Subjective and objective survival prediction in mechanically ventilated critically ill patients: a prospective cohort study.

BACKGROUND: ICU risk assessment tools, routinely used for predicting population outcomes, are not recommended for evaluating individual risk. The state of health of single patients is mostly subjectively assessed to inform relatives and presumably to decide on treatment decisions. However, little is known how subjective and objective survival estimates compare. METHODS: We performed a prospective cohort study in mechanically ventilated critically ill patients across five European centres, assessed 62 objective markers and asked the clinical staff to subjectively estimate the probability of surviving 28 days. RESULTS: Within the 961 included patients, we identified 27 single objective predictors for 28-day survival (73.8%) and pooled them into predictive groups. While patient characteristics and treatment models performed poorly, the disease and biomarker models had a moderate discriminative performance for predicting 28-day survival, which improved for predicting 1-year survival. Subjective estimates of nurses (c-statistic [95% CI] 0.74 [0.70-0.78]), junior physicians (0.78 [0.74-0.81]) and attending physicians (0.75 [0.72-0.79]) discriminated survivors from non-survivors at least as good as the combination of all objective predictors (c-statistic: 0.67-0.72). Unexpectedly, subjective estimates were insufficiently calibrated, overestimating death in high-risk patients by about 20% in absolute terms. Combining subjective and objective measures refined discrimination and reduced the overestimation of death. CONCLUSIONS: Subjective survival estimates are simple, cheap and similarly discriminative as objective models; however, they overestimate death risking that live-saving therapies are withheld. Therefore, subjective survival estimates of individual patients should be compared with objective tools and interpreted with caution if not agreeing. Trial registration ISRCTN ISRCTN59376582 , retrospectively registered October 31st 2013.

Intensified Therapy with Inhaled Corticosteroids and Long-Acting ß2-Agonists at the Onset of Upper Respiratory Tract Infection to Prevent Chronic Obstructive Pulmonary Disease Exacerbations. A Multicenter, Randomized, Double-Blind, Placebo-controlled Trial.

RATIONALE: The efficacy of intensified combination therapy with inhaled corticosteroids (ICS) and long-acting ß2-agonists (LABA) at the onset of upper respiratory tract infection (URTI) symptoms in chronic obstructive pulmonary disease (COPD) is unknown. OBJECTIVES: To evaluate whether intensified combination therapy with ICS/LABA, at the onset of URTI symptoms, decreases the incidence of COPD exacerbation occurring within 21 days of the URTI. METHODS: A total of 450 patients with stable, moderate to very severe COPD, were included in this investigator-initiated and -driven, double-blind, randomized, placebo-controlled study. At inclusion, patients were assigned to open-labeled low-maintenance dose ICS/LABA. Each patient was randomized either to intensified-dose ICS/LABA or placebo and instructed to start using this medication only in case of a URTI, at the onset of symptoms, twice daily, for 10 days. MEASUREMENTS AND MAIN RESULTS: The incidence of any exacerbation following a URTI was not significantly decreased in the ICS/LABA group, as compared with placebo (14.6% vs. 16.2%; hazard ratio, 0.77; 95% confidence interval, 0.46-1.33; P = 0.321) but the risk of severe exacerbation was decreased by 72% (hazard ratio, 0.28; 95% confidence interval, 0.11-0.74%; P = 0.010). In the stratified analysis, effect size was modified by disease severity, fractional exhaled nitric oxide, and the body mass index-airflow obstruction-dyspnea, and exercise score. Compared with the stable period, evidence of at least one virus was significantly more common at URTI, 10 days after URTI, and at exacerbation. CONCLUSIONS: Intensified combination therapy with ICS/LABA for 10 days at URTI onset did not decrease the incidence of any COPD exacerbation but prevented severe exacerbation. Patients with more severe disease had a significant risk reduction for any exacerbation. Clinical trial registered with www.isrctn.com (ISRCTN45572998).

Treatment with long acting muscarinic antagonists stimulates serum levels of irisin in patients with COPD.

Long acting muscarinic antagonists (LAMA) are currently considered the therapeutic mainstay for patients with COPD and have been shown to improve clinical outcomes including symptoms, exercise capacity and airflow limitation. Irisin, is a newly discovered hormone-like myokine generated by skeletal muscle cells in response to exercise and it is suggested to regulate energy expenditure and exercise capacity. The aim of the present study was to investigate if treatment with LAMA alters serum irisin levels in patients with COPD. Irisin was assessed by ELISA in the serum of 506 patients with COPD, GOLD II-IV, with a smoking history >10 PY, who were included in the PROMISE-COPD cohort. The effect of inhaled LAMA on serum irisin levels was evaluated in a proof-of-concept cohort of 40 COPD patients. Univariate linear regression analysis revealed that there was a significant negative association of irisin with age-adjusted Charlson score (p = 0.003) and a positive association of irisin with 6-min walking distance (6MWD) (p = 0.018) and treatment with LAMA (p = 0.004) but not with LABA or ICS. Multivariate analysis revealed that the association of irisin with LAMA treatment remains significant after adjustment for age-adjusted score and 6MWD. In the proof-of-concept cohort a single inhalation of LAMA stimulated serum irisin levels after 4 h. These findings imply that treatment of COPD patients with LAMA increase circulating irisin, thus explaining some of the beneficial extra-pulmonary effects of these drugs when used in the treatment of COPD.

Prognostic assessment in COPD without lung function: the B-AE-D indices.

Several composite markers have been proposed for risk assessment in chronic obstructive pulmonary disease (COPD). However, choice of parameters and score complexity restrict clinical applicability. Our aim was to provide and validate a simplified COPD risk index independent of lung function.The PROMISE study (n=530) was used to develop a novel prognostic index. Index performance was assessed regarding 2-year COPD-related mortality and all-cause mortality. External validity was tested in stable and exacerbated COPD patients in the ProCOLD, COCOMICS and COMIC cohorts (total n=2988).Using a mixed clinical and statistical approach, body mass index (B), severe acute exacerbations of COPD frequency (AE), modified Medical Research Council dyspnoea severity (D) and copeptin (C) were identified as the most suitable simplified marker combination. 0, 1 or 2 points were assigned to each parameter and totalled to B-AE-D or B-AE-D-C. It was observed that B-AE-D and B-AE-D-C were at least as good as BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity), ADO (age, dyspnoea, airflow obstruction) and DOSE (dyspnoea, obstruction, smoking, exacerbation) indices for predicting 2-year all-cause mortality (c-statistic: 0.74, 0.77, 0.69, 0.72 and 0.63, respectively; Hosmer-Lemeshow test all p>0.05). Both indices were COPD specific (c-statistic for predicting COPD-related 2-year mortality: 0.87 and 0.89, respectively). External validation of B-AE-D was performed in COCOMICS and COMIC (c-statistic for 1-year all-cause mortality: 0.68 and 0.74; c-statistic for 2-year all-cause mortality: 0.65 and 0.67; Hosmer-Lemeshow test all p>0.05).The B-AE-D index, plus copeptin if available, allows a simple and accurate assessment of COPD-related risk.

Therapy with proton-pump inhibitors for gastroesophageal reflux disease does not reduce the risk for severe exacerbations in COPD.

BACKGROUND AND OBJECTIVE: Gastroesophageal reflux disease (GERD) symptoms are associated with a higher risk of chronic obstructive pulmonary disease (COPD) exacerbation. We hypothesize that treatment with proton pump inhibitors reduces the risk of exacerbation in patients with stable COPD. METHODS: A total of 638 patients with stable COPD for ≥6 weeks, ≥10 pack-years of smoking and Global Initiative for Chronic Obstructive Lung Disease II-IV seeking care in tertiary hospitals in eight European countries in the Predicting Outcome using Systemic Markers in Severe Exacerbations-COPD cohort was prospectively evaluated by us. Comorbidities including associated medical treatment were assessed at baseline, at exacerbation and at biannual visits. Median observation time was 24 months. The primary study outcomes were exacerbation and/or death. RESULTS: A total of 85 (13.3%) of COPD patients were on anti-GERD therapy. These patients had higher annual and higher severe exacerbation rates (P = 0.009 and P = 0.002), decreased quality of life (SF-36: activity score P = 0.004, St. George's Respiratory Questionnaire: physical functioning P = 0.013 and social functioning P = 0.007), higher body mass airflow obstruction, dyspnea and exercise capacity index (P = 0.033) and Modified Medical Research Council scores (P = 0.002), shorter 6-min walking distance (P = 0.0004) and a higher adjusted Charlson score (P < 0.0001). Anti-GERD therapy was associated with a shorter time to severe exacerbation (HR 2.05 95% CI 1.37-3.08). Using three multivariable Cox-regression models, this association was independent of the following: (i) adjusted Charlson score and FEV1% predicted (HR 1.91 95% CI 1.26-2.90); (ii) adjusted Charlson score, body mass, airflow obstruction, dyspnea and exercise capacity index and Modified Medical Research Council (HR 1.62 95% CI 1.04-2.54); and (iii) adjusted Charlson score, FEV1% predicted and nine classes of medication for comorbidities (HR 1.63 95% CI 1.04-2.53). CONCLUSION: These findings suggest that patients with stable COPD receiving acid-suppressive therapy with proton pump inhibitors remain at high risk of frequent and severe exacerbations.

Longitudinal Measurement of Serum Vascular Endothelial Growth Factor in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: Impaired vascular endothelial growth factor (VEGF) signaling causes emphysema in animal models. In chronic obstructive pulmonary disease (COPD) patients, alterations in VEGF tissue expression have been observed. We hypothesize that circulating VEGF may be a biomarker to phenotype COPD patients. OBJECTIVE: The aim of this study was to investigate VEGF serum levels in stable and exacerbated COPD. METHODS: VEGF serum levels as well as parameters of short- and long-term outcome were assessed and analyzed in two COPD cohorts [PROMISE, n = 117; ProCOLD (PC), n = 191]. RESULTS: VEGF serum levels at stable COPD were neither related to forced expiratory volume in 1 s nor to the Modified Medical Research Council dyspnea score, 6-min walking distance or BODE index. There was no association between single VEGF levels and COPD exacerbation frequency or mortality at 1 and 2 years of follow-up. In PC an increase in VEGF over time (ΔVEGF) was associated with the exacerbation frequency as well as the 1- and 2-year hospitalization rate (p = 0.046, 0.009 and 0.006, respectively). Furthermore, in PC ΔVEGF was associated with 1- and 2-year survival (p = 0.009 and 0.041, respectively). CONCLUSIONS: Single serum VEGF levels, at stable and exacerbated COPD, were not associated with clinically significant outcomes in COPD. Conversely, the VEGF course seems related to COPD prognosis.

Vasoactive Intestinal Peptide for Diagnosing Exacerbation in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Vasoactive intestinal peptide (VIP) is the most abundant neuropeptide in the lung. VIP has been linked to pulmonary arterial hypertension and hypoxia. OBJECTIVES: We aimed to assess circulating VIP levels at exacerbation and at stable chronic obstructive pulmonary disease (COPD) and to evaluate the diagnostic performance in a well-characterized cohort of COPD patients. METHODS: The nested cohort study included patients with Global Initiative for Chronic Obstructive Lung Disease stage II-IV. Patients were examined at stable state and at acute exacerbation of COPD (AE-COPD), and dedicated serum was collected at both conditions. Serum VIP levels were determined by enzyme-linked immunosorbent assay. Diagnostic accuracy was analyzed by receiver operating characteristic curve and area under the curve (AUC). RESULTS: Patients with acute exacerbation (n = 120) and stable COPD (n = 163) had similar characteristics at baseline. Serum VIP levels did not correlate with oxygen saturation at rest (p = 0.722) or at exercise (p = 0.168). Serum VIP levels were significantly higher at AE-COPD (130.25 pg/ml, 95% CI 112.19-151.83) as compared to stable COPD (40.07 pg/ml, 95% CI 37.13-43.96, p < 0.001). The association of increased serum VIP with AE-COPD remained significant after propensity score matching (p < 0.001). Analysis of the Youden index indicated the optimal serum VIP cutoff value as 56.6 pg/ml. The probability of AE-COPD was very low if serum VIP was ≤35 pg/ml (sensitivity >90%) and very high if serum VIP was ≥88 pg/ml (specificity >90%). Serum VIP levels presented a robust performance to diagnose AE-COPD (AUC 0.849, 95% CI 0.779-0.899). CONCLUSIONS: Increased serum VIP levels are associated with AE-COPD.

Mortality risk prediction in COPD by a prognostic biomarker panel.

Chronic obstructive pulmonary disease (COPD) is a complex disease with various phenotypes. The simultaneous determination of multiple biomarkers reflecting different pathobiological pathways could be useful in identifying individuals with an increased risk of death. We derived and validated a combination of three biomarkers (adrenomedullin, arginine vasopressin and atrial natriuretic peptide), assessed in plasma samples of 385 patients, to estimate mortality risk in stable COPD. Biomarkers were analysed in combination and defined as high or low. In the derivation cohort (n = 142), there were 73 deaths during the 5-year follow-up. Crude hazard ratios for mortality were 3.0 (95% CI 1.8-5.1) for one high biomarker, 4.8 (95% CI 2.4-9.5) for two biomarkers and 9.6 (95% CI 3.3-28.3) for three high biomarkers compared with no elevated biomarkers. In the validation cohort (n = 243), 87 individuals died. Corresponding hazard ratios were 1.9 (95% CI 1.1-3.3), 3.1 (95% CI 1.8-5.4) and 5.4 (95% CI 2.5-11.4). Multivariable adjustment for clinical variables as well as the BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index and stratification by the Global Initiative for Chronic Obstructive Lung Disease stages provided consistent results. The addition of the panel of three biomarkers to the BODE index generated a net reclassification improvement of 57.9% (95% CI 21.7-92.4%) and 45.9% (95% CI 13.9-75.7%) at 3 and 5 years, respectively. Simultaneously elevated levels of adrenomedullin, arginine vasopressin and atrial natriuretic peptide are associated with increased risk of death in patients with stable COPD.

Adrenomedullin refines mortality prediction by the BODE index in COPD: the "BODE-A" index.

The BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index is well-validated for mortality prediction in chronic obstructive pulmonary disease (COPD). Concentrations of plasma pro-adrenomedullin, a surrogate for mature adrenomedullin, independently predicted 2-year mortality among inpatients with COPD exacerbation. We compared accuracy of initial pro-adrenomedullin level, BODE and BODE components, alone or combined, in predicting 1-year or 2-year all-cause mortality in a multicentre, multinational observational cohort with stable, moderate to very severe COPD. Pro-adrenomedullin was significantly associated (p<0.001) with 1-year mortality (4.7%) and 2-year mortality (7.8%) and comparably predictive to BODE regarding both (C statistics 0.691 versus 0.745 and 0.635 versus 0.679, respectively). Relative to using BODE alone, adding pro-adrenomedullin significantly improved 1-year and 2-year mortality prognostication (C statistics 0.750 and 0.818, respectively; both p<0.001). Pro-adrenomedullin plus BOD was more predictive than the original BODE including 6-min walk distance. In multivariable analysis, pro-adrenomedullin (likelihood ratio Chi-squared 13.0, p<0.001), body mass index (8.5, p=0.004) and 6-min walk distance (7.5, p=0.006) independently foretold 2-year survival, but modified Medical Research Council dyspnoea score (2.2, p=0.14) and forced expiratory volume in 1 s % predicted (0.3, p=0.60) did not. Pro-adrenomedullin plus BODE better predicts mortality in COPD patients than does BODE alone; pro-adrenomedullin may substitute for 6-min walk distance in BODE when 6-min walk testing is unavailable.

Mycobacterium tuberculosis infection associated immune perturbations correlate with antiretroviral immunity.

Infection with Mycobacterium tuberculosis (MTB) remains one of the most important opportunistic infections in people with HIV-1 (PWH). While active Tuberculosis (TB) leads to rapid progression of immunodeficiency in PWH, the interaction between MTB and HIV-1 during the asymptomatic phase of both infections remains poorly understood. In a cohort of individuals with HIV (PWH) with and without suppressed HIV-1 viral load, the transcriptomic profiles of peripheral blood mononuclear cells (PBMC) clustered in individuals infected with Mycobacterium tuberculosis (MTB) compared to carefully matched controls. Subsequent functional annotation analysis disclosed alterations in the IL-6, TNF, and KRAS pathways. Notably, MTB-associated genes demonstrated an inverse correlation with HIV-1 viremia, evident at both on individual gene level and when employed as a gene score. In sum, our data show that MTB infection in PWH is associated with a shift in the activation state of the immune system, displaying an inverse relationship with HIV-1 viral load. These results could provide an explanation for the observed increased antiretroviral control associated with MTB infection in PWH.

Antibiotic tolerance: targeting bacterial survival.

Antimicrobial susceptibility testing is the cornerstone of antibiotic treatments. Yet, active drugs are frequently unsuccessful in vivo and most clinical trials investigating antibiotics fail. So far, bacterial survival strategies, other than drug resistance, have been largely ignored. As such, drug tolerance and persisters, allowing bacterial populations to survive during antibiotic treatments, could fill a gap in antibiotic susceptibility testing. Therefore, it remains critical to establish robust and scalable bacterial viability measures and to define the clinical relevance of bacterial survivors across various bacterial infections. If successful, these tools could improve drug design and development to prevent tolerance formation or target bacterial survivors, to ultimately reduce treatment failures and curb resistance evolution.

Mycobacterium abscessus pathogenesis identified by phenogenomic analyses.

The medical and scientific response to emerging and established pathogens is often severely hampered by ignorance of the genetic determinants of virulence, drug resistance and clinical outcomes that could be used to identify therapeutic drug targets and forecast patient trajectories. Taking the newly emergent multidrug-resistant bacteria Mycobacterium abscessus as an example, we show that combining high-dimensional phenotyping with whole-genome sequencing in a phenogenomic analysis can rapidly reveal actionable systems-level insights into bacterial pathobiology. Through phenotyping of 331 clinical isolates, we discovered three distinct clusters of isolates, each with different virulence traits and associated with a different clinical outcome. We combined genome-wide association studies with proteome-wide computational structural modelling to define likely causal variants, and employed direct coupling analysis to identify co-evolving, and therefore potentially epistatic, gene networks. We then used in vivo CRISPR-based silencing to validate our findings and discover clinically relevant M. abscessus virulence factors including a secretion system, thus illustrating how phenogenomics can reveal critical pathways within emerging pathogenic bacteria.

Specific cytokine patterns of pulmonary tuberculosis in Central Africa.

Different cytokines have been suggested to be involved in the pathogenesis of pulmonary tuberculosis (TB). The frequencies of Mycobacterium tuberculosis (MTB) specific CD4(+) and CD8(+) T cells, CD4(+)CD25(+) Forkhead Box Protein (FoxP)3(+) T cells, interleukin (IL)-6, interferon (IFN)-γ, Tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß and IL-10 were assessed in HIV-negative, pulmonary tuberculosis (TB) patients (n=30) and in healthy controls (n=23) in Gabon. Peripheral blood mononuclear cells (PBMC) were stimulated with purified protein derivative (PPD) and early secretory antigenic target-6 (ESAT-6). In patients, a pronounced pro-inflammatory cytokine response with highly significant increased levels of IL-6 and TNF-α accompanied by increased TGF-ß was detectable. Differences in IFN-γ responses between patients and healthy individuals were less pronounced than expected. FoxP3 expression did not differ between groups. A distinct cytokine pattern is associated with active pulmonary TB in patients from Central Africa.

Single-Breath Washout Tests to Assess Small Airway Disease in COPD.

BACKGROUND: Current functional assessments do not allow a reliable assessment of small airways, which are a major site of disease in COPD. Single-breath washout (SBW) tests are feasible and reproducible methods for evaluating small airway disease. Their relevance in COPD remains unknown. METHODS: We performed a cross-sectional study in 65 patients with moderate to severe COPD. Phase III slope of nitrogen (SIIIN2) and double tracer gas (SIIIDTG) SBW tests were used as a measure of ventilation inhomogeneity. The association of both markers with established physiological and clinical features of COPD was assessed. RESULTS: Ventilation inhomogeneity as measured by SIIIN2 and SIIIDTG was increased in patients with COPD compared with healthy subjects (P < .001 and P < .001, respectively). SIIIN2 was associated with FEV1 predicted, residual volume (RV)/total lung capacity (TLC) and diffusing capacity of the lung for carbon monoxide (Dlco) (all P < .001). Furthermore, SIIIN2 was related to dyspnea, exercise-induced desaturation, and exercise capacity (P = .001, P < .001, and P = .047, respectively). SIIIDTG was associated with TLC, Dlco, and cough (P < .001, P = .001, and P = .009, respectively). In multivariate regression models, we demonstrated that these associations are largely independent of FEV1 and mostly stronger than associations with FEV1. In contrast, FEV1 was superior in predicting emphysema severity. CONCLUSIONS: SIIIN2 and SIIIDTG, two fast and clinically applicable measures of small airway disease, reflect different physiological and clinical aspects of COPD, largely independent of spirometry. TRIAL REGISTRY: ISRCTN99586989, Ethics committee Beider Basel (approval number 295/07).

Adenovirus-specific IgG maturation as a surrogate marker in acute exacerbations of COPD.

BACKGROUND: B cells in airways and lung parenchyma may be involved in COPD evolution; however, whether their pathogenic role is beneficial or harmful remains controversial. The objective of this study was to investigate the maturation of adenovirus-specific immunoglobulins in patients with COPD with respect to clinical outcome. METHODS: The presence of adenovirus-specific immunoglobulins during acute exacerbation of COPD (AECOPD) was analyzed at exacerbation and 2 to 3 weeks later. Patients with detectable adenovirus-specific IgM and low IgG avidity were grouped into fast and delayed IgG maturation. The clinical outcome of both groups was evaluated. RESULTS: Of 208 patients, 43 (20.7%) had serologic evidence of recent adenovirus infection and were grouped by fast IgG maturation (26 patients) and delayed IgG maturation (17 patients). Baseline characteristics, AECOPD therapy, and duration of hospitalization were similar in both groups, but the AECOPD recurrence rate within 6 months was higher (P = .003), and there was a trend for earlier AECOPD-related rehospitalizations (P = .061) in the delayed IgG maturation group. The time to rehospitalization or death within 2 years was shorter in patients with delayed IgG maturation (P = .003). Adenovirus-specific IgG maturation was an independent predictor of the number of AECOPD recurrences within 6 months (P = .001) and the occurrence of hospitalization or death within 2 years (P = .005). CONCLUSIONS: Delayed immunoglobulin avidity maturation following COPD exacerbation is associated with worse outcomes. TRIAL REGISTRY: ISRCTN Register; No.: ISRCTN77261143; URL: www.isrctn.org.

Exertional hypoxemia in stable COPD is common and predicted by circulating proadrenomedullin.

BACKGROUND: The prevalence of exertional hypoxemia in unselected patients with COPD is unknown. Intermittent hypoxia leads to adrenomedullin (ADM) upregulation through the hypoxia-inducible factor-1 pathway. We aimed to assess the prevalence and the annual probability to develop exertional hypoxemia in stable COPD. We also hypothesized that increased ADM might be associated with exertional hypoxemia and envisioned that adding ADM to clinical variables might improve its prediction in COPD. METHODS: A total of 1,233 6-min walk tests and circulating proadrenomedullin (proADM) levels from 574 patients with clinically stable, moderate to very severe COPD enrolled in a multinational cohort study and followed up for 2 years were concomitantly analyzed. RESULTS: The prevalence of exertional hypoxemia was 29.1%. In a matrix derived from a fitted-multistate model, the annual probability to develop exertional hypoxemia was 21.6%. Exertional hypoxemia was associated with greater deterioration of specific domains of health-related quality of life, higher severe exacerbation, and death annual rates. In the logistic linear and conditional Cox regression multivariable analyses, both FEV1% predicted and proADM proved independent predictors of exertional hypoxemia (P < .001 for both). Adjustment for comorbidities, including cardiovascular disorders, and exacerbation rate did not influence results. Relative to using FEV1% predicted alone, adding proADM resulted in a significant improvement of the predictive properties (P = .018). Based on the suggested nonlinear nomogram, patients with moderate COPD (FEV1% predicted = 50%) but high proADM levels (> 2 nmol/L) presented increased risk (> 30%) for exertional desaturation. CONCLUSIONS: Exertional desaturation is common and associated with poorer clinical outcomes in COPD. ADM improves prediction of exertional desaturation as compared with the use of FEV1% predicted alone. TRIAL REGISTRY: ISRCTN Register; No.: ISRCTN99586989; URL: www.controlled-trials.com.

Acute effects of aerosolized iloprost in COPD related pulmonary hypertension - a randomized controlled crossover trial.

BACKGROUND: Inhaled iloprost potentially improves hemodynamics and gas exchange in patients with chronic obstructive pulmonary disease (COPD) and secondary pulmonary hypertension (PH). OBJECTIVES: To evaluate acute effects of aerosolized iloprost in patients with COPD-associated PH. METHODS: A randomized, double blind, crossover study was conducted in 16 COPD patients with invasively confirmed PH in a single tertiary care center. Each patient received a single dose of 10 µg iloprost (low dose), 20 µg iloprost (high dose) and placebo during distinct study-visits. The primary end-point of the study was exercise capacity as assessed by the six minute walking distance. RESULTS: Both iloprost doses failed to improve six-minute walking distance (p = 0.36). Low dose iloprost (estimated difference of the means -1.0%, p = 0.035) as well as high dose iloprost (-2.2%, p<0.001) significantly impaired oxygenation at rest. Peak oxygen consumption and carbon dioxide production differed significantly over the three study days (p = 0.002 and p = 0.003, accordingly). As compared to placebo, low dose iloprost was associated with reduced peak oxygen consumption (-76 ml/min, p = 0.002), elevated partial pressure of carbon dioxide (0.27 kPa, p = 0.040) and impaired ventilation during exercise (-3.0l/min, p<0.001). CONCLUSIONS: Improvement of the exercise capacity after iloprost inhalation in patients with COPD-associated mild to moderate PH is very unlikely. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN61661881.

The Sequential Organ Failure Assessment score and copeptin for predicting survival in ventilator-associated pneumonia.

INTRODUCTION: Ventilator-associated pneumonia remains the most common nosocomial infection in the critically ill and contributes to significant morbidity. Eventual decisions regarding withdrawal or maximal therapy are demanding and rely on physicians' experience. Additional objective tools for risk assessment may improve medical judgement. Copeptin, reflecting vasopressin release, as well as the Sequential Organ Failure Assessment (SOFA) score, reflecting the individual degree of organ dysfunction, might qualify for survival prediction in ventilator-associated pneumonia. We investigated the predictive value of the SOFA score and copeptin in ventilator-associated pneumonia. METHODS: One hundred one patients with ventilator-associated pneumonia were prospectively assessed. Death within 28 days after ventilator-associated pneumonia onset was the primary end point. RESULTS: The SOFA score and the copeptin levels at ventilator-associated pneumonia onset were significantly elevated in nonsurvivors (P = .002 and P = .017, respectively). Both markers had different time courses in survivors and nonsurvivors (P < .001 and P = .006). Mean SOFA (average SOFA of 10 days after VAP onset) was superior in predicting 28-day survival as compared with SOFA and copeptin at ventilator-associated pneumonia onset (area under the curve, 0.90 vs 0.73 and 0.67, respectively). CONCLUSIONS: The predictive value of serial-measured SOFA significantly exceeds those of single SOFA and copeptin measurements. Serial SOFA scores accurately predict outcome in ventilator-associated pneumonia.