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Background Mechanical power (MP) refers to the energy delivered by a ventilator to the respiratory system per unit of time. MP referenced to predicted body weight (PBW) or respiratory system compliance have better predictive value for mortality than MP alone in acute respiratory distress syndrome (ARDS). Our objective was to assess the potential impact of consecutive changes of MP on hospital mortality among ARDS patients receiving extracorporeal membrane oxygenation (ECMO). Methods We performed a retrospective analysis of patients with severe ARDS receiving ECMO in a tertiary care referral center in Taiwan between May 2006 and October 2015. Serial changes of MP during ECMO were recorded. Results A total of 152 patients with severe ARDS rescued with ECMO were analyzed. Overall hospital mortality was 53.3%. There were no significant differences between survivors and nonsurvivors in terms of baseline values of MP or other ventilator settings. Cox regression models demonstrated that mean MP alone, MP referenced to PBW, and MP referenced to compliance during the first 3 days of ECMO were all independently associated with hospital mortality. Higher MP referenced to compliance (HR 2.289 [95% CI 1.214–4.314], p = 0.010) was associated with a higher risk of death than MP itself (HR 1.060 [95% CI 1.018–1.104], p = 0.005) or MP referenced to PBW (HR 1.004 [95% CI 1.002–1.007], p 14.4 J/min) during the first 3 days of ECMO was significantly higher than that of patients with low MP (≦ 14.4 J/min) (70.7% vs. 46.8%, p = 0.004), and the 90-day hospital mortality of patients with high MP referenced to compliance (> 0.53 J/min/ml/cm H2O) during the first 3 days of ECMO was significantly higher than that of patients with low MP referenced to compliance (≦ 0.53 J/min/ml/cm H2O) (63.6% vs. 29.7%, p Conclusions MP during the first 3 days of ECMO was the only ventilatory variable independently associated with 90-day hospital mortality, and MP referenced to compliance during ECMO was more predictive for mortality than was MP alone.

Background: Mechanical ventilation is the most important support treatment for acute respiratory distress syndrome (ARDS); however, it brings with it the risk of ventilator-induced lung injury, which can lead to pulmonary fibrosis and prolonged mechanical ventilation. Our objective in this study was to examine the correlation between ventilator settings and histological fibrosis in ARDS patients. We also examined the impact of histological fibrosis on clinical outcomes and mortality. Methods: We performed a retrospective analysis of patients with ARDS who received open lung biopsy in a tertiary care referral center in Taiwan between March 2006 and December 2019. Mechanical ventilator settings were recorded at the time of ARDS diagnosis and on the day of biopsy. Results: A total of 68 ARDS patients who had received open lung biopsy with diffuse alveolar damage (DAD; the hallmark pathology of ARDS) were analyzed and stratified into non-fibrosis (n = 56) and fibrosis groups (n = 12). Mechanical power and airway pressures at the time of ARDS diagnosis and airway pressures on the day of biopsy were significantly higher in the fibrosis group than in the non-fibrosis group, and lung compliance on the day of biopsy was significantly lower. The duration of ventilator usage and time spent in the intensive care unit and hospital stay were all significantly higher in the fibrosis group. Hospital mortality was higher in the fibrosis than in the non-fibrosis group (67% vs. 57%, p = 0.748). In the fibrosis group, patients with AE-IPF (n = 5) received higher ventilator load and faced higher hospital mortality than DAD with fibrotic phase (n = 7) (80% vs. 57%, p = 0.242). A multivariable logistic regression model demonstrated that mechanical power at ARDS diagnosis and ARDS duration before biopsy were independently associated with histological fibrosis at open lung biopsy (odds ratio 1.493 [95% CI 1.014–2.200], p = 0.042; odds ratio 1.160 [95% CI 1.052–1.278], p = 0.003, respectively). Conclusions: Our findings indicate that prompt action aimed at staving off injurious mechanical stretching of lung parenchyma and subsequent progression to fibrosis may have a positive effect on clinical outcomes. Keywords: Mechanical ventilation, Acute respiratory distress syndrome, Open lung biopsy, Histology, Diffuse alveolar damage, Pulmonary fibrosis, Idiopathic pulmonary fibrosis, Outcomes

Accumulated secretion above the endotracheal tube cuff can be aspirated during extubation after deflation. The possible techniques for minimizing pulmonary aspiration from subglottic secretion during extubation have not been well explored. This study aimed to determine the effect of different extubation techniques on secretion leakage. An endotracheal tube was placed in a tube mimicking an airway. We measured the leak volume of water or artificial sputum of different viscosities with three extubation techniques—negative pressure with suctioning; positive pressure with a resuscitator; and continuous positive airway pressure set at 5, 10, and 20 cm H2O. Extubation with continuous positive airway pressure resulted in lower secretion leakage than that with negative pressure with suctioning and positive pressure with a resuscitator. Increasing the continuous positive airway pressure level decreased secretion leakage volume during extubation. We further determined a correlation of leak volume with sputum viscosity. Continuous positive airway pressure at 5 cm H2O produced lower volume secretion leakage than the other two techniques, even with higher secretion viscosity. Based on these results, using continuous positive airway pressure with a previous ventilator continuous positive airway pressure/positive end-expiratory pressure setting for extubation is recommended.

Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome caused by direct (local damage to lung parenchyma) or indirect lung injury (insults from extrapulmonary sites with acute systemic inflammatory response), the clinical and biological complexity can have a profound effect on clinical outcomes. We performed a retrospective analysis of 152 severe ARDS patients receiving extracorporeal membrane oxygenation (ECMO). Our objective was to assess the differences in clinical characteristics and outcomes of direct and indirect ARDS patients receiving ECMO. Overall hospital mortality was 53.3%. A total of 118 patients were assigned to the direct ARDS group, and 34 patients were assigned to the indirect ARDS group. The 28-, 60-, and 90-day hospital mortality rates were significantly higher among indirect ARDS patients (all p &lt, 0.05). Cox regression models demonstrated that among direct ARDS patients, diabetes mellitus, immunocompromised status, ARDS duration before ECMO, and SOFA score during the first 3 days of ECMO were independently associated with mortality. In indirect ARDS patients, SOFA score and dynamic compliance during the first 3 days of ECMO were independently associated with mortality. Our findings revealed that among patients receiving ECMO, direct and indirect subphenotypes of ARDS have distinct clinical outcomes and different predictors for mortality.

Extracorporeal membrane oxygenation (ECMO) is considered a salvage therapy in cases of severe acute respiratory distress syndrome (ARDS) with profound hypoxemia. However, the need for high-volume fluid resuscitation and blood transfusions after ECMO initiation introduces a risk of fluid overload. Positive fluid balance is associated with mortality in critically ill patients, and conservative fluid management for ARDS patients has been shown to shorten both the duration of mechanical ventilation and time spent in intensive care, albeit without a significant effect on survival. Nonetheless, few studies have addressed the influence of fluid balance on clinical outcomes in severe ARDS patients undergoing ECMO. In the current retrospective study, we examined the impact of cumulative fluid balance (CFB) on hospital mortality in 152 cases of severe ARDS treated using ECMO. Overall hospital mortality was 53.3%, and we observed a stepwise positive correlation between CFB and the risk of death. Cox regression models revealed that CFB during the first 3 days of ECMO was independently associated with higher hospital mortality (adjusted hazard ratio 1.110 [95% CI 1.027–1.201], p = 0.009). Our findings indicate the benefits of a conservative treatment approach to avoid fluid overload during the early phase of ECMO when dealing with severe ARDS patients.

The high mortality rate of patients with severe acute respiratory distress syndrome (ARDS) warrants aggressive clinical intervention. Extracorporeal membrane oxygenation (ECMO) is a salvage therapy for life-threatening hypoxemia. Randomized controlled trials of ECMO for severe ARDS comprise a number of ethical and methodological issues. Therefore, indications and optimal timing for implementation of ECMO, and predictive risk factors for outcomes have not been adequately investigated. We performed propensity score matching to match ECMO-supported and non-ECMO-supported patients at 48 h after ARDS onset for comparisons based on clinical outcomes and hospital mortality. A total of 280 severe ARDS patients were included, and propensity score matching of 87 matched pairs revealed that the 90-d hospital mortality rate was 56.3% in the ECMO group and 74.7% in the non-ECMO group (p = 0.028). Subgroup analysis revealed that greater severity of ARDS, higher airway pressure, or a higher Sequential Organ Failure Assessment score tended to benefit from ECMO treatment in terms of survival. Multivariate logistic regression revealed that hospital mortality was significantly lower among patients who received ECMO than among those who did not. Our findings suggested that early initiation of ECMO (within 48 h) may increase the likelihood of survival for patients with severe ARDS.

Background Air pollution exposure and idiopathic pulmonary fibrosis (IPF) cause a poor prognosis after SARS-CoV-2 infection, but the underlying mechanisms are not well explored. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are the keys to the entry of SARS-CoV-2. We therefore hypothesized that air pollution exposure and IPF may increase the expression of ACE2 and TMPRSS2 in the lung alveolar region. We measured their expression levels in lung tissues of control non-IPF and IPF patients, and used murine animal models to study the deterioration of IPF caused by particulate matter (PM) and the molecular pathways involved in the expression of ACE2 and TMPRSS2. Results In non-IPF patients, cells expressing ACE2 and TMPRSS2 were limited to human alveolar cells. ACE2 and TMPRSS2 were largely upregulated in IPF patients, and were co-expressed by fibroblast specific protein 1 (FSP-1) + lung fibroblasts in human pulmonary fibrotic tissue. In animal models, PM exposure increased the severity of bleomycin-induced pulmonary fibrosis. ACE2 and TMPRSS2 were also expressed in FSP-1+ lung fibroblasts in bleomycin-induced pulmonary fibrosis, and when combined with PM exposure, they were further upregulated. The severity of pulmonary fibrosis and the expression of ACE2 and TMPRSS2 caused by PM exposure were blocked by deletion of KC, a murine homologue of IL-8, or treatment with reparixin, an inhibitor of IL-8 receptors CXCR1/2. Conclusions These data suggested that risk of SARS-CoV-2 infection and COVID-19 disease severity increased by air pollution exposure and underlying IPF. It can be mediated through upregulating ACE2 and TMPRSS2 in pulmonary fibroblasts, and prevented by blocking the IL-8/CXCR1/2 pathway.

Additional file 1: Table S1. Ventilator settings before and during the first 3 days of ECMO between the earlier years and later years.

Additional file 2: Table S2. Ventilator settings parameters during the first 3 days of ECMO.

Additional file 4: Table S4. Cox proportional hazard regression analysis of factors associated with 90-day hospital mortality.

Additional file 1: Figure S1. Expression of ACE2 and TMPRSS2 in normal lung tissue. (A) Immunohistochemistry for ACE2 and TMPRSS2 was performed in normal human lung tissue. Positive staining for ACE2 is clearly observed on alveolar cells in normal lung tissues. Weak positive staining for TMPRSS2 is observed on alveolar cells. For negative control samples, the primary antibody was omitted. 20X magnification, scale bar: 50 μm. (B, C) Double immunofluorescence was performed in continuous lung tissue sections from normal patients. Representative images show the colocalizationof (B) ACE2 or (C) TMPRSS2 with surfactant protein C (SP-C) as the marker of type II alveolar cells. The rectangle frames are magnified on the right upper corners. 40X magnification, scale bar: 50 μm. ACE2: angiotensin-converting enzyme 2; TMPRSS2: transmembrane serine protease 2; SP-C: surfactant protein C. Figure S2. Expression of fibrosis in IPF lung tissue. The fibrosis areas in the lung tissues of IPF patients were stained with Masson’s trichrome, PicroSirius Red and Elastin staining. Almost all of these stains show the same fibrotic areas. 20X magnification, scale bar: 50μm. Figure S3. Expression of ACE2 and TMPRSS2 in FSP-1 positive murine pulmonary fibrosis areas. The mice treated with bleomycin plus PM were sacrificed and the lung tissue sections were subjected to double immunofluorescence. Representative images show the colocalizationof (A) ACE2 or (B) TMPRSS2 with fibroblast marker, FSP-1. (C) Representative immunofluorescence staining for TMPRSS2 (red) and ACE2 (green) show colocalizationin the same cells. The rectangle frames are magnified on the right upper corners. 40X magnification, scale bar: 50 μm. ACE2: angiotensin-converting enzyme 2; TMPRSS2: transmembrane serine protease 2; FSP-1: fibroblast-specific protein 1; PM: particulate matter.

Additional file 3: Table S3. Cox proportional hazard regression analysis of factors associated with 90-day hospital mortality.

We aimed to quantify Soft Mist Inhalers (SMI) delivery to spontaneous breathing model and compare with different adapters via endotracheal tube during mechanical ventilation or by manual resuscitation. A tiotropium SMI was used with a commercial in-line adapter and a T-adapter placed between the Y-adapter and the inspiratory limb of the ventilator circuit during mechanical ventilation. The SMI was actuated at the beginning of inspiration and expiration. In separate experiments, a manual resuscitator with T-adapter was attached to endotracheal tube, collecting filter, and a passive test lung. Drug was eluted from collecting filters with salt-based solvent and analyzed using high-performance liquid chromatography. Results showed the percent of SMI label dose inhaled was 3-fold higher with the commercial in-line adapter with actuation during expiration than when synchronized with inspiration. SMI with T-adapter delivery via ventilator was similar to inhalation (1.20%) or exhalation (1.02%), and both had lower delivery dose than with manual resuscitator (2.80%, p = 0.01). The inhaled dose via endotracheal tube was much lower than inhaled dose with spontaneous breathing (22.08%). In conclusion, the inhaled dose with the commercial adapter was higher with SMI actuated during expiration, but still far less than reported spontaneous inhaled dose.

Supplemental material, Reviewer_2_v.1 for Reclassifying severity after 48 hours could better predict mortality in acute respiratory distress syndrome by Li-Chung Chiu, Shih-Wei Lin, Pi-Hua Liu, Li-Pang Chuang, Chih-Hao Chang, Chen-Yiu Hung, Shih-Hong Li, Chung-Shu Lee, Huang-Pin Wu, Chung-Chi Huang, Hsin-Hsien Li, Kuo-Chin Kao and Han-Chung Hu in Therapeutic Advances in Respiratory Disease

Supplemental material, Author_Response_2 for Reclassifying severity after 48 hours could better predict mortality in acute respiratory distress syndrome by Li-Chung Chiu, Shih-Wei Lin, Pi-Hua Liu, Li-Pang Chuang, Chih-Hao Chang, Chen-Yiu Hung, Shih-Hong Li, Chung-Shu Lee, Huang-Pin Wu, Chung-Chi Huang, Hsin-Hsien Li, Kuo-Chin Kao and Han-Chung Hu in Therapeutic Advances in Respiratory Disease

Prostacyclin agonists that bind the prostacyclin receptor (IP) to stimulate cAMP synthesis are effective vasodilators for the treatment of idiopathic pulmonary arterial hypertension (IPAH), but this signaling may occur through nuclear peroxisome proliferator-activated receptor-γ (PPARγ). There is evidence of scant IP and PPARγ expression but stable prostanoid EP4 receptor (EP4) expression in IPAH patients. Both IP and EP4 functionally couple with stimulatory G protein (Gs), which activates signal transduction. We investigated the effect of an EP4-specific agonist on pulmonary arterial remodeling and its regulatory mechanisms in pulmonary arterial smooth muscle cells (PASMCs). Immunoblotting evealed IP, EP4, and PPARγ expression in human pulmonary arterial hypertension (PAH) and monocrotaline (MCT)-induced PAH rat lung tissue. Isolated PASMCs from MCT-induced PAH rats (MCT-PASMCs) were treated with L-902,688, a selective EP4 agonist, to investigate the anti-vascular remodeling effect. Scant expression of IP and PPARγ but stable expression of EP4 was observed in IPAH patient lung tissues and MCT-PASMCs. L-902,688 inhibited IP-insufficient MCT-PASMC proliferation and migration by activating PPARγ in a time- and dose-dependent manner, but these effects were reversed by AH-23848 (an EP4 antagonist) and H-89 [a protein kinase A (PKA) inhibitor], highlighting the crucial role of PPARγ in the activity of this EP4 agonist. L-902,688 attenuated pulmonary arterial remodeling in hypoxic PAH mice and MCT-induced PAH rats; therefore, we conclude that the selective EP4 agonist L-902,688 reverses vascular remodeling by activating PPARγ. This study identified a novel EP4-PKA-PPARγ pathway, and we propose EP4 as a potential therapeutic target for PAH.

Background: Disease severity may change in the first week after acute respiratory distress syndrome (ARDS) onset. The aim of this study was to evaluate whether the reclassification of disease severity after 48 h (i.e. day 3) of ARDS onset could help in predicting mortality and determine factors associated with ARDS persistence and mortality. Methods: We performed a secondary analysis of a 3-year prospective, observational cohort study of ARDS in a tertiary care referral center. Disease severity was reclassified after 48 h of enrollment, and cases that still fulfilled the Berlin criteria were regarded as nonresolving ARDS. Results: A total of 1034 ARDS patients were analyzed. Overall hospital mortality was 57.7% (56.7%, 57.5%, and 58.6% for patients with initial mild, moderate, and severe ARDS, respectively, p = 0.189). On day 3 reclassification, the hospital mortality rates were as follows: resolved (42.1%), mild (47.9%), moderate (62.4%), and severe ARDS (76.1%) ( p 2/FiO2, or higher positive end-expiratory pressure on day 1 were significantly associated with nonresolving ARDS on day 3. A Cox regression model with ARDS severity as a time-dependent covariate and competing risk analysis demonstrated that ARDS severity was independently associated with hospital mortality, and nonresolving ARDS had significantly increased hazard of death than resolved ARDS ( p Conclusions: Reclassification of disease severity after 48 h of ARDS onset could help to divide patients into subgroups with greater separation in terms of mortality. The reviews of this paper are available via the supplemental material section.

Right ventricular (RV) hypertrophy is characterized by cardiac fibrosis due to endothelial-mesenchymal transition (EndMT) and increased collagen production in pulmonary arterial hypertension (PAH) patients, but the mechanisms for restoring RV function are unclear. Prostanoid agonists are effective vasodilators for PAH treatment that bind selective prostanoid receptors to modulate vascular dilation. The importance of prostanoid signaling in the RV is not clear. We investigated the effects of the EP4-specific agonist L-902,688 on cardiac fibrosis and TGF-β-induced EndMT. EP4-specific agonist treatment reduced right ventricle fibrosis in the monocrotaline (MCT)-induced PAH rat model. L-902,688 (1 µM) attenuated TGF-β-induced Twist and α-smooth muscle actin (α-SMA) expression, but these effects were reversed by AH23848 (an EP4 antagonist), highlighting the crucial role of EP4 in suppressing TGF-β-induced EndMT. These data indicate that the selective EP4 agonist L-902,688 attenuates RV fibrosis and suggest a potential approach to reducing RV fibrosis in patients with PAH.

Prostacyclin agonists that bind the prostacyclin receptor (IP) to stimulate cAMP synthesis are effective vasodilators for the treatment of idiopathic pulmonary arterial hypertension (IPAH), but this signaling may occur through nuclear peroxisome proliferator-activated receptor-γ (PPARγ). There is evidence of scant IP and PPARγ expression but stable prostanoid EP

A novel charge-pumping method using dc source/drain biases and specified gate waveforms is proposed to extract the lateral distributions of interface-trap and effective oxide-trapped charge densities. The surface potential redistribution due to the oxide-trapped charges is treated by an iteration process in order to accurately determine their lateral distributions. The proposed novel method is feasible for accurately extracting the distributions of interface-trap and effective oxide-trapped charge densities generated by the hot-carrier stress and can be further used to predict the device lifetime.

Using the Shockley-Read-Hall (SRH) theory, a simple analytic charge pumping current model has been developed and its accuracy verified by exact numerical analysis. It is shown that the derived analytic charge pumping current model with constant capture cross sections for electrons and holes does not correctly simulate the rising (falling) edges of the experimental charge pumping current. According to the slopes of the logarithmic charge pumping current, effective capture-cross-section models for elections and holes are proposed and are incorporated into the developed analytic charge pumping current model. It is shown that the experimental charge pumping current can be simulated very well by using the modified analytic model.

A novel method using the charge pumping technique for extracting the effective channel length of MOSFET devices is presented, in which the effective area approach is used and the edges of the area are defined clearly. It is shown that the extracted effective channel length is independent of the measuring biases and the proposed new method is simple, accurate, and reliable, as compared to those using the I-V method. With the knowledge of the device dopant profiles, the extracted channel length with 0.01 /spl mu/m accuracy can be achieved. Moreover, the proposed method is applicable to either n- or p-channel, conventional or LDD, surface or buried channel MOSFET's. >

An efficient and accurate 2D numerical simulation technique is developed to study the hot-electron effects on short-channel n -MOSFETs. The 1D substrate injection probability used by Ning et al. has been further modified by considering the channel hot-electron-enhanced injection probability. Moreover, the hot-electron-injection-induced Si/SiO 2 interface-trap generation and its effects on MOSFET drain, substrate and gate currents have also been taken into consideration. It is shown that the generated electron traps at the Si/SiO 2 interface enhance both the impact ionization rate and the degradation of MOSFET characteristics but retard the injection probability of hot electrons into the gate oxide. The spatial distribution of the generated Si/SiO 2 interface traps calculated by our model has been well verified by the charge pumping measurement. In addition, the simulated substrate current, gate current, and degradation of drain current are in good agreement with the experimental results of a short-channel n -MOSFET with the oxide thickness of 100 A and the effective channel length of 0.45 μm for wide ranges of drain and gate biases.

A new charge-pumping method with dc source/drain biases and specified gate waveforms is proposed to extract the metallurgical channel length of MOSFETs by using a single device. Using two charge-pumping currents of a single nMOSFET measured under different V/sub GL/ (V/sub GH/ for pMOSFETs), the metallurgical channel length can be easily extracted with an accuracy of 0.02 /spl mu/m. It is shown that the proposed novel method is self-consistent with the results obtained by the charge-pumping current measured from multidevices under different gate pulse waveforms and bias conditions.