Ulinastatin for acute lung injury and acute respiratory distress syndrome: A systematic review and meta-analysis

Abstract

AIM: To investigate the efficacy and safety of ulinastatin for patients with acute lung injury (ALI) and those with acute respiratory distress syndrome (ARDS).

METHODS: A systematic review of randomized controlled trials (RCTs) of ulinastatin for ALI/ARDS was conducted. Oxygenation index, mortality rate [intensive care unit (ICU) mortality rate, 28-d mortality rate] and length of ICU stay were compared between ulinastatin group and conventional therapy group. Meta-analysis was performed by using Rev Man 5.1.

RESULTS: Twenty-nine RCTs with 1726 participants were totally included, the basic conditions of which were similar. No studies discussed adverse effect. Oxygenation index was reported in twenty-six studies (1552 patients). Ulinastatin had a significant effect in improving oxygenation [standard mean difference (SMD) = 1.85, 95%CI: 1.42-2.29, P < 0.00001, I² = 92%]. ICU mortality and 28-d mortality were respectively reported in eighteen studies (987 patients) and three studies (196 patients). We found that ulinastatin significantly decreased the ICU mortality [I² = 0%, RR = 0.48, 95%CI: 0.38-0.59, number needed to treat (NNT) = 5.06, P < 0.00001], while the 28-d mortality was not significantly affected (I² = 0%, RR = 0.78, 95%CI: 0.51-1.19, NNT = 12.66, P = 0.24). The length of ICU stay (six studies, 364 patients) in the ulinastatin group was significantly lower than that in the control group (SMD = -0.97, 95%CI: -1.20--0.75, P < 0.00001, I² = 86%).

CONCLUSION: Ulinastatin seems to be effective for ALI and ARDS though most trials included were of poor quality and no information on safety was provided.

Key Words: Ulinastatin; Acute lung injury; Acute respiratory distress syndrome; Mortality; Oxygenation index

Core tip: Currently, many studies highlight the advantages of ulinastatin in lung protection, which is likely because acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) share a common pathogenesis with sepsis. We tried to provide more specific evidence on this practice by performing a meta-analysis. In our study (29 clinical trials included), we found that though all the studies were of low quality, ulinastatin might improve oxygenation and mortality and be truly effective in patients with ALI/ARDS.

INTRODUCTION

Ulinastatin, also known as human urinary trypsin inhibitor, can be found in urine, plasma and all organs[1]. It is a glycoprotein marketed as an experimental medication for acute pancreatitis and septic shock in Asia for its involvement in suppressing the systemic inflammation and proteolytic process[2-5]. Currently, many animal studies and clinical trials highlight its advantages in lung protection[6-38], which is likely because acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) share a common pathogenesis with sepsis, which is systemic inflammatory response syndrome. However, it remains uncertain whether ulinastatin can be recommended as a standard medication for ALI and ARDS. Without the support of large-scale, high-quality trials, it is difficult to draw a definite conclusion. Therefore, we perform a systematic review to evaluate the efficacy and safety of ulinastatin for ALI and ARDS to provide more specific evidence.

MATERIALS AND METHODS

Search strategy

We searched the published randomized controlled trials (RCTs) (from 1^st January 2006 to 20^th August 2012) from eight databases including Pubmed, Medline (Ovid SP), The Cochrane Library, Wanfang Database, China Biology Medicine Database, Chinese Periodical Database, China Knowledge Resource Integrated Database and Chinese Clinical Trial Registry with the following search terms: “Ulinastatin” or “Protease-Inhibitors” or “Glycoprotein” and “Acute Respiratory Distress Syndrome” or “ARDS” or “Acute Lung Injury” or “ALI”. There were no language restrictions on inclusive studies. All potentially relevant papers based on titles and abstracts were retrieved for full text screening. We also collected relevant articles by checking the references of the retrieved papers.

Study selection

Both the study selection (Leng YX, Song YF) and data extraction processes (Leng YX, Yang SG) were performed by two authors independently. Disagreements were resolved by group discussion. Figure 1 showed the flow chart of study selection process.

Figure 1 Flow chart of reviewed articles. RCT: Randomized controlled trial; NPPV: Noninvasive positive-pressure ventilation; ICU: Intensive care unit.

We included the RCT studies comparing ulinastatin plus routine treatment (treatment group) versus routine treatment alone or placebo plus routine treatment (control group) for ALI and ARDS. ALI and ARDS were diagnosed as: acute onset; pulmonary artery wedge pressure ≤ 18 mmHg or absence of clinical evidence of left atrial hypertension; bilateral infiltrates on chest radiography; ALI is present if PaO₂/FiO₂ ratio is ≤ 300; ARDS is present if PaO₂/FiO₂ ratio ≤ 200. Any dose and duration of ulinastatin were permitted. The outcomes included intensive care unit (ICU) mortality rate or PaO₂/FiO₂ ratio.

Data extraction and quality assessment

The following parameters were extracted from each inclusive study: (1) first author and year of the publication; (2) patients’ characteristics and study design; and (3) clinical outcomes (ICU mortality, 28-d mortality, PaO₂/FiO₂ ratio, length of ICU stay and adverse effect). The quality of all selected articles was evaluated according to the Jadad scale[39], which bases on the random assignment, double blinding, and flow of patients. The range of score is 0 (bad) to 5 (good).

Statistical analysis

Meta-analysis was conducted using RevMan 5.1 software. For dichotomous variables (ICU mortality, 28-d mortality) we estimated the pooled risk ratios (RRs) and 95%CI. For continuous variables (PaO₂/FiO₂ ratio and length of ICU stay), we calculated the estimation of standard mean difference (SMD). Heterogeneity was explored by the I² test. If I² < 50%, the fixed-effect model (Mantel-Haenszel) was employed, otherwise the random-effect model (DerSimonian and Laird) was used. The significance of pooled RR was determined by Z test. P < 0.05 was considered statistically significant. Funnel plots were used to detect the potential publication bias if more than ten studies were included. The sensitivity analysis was conducted by taking each single study away from the total and re-analyzing the remainder.

RESULTS

Study characteristics

After full text screening, 34 potentially relevant studies were identified. Among these studies, five were excluded because there were incomplete data (1 study), other interventions besides ulinastatin were included (2 studies), the abstract and full text were inconsistent (1 study), and no relative outcomes were reported (1 study) (Figure 1). Finally, 29 studies involving 1726 participants were included[10-38], the basic conditions of which were similar. The conventional therapy included mechanical ventilation, low dose hormone, nutritional support, treatment of primary diseases, etc. Of the included studies, no one discussed the adverse effect of ulinastatin. Oxygenation index was reported in 26 studies (1552 patients). Eighteen studies (987 patients) and three studies (196 patients) analyzed the ICU mortality and 28-d mortality, respectively. The length of ICU stay was reported in six studies (364 patients). Although all the trials announced the randomization, only four studies mentioned the allocation concealment without detailed description of mechanisms. Table 1 displays the quality and characteristics of these studies.

Table 1 Quality and characteristics of all included studies.

Ref.	Yr	Jadad score	Design	Sample size	Gender (male/female)	Age (yr, mean or range )	Dosage	Frequency	Duration (d)	Outcomes
Chen et al[10]	2006	1	NRCT	70	40/30	36.6	200000	bid	2-7	Oxygenation index
Gu et al[11]	2011	1	NRCT	120	65/55	56.2	100000	tid	5	Oxygenation index
Hu et al[12]	2009	1	NRCT	54	39/15	41.2	300000	tid	7	Oxygenation index Length of ICU stay 28-d mortality rate
Huang et al[13]	2010	1	NRCT	80	41/39	49	100000	tid	5	Oxygenation index Length of ICU stay ICU Mortality rate
Jiang et al[14]	2006	1	NRCT	57	32/25	58.1	200000	qd	7-10	Oxygenation index ICU Mortality rate
Liang et al[15]	2011	1	NRCT	62	36/26	38.8	200000	bid	7	Oxygenation index Length of ICU stay
Liang et al[16]	2008	1	NRCT	76	42/34	57	200000	bid	6	Oxygenation index ICU Mortality rate
Lu et al[17]	2008	1	NRCT	60	42/18	39.7	50000	qd	3	Oxygenation index
Ou et al[18]	2008	1	NRCT	36	24/12	63.7	200000-300000	bid	5-7	Oxygenation index ICU Mortality rate Incidence of MODS
Pi et al[19]	2009	1	NRCT	40	25/15	37	200000-	bid	5-7	Incidence of MODS ICU Mortality rate
Qian et al[20]	2009	1	NRCT	48	35/13	48	200000	qid	6	Oxygenation index ICU Mortality rate Length of ICU stay
Qin[21]	2007	1	NRCT	60	40/20	35	300000	bid	3	Oxygenation index
Shang et al[22]	2008	2	RCT	60	48/12	14-72	200000	tid	7	Oxygenation index ICU Mortality rate
Shi et al[23]	2011	1	NRCT	50	34/16	59.4	300000	bid	7-10	Oxygenation index ICU Mortality rate
Wang et al[24]	2011	1	NRCT	52	32/20	55.4	200000	tid	10	ICU Mortality rate
Wang et al[25]	2011	1	NRCT	60	44/16	18-60	200000	bid	5	Oxygenation index
Xiang et al[26]	2011	1	NRCT	72	46/26	46.8	200000	tid	7	Oxygenation index
Xiong[27]	2008	1	NRCT	50	28/22	35	300000	bid	7	Oxygenation index
Yang et al[28]	2011	1	NRCT	40	NA	NA	200000	tid	10	Oxygenation index
Yang et al[29]	2006	2	NRCT	80	58/22	14-72	300000	bid	7	Oxygenation index ICU Mortality rate
Zhang et al[30]	2009	1	NRCT	34	22/12	9-61	200000	tid	10	Oxygenation index ICU Mortality rate
Zhang et al[31]	2011	1	NRCT	82	43/39	18-65	200000	bid	7	Oxygenation index 28-d mortality rate
Zhang[32]	2010	2	RCT	60	45/15	43.3	300000	bid	7	Oxygenation index
Zhang et al[33]	2010	1	RCT	60	30/30	55.7	500000	bid	7	Oxygenation index Length of ICU stay 28-d mortality rate
Zhang et al[34]	2009	1	NRCT	61	54/7	61.9	200000	bid	7	Oxygenation index
Zhao et al[35]	2012	2	RCT	56	37/19	46.2	200000	bid	4	Oxygenation index
Zhao et al[36]	2007	1	NRCT	37	29/8	42.6	100000	bid	5	Oxygenation index ICU Mortality rate
Zheng et al[37]	2011	1	NRCT	60	42/18	40.2	50000	qd	3	Oxygenation index ICU mortality rate Length of ICU stay
Zhou et al[38]	2011	1	NRCT	40	NA	40.2	600000	qid	5	Oxygenation index ICU Mortality rate

NA: Not available; NRCT: Non-randomized controlled trial; RCT: Randomized controlled trial; ICU: Intensive care unit.

Oxygenation index

The basal oxygenation indexes in all studies were similar. After treatment with standard strategy or ulinastatin, the patients’ oxygenation indexes were improved in all studies. The effect of ulinastatin was more significant (Figure 2), which was confirmed by the meta-analysis (SMD = 1.85, 95%CI: 1.42-2.29, P < 0.00001, I² = 92%, Figure 3A).

Figure 2 Oxygenation indexes of different groups before and after treatment. The horizontal axis, number of references.

Figure 3 Meta-analysis of patients’ oxygenation index (A) and intensive care unit mortality rate (B) after treatment with conventional therapy vs with ulinastatin (random effects). A: Random effects model; B: Fixed effects model.

Mortality rate

Most studies (15/18) reported that the ICU mortality rate was not significantly different between ulinastatin treatment and conventional treatment. The 95%CI crossed 1.00. Nevertheless, the result of meta-analysis indicated that ulinastatin actually reduced the patients’ ICU mortality rate, and the pooled RR was 0.48 (95%CI: 0.38-0.59, I² = 0%, Figure 3B). The number needed to treat (NNT) was 5.06. However, the 28-d mortality was not significantly different between the two groups (RR = 0.78, 95%CI: 0.51-1.19, I² = 0%, Figure 4A), and the NNT was 12.66.

Figure 4 Meta-analysis of 28-d mortality rate (A) and length of intensive care unit stay (B) between treatment with conventional therapy and with ulinastatin. A: Fixed effects model; B: Random effects model.

Length of ICU stay

Five of the six studies reporting the length of ICU stay suggested that compared with conventional therapy, ulinastatin significantly decreased the length of ICU stay, which was confirmed by the result of meta-analysis (SMD = -0.97, 95%CI: -1.20--0.75, P < 0.00001, I² = 86%, Figure 4B).

Publication bias and sensitivity analysis

Funnel plots of ICU mortality and oxygenation index are shown in Figure 5, which indicated that the publication bias did exist. The language bias may be the main bias because all the inclusive studies were written in Chinese. The sensitivity analysis showed that exclusion of any single study from the meta-analysis did not alter the overall conclusion. Though I² of the oxygenation index and ICU stay were larger than 50%, we considered that those heterogeneities were probably related to great difference among studies.

Figure 5 Funnel plots of intensive care unit mortality (A) and oxygenation index (B). SMD: Standard mean difference.

DISCUSSION

ARDS is a common severe lung complication with direct and indirect causes in ICU. In the past 20 years, the mortality rate decreased from 40%-70% to 30%-40%. This survival improvement is considered to be partly related with the better understanding and treatment of sepsis[40]. Since ulinastatin is marketed as an experimental medication for septic shock, the probable efficacy of ulinastatin for ALI and ARDS gains more and more attention.

It is reported that ulinastatin inhibits pathogenic changes in animal models of ALI/ARDS induced by many factors (including scald, seawater, LPS, phosgene)[6-9]. Immunoregulation and the mitigation of excessive inflammatory reaction might be involved. Downregulation of the human major histocompatibility complex class I chain-related antigen A (MICA), mitigation of lipid peroxidation and apoptosis may play important roles. Upregulation of MICA in scald induced lung injury can be ameliorated by ulinastatin[6]. Moreover, ulinastatin treatment can reduce the level of cytokines like serum E, P-selectin and VCAM-1, which are considered to be critical in the development of inflammatory responses[41]. Nevertheless, the effect of ulinastatin on pulmonary injury and the molecular mechanism(s) by which ulinastatin exerts its organ-protective activity remain obscurely studied. In addition, clinical trials also recommended application of ulinastatin for ALI/ARDS though no high quality evidence was reported. Only one meta-analysis on ulinastatin for ALI/ARDS was reported till now[42], in which only Chinese databases were detected. Accordingly, we yet have no enough evidence to support the recommendation of ulinastatin for ALI/ARDS. We performed this meta-analysis to evaluate the existing clinical trials objectively and to provide more specific evidence for ulinastatin selection for ALI/ARDS.

Our results seem to be inspiring. Compared with routine treatment alone, ulinastatin plus routine treatment significantly improved the oxygenation index (SMD = 1.85, 95%CI: 1.42-2.29, P < 0.00001) and reduced the ICU mortality rate (RR = 0.48, 95%CI: 0.38-0.59, NNT = 5.06, P <0.00001) and the length of ICU stay (SMD = -0.97, 95%CI: -1.20--0.75, P < 0.00001). Nevertheless, the validity of this meta-analysis to some extent is limited. No studies reported the adverse effect. Most of the clinical trials were of poor quality without description of randomization and allocation mechanisms. Meanwhile, the language bias is introduced in this review, because all the included trials were published in Chinese. Then, how should we interpret these clinical trials and the systematic review based on these trials Should the clinical practitioners consider ulinastatin as a first-line treatment Obviously, we can not draw a definite conclusion right now. Although ulinastatin seems to be effective for ALI/ARDS, high-quality RCTs discussing the efficacy and safety are needed in the future.

COMMENTS

Background

Ulinastatin is marketed as an experimental medication for septic shock in Asia for its involvement in suppressing the systemic inflammation and proteolytic process. Currently, many studies highlight its advantages in lung protection, which is because acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) share a common pathogenesis with sepsis. However, it remains uncertain whether ulinastatin can be recommended as a standard medication for ALI and ARDS.

Research frontiers

No large-scale randomized controlled trials (RCTs) studies or high quality meta-analysis on ulinastatin for ALI and ARDS were performed till now. Whether the application of ulinastatin in ALI and ARDS is appropriate remains unclear.

Innovations and breakthroughs

To provide more specific evidence for clinical practice, the authors performed a meta-analysis on ulinastatin for ALI and ARDS.

Applications

This study indicated that ulinastatin might be truly effective for ALI and ARDS though most RCT studies included were of poor quality.

Peer review

The authors conducted a systematic review and meta-analysis of the retrieved studies on the effects of ulinastatin on ALI and ARDS. The paper is essentially well written, and provides some information.