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Ulinastatin Treatment for Acute Respiratory Distress Syndrome In Zhang et al. BMC Pulmonary Medicine (2019) 19:196 https://doi.org/10.1186/s12890-019-0968-6 RESEARCH ARTICLE Open Access Ulinastatin treatment for acute respiratory distress syndrome in China: a meta-analysis of randomized controlled trials Xiangyun Zhang1,2†, Zhaozhong Zhu3†, Weijie Jiao2, Wei Liu1, Fang Liu1* and Xi Zhu4* Abstract Background: Epidemiologic studies have shown inconsistent conclusions about the effect of ulinastain treatment for acute respiratory distress syndrome (ARDS). It is necessary to perform a meta-analysis of ulinastatin’s randomized controlled trials (RCTS) to evaluate its efficacy for treating ARDS. Methods: We searched the published RCTs of ulinastatin treatment for ARDS from nine databases (the latest search on April 30th, 2017). Two authors independently screened citations and extracted data. The meta-analysis was performed using Rev. Man 5.3 software. Results: A total of 33 RCTs involving 2344 patients satisfied the selection criteria and were included in meta- analysis. The meta-analysis showed that, compared to conventional therapy, ulinastatin has a significant benefit for ARDS patients by reducing mortality (RR = 0.51, 95% CI:0.43~0.61) and ventilator associated pneumonia rate (RR = 0.50, 95% CI: 0.36~0.69), and shortening duration of mechanical ventilation (SMD = -1.29, 95% CI: -1.76~-0.83), length of intensive care unit stay (SMD = -1.38, 95% CI: -1.95~-0.80), and hospital stay (SMD = -1.70, 95% CI:-2.63~−0.77). Meanwhile, ulinastatin significantly increased the patients’ oxygenation index (SMD = 2.04, 95% CI: 1.62~2.46) and decreased respiratory rate (SMD = -1.08, 95% CI: -1.29~-0.88) and serum inflammatory factors (tumor necrosis factor-α: SMD = -3.06, 95% CI:-4.34~-1.78; interleukin-1β: SMD = -3.49, 95% CI: -4.64~-2.34; interleukin-6: SMD = -2.39, 95% CI: -3.34~-1.45; interleukin-8: SMD = -2.43, 95% CI: -3.86~-1.00). Conclusions: Ulinastatin seemly showed a beneficial effect for ARDS patients treatment and larger sample sized RCTs are needed to confirm our findings. Keywords: Ulinastatin, ARDS, RCTs, Efficacy, Meta-analysis Background pneumonia have likely contributed to this reduction [3]. Acute respiratory distress syndrome (ARDS) is a multi- Drug research of ARDS has been involved in all the factorial lung injury that continues to be associated with currently recognized stages of disease pathogenesis, which high levels of morbidity and mortality [1]. Although the included anti-inflammatory therapy of glucocorticoid, risk of ARDS was significantly reduced over the past 20 selective expansion of pulmonary vascular therapy of years, its incidence is still as high as 20%~ 30% [2]. Low nitric oxide and prostacyclin, and alternative treatment of tidal volume ventilation, timely resuscitation and anti- exogenous surfactant. However, no drugs are utilized in microbial administration, restrictive transfusion practices, clinical practice for ARDS due to their contradictory find- and primary prevention of aspiration and nosocomial ings across studies. Due to the lack of capable drugs for ARDS treatment, the mortality remains high, up to 45% * Correspondence: [email protected]; [email protected] [4]. Neutrophil and neutrophil elastase are important †Xiangyun Zhang and Zhaozhong Zhu contributed equally to this work. components of the inflammatory response that character- 1Department of Pharmacy, Peking University Third Hospital, 49 North Garden izes ARDS [5–7]. Current notion holds that activated Road, Beijing 100191, China 4Department of Critical Care Medicine, Peking University Third Hospital, 49 neutrophil releases a large number of neutrophil elastase North Garden Road, Beijing 100191, China when it serves as a powerful host defense [5]. Neutrophil Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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. Zhang et al. BMC Pulmonary Medicine (2019) 19:196 Page 2 of 9 elastase is able to escape from regulation by multiple Methods protease inhibitors at inflammatory sites. Excessive Search strategy neutrophil elastase, beyond levels controlled by en- We searched all published randomized controlled trials dogenous proteinase inhibitors, disturbs the function of (RCTs) assessing the efficacy of ulinastatin for ARDS the lung permeability barrier and induces the release of from 9 databases: Pubmed, Ovid, the Cochrane Library, pro-inflammatory cytokines. Then, these actions will ClinicalTrials.gov, Elsevier, Web of Science, Wanfang cause a series of symptoms that are typical in the database, China Knowledge Resource Integrated data- pathophysiology of ARDS [5, 6, 8, 9]. Further support- base, and VIP database. We used the following search ingthisproposedpathogenesis,animalmodelstudies terms: “ulinastatin” and “acute respiratory distress syn- have shown that supplements of proteinase inhibitors drome” or “ARDS”. The search deadline was April 30, reduce symptoms of acute lung injury [10]. Currently, 2017. No other restrictions were placed on the search ulinastatin is a glycoprotein that acts as a protease criteria. All potentially relevant papers based on titles inhibitor and has been used to treat ARDS [11, 12], and abstracts were retrieved for full text screening. We pancreatitis [13], multi-organ failure [14]andsepsis also collected relevant articles by checking the references [15] in Asia for several years. A summary of the of the retrieved papers. potential mechanisms accounting for the effects of ulinatistin in ARDS is shown in Table 1. For example, Study selection ulinatistin can inhibit the serine proteases (such as Patients, 18 years of age or older, diagnosed with ARDS trypsin and α-chymotrypsin) and different enzymes were eligible for inclusion. ARDS was defined as acute (such as granulocyte elastase and hyaluronidase) as well onset, pulmonary artery wedge pressure ≤ 18 mmHg and as stabilizing lysosomal membranes to prevent the absence of clinical evidence of left atrial hypertension or release of lysosomal enzymes [20–22]. Moreover, bilateral infiltrates on chest radiography and oxygenation ulinastatin possesses anti-inflammatory properties by index (PaO /FiO ≤ 200) [27]. There were no limitations reducing the elevation of tumor necrosis factor-α 2 2 on dose or duration of ulinastatin. The intervention (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8), comparisons were made between ulinastatin plus con- which are produced by neutrophil elastase [17–19]. ventional treatment and conventional treatment. The Currently, several animal studies [23, 24], clinical trials primary efficacy outcomes were mortality, rate of venti- [19, 25] and systematic reviews [11, 12] have confirmed lator associated pneumonia (VAP), duration of mechan- its beneficial effect in lung protection. However, ical ventilation, length of intensive care unit (ICU) and whether ulinastatin can be recommended as a standard hospital stay. Secondary efficacy outcomes were PaO / medication for ARDS remains uncertain, since its clin- 2 FiO , respiratory rate, serum inflammatory factors ical benefit has not been fully understood [26]. There- 2 (TNF-a, IL-1β, IL-6, IL-8). fore, a meta-analysis to quantitatively evaluate the efficacy of ulinastatin for ARDS is essential. Data extraction and quality assessment Both the study selection (XYZ and WJ) and data extrac- tion processes (XYZ and WL) were performed by two Table 1 Potential mechanisms for the effect of ulinatistin on authors independently. Disagreements were resolved ARDS through consensus or arbitration by a third author (XZ ARDS risk factors Potential mechanisms for the effect of or FL). Data for basic characteristics of included trials ulinatistin on ARDS extracted from full-text articles included the following Acute pancreatitis Deactivation of the chain reaction of terms: first author, year of publication, mean age or pancreatic enzymes, such as trypsin, α- chymotrypsin, lipase, amylase, elastase and range, the number of patients, intervention information, carboxypeptidase [13] Jadad score and duration of intervention. We obtained Multiple organ Suppression of the activation of mean ± standard deviation values for continuous vari- dysfunction syndrome polymorphonuclear leukocytes (e.g. ables in the original manuscripts for the meta-analysis. neutrophils), macrophages and platelets [14, Trials in which specific endpoints were not reported 16] were excluded from the pooled analyses of the specific Sepsis Inhibition of various serine proteases, such as endpoints that were reported. Study quality was assessed trypsin, thrombin, chymotrypsin, kallikrein, plasmin, elastase and cathepsin [15] by the Jadad scale, which assesses adequacy of Systemic inflammation Inhibition of polymorphonuclear leukocytes randomization, blinding and attrition. The Jadad scale (e.g. neutrophils) and pro-inflammatory cyto- ranges from 0 to 5 points, with a low-quality study kines including interleukins (e.g. IL-1, IL-6 and receiving a score of 2 or less and a high-quality study
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