Intravenous administration of ulinastatin (human urinary trypsin inhibitor) in severe sepsis: a multicenter randomized controlled study

被引:232
作者
Karnad, Dilip R. [1 ]
Bhadade, Rakesh [2 ,3 ]
Verma, Pradeep K. [4 ,5 ]
Moulick, Nivedita D. [6 ]
Daga, Mradul K. [7 ]
Chafekar, Neelima D. [8 ]
Iyer, Shivakumar [9 ]
机构
[1] Jupiter Hosp, Thana, India
[2] BYL Nair Charitable Hosp, Dept Med, Mumbai, Maharashtra, India
[3] TN Med Coll & BYL Nair Ch Hosp, Mumbai, Maharashtra, India
[4] Vardhaman Mahavir Med Coll, Dept Anesthesia, New Delhi, India
[5] Safdarjang Hosp, New Delhi, India
[6] Lokmanya Tilak Muncipal Gen Hosp & Med Coll, Dept Med, Mumbai, Maharashtra, India
[7] Maulana Azad Med Coll, Dept Med, New Delhi, India
[8] NDMVP Samaj Med Coll, Dept Med, Nasik, India
[9] Jehangir Clin Dev Ctr, Pune, Maharashtra, India
关键词
Serine protease inhibitor; Inflammatory mediators; Bacterial infection; Septic shock; Pneumonia; Abdominal sepsis; SERINE-PROTEASE INHIBITORS; INFLAMMATORY RESPONSE; ICU PATIENTS; ALPHA; INFECTION; STRATEGY; MODEL;
D O I
10.1007/s00134-014-3278-8
中图分类号
R4 [临床医学];
学科分类号
100218 [急诊医学];
摘要
Ulinastatin, a serine protease inhibitor, inhibits several pro-inflammatory proteases and decreases inflammatory cytokine levels and mortality in experimental sepsis. We studied the effect of ulinastatin on 28-day all-cause mortality in a double-blind trial in patients with severe sepsis in seven Indian hospitals. Patients with sepsis were randomized within 48 h of onset of one or more organ failures to receive intravenous administration of ulinastatin (200,000 IU) or placebo 12 hourly for 5 days. Of 122 randomized subjects, 114 completed the study (55 receiving ulinastatin, 59 receiving placebo). At baseline, the mean APACHE II score was 13.4 (SD = 4.4), 48 (42 %) patients were receiving mechanical ventilation, 58 (51 %) were on vasopressors, and 35 % had multiple organ failure. In the modified intention-to-treat analysis (patients receiving six or more doses of study drugs), 28-day all-cause mortality was 7.3 % with ulinastatin (4 deaths) versus 20.3 % (12 deaths) with placebo (p = 0.045). On multivariate analysis too, treatment with ulinastatin (odds ratio 0.26, 95 % CI 0.07-0.95; p = 0.042) independently decreased 28-day all-cause mortality. However, the mortality difference did not reach statistical significance in the intention-to-treat analysis [10.2 % (6/59 deaths) with ulinastatin versus 20.6 % (13/63 deaths) in the placebo group; p = 0.11]. The ulinastatin group had lower incidence of new-onset organ failure (10 vs. 26 patients, p = 0.003), more ventilator-free days (mean +/- A SD 19.4 +/- A 10.6 days vs. 10.2 +/- A 12.5 days, p = 0.019), and shorter hospital stay (11.8 +/- A 7.1 days vs. 24.2 +/- A 7.2 days, p < 0.001). In this pilot study, intravenous administration of ulinastatin reduced mortality in patients with severe sepsis in the modified intention-to-treat analysis, but not in the intention-to-treat analysis.
引用
收藏
页码:830 / 838
页数:9
相关论文
共 45 条
[1]
Abe M, 2004, CRIT CARE S1, V8, P199
[2]
Ulinastatin, a human trypsin inhibitor, inhibits endotoxin-induced thromboxane B-2 production in human monocytes [J].
Aibiki, M ;
Cook, JA .
CRITICAL CARE MEDICINE, 1997, 25 (03) :430-434
[3]
Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care [J].
Angus, DC ;
Linde-Zwirble, WT ;
Lidicker, J ;
Clermont, G ;
Carcillo, J ;
Pinsky, MR .
CRITICAL CARE MEDICINE, 2001, 29 (07) :1303-1310
[4]
Severe Sepsis and Septic Shock REPLY [J].
Angus, Derek C. ;
van der Poll, Tom .
NEW ENGLAND JOURNAL OF MEDICINE, 2013, 369 (21) :2063-2063
[5]
Immunomodulation in sepsis: state of the art and future perspective [J].
Antonopoulou, Anastasia ;
Giamarellos-Bourboulis, Evangelos J. .
IMMUNOTHERAPY, 2011, 3 (01) :117-128
[6]
Effects of Urinary Trypsin Inhibitor on Lipopolysaccharide-Induced Acute Lung Injury in Rabbits [J].
Bae, Hong-Beom ;
Jeong, Cheol-Won ;
Li, Mei ;
Kim, Hyung-Seok ;
Kwak, Sang-Hyun .
INFLAMMATION, 2012, 35 (01) :176-182
[7]
Efficacy and safety of recombinant human activated protein C for severe sepsis. [J].
Bernard, GR ;
Vincent, JL ;
Laterre, P ;
LaRosa, SP ;
Dhainaut, JF ;
Lopez-Rodriguez, A ;
Steingrub, JS ;
Garber, GE ;
Helterbrand, JD ;
Ely, EW ;
Fisher, CJ .
NEW ENGLAND JOURNAL OF MEDICINE, 2001, 344 (10) :699-709
[8]
Protective effect of Ulinastatin against murine models of sepsis: Inhibition of TNF-α and IL-6 and augmentation of IL-10 and IL-13 [J].
Cao, Yi-Zhan ;
Tu, Yan-Yang ;
Chen, Xiang ;
Wang, Bo-Liang ;
Zhong, Yue-Xia ;
Liu, Ming-Hua .
EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY, 2012, 64 (06) :543-547
[9]
Treatment of patients with severe sepsis using Ulinastatin and Thymosin α1: a prospective, randomized, controlled pilot study [J].
Chen Hao ;
He Ming-yan ;
Li Yu-min .
CHINESE MEDICAL JOURNAL, 2009, 122 (08) :883-888
[10]
ENDO S, 1990, CLIN THER, V12, P323