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

Acute respiratory distress syndrome (ARDS) is a multifactorial lung injury that continues to be associated with high levels of morbidity and mortality [1]. Although the risk of ARDS was significantly reduced over the past 20 years, its incidence is still as high as 20%~ 30% [2]. Low tidal volume ventilation, timely resuscitation and antimicrobial administration, restrictive transfusion practices, and primary prevention of aspiration and nosocomial pneumonia have likely contributed to this reduction [3]. Drug research of ARDS has been involved in all the currently recognized stages of disease pathogenesis, which included anti-inflammatory therapy of glucocorticoid, selective expansion of pulmonary vascular therapy of nitric oxide and prostacyclin, and alternative treatment of exogenous surfactant. However, no drugs are utilized in clinical practice for ARDS due to their contradictory findings across studies. Due to the lack of capable drugs for ARDS treatment, the mortality remains high, up to 45% [4]. Neutrophil and neutrophil elastase are important components of the inflammatory response that characterizes ARDS [5‐7]. Current notion holds that activated neutrophil releases a large number of neutrophil elastase when it serves as a powerful host defense [5]. Neutrophil elastase is able to escape from regulation by multiple protease inhibitors at inflammatory sites. Excessive neutrophil elastase, beyond levels controlled by endogenous proteinase inhibitors, disturbs the function of the lung permeability barrier and induces the release of pro-inflammatory cytokines. Then, these actions will cause a series of symptoms that are typical in the pathophysiology of ARDS [5, 6, 8, 9]. Further supporting this proposed pathogenesis, animal model studies have shown that supplements of proteinase inhibitors reduce symptoms of acute lung injury [10]. Currently, ulinastatin is a glycoprotein that acts as a protease inhibitor and has been used to treat ARDS [11, 12], pancreatitis [13], multi-organ failure [14] and sepsis [15] in Asia for several years. A summary of the potential mechanisms accounting for the effects of ulinatistin in ARDS is shown in Table 1. For example, ulinatistin can inhibit the serine proteases (such as trypsin and α-chymotrypsin) and different enzymes (such as granulocyte elastase and hyaluronidase) as well as stabilizing lysosomal membranes to prevent the release of lysosomal enzymes [20‐22]. Moreover, ulinastatin possesses anti-inflammatory properties by reducing the elevation of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8), which are produced by neutrophil elastase [17‐19]. Currently, several animal studies [23, 24], clinical trials [19, 25] and systematic reviews [11, 12] have confirmed its beneficial effect in lung protection. However, whether ulinastatin can be recommended as a standard medication for ARDS remains uncertain, since its clinical benefit has not been fully understood [26]. Therefore, a meta-analysis to quantitatively evaluate the efficacy of ulinastatin for ARDS is essential.

ARDS is a syndrome with acute lung and systemic inflammation, which are because of activation and accumulation of neutrophils and cytokines [7, 64]. ARDS remains a major public health problem that incurs high health care costs and causes major mortality in ICU despite some improvements in conventional therapeutic approach and managements in the past decades, including mechanical ventilation, systemic steroid, and nitric oxide [65]. Ulinastatin, known as a protease inhibitor, is found in the urine, plasma and all organs [66] and has been used to treat acute pancreatitis [67], acute circulatory failure [68], and severe sepsis [69, 70]. However, it remains uncertain whether ulinastatin can be recommended as a standard medication for and ARDS. In animal models, ulinastatin attenuates the pathophysiological process of acute lung injury induced by lipopolysaccharide, scald injury, phosgene and seawater, among other injuries [23, 24, 71‐73]. These benefits are mainly associated with inhibiting the activation of neutrophils, blocking nuclear factor-κB pathway, which plays a critical role in the regulation of pro-inflammatory (e.g. TNF-α, IL-1β, IL-6), down-regulate chemokines (e.g. IL-8, macrophage inflammatory protein-2), and increases neutrophils apoptosis [5, 23, 24, 67, 68, 71‐73]. In theory, ulinastatin could be a new option in ARDS treatment. Several clinical trials and systematic reviews [11, 12] have also confirmed the lung protection of ulinastatin. We performed this meta-analysis to present a comprehensive evaluation to date of ulinastatin in patients with ARDS.

The primary efficacy outcomes were directly associated with clinical benefit, including mortality and VAP rate, duration of mechanical ventilation, and length of stay (ICU stay, hospital stay). Over the past decades, a significant decline has been found in mortality of ARDS, but still as high as 45% [4]. The majority of deaths are attributable to sepsis or multiple organ dysfunction rather than primary respiratory causes, but in some cases death is directly related to lung injury [64]. Ulinastatin has an exact lung protection pharmacological mechanism. In our study, compared to conventional therapy, the results clearly showed that ulinastatin could reduce mortality by 49%, which provided convincing evidence that the pharmacological effect of ulinastatin could be translated into a clinical benefit. Additionally, the results provided more evidence to prompt ulinastatin to become a new hope for ARDS treatment. Ulinastatin significantly reduced patients’ VAP rate by 50% and shorten duration of mechanical ventilation (WMD = -4.60 days, 95% CI: -6.83 ~-2.37), which contributed to a reduced risk of death from another perspective. Ulinastatin also shorten more patients’ hospital stay (WMD = -10.09 days, 95% CI: -17.24 ~-2.94) than ICU stay (WMD = -4.18 days, 95% CI: -5.98 ~-2.38), so it might be able to drastically reduce the cost of medical treatment for patients and government.

Secondary efficacy outcomes were indirectly associated with clinical benefit, including PaO₂/FiO₂, respiratory rate, and serum inflammatory factors (TNF-α, IL-1β, IL-6, IL-8). Our meta-analysis result found ulinastatin could increase patients’ PaO₂/FiO_2, and the improvement of PaO₂/FiO₂ has been suggested to be positively related to mortality [65], which was consistent with our findings. Moreover, our study showed ulinastatin could decrease respiratory rate and serum inflammatory factors (TNF-α, IL-1β, IL-6, IL-8), which was consistent with animal models’ results [24, 73, 74]. Although, our study supported ulinastatin to be an effective treatment for ARDS, we found an older study [75] indicates intra-alveolar ulinastatin cannot inhibit polymorphonuclear elastase activity in the lung in postsurgical patients with ARDS. The statistical significance of this conclusion is questionable as the sample size is too small (only 8 patients). Compared to this study, our study increased the sample size to include 2344 patients and took into account multiple clinically relevant outcomes, so our findings were robust and more reliable.

Although, our study suggested that ulinastatin was relatively effective for the treatment of ARDS and provided a justification for large, well-designed, RCTs to examine the effects of ulinastatin in ARDS, by limiting the study population to patients with ARDS, and increasing the sample size, and expanding the research outcomes, but there were still several limitations. First, publication bias existed in mortality and secondary efficacy outcomes, which probably stemmed from small-study effects [76], all of the trials published in Chinese and the exclusion of trials published as abstracts and conference articles. Second, significant heterogeneity was shown for all the continuous outcomes (ie, duration of mechanical ventilation, ICU stay, hospital stay). Mostly, potential sources of heterogeneity have been identified by sensitivity analyses and random effect model, but some residual heterogeneity still existed in this meta-analysis, which might have originated from the included studies’ low quality (most studies’ Jadad score of only 2), small sample size (range 36–160), or variations in conventional interventions. Therefore, more large-scale multicenter, well designed, RCTs are needed to verify ulinastatin’s efficacy. Lastly, no information on safety was provided by the trials included in our meta-analysis, which is especially needed for future studies.

The findings of this meta-analysis seemly support ulinastatin to be an effective treatment for ARDS. This drug might reduce mortality, ventilator associated pneumonia rate, shortening duration of mechanical ventilation, length of ICU stay and hospital stay in ARDS patients, which needs large, well-designed, RCTs to confirm.