Kang-Cheng Su

Spontaneous breathing trial needs to be prolonged in critically ill and older patients requiring mechanical ventilation

PURPOSE To investigate a modified weaning procedure to predict extubation outcome in critically older and ventilated patients. METHODS We retrospectively analyzed extubation outcome in older (≥ 70 years) and ventilated patients. In period I (2007), patients passing a 2-hour spontaneous breathing trial (SBT) were extubated. In period II (2008), patients underwent an 8-hour SBT on day 1 and a 2-hour SBT, followed by extubation on day 2. Weaning parameters were recorded at baseline (T(0)) (periods I and II), 2 and 8 (T(8)) hours after SBT (period II). RESULTS The demographic data of patients in each period (n = 64 and 67, respectively) were similar. Patients in period II demonstrated a higher rate of SBT failure but a significantly lower rate of extubation failure and reintubation mortality. In period II, successfully extubated patients demonstrated a significantly lower value of rapid shallow breathing index (RSBI) at T(8). The ratio of RSBI at T(8) over T(0) (T(8)/T(0) ≤ 1.4) demonstrated good diagnostic value (sensitivity 89.5%, specificity 80.0%, accuracy 88.4%) in predicting successful extubation. CONCLUSIONS For critically older and ventilated patients, a prolonged SBT in conjunction with evolution of the RSBI ratio over baseline during SBT may serve as a useful procedure to predict extubation outcome.

Sleep Apnea and Risk of Deep Vein Thrombosis: A Non-randomized, Pair-matched Cohort Study

BACKGROUND Patients with sleep apnea have been reported to be associated with increased prevalence of deep vein thrombosis (DVT) in some papers, which were criticized for either a small sample size or lack of a prospective control. Our study strived to explore the relationship of sleep apnea and the subsequent development of DVT using a nationwide, population-based database. METHODS From 2000 to 2007, we identified a study cohort consisting of newly diagnosed sleep apnea cases in the National Health Insurance Research Database. A control cohort without sleep apnea, matched for age, sex, comorbidities, major operation, and fractures, was selected for comparison. The 2 cohorts were followed-up, and we observed the occurrence of DVT by registry of DVT diagnosis. RESULTS Of the 10,185 sampled patients (5680 sleep apnea patients vs. 4505 control), 40 (0.39%) cases developed DVT during a mean follow-up period of 3.56 years, including 30 (0.53%) from the sleep apnea cohort and 10 (0.22 %) from the control group. Subjects with sleep apnea experienced a 3.113-fold (95% confidence interval, 1.516-6.390; P=.002) increase in incident DVT, which was independent of age, sex, and comorbidities. Kaplan-Meier analysis also revealed the tendency of sleep apnea patients toward DVT development (log-rank test, P=.001). The risk of DVT was even higher in sleep apnea cases who needed continuous positive airway pressure treatment (hazard ratio 9.575; 95% confidence interval, 3.181-28.818; P <.001). CONCLUSION Sleep apnea may be an independent risk factor for DVT.

Matrix metalloprotease-9 induces transforming growth factor-β1 production in airway epithelium via activation of epidermal growth factor receptors

AIMS Matrix metalloprotease (MMP)-9 is present in abundance in various chronic airway disorders and is involved in lung remodeling. MMP may cleave membrane-bound precursor proteins and release epidermal growth factor-like ligands that subsequently bind to epidermal growth factor receptor (EGFR). We hypothesized that MMP-9 may stimulate the airway epithelium to produce fibrogenic mediators through activation of membrane-bound receptors. MAIN METHODS Human airway epithelial cells were grown on air-liquid interface culture inserts. MMP-9 was employed to stimulate the cells. Conditioned medium following MMP-9 stimulation was co-incubated with human lung fibroblasts. KEY FINDINGS MMP-9 stimulated human airway epithelial cells to produce transforming growth factor (TGF)-β(1) at both the mRNA and protein level. Using a microarray, increased phosphorylation of EGFR tyrosine kinase (TK) was identified and further confirmed by immunoprecipitation and Western blot analysis. A significant increase in EGF and TGF-α release was observed after MMP-9 had been added for 30min. Protease inhibitor, EGFR monoclonal antibody and EGFR-TK inhibitor blocked this action and subsequent TGF-β(1) production. Neutralizing antibodies against EGF and TGF-α substantially inhibited TGF-β(1) production following MMP-9 stimulation. MMP-9-induced TGF-β(1) production occurred through MAP kinase p44/42 phosphorylation. Selective p44/42 kinase inhibitor UO126 successfully inhibited TGF-β(1) production. Conditioned medium from epithelial cells treated with MMP-9 significantly induced Smad3 phosphorylation and subsequent fibroblast proliferation after 24h culture. SIGNIFICANCE These data indicate that MMP-9 induces TGF-β(1) production in the airway epithelium through the cleavage of EGF and EGF-like ligands and activating EGFR, suggesting potential targets of therapeutic intervention in airway fibrotic disorders.

Sleep apnea and risk of peptic ulcer bleeding: a nationwide population-based study.

OBJECTIVE Patients with sleep apnea sustain cessation of breath during sleep, leading to intermittent hypoxia, systemic inflammation, and sympathetic activation. These insults may contribute to initiation or progression of peptic ulcers. This retrospective matched-control cohort study explored the relationship of sleep apnea and subsequent development of peptic ulcer bleeding. METHODS From 2000 to 2009, patients with newly diagnosed sleep apnea were identified from the Taiwan National Health Insurance Research Database. A control group without sleep apnea, matched for age, gender, comorbidities, and medications, was selected for comparison. In both groups, subjects with history of peptic ulcer bleeding, nonspecific gastrointestinal bleeding, or malignancy were excluded. The 2 cohorts were followed up and observed for occurrence of peptic ulcer bleeding. RESULTS Of the 35,480 sampled patients (7096 patients with sleep apnea vs 28,384 controls), 84 (0.24%) experienced peptic ulcer bleeding during a follow-up period of 3.57±2.61 years, including 32 (0.45% of patients with sleep apnea) from the sleep apnea cohort and 52 (0.18% of control) from the control group (log-rank test, P<.0001). In comparison with subjects without development of peptic ulcer bleeding, those with peptic ulcer bleeding were older and had a higher percentage of sleep apnea, coronary artery disease, peptic ulcer, ischemic stroke, and medication for nonsteroidal anti-inflammatory drugs. By Cox regression analysis, sleep apnea, older age, and peptic ulcer history were independent predictors of peptic ulcer bleeding. Patients with sleep apnea experienced a 2.400-fold (95% confidence interval, 1.544-3.731; P<.001) higher risk for incident peptic ulcer bleeding after adjusting for other variables. CONCLUSIONS Sleep apnea may be an independent risk factor for peptic ulcer bleeding.

Long-acting β2 agonists and corticosteroids restore the reduction of histone deacetylase activity and inhibit H2O2-induced mediator release from alveolar macrophages.

BACKGROUND Treatment of COPD with a combination of long-acting β(2) agonists and corticosteroids is currently used worldwide. The mechanisms of the anti-inflammatory effects and their associations with histone deacetylase (HDAC) activity remain unclear. METHODS Human alveolar macrophages were isolated and stimulated with H(2)O(2) in the presence of varying concentrations of long-acting β(2) agonists and corticosteroids. Supernatants were collected for IL-8 and MMP-9 measurements. Cell lysates were analyzed for HDAC (mainly HDAC1/HDAC2) activity. Quantitative real-time PCR was performed to determine the levels of IL-8 and MMP-9 mRNA. RESULTS Both long-acting β(2) agonists, salmeterol and formoterol, and corticosteroids, fluticasone and budesonide, showed anti-inflammatory effects to a certain extent on H(2)O(2)-induced IL-8 and MMP-9 release in alveolar macrophages. Combinations of long-acting β(2) agonists and corticosteroids exerted greater effects to suppress mediator release, and both transcription and translation of IL-8 and MMP-9 were inhibited. It seemed that the levels of IL-8 and MMP-9 after H(2)O(2) stimulation were inversely associated with the activity of HDAC. H(2)O(2) stimulation resulted in a significant decrease in HDAC activity and was associated with an increase in mediator release. In contrast, treatment with long-acting β(2) agonists, corticosteroids or theophylline restored the H(2)O(2)-induced decrease in HDAC activity and inhibited mediator release. CONCLUSION Combinations of long-acting β(2) agonists and corticosteroids exerted greater effects on the suppression of mediator release in relation to the enhancement of HDAC activity. This supports at least in part the likely contribution of anti-inflammatory effects of long-acting β(2) agonists and corticosteroids to the clinical benefits seen in COPD patients.

Bile acids increase alveolar epithelial permeability via mitogen-activated protein kinase, cytosolic phospholipase A2, cyclooxygenase-2, prostaglandin E2 and junctional proteins

Bile acid (BA) aspiration is associated with various lung diseases. It was hypothesized that BA may induce changes in alveolar epithelium permeability and contribute to the pathogenesis of lung injury.

Hospital Outcomes for Patients with Stage III and IV Lung Cancer Admitted to the Intensive Care Unit for Sepsis-Related Acute Respiratory Failure

BACKGROUND In recent years, intensive care for cancer patients has improved and treatment of critically ill cancer patients has become increasingly aggressive over time. However, not all cancer patients would benefit from aggressive care, especially those with late-stage cancer. OBJECTIVE We aimed to investigate the outcome of late-stage lung cancer patients with sepsis-related respiratory failure and identify predictors of mortality. METHODS From 2007 to 2008, consecutive stage III and IV lung cancer patients admitted to an intensive care unit (ICU) of a teritiary medical center in Taiwan for sepsis-related respiratory failure were retrospectively enrolled. Data at baseline and upon ICU admission were collected. In-hospital survival was analyzed. Variables of the survivors to hospital discharge and patients who died were compared by uni- and multivariate analyses. RESULTS Seventy patients were enrolled. During a mean follow-up period of 30.10 days, 29 (41.4%) patients survived to hospital discharge and 41(58.6%) died. Compared with the survivors, the patients who died had poor performance status, lower serum albumin level, higher percentage of disseminated intravascular coagulation, and more severe organ dysfunction as disclosed by higher Sequential Organ Failure Assessment (SOFA) scores. Multivariate analyses revealed that SOFA score (p=0.026) was the only independent predictor of mortality; 44.8 % (13/29) of survivors were weaned from ventilator during hospitalization. CONCLUSION Among late-stage lung cancer patients with sepsis-related respiratory failure, those with lower SOFA scores seemed to have better survival rate and may benefit from intensive care in the ICU. Early palliative care should be considered for all patients with advanced lung cancer, and hospice care is suggested for those with sepsis-respiratory failure and high SOFA scores.

The roles of transforming growth factor-β1 and vascular endothelial growth factor in the tracheal granulation formation

BACKGROUND Acquired tracheal stenosis is common in patients with a long-term tracheostomy and granulation is one of the most commonly observed lesions in benign airway stenosis. The aim of this study was to investigate the mechanisms of tracheal granulation formation and find the potential therapeutic targets to prevent the granulation formation. RESULTS In granulation tissue obtained from patients during interventional bronchoscopy for the relief of airway obstruction, increased expression of transforming growth factor (TGF)-β₁ and vascular endothelial growth factor (VEGF), as well as increased numbers of fibroblasts, was found by immunohistochemical staining. TGF-β₁ expression was detected in both the epithelial and submucosal layers. The highest levels of VEGF and vimentin expression occurred in the submucosal layers. In comparison with the control, significantly increased numbers of small vessels were observed in the submucosal layers of the granulation tissue. In vitro, TGF-β₁ stimulated production of VEGF by cultured fibroblasts at both the mRNA and protein level. VEGF siRNA treatment resulted in a significant decrease of TGF-β₁-induced VEGF production. SIS3, a selective Smad3 inhibitor, and UO126 both inhibited p44/42 MAP kinase phosphorylation and attenuated subsequent VEGF production by fibroblasts. A low concentration of erythromycin (1 μg/ml), but not dexamethasone (100 μM), inhibited TGF-β₁-induced VEGF production. CONCLUSION This study provides important information that facilitates an understanding, at least in part, of the mechanisms of granulation formation. Targeting these mediators and cells may help to prevent the formation of granulation tissue in long-term tracheostomy or prolonged endotracheal intubation patients.

Allergic rhinitis and risk of erectile dysfunction – a nationwide population‐based study

A growing body of evidence has disclosed that allergic rhinitis (AR) is a systemic inflammatory disease. Inflammatory mediators and cells involved in AR have also been reported to be implicated in the process of atherosclerosis, which is relevant to the occurrence of erectile dysfunction (ED). Our objective was to explore the relationship between AR and future ED events.

Chronic obstructive pulmonary disease treated with inhaled medium- or high-dose corticosteroids: a prospective and randomized study focusing on clinical efficacy and the risk of pneumonia.

Purpose Complications of pneumonia development in patients with chronic obstructive pulmonary disease (COPD) receiving inhaled corticosteroid (ICS) therapy have been documented. The aim of this study was to focus on clinical efficacy and the incidence of pneumonia between COPD patients receiving medium and high doses of ICS. Patients and methods This prospective, randomized study included COPD patients identified from three tertiary medical centers from 2010 to 2012. The patients were randomized into two groups: high dose (HD; fluticasone 1,000 μg + salmeterol 100 μg/day) and medium dose (MD; fluticasone 500 μg + salmeterol 100 μg/day). Lung function with forced expiratory volume in 1 second (FEV1), forced vital capacity, and COPD-assessment test (CAT) were checked every 2 months. The frequency of acute exacerbations and number of pneumonia events were measured. The duration of the study period was 1 year. Results In total, 237 COPD patients were randomized into the two treatment arms (115 in the HD group, 122 in the MD group). The FEV1 level was significantly improved in the patients in the HD group compared with those in the MD group (HD 103.9±26.6 mL versus MD 51.4±19.7 mL, P<0.01) at the end of the study. CAT scores were markedly improved in patients using an HD compared to those using an MD (HD 13±5 versus MD 16±7, P=0.05). There was a significant difference in the percentage of annual rates in acute exacerbations (HD 0.16 versus MD 0.34, P<0.01) between the two groups. The incidence of pneumonia was similar in the two groups (HD 0.08 versus MD 0.10, P=0.38). Conclusion COPD patients treated with high doses of ICS had more treatment benefits and no significant increases in the incidence in pneumonia. Higher-dose ICS treatment may be suitable for COPD therapy.