Horng Chyuan Lin

The impact of delirium on the survival of mechanically ventilated patients

Objectives:To revalidate a means of assessing delirium in intensive care unit patients and to investigate the independent effect of delirium on the mortality of mechanically ventilated patients. Design:A prospective cohort study. Setting:A 37-bed medical intensive care unit of a tertiary care hospital. Patients:Subjects were 102 of 131 consecutive mechanically ventilated patients. Measurements:All the enrolled patients were assessed for delirium using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Mortality rate were compared between patients with or without delirium, and the predictors of death were investigated. Results:The two CAM-ICU assessors’ sensitivities in diagnosing delirium compared with reference standard were 91% and 95%, whereas their specificities were both 98%. They also demonstrated high interrater reliability with kappa statistics of 0.91. Delirium was present in 22 of 102 (22%) patients in the first 5 days. The delirious patients had higher intensive care unit mortality rate than nondelirious patients (63.6% vs. 32.5%, respectively), with a hazard ratio of 2.57 (95% confidence interval, 1.56–8.15). In multivariate analysis, delirium (odds ratio, 13.0; 95% confidence interval, 2.69–62.91), shock (odds ratio, 12.91; 95% confidence interval, 2.93–56.92), and illness severity (odds ratio, 9.61; 95% confidence interval, 2.24–41.18) were independent predictors of mortality. Conclusions:This study confirms previous work showing that delirium is an independent predictor for increased mortality among mechanically ventilated patients.

Serum thrombomodulin level relates to the clinical course of disseminated intravascular coagulation, multiorgan dysfunction syndrome, and mortality in patients with sepsis.

Objective:To determine serum concentrations of thrombomodulin, the marker of endothelial injury, in patients with sepsis-induced disseminated intravascular coagulation and multiple organ dysfunction syndrome and to investigate the independent association between this marker and the development of disseminated intravascular coagulation, multiple organ dysfunction syndrome, and mortality. Design:A prospective cohort study. Setting:A 37-bed intensive care unit of a tertiary care hospital. Patients:One hundred consecutive patients with sepsis. Interventions:Serum thrombomodulin concentrations and the development of disseminated intravascular coagulation and multiple organ dysfunction syndrome were determined in patients on days 1 and 3 of sepsis. These data were used to determine an association between day 1 thrombomodulin concentrations and development of disseminated intravascular coagulation, multiple organ dysfunction syndrome, and mortality during intensive care unit stay. These connections were determined by the Cox proportional hazards model and plotting of receiver operating characteristic curves. Measurements and Main Results:Day 1 serum concentrations of thrombomodulin were higher in patients with disseminated intravascular coagulation (11.1 ± 1.0 vs. 5.3 ± 0.5 ng/mL; p < .0001) or multiple organ dysfunction syndrome (10.3 ± 0.7 vs. 4.3 ± 0.4 ng/mL; p < .0001) than those without, respectively. In patients with resolved disseminated intravascular coagulation (4.9 ± 0.5 vs. 8.9 ± 0.9 ng/mL, day 3 vs. day 1, p = .005) or multiple organ dysfunction syndrome (6.3 ± 1.4 vs. 12.0 ± 1.6 ng/mL, day 3 vs. day 1, p < .0001) on day 3 of sepsis, day 3 levels of thrombomodulin were down from day 1. Thrombomodulin concentration independently predicted the development of disseminated intravascular coagulation (hazard ratio 1.13, p < .0001), multiple organ dysfunction syndrome (hazard ratio 1.12, p < .0001), and mortality (hazard ratio 1.19, p < .0001) during intensive care unit stay. The area under the receiver operating characteristic curve showed that day 1 serum thrombomodulin levels had good discriminative power in predicting the development of disseminated intravascular coagulation (0.811), multiple organ dysfunction syndrome (0.896), and mortality (0.803) during intensive care unit stay. Conclusions:Endothelial cell injury is critical in the progression from disseminated intravascular coagulation to multiple organ dysfunction syndrome and subsequent mortality in septic patients. Serum concentrations of thrombomodulin may be used in monitoring disseminated intravascular coagulation and multiple organ dysfunction syndrome in these patients.

Apoptotic Neutrophils Undergoing Secondary Necrosis Induce Human Lung Epithelial Cell Detachment

Clearance of apoptotic neutrophils by alveolar macrophages plays an important role in the resolution phase of lung inflammation. If not cleared, apoptotic neutrophils are postulated to release histotoxic granular contents. Since numerous cellular proteins are degraded during apoptosis, we sought to determine whether functional serine proteinases are indeed released by apoptosing neutrophils in vitro. In a coculture system, cytokine-activated neutrophils induced detachment in the human epithelial cell line, A549. This process was CD18- and serine proteinase-dependent. Early apoptotic neutrophils induced significant detachment, but live, senescent, resting neutrophils and terminal, secondary necrotic neutrophils had a different effect. This detachment process was CD18-independent but serine proteinase-dependent. Similarly, detachment occurred with primary human small airway epithelial cells. Notably, epithelial cell detachment correlated with the transition of early apoptotic neutrophils to secondary necrosis and with the accumulation of elastase in the supernatant. The membrane integrity of lung epithelial cells was damaged in advance of significant cell detachment. These observations suggest that not only live activated neutrophils but also apoptosing neutrophils can reveal functional elastase activities. Furthermore, the rapidity of the transition emphasizes the importance of the prompt clearance of apoptotic neutrophils before they progress to secondary necrosis at the site of lung inflammation.

Diagnostic value of endobronchial ultrasound-guided transbronchial lung biopsy in peripheral lung cancers.

BACKGROUND AND PURPOSE The diagnostic yield of flexible fiberoptic bronchoscopy for peripheral lung cancers is still limited. This study evaluated whether endobronchial ultrasound (EBUS) may help localize and improve the diagnostic yield of bronchoscopic transbronchial lung biopsy in peripheral lung cancer. METHODS Between July 2001 and May 2002, 218 patients received transbronchial lung biopsy during bronchoscopic examinations with (n = 122) or without EBUS guidance (n = 96) and had the presence of peripheral lung cancers subsequently confirmed. These 218 patients were included in this retrospective analysis. RESULTS The diagnostic accuracy of transbronchial lung biopsy was significantly increased under EBUS guidance for small cell carcinoma (65.6%) and for non-small cell carcinoma (42.7%) [p < 0.01]. For peripheral lung cancer either smaller than 2 cm or larger than 2 cm, the diagnostic yield of transbronchial lung biopsy with EBUS guidance was significantly higher (66.0% vs 42.3%, p < 0.002 for mass larger than 2 cm; 54.5% vs 0%, p < 0.04 for mass smaller than 2 cm). EBUS provided a better diagnostic yield (p = 0.014; odds ratio, 0.219) for lesions localized at the left upper lobe, which are generally thought to be more difficult to approach through bronchoscopy. There were no significant differences in complications between patients who underwent bronchoscopy with or without EBUS guidance. CONCLUSIONS Under EBUS guidance, the diagnostic yield of transbronchial lung biopsy in peripheral lung cancer by bronchoscopic examination was significantly improved without difference in the complication rate.

Diagnostic value of endobronchial ultrasonography for pulmonary tuberculosis

OBJECTIVES We sought to compare the diagnostic yields of acid-fast bacilli smears and Mycobacterium tuberculosis cultures in terms of bronchoalveolar lavage fluid and histologic examination of transbronchial lung biopsy specimens for pulmonary tuberculosis by using bronchoscopy with versus without endobronchial ultrasonography in patients with negative acid-fast bacilli smears or no sputum production. METHODS From June 2005 to July 2006, a total of 451 patients were given diagnoses of and treated for pulmonary tuberculosis in a university-affiliated hospital. Among them, 121 patients who received bronchoscopy because of sputum-negative conditions were recruited. Of these, 73 patients received bronchoscopy with endobronchial ultrasonography, and 48 patients received conventional bronchoscopy. RESULTS Patients who received bronchoscopy with endobronchial ultrasonography had higher diagnostic yields of acid-fast bacilli smears (31.5% vs 12.5%, P = .018) in bronchoalveolar lavage fluid, M tuberculosis in bronchoalveolar lavage fluid (67.1% vs 47.9%, P = .024), and pathologic reports of tuberculosis in transbronchial lung biopsy specimens (32.9% vs 4.2%, P < .0001) than patients who received conventional bronchoscopy. With the aid of endobronchial ultrasonography, the overall diagnostic yield for tuberculosis by using bronchoscopic procedures (smears and cultures of bronchoalveolar lavage fluid and transbronchial lung biopsy specimens) was higher (80.8%) than for those who did not undergo endobronchial ultrasonography (58.3%, P = .035). CONCLUSIONS The addition of endobronchial ultrasonography to diagnostic bronchoscopy increased the sensitivity for proving the presence of tuberculosis in a population of patients with negative acid-fast bacilli smears or no sputum production.

Ventilator-induced injury augments interleukin-1beta production and neutrophil sequestration in lipopolysaccharide-treated lungs.

ABSTRACT Mechanical ventilators are commonly used to support critically ill patients; however, inappropriate ventilator settings might initiate or augment lung injury. To determine whether a large tidal volume (Vt) augments inflammatory responses and neutrophil sequestration in the lungs of rats receiving intratracheal lipopolysaccharides (LPS). Rats received intratracheal instillation of LPS (0.5 mg/kg) followed by 4 h of mechanical ventilation (MV) at 60 strokes per min with a Vt of 10 mL/kg as control MV, or 30 strokes per min with a Vt of 20 mL/kg of body weight as high-volume MV (HMV). In addition, monoclonal antibodies against rat intercellular adhesion molecule 1 (ICAM-1) or immunoglobulin G (50 mg/kg) were administered 30 min before LPS instillation and MV. Our study demonstrates that HMV enhances pulmonary permeability and induces neutrophil recruitment into the alveolar space and pulmonary edema. Intratracheal instillation of LPS caused marked lung injury, neutrophil recruitment, and production of cytokines and chemokines. Combining LPS instillation and HMV synergistically upregulated interleukin 1&bgr; (IL-1&bgr;) production and neutrophil sequestration in lung tissues. The ICAM-1 expression in lung tissues was responsible for the synergistic effects of neutrophil sequestration. Synergistic upregulation of IL-1&bgr; production and neutrophil sequestration was attenuated by blocking ICAM-1 by neutralizing antibody pretreatment. High Vt MV in LPS-injured lung causes synergistic production of IL-1&bgr; and sequestration of neutrophil via ICAM-1-dependent effects.

Eosinophils from asthmatics release IL-5 in an autocrine fashion to prevent apoptosis through upregulation of Bcl-2 expression

Interleukin (IL)-5 plays an important role in maintaining the survival of eosinophils via the specific α-subunit of its receptor. Apoptosis, a form of programmed cell death, is thought to represent a mechanism that promotes the resolution of eosinophilic inflammation in asthma. The aim of our present study is to investigate whether IL-5 acts in an autocrine fashion on eosinophil apoptosis in asthmatics. Immunoreactivities of intracellular IL-5 and IL-5 receptor α-subunit (Rα) were detected uniquely on the eosinophils. The magnitude of IL-5 and IL-5 Rα expression on eosinophils was significantly higher in asthmatics than that of normal subjects (p < 0.05) determined by flow cytometry. Apoptosis of eosinophils was measured by the propidium iodide staining method and DNA ladder. The percent of apoptotic eosinophils from asthmatics was significantly increased by coincubation with anti-hIL-5 Rα Ab (0.1, 0.5, and 2.5 µg/mL) for 1, 2, or 16 hours than was those of corresponding controls (p < 0.05, n = 8). However, there was no significant effect of anti-hIL-5 Rα Ab on eosinophil apoptosis in normal subjects. Furthermore, the expression of B-cell lymphoma-2 (Bcl-2) proteins was significantly inhibited by the anti-hIL-5 Rα Ab or antisense IL-5 oligonucleotides in asthmatics (p < 0.05, n = 8), but there was no significant change in eosinophils from normal subjects. This study demonstrates that eosinophils from asthmatics release IL-5 in an autocrine fashion to act on their own IL-5 receptors in prevention of apoptosis through the upregulation of Bcl-2 expression.

Matrix Metalloproteinase-1 Polymorphism (-1607G) and Disease Severity in Non-Cystic Fibrosis Bronchiectasis in Taiwan

Objectives Bronchiectasis is characterized by an irreversible dilatation of bronchi and is associated with lung fibrosis. MMP-1 polymorphism may alter its transcriptional activity, and differentially modulate bronchial destruction and lung fibrosis. Design To investigate the association of MMP-1 polymorphisms with disease severity in non-cystic fibrosis (CF) bronchiectasis patients, 51 normal subjects and 113 patients with bronchiectasis were studied. The associations between MMP-1 polymorphisms, lung function, and disease severity evaluated by high resolution computed tomography (HRCT) were analyzed. Results The frequency of MMP-1(-1607G) allele was significantly higher in patients with bronchiectasis than normal subjects (70.8% vs 45.1%, p<0.01). Forced expiratory volume in 1 second (FEV1) was decreased in bronchiectasis patients with 1G/1G (1.2±0.1 L, n = 14) and 1G/2G (1.3±0.1 L, n = 66) genotypes compared to the 2G/2G genotype (1.7±0.1 L, n = 33, p<0.01). Six minute walking distance was decreased in bronchiectasis patients with 1G/1G and 1G/2G compared to that of 2G/2G genotype. Disease severity evaluated by HRCT score significantly increased in bronchiectasis patients with 1G/1G and 1G/2G genotypes compared to that of 2G/2G genotype. Bronchiectasis patients with at least one MMP-1 (-1607G) allele showed increased tendency for hospitalization. Serum levels of pro-MMP-1, active MMP-1 and TGF-β1 were significantly increased in patients with bronchiectasis with 1G/1G and 1G/2G genotype compared with 2G/2G genotype or normal subjects. Under IL-1β stimulation, peripheral blood monocytes from subjects with 1G/2G or 1G/1G genotype secreted higher levels of TGF-β1compared to subjects with 2G/2G genotype. Conclusion This is the first report to address the influence of MMP-1 polymorphisms on lung function and airway destruction in non-CF bronchiectasis patients. Bronchiectasis patients with MMP-1(-1607G) polymorphism may be more vulnerable to permanent lung fibrosis or airway destruction due to the enhanced MMP-1 and TGF-β1 activity. Upregulated MMP-1 activity results in proteolytic destruction of matrix, and leads to subsequent fibrosis.

Domiciliary Positive Expiratory Pressure Improves Pulmonary Function and Exercise Capacity in Patients with Chronic Obstructive Pulmonary Disease

BACKGROUND/PURPOSE This study assessed how positive expiratory pressure (PEP) affected pulmonary function, functional capacity, and subjective cough difficulty in individuals with chronic obstructive pulmonary diseases (COPD). METHODS This was a prospective, randomized, controlled study. Subjects were recruited from an outpatient department at a university hospital. Thirty-two patients with COPD were allocated to either PEP + FET (forced expiratory technique) group (n = 16) or FET only group (n = 16). Subjects in PEP + FET and FET groups were in a clinically stable condition before and during the study. Subjects in the PEP + FET group received PEP breathing using a mouth adjunct to FET, and the FET group was administered FET for 4 weeks only. Patients received weekly follow-up during the study period. Pulmonary function, 6-minute walk tests, and subjective cough difficulty scores were measured before and after the 4-week interventions. RESULTS Subjects in the PEP + FET group had a significantly increased diffusing capacity (DLCO) compared to preintervention (p < 0.05) and after intervention in the FET group (p < 0.05). DLCO significantly increased in the PEP + FET group from 18.0 +/- 7.3 to 20.1 +/- 7.2 mL/min/mmHg. The 6-minute walking distance (6MWD) also increased significantly from 516.8 +/- 94.1 to 570.6 +/- 60.4 m in the PEP + FET group (p < 0.001) after intervention, compared to that for the FET group (p < 0.05). Additionally, the PEP + FET group had significantly lower cough difficulty scores compared to those at baseline and in the FET group. CONCLUSION Four-week PEP therapy as an adjunct to FET further enhanced DLCO and 6MWD, and reduced cough difficulty compared to FET only in COPD patients with mucus hypersecretion.

Matrix Metalloproteinase-1 Polymorphism is Associated with Persistent Airway Obstruction in Asthma in the Taiwanese Population

Background and objective: Overexpression of matrix metalloproteinase (MMP)-1 has been demonstrated in asthma, and MMP polymorphisms are known to enhance disease susceptibility. We investigated whether MMP-1 polymorphism is associated with persistent airway obstruction in asthma in the Taiwanese population. Methods: A total of 131 unrelated Taiwanese subjects were enrolled, age-matched, and divided as follows: (1) those who had asthma with persistent airway obstruction with forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC) values less than 75% predicted (n = 41); (2) those with asthma without airway obstruction with FEV1 and FEV1/FVC values ≥ 75% predicted (n = 47); and (3) normal control subjects (n = 43). All were genotyped for the 1G/2G polymorphism of MMP-1 promoter (−1607bp). Results: 1G genotypes of MMP-1 containing at least one 1G allele were found in asthmatic patients with persistent airway obstruction (OR = 3.696, 95% CI: 1.489–9.173, p = 0.027), but not in asthmatic patients without airway obstruction (OR = 2.065, 95% CI: 0.890–4.790, p = 0.091) when compared with homozygous 2G (2G/2G). The heterozygous 1G genotype (1G/2G) was more associated with persistent airway obstruction than homozygous 2G (2G/2G) (OR: 4.727, 95% CI: 1.759–12.703, p = 0.012). The adjusted risk estimate of 1G genotypes for asthmatics with persistent airway obstruction was 4.416 (95% CI: 1.651–11.812, p = 0.003). Conclusion: 1G genotypes of MMP-1 polymorphism are associated with asthma with persistent airway obstruction, and the heterozygous 1G genotype (1G/2G) poses the most susceptibility to persistent airway obstruction in asthma.