Neutrophil activation plays a crucial role in initiating SIRS, which is thought to be an important trigger factor of ALI/ARDS [19]. Sivelestat sodium is a promising anti-inflammatory agent that has shown beneficial effects by improving oxygenation index and reducing the duration of mechanical ventilation in ARDS patients [20–22]. However, the timing of drug initiation and its therapeutic effect on different severities of ARDS are still controversial.
The complexity of ARDS stems from multiple factors which could trigger inflammatory responses, including trauma, infection, and other systemic inflammatory states [23,24]. Our preliminary clinical observations suggested that sivelestat sodium administration (≤ 48hrs) to patients with mild to moderate ARDS of various etiologies such as drowning, aspiration pneumonia, and chemical lung injury could improve oxygenation index and clinical outcomes [25]. Conversely, sivelestat sodium may have limited therapeutic effect on severe ARDS patients especially those requiring endotracheal intubation and mechanical ventilation, including worldwide pandemic covid-19 virus [26,27]. We speculate sivelestat sodium is not a cure for ARDS but rather a therapeutic option to improve patient outcomes by alleviating SIRS.
In order to confirm the efficacy of sivelestat sodium compared to conventional therapy, we designed a prospective, multicenter randomized cohort clinical study. In this study, sivelestat sodium therapy did not result in a lower risk of invasive mechanical ventilation than conventional therapy (with adjustment for age, sex, etiology, disease severity and clinical examination) among SIRS patients. However, referring to VFDs, we observed a longer time in sivelestat group when compared with conventional group. Among three P/F ratio subgroups, P/F 200 to 300 seems to account for the most significant difference, which suggested that patients with mild ARDS may have a favorable response to therapy with sivelestat sodium. We also noticed a slower drop of the percentage of non-mechanical ventilation patients in the sivelestat group from day 2 to day 5. Although the result was not statistically significant, it may be restricted by the number of patients enrolled and a short observation period.
As research in the field of pathophysiology advances, the understanding of ARDS has led to novel therapeutic treatments (such as granulocyte colony stimulating factor, PD-L1) that could potentially be targeted for therapeutic intervention [28–30]. Moreover, given the complexity of ARDS, it is unlikely that any single agent will be a panacea. Therefore, the decision to administer sivelestat sodium would not be taken arbitrarily. Clinicians should consider factors such as the patient's overall health, comorbidities, especially the severity of ARDS. In the present study, findings were similar for secondary end points. We found no effect of sivelestat sodium as compared with conventional therapy on the numbers of ΔP/F reduced patients or severe ARDS patients. While, sivelestat sodium could decrease ΔP/F reduced patients in P/F ratio 300 to 400 mmHg subgroup. The finding appears to be inconsistent with the results observed in longer VFDs subgroup (P/F 200–300 mmHg). To further confirm the effect of sivelestat sodium on P/F ratio, we analyzed ΔP/F before and after therapy, as well as daily ΔP/F between the two groups. The study found that sivelestat sodium significantly improved ΔP/F ratio compared to conventional therapy. In addition, the most prominent ΔP/F ratio happened on the 5th day. No significant differences were observed in the changes of P/F ratio among the three subgroups. Although there is no statistically significant, sivelestat sodium tended to increase the P/F ratio on day 5 compared to conventional therapy in both P/F 200 to 300 mmHg and P/F 300 to 400 mmHg groups. Compared to the P/F 200 to 300 mmHg group, fewer patients in the P/F 300 to 400 mmHg group progressed to invasive mechanical ventilation, which explains the rarely improved VFDs by sivelestat sodium.
The adoption of precision medicine in the treatment of ARDS aims to identify and target specific biomarkers that could predict patient response to sivelestat sodium therapy. The biomarker could seek for individualize therapy plans, lead to more effective management and ultimately improve patient outcomes. Activated neutrophils in sepsis had reduced deformability and increased stiffness, which negatively affected the rheologic properties of whole blood [31]. Sivelestat also attenuated leukocyte adhesion in pulmonary capillaries and appeared to decrease leukocyte deformability in an animal model of ALI. In our study, we attempted to identify inflammatory markers that could guide the clinical efficacy of sivelestat sodium, and the result suggested that CRP is a potential indicator. Although the decrease of inflammatory factors before and after treatment suggested that PCT has statistical significance, as a predictor of infectious diseases, PCT is often influenced by antibiotic drug usage and its intensity. Therefore, apart from CRP, PCT requires further clinical trials for validation.
Despite its benefits, sivelestat sodium still have potential side effects. The most common adverse reactions include headache, nausea, diarrhea, and hypotension. According to present studies, sivelestat sodium has been increasingly reported to alleviate the progression of chronic diseases such as renal failure. [32, 33]. The vital data and safety monitoring board found no substantial differences in the incidence of adverse reactions between the two groups.