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      Effect of a selective neutrophil elastase inhibitor on mortality and ventilator-free days in patients with increased extravascular lung water: a post hoc analysis of the PiCCO Pulmonary Edema Study

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          Abstract

          Background

          Neutrophil elastase plays an important role in the development and progression of acute respiratory distress syndrome (ARDS). Although the selective elastase inhibitor, sivelestat, is widely used in Japan for treating ARDS patients, its effectiveness remains controversial. The aim of the current study was to investigate the effects of sivelestat in ARDS patients with evidence of increased extravascular lung water by re-analyzing a large multicenter study database.

          Methods

          A post hoc analysis of the PiCCO Pulmonary Edema Study was conducted. This multicenter prospective cohort study included 23 institutions in Japan. Adult mechanically ventilated ARDS patients with an extravascular lung water index of >10 mL/kg were included and propensity score analyses were performed. The endpoints were 28-day mortality and ventilator-free days (VFDs).

          Results

          Patients were categorized into sivelestat ( n = 87) and control ( n = 77) groups, from which 329 inverse probability-weighted group patients (162 vs. 167) were generated. The overall 28-day mortality was 31.1% (51/164). There was no significant difference in 28-day mortality between the study groups (sivelestat vs. control; unmatched: 29.9% vs. 32.5%; difference, −2.6%, 95% confidence interval (CI), −16.8 to 14.2; inverse probability-weighted: 24.7% vs. 29.5%, difference, −4.8%, 95% CI, −14.4 to 9.6). Although administration of sivelestat did not alter the number of ventilator-free days (VFDs) in the unmatched (9.6 vs. 9.7 days; difference, 0.1, 95% CI, −3.0 to 3.1), the inverse probability-weighted analysis identified significantly more VFDs in the sivelestat group than in the control group (10.7 vs. 8.4 days, difference, −2.3, 95% CI, −4.4 to −0.2).

          Conclusions

          Although sivelestat did not significantly affect 28-day mortality, this treatment may have the potential to increase VFDs in ARDS patients with increased extravascular lung water. Prospective randomized controlled studies are required to confirm the results of the current study.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s40560-014-0067-y) contains supplementary material, which is available to authorized users.

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          Most cited references 42

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          Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome.

          Trials of potential new therapies in acute lung injury are difficult and expensive to conduct. This article is designed to determine the utility, behavior, and statistical properties of a new primary end point for such trials, ventilator-free days, defined as days alive and free from mechanical ventilation. Describing the nuances of this outcome measure is particularly important because using it, while ignoring mortality, could result in misleading conclusions. To develop a model for the duration of ventilation and mortality and fit the model by using data from a recently completed clinical trial. To determine the appropriate test statistic for the new measure and derive a formula for power. To determine a formula for the probability that the test statistic will reject the null hypothesis and mortality will simultaneously show improvement. To plot power curves for the test statistic and determine sample sizes for reasonable alternative hypotheses. Intensive care units. Patients with acute respiratory distress syndrome or acute lung injury as defined by the American-European Consensus Conference. The proposed model fit the clinical data. Ventilator-free days were improved by lower tidal volume ventilation, but the improvement was mostly caused by the improved mortality rate, so trials that expected similar effects would only have modest increase in power if they used ventilator-free days as their primary end point rather than 28-day mortality. Similar results were obtained using the model in two groups segregated by low or high Acute Physiology and Chronic Health Evaluation score. On the other hand, if patients are divided into two groups on the basis of the lung injury score, both the duration of ventilation and mortality are lower in the low lung injury score group. A trial of a treatment that had a similar clinical effect would have a large increase in power, allowing for a reduction in the required sample size. Use of ventilator-free days as a trial end point allows smaller sample sizes if it is assumed that the treatment being tested simultaneously reduces the duration of ventilation and improves mortality. It is unlikely that a treatment that led to higher mortality could lead to a statistically significant improvement in ventilator-free days. This would be especially true if the treatment were also required to produce a nominal improvement in mortality.
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            Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: a systematic review and meta-analysis.

            Controversy remains as to whether low-dose corticosteroids can reduce the mortality and morbidity of acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS) without increasing the risk of adverse reactions. We aimed to evaluate all studies investigating prolonged corticosteroids in low-to-moderate dose in ALI or ARDS. MEDLINE, EMBASE, Current Content, and Cochrane Central Register of Controlled Trials, and bibliographies of retrieved articles. Randomized controlled trials (RCTs) and observational studies reported in any language that used 0.5-2.5 mg.kg.d of methylprednisolone or equivalent to treat ALI/ARDS. Data were extracted independently by two reviewers and included study design, patient characteristics, interventions, and mortality and morbidity outcomes. Both cohort studies (five studies, n = 307) and RCTs (four trials, n = 341) showed a similar trend toward mortality reduction (RCTs relative risk 0.51, 95% CI 0.24-1.09; p = 0.08; cohort studies relative risk 0.66, 95% CI 0.43-1.02; p = 0.06). The overall relative risk was 0.62 (95% CI 0.43-0.91; p = 0.01). There was also improvement in length of ventilation-free days, length of intensive care unit stay, Multiple Organ Dysfunction Syndrome Score, Lung Injury Scores, and improvement in Pao2/Fio2. There was no increase in infection, neuromyopathy, or any major complications. There was significant heterogeneity in the pooled studies. Subgroup and meta-regression analyses showed that heterogeneity had minimal effect on treatment efficacy; however, these findings were limited by the small number of studies used in the analyses. The use of low-dose corticosteroids was associated with improved mortality and morbidity outcomes without increased adverse reactions. The consistency of results in both study designs and all outcomes suggests that they are an effective treatment for ALI or ARDS. The mortality benefits in early ARDS should be confirmed by an adequately powered randomized trial.
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              Assessing pulmonary permeability by transpulmonary thermodilution allows differentiation of hydrostatic pulmonary edema from ALI/ARDS.

              To test whether assessing pulmonary permeability by transpulmonary thermodilution enables to differentiate increased permeability pulmonary edema (ALI/ARDS) from hydrostatic pulmonary edema. Retrospective review of cases. A 24-bed medical intensive care unit of a university hospital. Forty-eight critically ill patients ventilated for acute respiratory failure with bilateral infiltrates on chest radiograph, a PaO(2)/FiO(2) ratio /= 12 ml/kg. We assessed pulmonary permeability by two indexes obtained from transpulmonary thermodilution: extravascular lung water/pulmonary blood volume (PVPI) and the ratio of extravascular lung water index over global end-diastolic volume index. The cause of pulmonary edema was determined a posteriori by three experts, taking into account medical history, clinical features, echocardiographic left ventricular function, chest radiography findings, B-type natriuretic peptide serum concentration and the time-course of these findings with therapy. Experts were blind for pulmonary permeability indexes and for global end-diastolic volume. ALI/ARDS was diagnosed in 36 cases. The PVPI was 4.7+/-1.8 and 2.1+/-0.5 in patients with ALI/ARDS and hydrostatic pulmonary edema, respectively (p /= 3 and an extravascular lung water index/global end-diastolic index ratio >/= 1.8 x 10(-2) allowed the diagnosis of ALI/ARDS with a sensitivity of 85% and specificity of 100%. These results suggest that indexes of pulmonary permeability provided by transpulmonary thermodilution may be useful for determining the mechanism of pulmonary edema in the critically ill.
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                Author and article information

                Contributors
                t-tagami@nms.ac.jp
                tosa@onchikai.jp
                mario@nms.ac.jp
                hidetada@naramed-u.ac.jp
                kaneyui-ygc@umin.ac.jp
                entomo@med.tohoku.ac.jp
                rinkahiroshi@hotmail.com
                akiramurai@mac.com
                yamaguchi.junko@nihon-u.ac.jp
                kyys0507@hotmail.co.jp
                nobu99@nms.ac.jp
                hideaki@med.kurume-u.ac.jp
                y.kase@jikei.ac.jp
                takatori@eagle.ocn.ne.jp
                izumino@nagasaki-u.ac.jp
                toshian@nagasaki-u.ac.jp
                ryutaro_seo@hotmail.com
                muuminqqe@yahoo.co.jp
                sugita-tky@umin.ac.jp
                h_takahashi@tobu.saiseikai.or.jp
                yuichi_kuroki@chukyo-hosp.jp
                iraira19@aol.com
                t-kane@qk2.so-net.ne.jp
                yokota@nms.ac.jp
                kussie@emergency-medicine.med.tohoku.ac.jp
                Journal
                J Intensive Care
                J Intensive Care
                Journal of Intensive Care
                BioMed Central (London )
                2052-0492
                31 December 2014
                31 December 2014
                2014
                : 2
                : 1
                Affiliations
                [ ]Department of Emergency and Critical Care Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603 Japan
                [ ]Department of Clinical Epidemiology and Health Economics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
                [ ]Department of Emergency and Critical Care Medicine, Aizu Chuo Hospital, Fukushima, Japan
                [ ]Department of Emergency and Critical Care Medicine, Nara Medical University, Nara, Japan
                [ ]Advanced Medical Emergency and Critical Care Center, Yamaguchi University Hospital, Yamaguchi, Japan
                [ ]Department of Emergency and Critical Care Medicine, Tohoku University Hospital, Miyagi, Japan
                [ ]Emergency and Critical Care Medical Center, Osaka City General Hospital, Osaka, Japan
                [ ]Department of Emergency and Critical Care Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
                [ ]Division of Emergency and Critical Care Medicine, Department of Acute Medicine, Nihon University School of Medicine, Tokyo, Japan
                [ ]Shock Trauma and Emergency Medical Center, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
                [ ]Department of Emergency and Critical Care Medicine, Nippon Medical School Chiba Hokusou Hospital, Chiba, Japan
                [ ]Department of Emergency and Critical Care Medicine, Kurume University School of Medicine, Fukuoka, Japan
                [ ]Critical Care Medicine, Jikei University School of Medicine, Tokyo, Japan
                [ ]Department of Anesthesia and Intensive Care, Hiroshima City Hospital, Hiroshima, Japan
                [ ]Advanced Emergency and Critical Care Center, Kansai Medical University Takii Hospital, Osaka, Japan
                [ ]Intensive Care Unit, Nagasaki University Hospital, Nagasaki, Japan
                [ ]Intensive Care Unit, Kobe City Medical Center General Hospital, Hyogo, Japan
                [ ]Department of Emergency and Critical Care Medicine, Kansai Medical University, Osaka, Japan
                [ ]Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Tokyo, Japan
                [ ]Department of Intensive Care Medicine, Saiseikai Yokohamashi Tobu Hospital, Kanagawa, Japan
                [ ]Department of Emergency and Critical Care Medicine, Social Insurance Chukyo Hospital, Aichi, Japan
                [ ]Department of Emergency and Critical Care Medicine, Nippon Medical School Tama Nagayama Hospital, Tokyo, Japan
                [ ]Emergency and Critical Care Medicine, National Hospital Organization Disaster Medical Center, Tokyo, Japan
                [ ]Division of Emergency Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan
                Article
                67
                10.1186/s40560-014-0067-y
                4336272
                25705423
                © Tagami et al.; licensee BioMed Central. 2014

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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