS frequently reveal diffuse alveolar damage, and laboratory studies have demonstrated both alveolar epithelial and lung endothelial injury, resulting in accumulation of protein-rich inflammatory oedematous fluid in the alveolar space. Diagnosis is based on consensus syndromic criteria, with modifications for under-resourced settings and in paediatric patients. Treatment focuses on lung-protective ventilation; no specific pharmacotherapies have been identified. Long-term outcomes of patients with ARDS are increasingly recognized as important research targets, as many patients survive ARDS only to have ongoing functional and/or psychological sequelae. Future directions include efforts to facilitate earlier recognition of ARDS, identifying responsive subsets of patients and ongoing efforts to understand fundamental mechanisms of lung injury to design specific treatments.

Ventilator-induced lung injury is aggravated by antibiotic mediated microbiota depletion in mice.

BACKGROUND: Antibiotic exposure alters the microbiota, which can impact the inflammatory immune responses. Critically ill patients frequently receive antibiotic treatment and are often subjected to mechanical ventilation, which may induce local and systemic inflammatory responses and development of ventilator-induced lung injury (VILI). The aim of this study was to investigate whether disruption of the microbiota by antibiotic therapy prior to mechanical ventilation affects pulmonary inflammatory responses and thereby the development of VILI. METHODS: Mice underwent 6-8 weeks of enteral antibiotic combination treatment until absence of cultivable bacteria in fecal samples was confirmed. Control mice were housed equally throughout this period. VILI was induced 3 days after completing the antibiotic treatment protocol, by high tidal volume (HTV) ventilation (34 ml/kg; positive end-expiratory pressure = 2 cmH2O) for 4 h. Differences in lung function, oxygenation index, pulmonary vascular leakage, macroscopic assessment of lung injury, and leukocyte and lymphocyte differentiation were assessed. Control groups of mice ventilated with low tidal volume and non-ventilated mice were analyzed accordingly. RESULTS: Antibiotic-induced microbiota depletion prior to HTV ventilation led to aggravation of VILI, as shown by increased pulmonary permeability, increased oxygenation index, decreased pulmonary compliance, enhanced macroscopic lung injury, and increased cytokine/chemokine levels in lung homogenates. CONCLUSIONS: Depletion of the microbiota by broad-spectrum antibiotics prior to HTV ventilation renders mice more susceptible to developing VILI, which could be clinically relevant for critically ill patients frequently receiving broad-spectrum antibiotics.

Deferoxamine preconditioning ameliorates mechanical ventilation-induced lung injury in rat model via ROS in alveolar macrophages: a randomized controlled study.

BACKGROUND: Mechanical ventilation (MV) can provide effective breathing support; however, ventilatior-induced lung injury (VILI) has also been widely recognized in clinical practice, including in the healthy lung. Unfortunately, the morbidity and mortality of VILI remain unacceptably high, and no satisfactory therapeutic effect can be achieved. The current study aimed to examine the effects of iron chelator preconditioning on the mitochondrial reactive oxygen species (ROS) in alveolar macrophages and pathological lung injury in VILI. METHODS: Twenty four healthy male Sprague-Dawley (SD) rats (250-300 g in weight) were randomly divided into 3 groups, including the control group (NC group, n = 8), the high-volume mechanical ventilation group (HV group, n = 8), and the deferoxamine treatment group (HV + DFO group, n = 8). Rats in the HV and HV + DFO groups were subjected to high-volume MV at a dose of 40 ml/kg. DFO was administered at a dose of 200 mg/kg 15 min prior to over-ventilation. Spontaneously breathing anesthetized rats were used as the controls. The animals were sacrificed after 4 h of high-volume ventilation or under control conditions, the animals were sacrificed. Purified alveolar macrophages from bronchoalveolar lavage fluid (BALF) and lung tissue were collected for further analysis through light microscopy and flow cytometry. RESULTS: Compared with the controls, the high-volume-ventilated rats had exhibited typical lung edema and histological lung injury, and ROS were markedly increased in alveolar macrophages and mitochondria. Moreover, all indices of VILI were remarkably different in rats treated with DFO preconditioning. DFO could ameliorate lung injury in the mechanically ventilated SD rat model. CONCLUSIONS: DFO preconditioning contributes to mitigating the histological lung damage while reducing ROS levels in alveolar macrophages and mitochondria, suggesting that iron metabolism in alveolar macrophages may participate in VILI.

Capturing the multifactorial nature of ARDS - "Two-hit" approach to model murine acute lung injury.

Severe acute respiratory distress syndrome (ARDS) presents typically with an initializing event, followed by the need for mechanical ventilation. Most animal models of ALI are limited by the fact that they focus on a singular cause of acute lung injury (ALI) and therefore fail to mimic the complex, multifactorial pathobiology of ARDS. To better capture this scenario, we provide a comprehensive characterization of models of ALI combining two injuries: intra tracheal (i.t.) instillation of LPS or hypochloric acid (HCl) followed by ventilator-induced lung injury (VILI). We hypothesized, that mice pretreated with LPS or HCl prior to VILI and thus receiving a ("two-hit injury") will sustain a superadditive lung injury when compared to VILI. Mice were allocated to following treatment groups: control with i.t. NaCl, ventilation with low peak inspiratory pressure (PIP), i.t. HCl, i.t. LPS, VILI (high PIP), HCl i.t. followed by VILI and LPS i.t. followed by VILI. Severity of injury was determined by protein content and MPO activity in bronchoalveolar lavage (BAL), the expression of inflammatory cytokines and histopathology. Mice subjected to VILI after HCl or LPS instillation displayed augmented lung injury, compared to singular lung injury. However, mice that received i.t. LPS prior to VILI showed significantly increased inflammatory lung injury compared to animals that underwent i.t. HCl followed by VILI. The two-hit lung injury models described, resulting in additive but differential acute lung injury recaptures the clinical relevant multifactorial etiology of ALI and could be a valuable tool in translational research.

Curcumin ameliorated ventilator-induced lung injury in rats.

BACKGROUND: Curcumin (CUR) is a Chinese medicine monomer with antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effects and mechanisms of CUR treatment on ventilator-induced lung injury (VILI) in rats. METHODS: Total 50 SD rats were divided into five groups: sham, VILI, VILI+CUR-50 (CUR 50?mg/kg pretreated intraperitoneal), VILI+CUR-200 (CUR 200?mg/kg pretreated intraperitoneal) and VILI?+?DXM (5?mg/kg pretreated intraperitoneal). The morphology and ultrastructure were observed by microscope and transmission electron microscope. The wet to dry ratio, protein concentration in bronchoalveolar lavage fluid (BALF), evans blue dye (EBD) content, nuclear factor kappa B (NF-?B) activity, myeloperoxidase (MPO), malondialdehyde (MDA), xanthine oxidase (XO) and total antioxidative capacity (TAOC) levels were measured. RESULTS: Histological studies revealed that inflammatory cells infiltration and alveolar edema were significantly severe in VILI as compared to other groups. CUR-200 and DXM treatment reversed lung injury significantly. The wet to dry ratio, protein concentration in BALF, EBD content, MPO activity, tumor necrosis factor (TNF)-? level and NF-?B activity were significantly increased in VILI group as compared to other groups. CUR-200 and DXM treatment significantly suppressed permeability and inflammation induced by ventilation. Furthermore, the significantly higher MDA content in VILI could be markedly decreased by CUR-200 and DXM treatment while the levels of XO and TAOC were markedly recovered only by CUR (200?mg/kg) treatment after VILI. CONCLUSION: CUR could inhibit the inflammatory response and oxidative stress during VILI, which is partly through NF-?B pathway.

Adverse Heart-Lung Interactions in Ventilator-induced Lung Injury.

RATIONALE: In the original 1974 in vivo study of ventilator-induced lung injury, Webb and Tierney reported that high Vt with zero positive end-expiratory pressure caused overwhelming lung injury, subsequently shown by others to be due to lung shear stress. OBJECTIVES: To reproduce the lung injury and edema examined in the Webb and Tierney study and to investigate the underlying mechanism thereof. METHODS: Sprague-Dawley rats weighing approximately 400 g received mechanical ventilation for 60 minutes according to the protocol of Webb and Tierney (airway pressures of 14/0, 30/0, 45/10, 45/0 cm H2O). Additional series of experiments (20 min in duration to ensure all animals survived) were studied to assess permeability (n = 4 per group), echocardiography (n = 4 per group), and right and left ventricular pressure (n = 5 and n = 4 per group, respectively). MEASUREMENTS AND MAIN RESULTS: The original Webb and Tierney results were replicated in terms of lung/body weight ratio (45/0 > 45/10 ≈ 30/0 ≈ 14/0; P < 0.05) and histology. In 45/0, pulmonary edema was overt and rapid, with survival less than 30 minutes. In 45/0 (but not 45/10), there was an increase in microvascular permeability, cyclical abolition of preload, and progressive dilation of the right ventricle. Although left ventricular end-diastolic pressure decreased in 45/10, it increased in 45/0. CONCLUSIONS: In a classic model of ventilator-induced lung injury, high peak pressure (and zero positive end-expiratory pressure) causes respiratory swings (obliteration during inspiration) in right ventricular filling and pulmonary perfusion, ultimately resulting in right ventricular failure and dilation. Pulmonary edema was due to increased permeability, which was augmented by a modest (approximately 40%) increase in hydrostatic pressure. The lung injury and acute cor pulmonale is likely due to pulmonary microvascular injury, the mechanism of which is uncertain, but which may be due to cyclic interruption and exaggeration of pulmonary blood flow.

Pre- and posttreatment with hydrogen sulfide prevents ventilator-induced lung injury by limiting inflammation and oxidation.

Although essential in critical care medicine, mechanical ventilation often results in ventilator-induced lung injury. Low concentrations of hydrogen sulfide have been proven to have anti-inflammatory and anti-oxidative effects in the lung. The aim of this study was to analyze the kinetic effects of pre- and posttreatment with hydrogen sulfide in order to prevent lung injury as well as inflammatory and oxidative stress upon mechanical ventilation. Mice were either non-ventilated or mechanically ventilated with a tidal volume of 12 ml/kg for 6 h. Pretreated mice inhaled hydrogen sulfide in low dose for 1, 3, or 5 h prior to mechanical ventilation. Posttreated mice were ventilated with air followed by ventilation with hydrogen sulfide in various combinations. In addition, mice were ventilated with air for 10 h, or with air for 5 h and subsequently with hydrogen sulfide for 5 h. Histology, interleukin-1ß, neutrophil counts, and reactive oxygen species formation were examined in the lungs. Both pre-and posttreatment with hydrogen sulfide time-dependently reduced or even prevented edema formation, gross histological damage, neutrophil influx and reactive oxygen species production in the lung. These results were also observed in posttreatment, when the experimental time was extended and hydrogen sulfide administration started as late as after 5 h air ventilation. In conclusion, hydrogen sulfide exerts lung protection even when its application is limited to a short or delayed period. The observed lung protection is mediated by inhibition of inflammatory and oxidative signaling.

One-hit Models of Ventilator-induced Lung Injury: Benign Inflammation versus Inflammation as a By-product.

BACKGROUND: One important explanation for the detrimental effects of conventional mechanical ventilation is the biotrauma hypothesis that ventilation may trigger proinflammatory responses that subsequently cause lung injury. This hypothesis has frequently been studied in so-called one-hit models (overventilation of healthy lungs) that so far have failed to establish an unequivocal link between inflammation and hypoxemic lung failure. This study was designed to develop a one-hit biotrauma model. METHODS: Mice (six per group) were ventilated for up to 7 h (positive end-expiratory pressure 2 cm H2O) and received 300 µl/h fluid support. Series_1: initial plateau pressures of 10, 24, 27, or 30 cm H2O. Series_2: ventilation with pressure release at 34 cm H2O and initial plateau pressure of 10, 24, 27, or 30 cm H2O. To study the significance of inflammation, the latter groups were also pretreated with the steroid dexamethasone. RESULTS: Within 7 h, 20 of 24 mice ventilated with plateau pressure of 27 cm H2O or more died of a catastrophic lung failure characterized by strongly increased proinflammatory markers and a precipitous decrease in pulmonary compliance, blood pressure, and oxygenation. Pretreatment with dexamethasone reduced inflammation, but prolonged median survival time by 30 min. CONCLUSIONS: Our findings demonstrate a sharp distinction between ventilation with 24 cm H2O that was well tolerated and ventilation with 27 cm H2O that was lethal for most animals due to catastrophic lung failure. In the former case, inflammation was benign and in the latter, a by-product that only accelerated lung failure. The authors suggest that biotrauma-when defined as a ventilation-induced and inflammation-dependent hypoxemia-is difficult to study in murine one-hit models of ventilation, at least not within 7 h. (Anesthesiology 2017; 126:909-22).

Fifty Years of Research in ARDS. Spontaneous Breathing during Mechanical Ventilation. Risks, Mechanisms, and Management.

Spontaneous respiratory effort during mechanical ventilation has long been recognized to improve oxygenation, and because oxygenation is a key management target, such effort may seem beneficial. Also, disuse and loss of peripheral muscle and diaphragm function is increasingly recognized, and thus spontaneous breathing may confer additional advantage. Reflecting this, epidemiologic data suggest that the use of partial (vs. full) support modes of ventilation is increasing. Notwithstanding the central place of spontaneous breathing in mechanical ventilation, accumulating evidence indicates that it may cause-or worsen-acute lung injury, especially if acute respiratory distress syndrome is severe and spontaneous effort is vigorous. This Perspective reviews the evidence for this phenomenon, explores mechanisms of injury, and provides suggestions for clinical management and future research.

Optimizing PEEP by Electrical Impedance Tomography in a Porcine Animal Model of ARDS.

BACKGROUND: Mechanical ventilation is necessary in diverse clinical circumstances. Especially in the context of ARDS, so-called protective ventilation strategies must be followed. It is already known that PEEP might enhance oxygenation in ARDS. However, determining the optimal PEEP settings in clinical routines is challenging. Electrical impedance tomography (EIT) is a promising technique with which to adjust ventilator settings. We investigated whether the combination of different EIT parameters, namely the global inhomogeneity and hyperdistension indices, may lead to a feasible and safe PEEP setting. METHODS: ARDS was induced by a double-hit approach in 18 pigs weighing, on average, 34.8 ± 3.97 kg. First, a surfactant washout was conducted; second, the tidal volume was increased to 20 mL/kg body weight, triggering a ventilator-induced lung injury. Subsequently, pigs were randomized to either the EIT or control groups, followed by an observation time of 24 h. In the control group, PEEP was set according to the ARDS network table. In the EIT group, a PEEP trial was conducted to determine an appropriate PEEP. At defined time points, hemodynamic measures, ventilation parameters, and EIT recordings, as well as blood samples, were taken. After euthanization, lungs were removed for subsequent histopathological and cytological examination. RESULTS: The combination of PEEP and FIO2 differed between groups, although respiratory compliance, gas exchange, and histopathological examinations, as well as hemodynamics, did not show any statistical differences between the EIT and control groups. However, in the control group, the PEEP/FIO2 settings followed the given coupling; in the EIT group, divergent individual combinations of PEEP and FIO2 ranges occurred. CONCLUSIONS: PEEP setting by EIT facilitates a more individual ventilation therapy. However, in our relatively short ARDS observation period of 24 h, no significant differences appeared in common clinical parameters compared with a control group.

Knockout Mice Reveal a Major Role for Alveolar Epithelial Type I Cells in Alveolar Fluid Clearance.

Active ion transport by basolateral Na-K-ATPase (Na pump) creates an Na(+) gradient that drives fluid absorption across lung alveolar epithelium. The α1 and ß1 subunits are the most highly expressed Na pump subunits in alveolar epithelial cells (AEC). The specific contribution of the ß1 subunit and the relative contributions of alveolar epithelial type II (AT2) versus type I (AT1) cells to alveolar fluid clearance (AFC) were investigated using two cell type-specific mouse knockout lines in which the ß1 subunit was knocked out in either AT1 cells or both AT1 and AT2 cells. AFC was markedly decreased in both knockout lines, revealing, we believe for the first time, that AT1 cells play a major role in AFC and providing insights into AEC-specific roles in alveolar homeostasis. AEC monolayers derived from knockout mice demonstrated decreased short-circuit current and active Na(+) absorption, consistent with in vivo observations. Neither hyperoxia nor ventilator-induced lung injury increased wet-to-dry lung weight ratios in knockout lungs relative to control lungs. Knockout mice showed increases in Na pump ß3 subunit expression and ß2-adrenergic receptor expression. These results demonstrate a crucial role for the Na pump ß1 subunit in alveolar ion and fluid transport and indicate that both AT1 and AT2 cells make major contributions to these processes and to AFC. Furthermore, they support the feasibility of a general approach to altering alveolar epithelial function in a cell-specific manner that allows direct insights into AT1 versus AT2 cell-specific roles in the lung.

Association of Patient Care with Ventilator-Associated Conditions in Critically Ill Patients: Risk Factor Analysis.

BACKGROUND: Ventilator-associated conditions (VACs), for which new surveillance definitions and methods were issued by the Center for Disease Control and Prevention (CDC), are respiratory complications occurring in conjunction with the use of invasive mechanical ventilation and are related to adverse outcomes in critically ill patients. However, to date, risk factors for VACs have not been adequately established, leading to a need for developing a better understanding of the risks. The objective of this study was to explore care-related risk factors as a process indicator and provide valuable information pertaining to VAC preventive measures. METHODS: This retrospective, single-center, cohort study was conducted in the intensive-care unit (ICU) of a university hospital in Japan. Patient data were automatically sampled using a computerized medical records system and retrospectively analyzed. Management and care-related, but not host-related, factors were exhaustively analyzed using multivariate analysis for risks of VACs. VAC correlation to mortality was also investigated. RESULTS: Of the 3122 patients admitted in the ICU, 303 ventilated patients meeting CDC-specified eligibility criteria were included in the analysis. Thirty-seven VACs (12.2%) were found with a corresponding rate of 12.1 per 1000 ventilator days. Multivariate analysis revealed four variables related to patient care as risk factors for VACs: absence of intensivist participation in management of ventilated patients [adjusted HR (AHR): 7.325, P < 0.001)], using relatively higher driving pressure (AHR: 1.216, P < 0.001), development of edema (AHR: 2.145, P = 0.037), and a larger body weight increase (AHR: 0.058, P = 0.005). Furthermore, this research confirmed mortality differences in patients with VACs and statistically derived risks compared with those without VACs (HR: 2.623, P = 0.008). CONCLUSION: Four risk factors related to patient care were clearly identified to be the key factors for VAC preventive measures.

Low tidal volume ventilation ameliorates left ventricular dysfunction in mechanically ventilated rats following LPS-induced lung injury.

BACKGROUND: High tidal volume ventilation has shown to cause ventilator-induced lung injury (VILI), possibly contributing to concomitant extrapulmonary organ dysfunction. The present study examined whether left ventricular (LV) function is dependent on tidal volume size and whether this effect is augmented during lipopolysaccharide(LPS)-induced lung injury. METHODS: Twenty male Wistar rats were sedated, paralyzed and then randomized in four groups receiving mechanical ventilation with tidal volumes of 6 ml/kg or 19 ml/kg with or without intrapulmonary administration of LPS. A conductance catheter was placed in the left ventricle to generate pressure-volume loops, which were also obtained within a few seconds of vena cava occlusion to obtain relatively load-independent LV systolic and diastolic function parameters. The end-systolic elastance / effective arterial elastance (Ees/Ea) ratio was used as the primary parameter of LV systolic function with the end-diastolic elastance (Eed) as primary LV diastolic function. RESULTS: Ees/Ea decreased over time in rats receiving LPS (p = 0.045) and high tidal volume ventilation (p = 0.007), with a lower Ees/Ea in the rats with high tidal volume ventilation plus LPS compared to the other groups (p < 0.001). Eed increased over time in all groups except for the rats receiving low tidal volume ventilation without LPS (p = 0.223). A significant interaction (p < 0.001) was found between tidal ventilation and LPS for Ees/Ea and Eed, and all rats receiving high tidal volume ventilation plus LPS died before the end of the experiment. CONCLUSIONS: Low tidal volume ventilation ameliorated LV systolic and diastolic dysfunction while preventing death following LPS-induced lung injury in mechanically ventilated rats. Our data advocates the use of low tidal volumes, not only to avoid VILI, but to avert ventilator-induced myocardial dysfunction as well.

Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), an illness characterized by life-threatening vascular leak, is a significant cause of morbidity and mortality in critically ill patients. Recent preclinical studies and clinical observations have suggested a potential role for the chemotherapeutic agent imatinib in restoring vascular integrity. Our prior work demonstrates differential effects of imatinib in mouse models of ALI, namely attenuation of LPS-induced lung injury but exacerbation of ventilator-induced lung injury (VILI). Because of the critical role of mechanical ventilation in the care of patients with ARDS, in the present study we pursued an assessment of the effectiveness of imatinib in a "two-hit" model of ALI caused by combined LPS and VILI. Imatinib significantly decreased bronchoalveolar lavage protein, total cells, neutrophils, and TNF-α levels in mice exposed to LPS plus VILI, indicating that it attenuates ALI in this clinically relevant model. In subsequent experiments focusing on its protective role in LPS-induced lung injury, imatinib attenuated ALI when given 4 h after LPS, suggesting potential therapeutic effectiveness when given after the onset of injury. Mechanistic studies in mouse lung tissue and human lung endothelial cells revealed that imatinib inhibits LPS-induced NF-κB expression and activation. Overall, these results further characterize the therapeutic potential of imatinib against inflammatory vascular leak.