Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Pulmonary Medicine
Published in: BMC Pulmonary Medicine 1/2019

Open Access 01-12-2019 | Acute Respiratory Distress-Syndrome | Research article

Ulinastatin treatment for acute respiratory distress syndrome in China: a meta-analysis of randomized controlled trials

Authors: Xiangyun Zhang, Zhaozhong Zhu, Weijie Jiao, Wei Liu, Fang Liu, Xi Zhu

Published in: BMC Pulmonary Medicine | Issue 1/2019

Login to get access

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.
Literature
1.
Henderson WR, Chen L, Amato MBP, Brochard LJ. Fifty years of research in ARDS. Respiratory mechanics in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017;196(7):822–33.PubMedCrossRef
2.
Li G, Malinchoc M, Cartin-Ceba R, Venkata CV, Kor DJ, Peters SG, Hubmayr RD, Gajic O. Eight-year trend of acute respiratory distress syndrome: a population-based study in Olmsted County, Minnesota. Am J Respir Crit Care Med. 2011;183(1):59–66.PubMedCrossRef
3.
4.
Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307(23):2526–33.
5.
6.
Kawabata K, Hagio T, Matsuoka S. The role of neutrophil elastase in acute lung injury. Eur J Pharmacol. 2002;451(1):1–10.PubMedCrossRef
7.
Wang T, Zhu Z, Liu Z, Yi L, Yang Z, Bian W, Chen W, Wang S, Li G, Li A, et al. Plasma neutrophil Elastase and Elafin as prognostic biomarker for acute respiratory distress syndrome: a multicenter survival and longitudinal prospective observation study. Shock. 2017;48(2):168–74.PubMedCrossRef
8.
Fitch PM, Roghanian A, Howie SE, Sallenave JM. Human neutrophil elastase inhibitors in innate and adaptive immunity. Biochem Soc Trans. 2006;34(Pt 2):279–82.PubMedCrossRef
9.
Fujishima S, Morisaki H, Ishizaka A, Kotake Y, Miyaki M, Yoh K, Sekine K, Sasaki J, Tasaka S, Hasegawa N, et al. Neutrophil elastase and systemic inflammatory response syndrome in the initiation and development of acute lung injury among critically ill patients. Biomed Pharmacother. 2008;62(5):333–8.PubMedCrossRef
10.
Pierrakos C, Karanikolas M, Scolletta S, Karamouzos V, Velissaris D. Acute respiratory distress syndrome: pathophysiology and therapeutic options. J Clin Med Res. 2012;4(1):7–16.PubMedPubMedCentral
11.
Leng YX, Yang SG, Song YH, Zhu X, Yao GQ. Ulinastatin for acute lung injury and acute respiratory distress syndrome: a systematic review and meta-analysis. World J Crit Care Med. 2014;3(1):34–41.PubMedPubMedCentralCrossRef
12.
Li S, Fnag M, Wang Y, Yu T, Li W, Yang W. Effects of ulinastatin in patients with acute respiratory distress syndrome: a meta-analysis. Chin J Clin (Electronic Edition). 2016;15(10):2319–24.
13.
Tsujino T, Komatsu Y, Isayama H, Hirano K, Sasahira N, Yamamoto N, Toda N, Ito Y, Nakai Y, Tada M, et al. Ulinastatin for pancreatitis after endoscopic retrograde cholangiopancreatography: a randomized, controlled trial. Clin Gastroenterol Hepatol. 2005;3(4):376–83.PubMedCrossRef
14.
Atal SS, Atal S. Ulinastatin - a newer potential therapeutic option for multiple organ dysfunction syndrome. J Basic Clin Physiol Pharmacol. 2016;27(2):91–9.PubMedCrossRef
15.
Linder A, Russell JA. An exciting candidate therapy for sepsis: ulinastatin, a urinary protease inhibitor. Intensive Care Med. 2014;40(8):1164–7.PubMedCrossRef
16.
Wang T, Liu Z, Wang Z, Duan M, Li G, Wang S, Li W, Zhu Z, Wei Y, Christiani DC, et al. Thrombocytopenia is associated with acute respiratory distress syndrome mortality: an international study. PLoS One. 2014;9(4):e94124.PubMedPubMedCentralCrossRef
17.
Inoue K, Takano H, Yanagisawa R, Sakurai M, Shimada A, Yoshino S, Sato H, Yoshikawa T. Protective role of urinary trypsin inhibitor in acute lung injury induced by lipopolysaccharide. Exp Biol Med (Maywood). 2005;230(4):281–7.CrossRef
18.
Inoue K, Takano H, Shimada A, Yanagisawa R, Sakurai M, Yoshino S, Sato H, Yoshikawa T. Urinary trypsin inhibitor protects against systemic inflammation induced by lipopolysaccharide. Mol Pharmacol. 2005;67(3):673–80.PubMedCrossRef
19.
Xu CE, Zou CW, Zhang MY, Guo L. Effects of high-dose ulinastatin on inflammatory response and pulmonary function in patients with type-a aortic dissection after cardiopulmonary bypass under deep hypothermic circulatory arrest. J Cardiothorac Vasc Anesth. 2013;27(3):479–84.PubMedCrossRef
20.
Gao DN, Zhang Y. Research progress of neutrophil elastase in the mechanism of acute lung injury. Chin Crit Care Med. 2006;18(8):510–2.
21.
Ma PP, Zhu D, Liu BZ, Zhong L, Zhu XY, Wang H, Zhang X, Gao YM. Hu XX: [neutrophil elastase inhibitor on proliferation and apoptosis of U937 cells]. Zhonghua Xue Ye Xue Za Zhi. 2013;34(6):507–11.PubMed
22.
Yuan L, Zhu X. The role of neutrophil elastase and its inhibitors in acute respiratory distress syndrome: an update. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2014;26(5):364–8.PubMed
23.
Tao Z, Hu FQ, Li CF, Zhang T, Cao BZ, Cui LQ. Effect of ulinastatin, a human urinary protease inhibitor, on heatstroke-induced apoptosis and inflammatory responses in rats. Exp Ther Med. 2017;13(1):335–41.PubMedCrossRef
24.
Luo Y, Che W, Zhao M. Ulinastatin post-treatment attenuates lipopolysaccharide-induced acute lung injury in rats and human alveolar epithelial cells. Int J Mol Med. 2017;39(2):297–306.PubMedCrossRef
25.
Sun R, Li Y, Chen W, Zhang F, Li T. Total ginsenosides synergize with ulinastatin against septic acute lung injury and acute respiratory distress syndrome. Int J Clin Exp Pathol. 2015;8(6):7385–90.PubMedPubMedCentral
26.
Qiu Y, Lin J, Yang Y, Zhou J, Gong LN, Qin Z, Du L. Lack of efficacy of Ulinastatin therapy during cardiopulmonary bypass surgery. Chin Med J. 2015;128(23):3138–42.PubMedPubMedCentralCrossRef
27.
Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R. The American-European consensus conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994;149(3 Pt 1):818–24.PubMedCrossRef
28.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1–12.PubMedCrossRef
29.
30.
31.
Zeng BI, Peng WH, Wang RJ, Zhang WJ, Xu LF. Clinical Effect Observation of Mechanical Ventilation Combined with Ulinastatin in Treatment of Acute Respiratory Distress Syndrome. Prog Mod Biomed. 2014;2(14):286–288+329.
32.
Tian ZT, Li H, Zhang SL, Li WW. Effects of ulinastatin on oxygenation index, serum hs-CRP level and extravascular lung water index in ARDS patients. Shandong Med. 2014;6(54):65–6.
33.
Cao YY, Li YF, Li GC. Effect of ulinastatin on oxygenation index and inflammatory factors in ARDS patients. China Med Eng. 2014;12(22):139–40.
34.
Zhang CG, Jiang X, Liu SJ. Effects of ulinastatin on oxygenation index and mortality in ARDS patients. Hainan Med J. 2011;16(22):8–10.
35.
Zhang YL, Pan LW, Zhuang R, Lin MX, Ying BY, Ruan H. Changes of plasma matrix metalloproteinase-2 and C-reactive protein in patients with acute respiratory distress syndrome after trauma and the effect of ulinastatin on them. Zhejiang J Trauma Surg. 2009;1(14):6–8.
36.
Zhou MH, Ren GL, Jiao FF. Study on clinical eficacy of ulinastatin in patients with acute respiratory distress syndrome. J Binzhou Med Coll. 2011;2(34):122–4.
37.
Wang ZH. Effect of ulinastatin on arterial blood gas and lactate clearance in patients with acute respiratory distress syndrome. Chin J Clin (Electronic Edition). 2017;2(45):58–60.
38.
Ji M, Chen T, Wang B, Chen M, Ding Q, Chen L, Fang Y, Yu X, Chen Y, Wang X, et al. Effects of ulinastatin combined with mechanical ventilation on oxygen metabolism, inflammation and stress response and antioxidant capacity of ARDS. Exp Ther Med. 2018;15(6):4665–70.PubMedPubMedCentral
39.
Zhang CQ, Wang YY, Gao ZL. Control clinical study of the effect of ulinastatin on prognosis of acute respiratory distress syndrome patient. Chin J Clin Pract Med. 2010;3(4):18–20.
40.
Huang ZX, Tao H, Xu W, Xu XK, Jin Z, Zhang J, Wei JD, He C, Li WF, Lin ZF. The impact of ulinastatin injection in patients plasma levels of CRP, PCT and lactate in ARDS patients with severe sepsis. J Pract Med. 2015;10(31):1692–4.
41.
Liu JX, Z.H. X, Huang YJ, Li JY, Wang RH, Jia XJ. Clinical study of ulinastatin for acute respiratory distress syndrome. J Guangxi Univ Tradit Chin Med. 2012;4(15):21–3.CrossRef
42.
Miu SX, Geng YQ, Song YK. Clinical efficacy of ulinastatin combined with lung recruitment in the treatment of acute respiratory distress syndrome. Chin J High Med Educ. 2016;4:132–5.
43.
Yan ZH, Zhao BQ, Cao SW. Effect of ulinastatin combined with mechanical ventilation on lung protection in patients with acute respiratory distress syndrome. J Clin Med Pract. 2015;17(19):112–3.
44.
Ding HH, Liu JD, Peng WP, Lin PH. Clinical efficacy of ulinastatin combined with mechanical ventilation in patients with acute respiratory distress syndrome. Guide China Med. 2014;30(12):42–3.
45.
Wei M, Zhong Q, Zhen HN, Hu HQ, Wan SB. Clinical efficacy of ulinastatin combined with continuous blood purification in 48 patients with acute respiratory distress syndrome. Herald Med. 2015;7(34):910–3.
46.
Huang QS, Zhang LX, Li Y. Clinical trial of ulinastatin combined with mechanical ventilation in patients with acute respiratory distress syndrome. Chin J Clin Pharmacol. 2016;14(32):1268–71.
47.
He B. Clinical efficacy of ulinastatin in the treatment of acute respiratory distress syndrome. Med Front. 2012;28:11–2.
48.
Gu JP, Yu J, Wang JS, Yang L, Liu L, Wang ZY. Clinical study of ulinastatin for acute respiratory distress syndrome. Prog Mod Biomed. 2012;14(12):2695–7.
49.
Mo ZM. Clinical efficacy of ulinastatin in the treatment of acute respiratory distress syndrome. China Foreign Med Treat. 2016;21(35):155–7.
50.
Xue HX, Yang AN, Zhao YD. Clinical efficacy of ulinastatin in the treatment of acute respiratory distress syndrome. Shandong Med. 2008;46(48):75.
51.
Huang HT. Clinical efficacy of ulinastatin in the treatment of acute respiratory distress syndrome. Med Aesthetics Cosmetology. 2014;10(23):270.
52.
Tan C, Huang W, Chang Z. Clinical study of ulinastatin for acute respiratory distress syndrome. Guide China Med. 2010;34(8):129–30.
53.
Ou SQ, Ma Y, Wen YM, Tao Y. Clinical study of ulinastatin for acute respiratory distress syndrome. Chongqing Med. 2008;12(37):1336–7.
54.
Wu YQ, Zhao JC, Yang K, Hu XY. Effect of noninvasive ventilator combined with ulinastatin on immunity, liver and kidney function in patients with acute respiratory distress syndrome. Hebei Med J. 2016;9(38):1327–9.
55.
He C, Huang ZX, Tao H, Xu W, Xu XK, Jin M, Wei JD, Zhang J, Li WF, Lin ZF. Changes of extra-vascular lung water and effects of ulinastatin in serious septic patients with acute respiratory distress syndrome. Chin J Respir Crit Care Med. 2015;3(14):291–4.
56.
Ye YY, Zhang W, Huang HX, Jia LP, Wang CF. Changes of extra-vascular lung water in severe sepsis with acute respiratory distress syndrome and the effect of ulinastatin. J Clin Pulmon Med. 2016;12(21):2264–7.
57.
Ye QD, Huang Q, Li XM. Clinical efficacy of ulinastatin in the treatment of acute respiratory distress syndrome. Guide China Med. 2012;18(10):87–8.
58.
Zhu GY, Xie J, Li T, Jiang ZM, Qiu J, Wang YP. Effects of ulinastatin on TNF-α, IL-1β, IL-6 and IL-8 in ARDS patients. Shandong Med. 2003;25(43):27.
59.
Hu MH, Xu XJ, Jin D, Ji CL, Chen YB, Zhang G. Effect of ulinastrtin on pulmonary endothelial permeability in patients with acute respiratory distress syndrome. Clin Educ Gen Pract. 2009;3(7):229–31 234.
60.
Duan PL. Application of ventilator combined with ulinastatin in acute respiratory distress syndrome. Med Recapitulate. 2015;4(20):740–2.
61.
Liu YX, Teng XH, Song L. Application of ventilator combined with ulinastatin in acute respiratory distress syndrome. Med Recapitulate. 2015;18(21):3424–6.
62.
Lin B. Clinical effect of ulinastatin on treatment of acute respiratory distress syndrome. Clin J Chin Med. 2015;6(7):35–7.
63.
Hu Y. Clinical diagnosis and treatment experience of 30 patients with severe acute respiratory distress syndrome. Mod Diagn Treat. 2014;17(25):4005–6.
64.
Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1334–49.PubMedCrossRef
65.
Cho YJ, Moon JY, Shin ES, Kim JH, Jung H, Park SY, Kim HC, Sim YS, Rhee CK, Lim J, et al. Clinical practice guideline of acute respiratory distress syndrome. Tuberc Respir Dis (Seoul). 2016;79(4):214–33.CrossRef
66.
Pugia MJ, Lott JA. Pathophysiology and diagnostic value of urinary trypsin inhibitors. Clin Chem Lab Med. 2005;43(1):1–16.PubMedCrossRef
67.
Wang LZ, Luo MY, Zhang JS, Ge FG, Chen JL, Zheng CQ. Effect of ulinastatin on serum inflammatory factors in Asian patients with acute pancreatitis before and after treatment: a meta-analysis. Int J Clin Pharmacol Ther. 2016;54(11):890–8.PubMedCrossRef
68.
Song J, Park J, Kim JY, Kim JD, Kang WS, Muhammad HB, Kwon MY, Kim SH, Yoon TG, Kim TY, et al. Effect of ulinastatin on perioperative organ function and systemic inflammatory reaction during cardiac surgery: a randomized double-blinded study. Korean J Anesthesiol. 2013;64(4):334–40.PubMedPubMedCentralCrossRef
69.
Feng Z, Shi Q, Fan Y, Wang Q, Yin W. Ulinastatin and/or thymosin alpha1 for severe sepsis: a systematic review and meta-analysis. J Trauma Acute Care Surg. 2016;80(2):335–40.PubMedCrossRef
70.
Karnad DR, Bhadade R, Verma PK, Moulick ND, Daga MK, Chafekar ND, Iyer S. Intravenous administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: a multicenter randomized controlled study. Intensive Care Med. 2014;40(6):830–8.PubMedPubMedCentralCrossRef
71.
Shen J, Gan Z, Zhao J, Zhang L, Xu G. Ulinastatin reduces pathogenesis of phosgene-induced acute lung injury in rats. Toxicol Ind Health. 2014;30(9):785–93.PubMedCrossRef
72.
Gao C, Liu Y, Ma L, Wang S. Protective effects of ulinastatin on pulmonary damage in rats following scald injury. Burns. 2012;38(7):1027–34.PubMedCrossRef
73.
Rui M, Duan YY, Zhang XH, Wang HL, Wang DP. Urinary trypsin inhibitor attenuates seawater-induced acute lung injury by influencing the activities of nuclear factor-kB and its related inflammatory mediators. Respiration. 2012;83(4):335–43.PubMedCrossRef
74.
Inoue K, Takano H, Yanagisawa R, Yoshikawa T. Protective effects of urinary trypsin inhibitor on systemic inflammatory response induced by lipopolysaccharide. J Clin Biochem Nutr. 2008;43(3):139–42.PubMedPubMedCentralCrossRef
75.
Nakane M, Iwama HJST. Intra-alveolar urinary trypsin inhibitor cannot inhibit polymorphonuclear elastase activity in the lung in postsurgical patients with acute respiratory distress syndrome. Surg Today. 1999;29(10):1030–3.PubMedCrossRef
76.
Harbord RM, Egger M, Sterne JA. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med. 2006;25(20):3443–57.PubMedCrossRef
Metadata
Title
Ulinastatin treatment for acute respiratory distress syndrome in China: a meta-analysis of randomized controlled trials
Authors
Xiangyun Zhang
Zhaozhong Zhu
Weijie Jiao
Wei Liu
Fang Liu
Xi Zhu
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Pulmonary Medicine / Issue 1/2019
Electronic ISSN: 1471-2466
DOI
https://doi.org/10.1186/s12890-019-0968-6

Other articles of this Issue 1/2019

BMC Pulmonary Medicine 1/2019 Go to the issue

Research article

A longitudinal study of cannabis use increasing the use of asthma medication in young Norwegian adults

Research article

“Characteristics of patients admitted to emergency department for asthma attack: a real-LIFE study”

Research article

Treatment outcomes of tuberculous meningitis in adults: a systematic review and meta-analysis

Research article

DNA-PKcs modulates progenitor cell proliferation and fibroblast senescence in idiopathic pulmonary fibrosis

Research article

Hemoptysis requiring bronchial artery embolization in patients with nontuberculous mycobacterial lung disease

Research article

Are there differences among operators in false-negative rates of endosonography with needle aspiration for mediastinal nodal staging of non-small cell lung cancer?

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits